ANTIVIRAL EFFECTS OF BACTERIOCIN AGAINST ANIMAL-TO-HUMAN TRANSMITTABLE MUTATED SARS-COV-2: A SYSTEMATIC REVIEW

Abstract

• Identification of bacteriocin sources

• Classification of bacteriocins

• Antiviral pathways of bacteriocins

The COVID-19 infections caused by SARS-CoV-2 have resulted in millions of people being infected and thousands of deaths globally since November 2019. To date, no unique therapeutic agent has been developed to slow the progression of this pandemic. Despite possessing antiviral traits the potential of bacteriocins to combat SARS-CoV-2 infection has not been fully investigated. This review summarizes the mechanisms by which bacteriocins can be manipulated and implemented as effective virus entry blockers with infection suppression potential properties to highly transmissible viruses through comprehensive immune modulations that are potentially effective against COVID-19. These antimicrobial peptides have been suggested as effective antiviral therapeutics and therapeutic supplements to prevent rapid virus transmission. This review also provides a new insight into the cellular and molecular alterations which have made SARS-CoV-2 self-modified with diversified infection patterns. In addition, the possible applications of antimicrobial peptides through both natural and induced mechanisms in infection prevention perspectives on changeable virulence cases are comprehensively analyzed. Specific attention is given to the antiviral mechanisms of the molecules along with their integrative use with synthetic biology and nanosensor technology for rapid detection. Novel bacteriocin based therapeutics with cutting-edge technologies might be potential substitutes for existing time-consuming and expensive approaches to fight this newly emerged global threat.

Graphical abstract

Keywords

antimicrobial proteins / antiviral profiling of bacteriocins / antiviral therapeutics / immunomodulation / nanosensor technology / mutated SARS-CoV-2

1 INTRODUCTION

The coronavirus disease 2019 (COVID-19) pandemic has affected 221 countries with about 20.27 million confirmed cases and nearly 2.87 million deaths with 100.6 million active infected cases globally since December 2019^[1] and is caused by a novel coronavirus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)^[2]. SARS-CoV-2 is a beta coronavirus (βCoV) of the subfamily Coronavirinae in the family Coronaviridae. Coronaviruses (CoVs) possess the largest RNA genomes, ranging from 26 to 32 kb in size, among all RNA virus families^[3]. Like other βCoVs, SARS-CoV-2 carries a non-segmented, positive-sense, single-stranded RNA genome of ~ 30 kb, along with an envelope surrounding the nucleocapsid^[4]. Instead of having high sequence similarity with a bat SARS-related coronavirus (BatCoV RaTG13) (about 96.2%) and SARS-CoV (about 79.6%)^[5], remarkable genetic variation has been found in the SARS-CoV-2 genome resulting in molecular and pathogenic divergence^[6]. Clinicians and researchers have been working hard to implement a global vaccination program.

Bacteriocins are antimicrobial peptides (AMPs) synthesized from ribosomes that function against closely- to distantly-related microorganisms^[7,8]. Both Gram-positive and Gram-negative bacteria and some archaea have been reported to be capable of producing these peptides^[7], especially the probiotic microorganisms including lactic acid bacteria (LABORATORY) that synthesize a wide variety of bacteriocins. These cationic peptides possess a broad spectrum of activities including antibiotic, antiviral, anticancer, and spermicidal activities^[9]. Because they have nano-target activities and antimicrobial properties against multidrug-resistant pathogens, even at lower concentrations, these bioactive compounds are currently proposed as substitutes for antibiotic therapies to treat infectious diseases^[10,11]. Numerous studies have demonstrated the antiviral traits of bacteriocins against numerous virus diseases^[12]. The therapeutic efficacies of these bacteriocins have recently been recognized by researchers but they have previously been used for food preservation^[13].

The development of nanotechnology has provided new opportunities to prevent and treat virus diseases. Nanomaterials can reduce the likelihood of the survival of viruses in intracellular environments^[14]. Their unique nanometric shapes^[15] and large area-to-volume ratios make it possible for them to inactivate viruses by delivering drugs effectively to target sites. In addition, the invention of synthetic peptide-like biomolecules with the potential to suppress viral threats^[16] can be used in treatment of the novel coronavirus. Nanotechnology has already provided us with new antiviral mechanisms along with its biosensing applications. Nano-biosensors are simple, specific and rapid and are promising diagnostic tools for the identification of analytes from viruses helping to eradicate virulence with nanoparticle conjugated antimicrobial peptides^[17].

Considering the above issues the objective of this review were to determine the classification and features of bacteriocins obtained from diverse sources and their intended applications after precise manipulation against SARS-CoV-2. Concurrently, the genomic divergence impacts on the COVID-19 transmission chain and altered infection modules were analyzed in detail. Finally, the prospects for antimicrobial bioactive components against coronavirus along with the integration of several state-of-the-art technologies including nanosensor technology are also discussed.

2 BACTERIOCIN RESEARCH LANDMARKS

The extraction and identification of the antimicrobial compounds from differential natural sources commenced in the early nineteenth century. Characterization of bacterial compounds from natural sources with antagonistic effects to syphilis and trypanosomiasis was conducted in 1909 and has been historically known as a ‘magic bullet’^[18]. Bacteriocins are bioactive peptides documented in several studies in the early 1900s^[19], with colicin the first bacteriocin discovered in 1925, with great efficacy against Enterobacteriaceae spp.^[20]. The discovery of the first antibiotic, isolated from Penicillium notatum, was another landmark in 1928^[21], leading to further use and wide investigation of antibiotics over the next few decades as part of bacteriocin research. In the mid 1930s the sulfonamide, p-aminobenzene sulfamide functional against microbes was characterized in France^[22]. Despite the important developments in antibiotics from 1941 to 1950^[23] the investigation of antimicrobial agents is still underway. Type-A lantibiotics isolated from a bacterial strain of streptococci in the 1960s followe antagonist activity toward human disease-causing pathogens. The lantibiotic salivaricin A is a good example that strongly inhibits Streptococcus pyogenes^[24]. The lantibiotic bacteriocin nisin, used as a food preservative approved by FAO/WHO, was isolated from a strain of Lactococcus lactis in 1969^[19].

Use of bacteriocins specifically in different cancer cell lines was examined in the 1970s as drugs such as pyocin, colicin, pediocin, microcin, and azurin, with azurin found to exert cytostatic and apoptotic effects on cancer cells but no pernicious activity on healthy cells^[25]. In 1988, lantibiotics type A and B, isolated from different microbial sources, were found to act against human infectious disease^[26] and several researchers isolated two peptide lantibiotics during the late 1990s. Linezolid and daptomycin were registered at the beginning of the twentieth century^[27]. In recent decades, discovery of new bacteriocins with novel properties, database development for these peptides, use of bacteriocins for alleviating microbial infections including novel coronavirus treatment, and increasing use in immunoinformatics and vaccinomics, have been emphasized (Fig.1).

3 BASIC PROPERTIES OF BACTERIOCINS

Bacteriocins exhibit outstanding antimicrobial properties and are secreted from both Gram-positive and Gram-negative microbes and archaea^[30]. The AMPs have a biologically active protein moiety attachment to specific cellular receptors, rendering the lethal effects to targeted pathogens by exploiting bactericidal activity. These bioactive peptides are stable over a wide pH range (5–8)^[31].

Lantibiotics, also known as Class I bacteriocins, have low molecular weights and are secreted by Gram-positive bacteria. They can withstand high temperatures and extremely acidic environments, and are resistant to certain enzymatic cleavage^[32]. Classification of lantibiotics is based on the presence of lanthionine or methyllanthionine bridges as well as dehydrated residues resulting from enzymatic actions^[33,34]. These are usually synthesized in their inactive precursor peptide state^[35] and are targeted for post-translational modification during their maturation stage leading to possessing modified amino acids in their mature peptide form^[33]. They have dual mode of action against susceptible bacteria. Lantibiotics work by becoming an obstacle to the bacterial cell wall, synthesized by binding either to the lipid II or by causing pore formation leading to disruptions in the cell membrane causing death of the bacterial cells^[32]. The combination of having antimicrobial properties along with their capability of developing low resistance against pathogens makes them promising candidates for use as therapeutic agents.

Non-lantibiotic bacteriocins are considered as class II bacteriocins. They are small globular-sized, heat stable, positively charged molecules with 30–60 amino acid residues. Post-translational modification is not always needed for efficacy^[35]. Their mode of action consists of inhibition of specific enzymes^[36] leading to disintegration of the cell wall. Currently, over 50 non-lantibiotics have been isolated and identified from probiotic LABORATORY^[37].

Bacteriocins can act on susceptible hosts by triggering bacterial cell lysis and sometimes through bacteriostatic effects^[38]. Bacteriocins can even attach to various negatively charged complexes or to lipophilic surfaces of microbial cells^[39]. In mammalian cellular systems, the AMPs act as proactive cationic peptides with diversified antagonism^[40]. Multiple research approaches have been pursued demonstrating that peptides like nisin induce protective mechanisms in the animal body against pathogenic infections through interactions with the host immune system^[41]. A number of bacteriocins have been reported to affect cell signaling pathways via positive immunization^[42].

4 CLASSIFICATION OF BACTERIOCINS

Bacteriocins have efficacy against bacterial^[43,44], virus^[44] and even fungal^[45] infections. The infection mechanism of viruses differs from other pathogens, being organ specific such as in the upper respiratory tract, hepatocytes or genital organs. In fact, influenza A virus, human respiratory syncytial virus and novel coronavirus are able to bind with the respiratory tract and cause mild to severe illness of the infected individuals^[46,47]. In addition, exposure to hepatitis B and C viruses can cause disorders of hepatocytes^[48].

Bacteriocins are synthesized by both pathogenic and probiotic microbes but bacteriocin production is considered as a probiotic trait for beneficial microbes^[49]. LABORATORY are recognized for synthesizing therapeutic bacteriocins for both humans and animals and have been isolated from goat milk^[50]. Different bacteriocins have been isolated from microorganisms from diverse sources. Cerein 7 bacteriocin was isolated from Bacillus cereus^[51] and is considered to be effective against a range of enteric pathogens. Recently cerein 7 from three different B. cereus strains was isolated from buffalo milk samples and found to have pronounced immune stimulation properties against induced allergic reactions in birds^[52].

Established bacteriocins can be classified into distinct classes based on morphological features, with specified antagonistic potential against the foreign bodies including viruses and bacteria inside the host (Tab.1), and this is important in understanding their group-specific antimicrobial properties. In addition, several bacteriocins are classified as antiviral bacteriocins due to their antagonism toward the life-threatening viruses (Tab.2). These bacteriocins should be analyzed further to understand their efficacy against SARS-CoV-2 and other influenza-type viruses given the lack of information on the use of bacteriocins against viruses.

5 SARS-COV-2 TRANSMISSION INTERFACE BETWEEN HUMANS AND ANIMALS

The transmission of viruses from species to species is a natural process. Humans can come into contact with the various animals as food or in many other ways^[76]. Normally the successful mutations of viruses for the transmission from animals to humans occurs at a frequency of one in 100 years^[77]. Virus transmission from one species to another is enabled by entry receptors for the viruses in the new host’s cytoplasmic membranes^[78]. Evolutionary theory suggests that minimal spontaneous selection mechanisms are responsible for infection efficiency, minimal lethality and, occasionally, contagiousness efficiency of the viruses^[79].

Most pandemic causing viruses are reported to have multiple mutations in their genome, which can generate cross-species infections^[80]. The four known types of coronavirus are HCOV-OC43, HCOV-NL63, HCOV-HKU1 and HCOV-229F^[81]. These can infect humans but this is accompanied only by a number of mild symptoms^[82]. The ages of these human-infectious coronaviruses are > 150 years^[83]. The SARS-CoV-2 is the fifth member of this group and is more organized in infecting the human communities than the other four^[86] (Fig.2).

6 HISTOPATHOLOGICAL STATUS OF SARS-COV-2 AS COMPARED TO SELECTIVE SIMILAR VIRUS TYPES

Antibody-dependent enhancement (ADE) is thought to be responsible for the acute clinical symptoms associated with COVID-19. However, ADE is not liable for the recognition and clearance of the virus, rather it forms virus-specific antibodies which can expedite the uptake and stimulate the replication of the virus^[87]. Additionally, this mechanism avoids innate immune sensors or pattern recognition receptors^[88]. Studies have been conducted on the ADE mechanisms which are found in Flaviviruses and they are responsible for 90% of patients who suffer from hemorrhagic fever and DENV shock syndrome related to dengue virus^[89]. Unwanted histopathological changes at virus infection sites were observed among the experimental animals when the SARS-CoV-1 vaccine trials commenced and these changes might have occurred due to filtration of lymphocytes, monocytes and eosinophils^[90]. Eosinophils can stimulate T-helper type 2 and 17 immune responses, which have an important role in the increase in viral expression of the SARS nucleocapsid protein^[91]. A strong association between T-helper type 17 responses and IL-6 is overexpressed in patients with COVID-19 and these patients experience a cytokine storm along with the stimulation of IL-8^[92]. In a recent pandemic the D480A/G had a tendency to escape from neutralizing antibody 80R which can form the D480 mutation. Most researchers discern the trimeric spike protein which mediates host cell binding and entry. This is a major factor in the neutralization of antibodies^[93]. Genetic modifications, particularly mutation and recombination, are common events occurring among RNA viruses due to having an error-prone RNA-dependent RNA polymerase (RDRP)^[94]. Both SARS-CoV-1 and SARS-CoV-2 spike proteins use the human angiotensin-converting enzyme 2 (hACE2) receptor for attachment and entry^[95]. The hACE2 receptor is found mainly on epithelia of the lungs, suggesting a likely cause of respiratory illness and lung damage in advanced stages of the infection. No amino acid substitutions have been reported in SARS-CoV spike protein^[96]. N501T^[97], V367F^[98] and V483A^[99] mutations in the receptor binding determining region (RBDR) result in the enhanced ACE2 receptor binding with SARS-CoV-2 spike protein making the human body more prone to infection. However, expression of this receptor in many other tissues is also reported^[100].

In contrast to SARS-CoV-1, the RBD in the S protein of SARS-CoV-2 exerts stronger binding affinity to the hACE2 receptor macromolecule. Consequently, cell entry occurs more effectively/efficiently^[98,101]. Different lines of research have explained the high hACE2 receptor binding affinity through genomic and proteomic analysis^[97,102]. In addition, these modifications give rise to the antigenicity of SARS-CoV-2. The genome organization of the SARS-CoV-2 is illustrated for further clarification (Fig.3).

Mutations and recombination have been studied to correlate with genome variability, pathogenicity, severity, transmission ability and, most importantly, evolvability of the SARS-CoV-2^[103–105]. In SARS-CoV-1, only a single amino acid is mutated inside the Spike D614/G protein. This single amino acid change was constant among infected individuals and was the predominant variant in the 2003–2004 SARS-CoV-1 epidemic^[106].

7 INTENDED IMMUNE SIMULATING ACTIVITY OF BACTERIOCINS AGAINST SARS-COV-2

Bacteriocins can induce innate immune response through the stimulation of immune cells^[107] which can generate phagocytosis reactions. Opsonins are the main precursor molecules that can induce phagocytosis acting as effective bridges between innate and adaptive immunization^[108] at the time of any alienating foreign particle such as when viruses coexist with other protective cells. Bacteria-secreted molecules interfere with virus entry by blocking the cell surface receptor (e.g., hACE2 receptor for stopping SARS-CoV-2) of the host, consequently reducing the virus load in the body and/or rupturing the virus at an early stage^[109]. Bacteriocins, in particular the lantibiotics, have immune modulatory properties and previous investigation reveals that the immune modulation mechanisms of nisin subunits are analogous to those of the human cationic peptides, including LL-37 and defensins^[110]. These antimicrobial peptides affect the innate immune system through the induction of IL-8, MCP-1 and Gro-α secretion and suppression of bacterial LPS- induced TNF-α synthesis in human peripheral blood mononuclear cells (PBMCs)^[110] (Fig.4).

The role of lantibiotic nisin in the alteration of innate immune responses was further assessed in human polymorphonuclear neutrophils in vitro^[116]. Neutrophils kill pathogens through neutrophil extracellular trap formation^[117,118] and phagocytosis accompanied by oxidative burst^[119]. Neutrophil extracellular traps (NETs) are a form of innate immune response which limits the spread of infection and its formation is usually triggered by phorbol myristate acetate PMA and IL-8 cytokine in response to bacterial LPS^[117]. Oral administration of nisin-containing food resulted in the elevation of both CD4⁺ and CD8⁺ T-lymphocytes and the depletion of B cells in mice^[118]. AMP-producing probiotics also modulate the immune response of different immune cells through stimulation of both anti-inflammatory and pro-inflammatory cytokines^[111]. The genetic loci containing genes for bacteriocin biosynthesis, identified in Lactobacillus plantarum, have been found to modulate the cytokine response of dendritic cells and human PBMCs and subsequent T-lymphocyte induction^[120–122].

Bacteriocins, including subtilosin and enterocin CRL35 and ST4V were found to manifest antiviral action against HSV-1 and HSV-2 grown on the Vero cell-line^[70,74,123]. Both in vivo and in vitro experiments showed the antiviral activity of staphylococcin 188 against influenza and Newcastle disease virus. SARS-CoV-2 is an influenza-like virus and bacteriocins can provide a similar type of infection-prevention mechanism as reported in other influenza-type viruses^[124]. The anti-HIV activity of Laby A1 peptide has been demonstrated in numerous studies. Laboratory A1 has consistent anti-HIV-1 activity against nine distinct HIV-1 clinical isolates. This carbocyclic lantibiotic further blocks intracellular virus transmission between persistent HIV-infected T-lymphocytes and uninfected CD4⁺ T-lymphocytes^[72].

Several strains of Laboratories capable of producing antimicrobial peptides function against influenza virus infection by multiple mechanisms such as activation of Th1- mediated immune response, stimulation of pro-inflammatory cytokine secretion and induction of B cell driven antibody production^[12]. The rejuvenation of innate and adaptive immune responses against influenza-like viruses including SARS-CoV-2 can be mediated by the oral delivery of Lactobacillus gasseri, a prominent candidate for production of antimicrobial peptides^[125]. A strain of Lactobacillus rhamnuosus conferred immunity against RSV (respiratory syncytial virus) infection by triggering the release of IFN-γ and other ILs^[126]. Laby A1 and A2 lantibiotics can inhibit respiratory syncytial virus cell entry through interaction with the phosphatidylethanolamine (PE) lipid moiety of the virus capsid which is similar in SARS-CoV-2 suppression. The anti-RSV activity of these peptides was documented both in human lung cells and their carcinoma-derived counterparts in vitro and in vivo^[127,128]. Recently the virolytic effect of Laby A1/A2 was observed against an array of enveloped viruses^[129] including SARS-CoV-2. The virolysis process can also be mediated through binding of these lanthipeptides with viral PE with no cytotoxicity to host cells observed. Bacteriocins possess antiviral activity along with other miscellaneous activities including antibiotic, anticancer and spermicidal activities^[9]. Bacteriocins are active toward the diverse respiratory tract infection prevention caused by influenza virus, human rhinovirus, respiratory syncytial virus, SARS-CoV-2 (COVID-19) and SARS-CoV-1^[130,131]. Some reports indicate that bacteriocins from supernatants of lactic acid bacteria have antagonistic activity toward the novel coronavirus-type influenza viruses including influenza viruses A (strain H7N7)^[132]. In addition, the antimicrobial peptide staphylococcin 188 can eliminate respiratory infection in humans^[12]. However, probiotic bacterial strains produce some potential antibiotic peptides (mainly bacteriocins) that may prevent the infection of human rhinovirus and/or respiratory syncytial virus^[133]. Also, some potential bacteriocins isolated from probiotics have significant activity toward SARS-CoV-2 infection^[128]. Conversely, Plantaricin BN, Plantaricin JLA-9, Plantaricin W, and Plantaricin D are active against the various receptors of SARS-CoV-2 along with receptors in humans with such antiviral agents showing better results during in silico simulations^[134].

8 PROSPECTS OF SARS-COV-2 RESEARCH WITH ANTIMICROBIAL MACROMOLECULES

In January 2020, China provided the genetic sequence of the SARS-CoV-2 in a publicly-available database enabling global development of therapeutic drugs and vaccines. Two months later a biotechnology company (Moderna Inc., Cambridge, MA) developed a specific and unique candidate vaccine, a lipid nanoparticle encapsulated nucleoside-mRNA vaccine^[135]. The mRNA vaccine stimulates the immune response via the spike glycoprotein which facilitates the entry of the virus particles into the host cells^[136]. Moderna completed phase 1 clinical trials on humans in mid-March and released their results indicating success in mid-May 2020. Infrequent adverse effects were mild to moderate and the vaccine brought about robust antibody responses against the spike proteins and the presence of the antibodies has been confirmed^[137]. After overcoming hurdles with ADE and cellular immunopathology concerns, the candidate vaccine was approved for phase 3 trials in early June with 30,000 participants in the United States^[138].

Enhancement of the efficacy of the COVID-19 vaccine is required to develop a novel treatment system for COVID-19 patients worldwide. Any effective vaccine must have the ability to enhance the T cell response in vivo to develop long-term protection. Here, the peptide vaccines are considered as an alternative to standard vaccines that aim to resolve the problems of potential side effects of vaccines due to heterogeneous multicomponent preparation vaccinations. In vitro synthesized peptides of 20–30 amino acids, considered to be highly immunogenic and activating the desired immune response, are based on peptide vaccines. Numerous preclinical and clinical studies generally demonstrate easy synthesis with low cost, improved stability and relative safety^[139]. As the situation deteriorated during the SARS-CoV-2 pandemic the need to design an effective SARS-CoV-2 peptide vaccine component grew and several pharmaceutical companies developed some SARS-CoV-2 peptide vaccines^[140]. In a toxoid vaccine made from bacteriocins which is harmless but provides an immune reaction to any type of infectious viruses, usually exotoxins are secreted by post pathogenic infections from the pathogens as cellular metabolites. The toxin invades the bloodstream and is subsequently responsible for the disease symptoms. The protein-based toxin is rendered harmless and the toxoid is adsorbed to aluminum or calcium salts which serve as adjuvants, in order to trigger and improve the immune response^[141].

A DNA vaccine has provided a promising gene therapy application by transfecting the cells of an immunized species with a particular antigen-coding DNA sequence^[142]. A groundbreaking approach to the induction of humoral and cell-mediated antigen-specific immune response in systemic and mucosal compartments is defined by DNA vaccines. Vaccines consist of DNA-encoding plasmid antigens that are expressed in host cells, including post-translational modifications unique to the species^[143]. In addition, the technology of recombinant DNA vaccines includes injecting an antigen (such as a bacterial surface protein) encoding DNA that induces an immune response into both bacterial and mammalian cells, expressing the antigen in these cells. In the proteasome of the transduced cell the antigens are gradually broken down and present in the form of MHC class I molecules as externalized peptides, thus increasing the response of CD8⁺ T cells^[144]. However, the recombinant protein vaccines create a range of issues related to vaccines based on purified macromolecules that need to be prevented, such as the possibility of co-purification of undesired contaminants or reversal of toxoids to their toxic forms if, for example, diphtheria or tetanus toxoid vaccines were being considered^[145].

The complementary strategy of the genome-based approach is used to produce proteomic vaccines in which both immune informatic and vaccinomic strategies are involved^[146]. Much research is needed to develop an effective proteomic vaccine against the SARS-CoV-2^[147]. In addition, synthetic biology vaccine technology typically involves the use of computer-assisted biological engineering to develop and construct new biological components, equipment and structures that do not exist in nature, and reconstruction of existing biological systems for the purpose of conducting activities against infectious viruses^[148,149] including SARS-CoV-2.

Recently, understanding the immune responses that can be modulated by nanoparticles to attain desirable effects has been an important issue in vaccine formulations based on nanoparticles. Nanoparticles can operate both as a delivery system to enhance antigen processing and as an immune stimulatory adjuvant to induce and heighten protective immunity^[150,151]. Also, a subunit vaccine is a vaccine that presents one or more antigens to the immune system without introducing pathogen particles, whole or otherwise. The Vi capsular polysaccharide vaccine is a subunit vaccine against typhoid caused by the Typhi serotype of Salmonella enterica^[152].

Synthetic biology and bioengineering interventions have already provided hyperactive bio-compounds with remarkable peptide stability^[153] and hyperactivity such as pyocin S-35, lactococcin G and microcin V^[16]. Integration of nanotechnology has enhanced the diagnosis of and research on COVID-19 in ways not possible in the past. To optimize drug administration methods for SARS-CoV-2, nanotechnology has attracted attention globally. Nanomaterials having nanometric shape^[15] and large surface area-to-volume ratios make it possible to deliver drugs across impermeable barriers^[154]. Oseltamivir is the most widely used antiviral drug for H1N1 influenza virus types A and B, which is also suggested as being potentially effective against novel coronaviruses. Oseltamivir OTV has been found to work more efficiently against H1N1 when this drug is delivered associated with SeNPs (selenium NPs)^[155]. Functionalized gold NPs (14 nm) blocked influenza A virus infection but 2 nm AuNPs (gold NPs) did not provide any significant benefit^[156]. In the 2009 influenza A virus, copper iodide NPs were used to inactivate virus proteins (e.g., hemagglutinin and neuraminidase) through reactive oxygen species^[157]. As SARS-CoV-2 is an influenza-type virus, a highly precise diagnosis strategy will be effective in its early detection and its potential treatment as with other influenza viruses^[158].

AgNPs (silver NPs) coated with polyvinylpyrrolidone (PVP), bovine serum albumin and carbon can hinder the interaction of HIV-1 (human immunodeficiency viruses) with living cells by binding to the gp120 glycoproteins of the virus envelope^[159]. Similarly, the ability to prevent HIV-1 infection of cells can be improved by the addition of 30–50 nm PVP coated AgNP neutralizing antibodies. AgNPs work against the hepatitis B virus by inhibiting the replication of viral DNA.

Carbon quantum dots (CQDs), derived from hydrothermal carbonization of ethylenediamine or citric acid as carbon precursor and further modified with boronic acid ligands resulting in the first-generation nanostructure, have demonstrated potential to inactivate HCoV (human coronavirus)^[160]. CQDs derived from 4-aminophenyl boronic acid are the second generation of anti-HCoV nano-materials. CQDs at 10nm have excellent dispersion in water and may be an advance in nano-medicine. According to the data cited above it is possible that the current SARS-CoV-2 pandemic can be brought under control by deployment of nanotechnology approaches.

NPs are in great demand as drugs for treatment purposes and also for any type of critical diagnosis. The detection of viruses using nano-materials was first attempted with AuNPs combined with silver staining for the diagnosis of human papillomavirus in cervical carcinoma cells^[161]. AuNPs have been used in advanced SARS diagnosis focusing on rapid and specific molecular detection through two main assays: a colorimetric assay for pp1ab (polyprotein 1ab) gene detection and an electrochemical assay for nucleocapsid protein gene detection. In the colorimetric assay the presence of target SARS nucleic acids can be seen from a change in color of the solution from red to blue. This change arises from the aggregation of AuNPs with the target particles. Electrode conductivity and the surface available for detection probe immobilization can be enhanced by using AuNPs in the electrochemical assay^[162]. In addition, a nano-biosensor which has three main modules, namely a transducer, a receptor and a detector (Fig.5), based on the principle of capturing of target and transformation of the responses to signals, has become a new and promising tool for SARS-CoV-2 virus detection^[17].

An electroluminescence sensor to identify the HIV-1 gene was promoted by scientists and it has been demonstrated to have useful specificity^[163]. A graphene-based nanosensor was developed to detect Zika virus antigens in human serum down to 450 pmol·L^−1[164]. The concepts of quantum dot-based nanosensor development can be considered one of most promising future methods for SARS-CoV-2 detection, bypassing the time-consuming and comparatively costlier RT-PCR techniques.

9 INTEGRATION OF TRADITIONAL CHINESE MEDICINE IN SARS-COV-2 RESEARCH WITH VACCINES AND BACTERIOCINS

Traditional Chinese medicine (TCM) has been used of thousands of years as a means of preventing and combating epidemic diseases and is known to provide important benefits. It integrates thousands of years of experience from the constantly emerging infectious disease that have occurred since ancient times in China^[165]. TCM is one of three major traditional medicines globally that holds a vital position in the Chinese national medical system and enjoys global popularity^[166]. TCM showed surprising results in the prevention and treatment of SAR-CoV-1 in 2003. Due to the great sequence and infectivity homology between the SARS-CoV-1 and SARS-CoV-2, it is expected that the strategies used for SARS-CoV-1 will provide precedence for the prevention and treatment of SARS-CoV-2^[167].

TCM theory states that a body will not succumb to a disease even if exposed to the pathogenic factors as long as the body is healthy and well-endowed with sufficient and balanced zhen qi and yin and yang. When it comes to the treatment of a disease, TMC treatment plans take a different route to recovery by keeping the prime focus on driving away the exogenous pathogen with the restoration of the self-healing of the body rather than directly eliminating the pathogen. This method, unlike modern medicines, keeps the host cells from any harm^[168]. Another theory upheld by TCM is the prevention of the disease, i.e., preventing the disease to fully establish itself in the body and also preventing the progression of the disease from mild to severe after it has occurred. Decades of experience show that TCM has greater potential in preventing and controlling epidemic diseases due to its treatment based on syndrome differentiation and also on clinical manifestations of individual patients^[169].

The National Health Commissions of China has issued seven editions of diagnosis and treatment protocols for COVID-19. The TCM treatment plan was first included in the third edition and as much information has been gathered about the SARS-CoV-2 the TCM was recommended in every edition of the protocol. Different TCM strategies have been formulated to treat each stage of the disease^[170]. TCM intervention in the early stages of the infection has shown increased cure rate, shortened disease course, fewer days of hospitalization and reduced mortality rate. COVID-19 can cause multi-organ failure and, ultimately, death by inducing hypersensitivity reactions and a cytokine storm. This is where TCM is efficient in battling the robust immune response by regulating the host inflammatory response via multicomponent, multitarget and multipathway mechanisms to alleviate the symptoms, prevent disease progression and complications, and also gain control of the virus suppression indirectly^[171]. An academician of the Chinese Academy of Engineering stated that a TCM-oriented makeshift hospital led by Zhang Boli, had no patient developing severe conditions or progressing from mild to severe cases of the disease after receiving all-inclusive TCM therapies.

TCM methods comprise Chinese herbal medicines (CHMs), acupuncture, aromatherapy and some Chinese patented medicines. The CHMs exhibit unique therapeutic effects on various infectious diseases based on the holistic treatment concept and multitarget, multicomponent pharmacological characteristics^[169]. If Chinese herbal medicines are used by Chinese herbal experts, it has been reported that this will result in no side effects which surpasses the benefits of modern medicines^[165]. Using the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform three CHM compounds were found to contain puerarin and uqercetin. Molecular docking analysis revealed that these compounds have good binding affinity for the ACE2 receptor, hindering the binding of the ACE2 receptor with the spike protein of the virus. Quercetin also has some potential to bind to the RBD domain of the S-protein indicating that it may neutralize SARS-CoV-2. These two compounds were found in one herb, Radix bupleuri (to satisfy the TCM theory, best results are expected when the two compounds reside in the same CHM, providing synergistic therapeutic effects to the patients) which also contains baicalin, which exhibits similar effects to puerarin and uqercetin^[172].

Decoctions are made using varieties of the Chinese herbal compounds including Huashi Baidu decoction, Qingfei Paidu decoction and Xuanfei Baidu formula. They provide immunity against the virus, enhance host immunity, reduce inflammation, lower lung pathogenesis, with occurrence of less liver and kidney damage, prevent worsening of the clinical manifestations and shorten the course of the disease and hospitalization. The efficacy of the Qingfei Paidu decoction was > 90%^[173]. Other TCMs are Huoxiang Zhengqi with aniti-inflammatory effects, improvement in oxygenation indexes and systematic symptoms; Lianhua Qingwen inhibits pro-inflammatory cytokine production resulting in the protection of the lungs from pneumonia; Shufeng Jiedu inhibits virus proliferation and lastly Xue Bijing injection reduces multi-organ damage via anti-inflammatory and immunomodulation effects^[171]. Chinese patented medicines are broadly being used due to their ready availability. COVID-19 diagnosis and treatment protocols have recommended the use of Chinese patented medicines at all stages of SARS-CoV-2 infection^[173]. Lianhua Qingwen capsules are commonly used for common colds and influenza. They prevent the advancement of moderate cases to severe ones and prompt improvement in the clinical symptoms along with inhibition of SARS-CoV-2 replication. Also, use of Jinhua Qinggan granules along with routine treatment alleviates the symptoms and reduces the psychological anxiety levels in patients^[174].

During the COVID-19 pandemic, TCM is the only treatment method that has been effective in China in contrast to modern medicines that have delivered only temporary relief to the suffering of COVID-19 patients. After close monitoring of SARS-CoV-2 patients receiving TCM treatment with and without modern medicine it has been concluded that the integrated use of the TCM with modern medicine under appropriate safety guidelines and measures can bring more rapid improved and permanent results^[167]. According to the clinical experts who have been treating COVID-19 patients in Wuhan, including Professor Boli Zhang and Professor Xiaolin Tong, TCM should be used at the earliest possible stage of the disease to gain its therapeutic benefit^[168]. All these significant and unique features of TCM make it the prime choice of treatment plan for combating an epidemic, while no dedicated drug is currently available except a few newly certified vaccines after phase 3 clinical trials.

10 CONCLUSIONS

SARS-CoV-2 has challenged humanity, creating a global pandemic with spontaneous mutations over time, and is actually an altered version of the previous SARS-CoV-1 with similarities to the MERS virus. It has been reported to infect the upper respiratory tract with manifestations of fever, dry cough, shortness of breath, fatigue and other symptoms. The fatality rate following severe infection is higher than in similar epidemics as there is no established vaccination or other treatment available. A number of recent studies have suggested that natural and modified antimicrobial peptides have adequate efficacy to suppress virus infections by blocking essential infection pathways by creating a cellular and molecular interaction in the human immune system against viruses. On the basis of this concept the induced immunization and antiviral infection prevention potentiality of bacteriocins have been summarized in this review and new pathways suggested for bacteriocin research to understand their use with other advanced technologies such as synthetic biology and nanotechnology in addressing the global threat of COVID-19. In addition, traditional Chinese medicine can also have a significant role if used appropriately with antimicrobial peptides against SARS-CoV-2 by blocking the virulent factors in the human respiratory system. To ensure maximum benefits, further research must be conducted on bacteriocins in vitro, in situ and in vivo in an integrative approach.

References

[1] World Health Organization (WHO). Emergency: coronavirus disease (COVID19) pandemic. Coronavirus Disease (COVID-19) Situation Dashboard. Available at WHO website on November 17, 2020

[2] Kim D, Lee J Y, Yang J S, Kim J W, Kim V N, Chang H. The architecture of SARS-CoV-2 transcriptome. Cell, 2020, 181(4): 914–921.e10

[3] Shereen M A, Khan S, Kazmi A, Bashir N, Siddique R. COVID-19 infection: origin, transmission, and characteristics of human coronaviruses. Journal of Advanced Research, 2020, 24: 91–98

[4] Uddin M, Mustafa F, Rizvi T A, Loney T, Al Suwaidi H, Al-Marzouqi A H H, Kamal Eldin A, Alsabeeha N, Adrian T E, Stefanini C, Nowotny N, Alsheikh-Ali A, Senok A C. SARS-CoV-2/COVID-19: viral genomics, epidemiology, vaccines, and therapeutic interventions. Viruses, 2020, 12(5): 526

[5] Zhou P, Yang X L, Wang X G, Hu B, Zhang L, Zhang W, Si H R, Zhu Y, Li B, Huang C L, Chen H D, Chen J, Luo Y, Guo H, Jiang R D, Liu M Q, Chen Y, Shen X R, Wang X, Zheng X S, Zhao K, Chen Q J, Deng F, Liu L L, Yan B, Zhan F X, Wang Y Y, Xiao G F, Shi Z L. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature, 2020, 579(7798): 270–273

[6] Wu A, Peng Y, Huang B, Ding X, Wang X, Niu P, Meng J, Zhu Z, Zhang Z, Wang J, Sheng J, Quan L, Xia Z, Tan W, Cheng G, Jiang T. Genome composition and divergence of the novel coronavirus (2019-nCoV) originating in China. Cell Host & Microbe, 2020, 27(3): 325–328

[7] Lopetuso L R, Giorgio M E, Saviano A, Scaldaferri F, Gasbarrini A, Cammarota G. Bacteriocins and bacteriophages: therapeutic weapons for gastrointestinal diseases? International Journal of Molecular Sciences, 2019, 20(1): 183

[8] Zheng J, Gänzle M G, Lin X B, Ruan L, Sun M. Diversity and dynamics of bacteriocins from human microbiome. Environmental Microbiology, 2015, 17(6): 2133–2143

[9] Dicks L M T, Dreyer L, Smith C, van Staden A D. A review: the fate of bacteriocins in the human gastro-intestinal tract: do they cross the gut–blood barrier? Frontiers in Microbiology, 2018, 9: 2297

[10] Hols P, Ledesma-García L, Gabant P, Mignolet J. Mobilization of microbiota commensals and their bacteriocins for therapeutics. Trends in Microbiology, 2019, 27(8): 690–702

[11] Newstead L L, Varjonen K, Nuttall T, Paterson G K. Staphylococcal-produced bacteriocins and antimicrobial peptides: their potential as alternative treatments for Staphylococcus aureus infections. Antibiotics, 2020, 9(2): 40

[12] Al Kassaa I, Hober D, Hamze M, Chihib N E, Drider D. Antiviral potential of lactic acid bacteria and their bacteriocins. Probiotics and Antimicrobial Proteins, 2014, 6(3-4): 177–185

[13] Zhang J, Zhong J. The journey of nisin development in China, a natural-green food preservative. Protein & Cell, 2015, 6(10): 709–711

[14] Antunes Filho S, dos Santos O A L, dos Santos M S, Backx B P. Exploiting nanotechnology to target viruses. Journal of Nanotechnology and Nanomaterials, 2020, 1(1)

[15] Mahajan S D, Aalinkeel R, Law W C, Reynolds J L, Nair B B, Sykes D E, Yong K T, Roy I, Prasad P N, Schwartz S A. Anti-HIV-1 nanotherapeutics: promises and challenges for the future. International Journal of Nanomedicine, 2012, 7: 5301–5314

[16] Ahmad V, Khan M S, Jamal Q M S, Alzohairy M A, Al Karaawi M A, Siddiqui M U. Antimicrobial potential of bacteriocins: in therapy, agriculture and food preservation. International Journal of Antimicrobial Agents, 2017, 49(1): 1–11

[17] Saylan Y, Denizli A. Virus detection using nanosensors. In: Han B, Tomer V K, Nguyen T A, Farmani A, Singh P K, eds. Micro and Nano Technologies, Nanosensors for Smart Cities. Elsevier, 2020, 501–511

[18] Zaffiri L, Gardner J, Toledo-Pereyra L H. History of antibiotics. From salvarsan to cephalosporins. Journal of Investigative Surgery, 2012, 25(2): 67–77

[19] Benmechernene Z, Fernandez-No I, Kihal M, Böhme K, Calo-Mata P, Barros-Velazquez J. Recent patents on bacteriocins: food and biomedical applications. Recent Patents on DNA & Gene Sequences (Discontinued), 2013, 7(1): 66–73

[20] Baquero F, Lanza V F, Baquero M R, Del Campo R, Bravo-Vázquez D A. Microcins in Enterobacteriaceae: peptide antimicrobials in the eco-active intestinal chemosphere. Frontiers in Microbiology, 2019, 10: 2261

[21] Tan S Y, Tatsumura Y. Alexander Fleming (1881–1955): discoverer of penicillin. Singapore Medical Journal, 2015, 56(7): 366–367

[22] Persidis A. Antibacterial and antifungal drug discovery. Nature Biotechnology, 1999, 17(11): 1141–1142

[23] Conover L H. Discovery of drugs from microbiological sources. Advances in Chemistry, 1971, 108(3): 33–80

[24] Nes I F, Diep D B, Holo H. Bacteriocin diversity in Streptococcus and Enterococcus. Journal of Bacteriology, 2007, 189(4): 1189–1198

[25] Nguyen C, Nguyen V D. Discovery of azurin-like anticancer bacteriocins from human gut microbiome through homology modeling and molecular docking against the tumor suppressor p53. BioMed Research International, 2016, 2016: 8490482

[26] Chatterjee C, Paul M, Xie L, van der Donk W A. Biosynthesis and mode of action of lantibiotics. Chemical Reviews, 2005, 105(2): 633–684

[27] Silver L L. Challenges of antibacterial discovery. Clinical Microbiology Reviews, 2011, 24(1): 71–109

[28] Delves-Broughton J, Blackburn P, Evans R J, Hugenholtz J. Applications of the bacteriocin, nisin. Antonie van Leeuwenhoek, 1996, 69(2): 193–202

[29] Diep D B, Skaugen M, Salehian Z, Holo H, Nes I F. Common mechanisms of target cell recognition and immunity for class II bacteriocins. Proceedings of the National Academy of Sciences of the United States of America, 2007, 104(7): 2384–2389

[30] Nes I F, Yoon S S, Diep D B. Ribosomally synthesiszed antimicrobial peptides (bacteriocins) in lactic acid bacteria: a review. Food Science and Biotechnology, 2007, 16(5): 675–690

[31] Nettles C G, Barefoot S F. Biochemical and genetic characteristics of bacteriocins of food-associated lactic acid bacteria. Journal of Food Protection, 1993, 56(4): 338–356

[32] Ben Lagha A, Haas B, Gottschalk M, Grenier D. Antimicrobial potential of bacteriocins in poultry and swine production. Veterinary Research, 2017, 48(1): 22

[33] Lee H, Kim H Y. Lantibiotics, class I bacteriocins from the genus Bacillus. Journal of Microbiology and Biotechnology, 2011, 21(3): 229–235

[34] Collins F W J, O’Connor P M, O’Sullivan O, Rea M C, Hill C, Ross R P. Formicin—a novel broad-spectrum two-component lantibiotic produced by Bacillus paralicheniformis APC 1576. Microbiology, 2016, 162(9): 1662–1671

[35] Heng N C K, Wescombe P A, Burton J P, Jack R W, Tagg J R. The diversity of bacteriocins in Gram-positive bacteria. In: Riley M A, Chavan M A, eds. Bacteriocins. Springer, 2007, 45–92

[36] Sharma R, Sanodiya B S, Bagrodia D, Pandey M, Sharma A, Bisen P S. Efficacy and potential of lactic acid bacteria modulating human health. International Journal of Pharma and Bio Sciences, 2012, 3(4): 935–948

[37] Nes I F, Holo H. Class II antimicrobial peptides from lactic acid bacteria. Peptide Science, 2000, 55(1): 50–61

[38] Gálvez A, Lopez R L, Abriouel H, Valdivia E, Omar N B. Application of bacteriocins in the control of foodborne pathogenic and spoilage bacteria. Critical Reviews in Biotechnology, 2008, 28(2): 125–152

[39] Bagley C P. Potential role of synthetic antimicrobial peptides in animal health to combat growing concerns of antibiotic resistance-a review. Wyno Academic Journal of Agricultural Sciences, 2014, 2(2): 19–28

[40] Nissen-Meyer J, Rogne P, Oppegård C, Haugen H S, Kristiansen P E. Structure-function relationships of the non-lanthionine-containing peptide (class II) bacteriocins produced by gram-positive bacteria. Current Pharmaceutical Biotechnology, 2009, 10(1): 19–37

[41] Derré-Bobillot A, Cortes-Perez N G, Yamamoto Y, Kharrat P, Couvé E, Da Cunha V, Decker P, Boissier M C, Escartin F, Cesselin B, Langella P, Bermúdez-Humarán L G, Gaudu P. Nuclease A (Gbs0661), an extracellular nuclease of Streptococcus agalactiae, attacks the neutrophil extracellular traps and is needed for full virulence. Molecular Microbiology, 2013, 89(3): 518–531

[42] Van Staden A D. In vitro and in vivo characterization of amyloliquecidin, a novel two-component lantibiotic produced by Bacillus amyloliquefaciens. Dissertation for the Doctoral Degree. Stellenbosch, South Africa: Stellenbosch University, 2015

[43] Cao L T, Wu J Q, Xie F, Hu S H, Mo Y. Efficacy of nisin in treatment of clinical mastitis in lactating dairy cows. Journal of Dairy Science, 2007, 90(8): 3980–3985

[44] Minahk C J, Dupuy F, Morero R D. Enhancement of antibiotic activity by sub-lethal concentrations of enterocin CRL35. Journal of Antimicrobial Chemotherapy, 2004, 53(2): 240–246

[45] Smaoui S, Elleuch L, Bejar W, Karray-Rebai I, Ayadi I, Jaouadi B, Mathieu F, Chouayekh H, Bejar S, Mellouli L. Inhibition of fungi and gram-negative bacteria by bacteriocin BacTN635 produced by Lactobacillus plantarum sp. TN635. Applied Biochemistry and Biotechnology, 2010, 162(4): 1132–1146

[46] Johnson J E, Gonzales R A, Olson S J, Wright P F, Graham B S. The histopathology of fatal untreated human respiratory syncytial virus infection. Modern Pathology, 2007, 20(1): 108–119

[47] Lai S, Qin Y, Cowling B J, Ren X, Wardrop N A, Gilbert M, Tsang T K, Wu P, Feng L, Jiang H, Peng Z, Zheng J, Liao Q, Li S, Horby P W, Farrar J J, Gao G F, Tatem A J, Yu H. Global epidemiology of avian influenza A H5N1 virus infection in humans, 1997–2015: a systematic review of individual case data. Lancet: Infectious Diseases, 2016, 16(7): e108–e118

[48] Rehermann B, Nascimbeni M. Immunology of hepatitis B virus and hepatitis C virus infection. Nature Reviews: Immunology, 2005, 5(3): 215–229

[49] Dobson A, Cotter P D, Ross R P, Hill C. Bacteriocin production: a probiotic trait? Applied and Environmental Microbiology, 2012, 78(1): 1–6

[50] Al-Mamun M, Hasan M J, Al Azad S, Uddin M G, Shahriyar S, Mondal K J. Evaluation of potential probiotic characteristics of isolated lactic acid bacteria from goat milk. British Biotechnology Journal, 2016, 14(2): 1–7

[51] Oscáriz J C, Lasa I Ã, Pisabarro A G. Detection and characterization of cerein 7, a new bacteriocin produced by Bacillus cereus with a broad spectrum of activity. FEMS Microbiology Letters, 1999, 178(2): 337–341

[52] Al Azad S, Moazzem Hossain K, Rahman S M M, Al Mazid M F, Barai P, Gazi M S. In ovo inoculation of duck embryos with different strains of Bacillus cereus to analyse their synergistic post-hatch anti-allergic potentialities. Veterinary Medicine and Science, 2020, 6(4): 992–999

[53] McAuliffe O, Ross R P, Hill C. Lantibiotics: structure, biosynthesis and mode of action. FEMS Microbiology Reviews, 2001, 25(3): 285–308

[54] Parisot J, Carey S, Breukink E, Chan W C, Narbad A, Bonev B. Molecular mechanism of target recognition by subtilin, a class I lanthionine antibiotic. Antimicrobial Agents and Chemotherapy, 2008, 52(2): 612–618

[55] Meade E, Slattery M A, Garvey M. Bacteriocins, potent antimicrobial peptides and the fight against multi drug resistant species: resistance is futile? Antibiotics, 2020, 9(1): 32

[56] Le Blay G, Hammami R, Lacroix C, Fliss I. Stability and inhibitory activity of pediocin PA-1 against Listeria sp. in simulated physiological conditions of the human terminal ileum. Probiotics and Antimicrobial Proteins, 2012, 4(4): 250–258

[57] Mokoena M P. Lactic acid bacteria and their bacteriocins: classification, biosynthesis and applications against uropathogens: a mini-review. Molecules, 2017, 22(8): 1255

[58] Allison G E, Ahn C, Stiles M E, Klaenhammer T R. Utilization of the leucocin A export system in Leuconostoc gelidum for production of a Lactobacillus bacteriocin. FEMS Microbiology Letters, 1995, 131(1): 87–93

[59] Wirawan R E, Swanson K M, Kleffmann T, Jack R W, Tagg J R. Uberolysin: a novel cyclic bacteriocin produced by Streptococcus uberis. Microbiology, 2007, 153(5): 1619–1630

[60] Ermolenko E I, Desheva Y A, Kolobov A A, Kotyleva M P, Sychev I A, Suvorov A N. Anti-influenza activity of enterocin B in vitro and protective effect of bacteriocinogenic enterococcal probiotic strain on influenza infection in mouse model. Probiotics and Antimicrobial Proteins, 2019, 11(2): 705–712

[61] Koehl J L, Muthaiyan A, Jayaswal R K, Ehlert K, Labischinski H, Wilkinson B J. Cell wall composition and decreased autolytic activity and lysostaphin susceptibility of glycopeptide-intermediate Staphylococcus aureus. Antimicrobial Agents and Chemotherapy, 2004, 48(10): 3749–3757

[62] Lai A C Y, Tran S, Simmonds R S. Functional characterization of domains found within a lytic enzyme produced by Streptococcus equi subsp. zooepidemicus. FEMS Microbiology Letters, 2002, 215(1): 133–138

[63] Ramnath M, Beukes M, Tamura K, Hastings J W. Absence of a putative mannose-specific phosphotransferase system enzyme IIAB component in a leucocin A-resistant strain of Listeria monocytogenes, as shown by two-dimensional sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Applied and Environmental Microbiology, 2000, 66(7): 3098–3101

[64] Nilsen T, Nes I F, Holo H. Enterolysin A, a cell wall-degrading bacteriocin from Enterococcus faecalis LMG 2333. Applied and Environmental Microbiology, 2003, 69(5): 2975–2984

[65] Miescher S, Stierli M P, Teuber M, Meile L. Propionicin SM1, a bacteriocin from Propionibacterium jensenii DF1: isolation and characterization of the protein and its gene. Systematic and Applied Microbiology, 2000, 23(2): 174–184

[66] Chen J, Stevenson D M, Weimer P J. Albusin B, a bacteriocin from the ruminal bacterium Ruminococcus albus 7 that inhibits growth of Ruminococcus flavefaciens. Applied and Environmental Microbiology, 2004, 70(5): 3167–3170

[67] Kawai Y, Saito T, Kitazawa H, Itoh T. Gassericin A; an uncommon cyclic bacteriocin produced by Lactobacillus gasseri LA39 linked at N- and C-terminal ends. Bioscience, Biotechnology, and Biochemistry, 1998, 62(12): 2438–2440

[68] Toba T, Samant S K, Yoshioka E, Itoh T. Reutericin 6, a new bacteriocin produced by Lactobacillus reuteri LA 6. Letters in Applied Microbiology, 1991, 13(6): 281–286

[69] Nomura M. Colicins and related bacteriocins. Annual Review of Microbiology, 1967, 21(1): 257–284

[70] Wachsman M B, Castilla V, de Ruiz Holgado A P, de Torres R A, Sesma F, Coto C E. Enterocin CRL35 inhibits late stages of HSV-1 and HSV-2 replication in vitro. Antiviral Research, 2003, 58(1): 17–24

[71] Maryam H, Maqsood S, Farooq U. Bacteriocins: a novel weapon against emerging resistance. Saudi Journal of Pathology and Microbiology, 2017, 2(7): 220–227

[72] Férir G, Petrova M I, Andrei G, Huskens D, Hoorelbeke B, Snoeck R, Vanderleyden J, Balzarini J, Bartoschek S, Brönstrup M, Süssmuth R D, Schols D. The lantibiotic peptide labyrinthopeptin A1 demonstrates broad anti-HIV and anti-HSV activity with potential for microbicidal applications. PLoS One, 2013, 8(5): e64010

[73] Torres M J, Brandan C P, Petroselli G, Erra-Balsells R, Audisio M C. Antagonistic effects of Bacillus subtilis subsp. subtilis and B. amyloliquefaciens against Macrophomina phaseolina: SEM study of fungal changes and UV-MALDI-TOF MS analysis of their bioactive compounds. Microbiological Research, 2016, 182: 31–39

[74] Todorov S D, Wachsman M B, Knoetze H, Meincken M, Dicks L M T. An antibacterial and antiviral peptide produced by Enterococcus mundtii ST4V isolated from soya beans. International Journal of Antimicrobial Agents, 2005, 25(6): 508–513

[75] Hernandez J M, Singam H, Babu A, Aslam S, Lakshmi S. SARS-CoV-2 infection (COVID-19) and herpes simplex virus-1 conjunctivitis: concurrent viral infections or a cause-effect result? Cureus, 2021, 13(1): e12592

[76] Holmes E C. The phylogeography of human viruses. Molecular Ecology, 2004, 13(4): 745–756

[77] Shao W, Li X, Goraya M U, Wang S, Chen J L. Evolution of influenza a virus by mutation and re-assortment. International Journal of Molecular Sciences, 2017, 18(8): 1650

[78] Voskarides K. Animal-to-human viral transitions: is SARS-CoV-2 an evolutionarily successful one? Journal of Molecular Evolution, 2020, 88(5): 421–423

[79] Plauzolles A, Lucas M, Gaudieri S. Influence of host resistance on viral adaptation: hepatitis C virus as a case study. Infection and Drug Resistance, 2015, 8: 63–74

[80] Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, Zhang L, Fan G, Xu J, Gu X, Cheng Z, Yu T, Xia J, Wei Y, Wu W, Xie X, Yin W, Li H, Liu M, Xiao Y, Gao H, Guo L, Xie J, Wang G, Jiang R, Gao Z, Jin Q, Wang J, Cao B. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet, 2020, 395(10223): 497–506

[81] Ye Z W, Yuan S, Yuen K S, Fung S Y, Chan C P, Jin D Y. Zoonotic origins of human coronaviruses. International Journal of Biological Sciences, 2020, 16(10): 1686–1697

[82] Vijaykrishna D, Smith G J D, Zhang J X, Peiris J S M, Chen H, Guan Y. Evolutionary insights into the ecology of coronaviruses. Journal of Virology, 2007, 81(8): 4012–4020

[83] Fehr A R, Perlman S. Coronaviruses: an overview of their replication and pathogenesis. Methods in Molecular Biology, 2015, 1282: 1–23

[84] Abd El-Aziz T M, Stockand J D. Recent progress and challenges in drug development against COVID-19 coronavirus (SARS-CoV-2)-an update on the status. Infection, genetics and evolution, 2020, 83: 104327

[85] Soufi G J, Hekmatnia A, Nasrollahzadeh M, Shafiei N, Sajjadi M, Iravani P, Fallah S, Iravani S, Varma R S. SARS-CoV-2 (COVID-19): new discoveries and current challenges. Applied Sciences, 2020, 10(10): 3641

[86] Lan J, Ge J, Yu J, Shan S, Zhou H, Fan S, Zhang Q, Shi X, Wang Q, Zhang L, Wang X. Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor. Nature, 2020, 581(7807): 215–220

[87] Khandia R, Munjal A, Dhama K, Karthik K, Tiwari R, Malik Y S, Singh R K, Chaicumpa W. Modulation of dengue/zika virus pathogenicity by antibody-dependent enhancement and strategies to protect against enhancement in zika virus infection. Frontiers in Immunology, 2018, 9: 597

[88] Tetro J A. Is COVID-19 receiving ADE from other coronaviruses? Microbes and Infection, 2020, 22(2): 72–73

[89] Guabiraba R, Ryffel B. Dengue virus infection: current concepts in immune mechanisms and lessons from murine models. Immunology, 2014, 141(2): 143–156

[90] Tseng C T, Sbrana E, Iwata-Yoshikawa N, Newman P C, Garron T, Atmar R L, Peters C J, Couch R B. Immunization with SARS coronavirus vaccines leads to pulmonary immunopathology on challenge with the SARS virus. PLoS One, 2012, 7(4): e35421

[91] Hotez P J, Bottazzi M E, Corry D B. The potential role of Th17 immune responses in coronavirus immunopathology and vaccine-induced immune enhancement. Microbes and Infection, 2020, 22(4–5): 165–167

[92] Keely S, Foster P S. Stop press: eosinophils drafted to join the Th17 team. Immunity, 2015, 43(1): 7–9

[93] Yu J, Tostanoski L H, Peter L, Mercado N B, McMahan K, Mahrokhian S H, Nkolola J P, Liu J, Li Z, Chandrashekar A, Martinez D R, Loos C, Atyeo C, Fischinger S, Burke J S, Slein M D, Chen Y, Zuiani A, Lelis F J N, Travers M, Habibi S, Pessaint L, Van Ry A, Blade K, Brown R, Cook A, Finneyfrock B, Dodson A, Teow E, Velasco J, Zahn R, Wegmann F, Bondzie E A, Dagotto G, Gebre M S, He X, Jacob-Dolan C, Kirilova M, Kordana N, Lin Z, Maxfield L F, Nampanya F, Nityanandam R, Ventura J D, Wan H, Cai Y, Chen B, Schmidt A G, Wesemann D R, Baric R S, Alter G, Andersen H, Lewis M G, Barouch D H. DNA vaccine protection against SARS-CoV-2 in rhesus macaques. Science, 2020, 369(6505): 806–811

[94] Duffy S. Why are RNA virus mutation rates so damn high? PLoS Biology, 2018, 16(8): e3000003

[95] Yan R, Zhang Y, Li Y, Xia L, Guo Y, Zhou Q. Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2. Science, 2020, 367(6485): 1444–1448

[96] Wu F, Zhao S, Yu B, Chen Y M, Wang W, Song Z G, Hu Y, Tao Z W, Tian J H, Pei Y Y, Yuan M L, Zhang Y L, Dai F H, Liu Y, Wang Q M, Zheng J J, Xu L, Holmes E C, Zhang Y Z. A new coronavirus associated with human respiratory disease in China. Nature, 2020, 579(7798): 265–269

[97] Cai H Y, Cai A. SARS-CoV-2 spike protein gene variants with N501T and G142D mutation dominated infections in minks in the US. medRix, 2021 doi: 10.1101/2021.03.18.21253734

[98] Ou J, Zhou Z, Dai R, Zhao S, Wu X, Zhang J, Lan W, Cui L, Wu J, Seto D, Chodosh J, Zhang G, Zhang Q. Emergence of RBD mutations in circulating SARS-CoV-2 strains enhancing the structural stability and human ACE2 receptor affinity of the spike protein. bioRxiv, 2020

[99] Laamarti M, Alouane T, Kartti S, Chemao-Elfihri M W, Hakmi M, Essabbar A, Laamarti M, Hlali H, Bendani H, Boumajdi N, Benhrif O, Allam L, El Hafidi N, El Jaoudi R, Allali I, Marchoudi N, Fekkak J, Benrahma H, Nejjari C, Amzazi S, Belyamani L, Ibrahimi A. Large scale genomic analysis of 3067 SARS-CoV-2 genomes reveals a clonal geo-distribution and a rich genetic variations of hotspots mutations. PLoS One, 2020, 15(11): e0240345

[100] Zhang H, Penninger J M, Li Y, Zhong N, Slutsky A S. Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target. Intensive Care Medicine, 2020, 46(4): 586–590

[101] Shang J, Wan Y, Luo C, Ye G, Geng Q, Auerbach A, Li F. Cell entry mechanisms of SARS-CoV-2. Proceedings of the National Academy of Sciences of the United States of America, 2020, 117(21): 11727–11734

[102] Shang J, Ye G, Shi K, Wan Y, Luo C, Aihara H, Geng Q, Auerbach A, Li F. Structural basis of receptor recognition by SARS-CoV-2. Nature, 2020, 581(7807): 221–224

[103] Bajaj A, Purohit H J. Understanding SARS-CoV-2: genetic diversity, transmission and cure in human. Indian Journal of Microbiology, 2020, 60(3): 398–401

[104] Phan T. Genetic diversity and evolution of SARS-CoV-2. Infection, Genetics and Evolution, 2020, 81: 104260

[105] van Dorp L, Acman M, Richard D, Shaw L P, Ford C E, Ormond L, Owen C J, Pang J, Tan C C S, Boshier F A T, Ortiz A T, Balloux F. Emergence of genomic diversity and recurrent mutations in SARS-CoV-2. Infection, Genetics and Evolution, 2020, 83: 104351

[106] Ren L, Zhang Y, Li J, Xiao Y, Zhang J, Wang Y, Chen L, Paranhos-Baccalà G, Wang J. Genetic drift of human coronavirus OC43 spike gene during adaptive evolution. Scientific Reports, 2015, 5(1): 11451

[107] Pickard J M, Zeng M Y, Caruso R, Núñez G. Gut microbiota: role in pathogen colonization, immune responses, and inflammatory disease. Immunological Reviews, 2017, 279(1): 70–89

[108] Al Azad S, Shahriyar S, Mondal K J. Opsonin and its mechanism of action in secondary immune. Journal of Molecular Studies and Medicine Research, 2016, 1(2): 48–56

[109] Maiti B K. Potential role of peptide-based antiviral therapy against SARS-CoV-2 infection. ACS Pharmacology & Translational Science, 2020, 3(4): 783–785

[110] Kindrachuk J, Jenssen H, Elliott M, Nijnik A, Magrangeas-Janot L, Pasupuleti M, Thorson L, Ma S, Easton D M, Bains M, Finlay B, Breukink E J, Georg-Sahl H, Hancock R E W. Manipulation of innate immunity by a bacterial secreted peptide: lantibiotic nisin Z is selectively immunomodulatory. Innate Immunity, 2013, 19(3): 315–327

[111] de Pablo M A, Gaforio J J, Gallego A M, Ortega E, Gálvez A M, Alvarez de Cienfuegos López G. Evaluation of immunomodulatory effects of nisin-containing diets on mice. FEMS Immunology and Medical Microbiology, 1999, 24(1): 35–42

[112] Bhattacharya A, Stacy A, Bashey F. Suppression of bacteriocin resistance using live, heterospecific competitors. Evolutionary Applications, 2019, 12(6): 1191–1200

[113] Elnagdy S, AlKhazindar M. The potential of antimicrobial peptides as an antiviral therapy against COVID-19. ACS Pharmacology & Translational Science, 2020, 3(4): 780–782

[114] Lange-Starke A, Petereit A, Truyen U, Braun P G, Fehlhaber K, Albert T. Antiviral potential of selected starter cultures, bacteriocins and D, L-lactic acid. Food and Environmental Virology, 2014, 6(1): 42–47

[115] Serkedjieva J. Antiviral activity of the red marine alga Ceramium rubrum. Phytotherapy Research, 2004, 18(6): 480–483

[116] Begde D, Bundale S, Mashitha P, Rudra J, Nashikkar N, Upadhyay A. Immunomodulatory efficacy of nisin—a bacterial lantibiotic peptide. Journal of Peptide Science, 2011, 17(6): 438–444

[117] Brinkmann V, Reichard U, Goosmann C, Fauler B, Uhlemann Y, Weiss D S, Weinrauch Y, Zychlinsky A. Neutrophil extracellular traps kill bacteria. Science, 2004, 303(5663): 1532–1535

[118] Zawrotniak M, Rapala-Kozik M. Neutrophil extracellular traps (NETs)—formation and implications. Acta Biochimica Polonica, 2013, 60(3): 277–284

[119] Witko-Sarsat V, Rieu P, Descamps-Latscha B, Lesavre P, Halbwachs-Mecarelli L. Neutrophils: molecules, functions and pathophysiological aspects. Laboratory Investigation, 2000, 80(5): 617–653

[120] Azad M A K, Sarker M, Wan D. Immunomodulatory effects of probiotics on cytokine profiles. BioMed Research International, 2018, 2018: 8063647

[121] Meijerink M, van Hemert S, Taverne N, Wels M, de Vos P, Bron P A, Savelkoul H F, van Bilsen J, Kleerebezem M, Wells J M. Identification of genetic loci in Lactobacillus plantarum that modulate the immune response of dendritic cells using comparative genome hybridization. PLoS One, 2010, 5(5): e10632

[122] van Hemert S, Meijerink M, Molenaar D, Bron P A, de Vos P, Kleerebezem M, Wells J M, Marco M L. Identification of Lactobacillus plantarum genes modulating the cytokine response of human peripheral blood mononuclear cells. BMC Microbiology, 2010, 10(1): 293

[123] Quintana V M, Torres N I, Wachsman M B, Sinko P J, Castilla V, Chikindas M. Antiherpes simplex virus type 2 activity of the antimicrobial peptide subtilosin. Journal of Applied Microbiology, 2014, 117(5): 1253–1259

[124] Saeed S, Rasool S A, Ahmad S, Zaidi S Z, Rehmani S. Antiviral activity of staphylococcin 188: a purified bacteriocin like inhibitory substance isolated from Staphylococcus aureus AB188. Research. Journal of Microbiology, 2007, 2(11): 796–806

[125] Nishihira J, Nishimura M, Moriya T, Sakai F, Kabuki T, Kawasaki Y. Lactobacillus gasseri potentiates immune response against influenza virus infection. In: Chatterjee S, Jungraithmayr W, Bagchi D, eds. Immunity and Inflammation in Health and Disease. Academic Press, 2018, 249–255

[126] Villena J, Oliveira M L S, Ferreira P C D, Salva S, Alvarez S. Lactic acid bacteria in the prevention of pneumococcal respiratory infection: future opportunities and challenges. International Immunopharmacology, 2011, 11(11): 1633–1645

[127] Blockus S, Sake S M, Wetzke M, Grethe C, Graalmann T, Pils M, Le Goffic R, Galloux M, Prochnow H, Rox K, Hüttel S, Rupcic Z, Wiegmann B, Dijkman R, Rameix-Welti M A, Eléouët J F, Duprex W P, Thiel V, Hansen G, Brönstrup M, Haid S, Pietschmann T. Labyrinthopeptins as virolytic inhibitors of respiratory syncytial virus cell entry. Antiviral Research, 2020, 177: 104774

[128] Tiwari S K, Dicks L M T, Popov I V, Karaseva A, Ermakov A M, Suvorov A, Tagg J R, Weeks R, Chikindas M L. Probiotics at war against viruses: what is missing from the picture? Frontiers in Microbiology, 2020, 11: 1877

[129] Prochnow H, Rox K, Birudukota N V S, Weichert L, Hotop S K, Klahn P, Mohr K, Franz S, Banda D H, Blockus S, Schreiber J, Haid S, Oeyen M, Martinez J P, Süssmuth R D, Wink J, Meyerhans A, Goffinet C, Messerle M, Schulz T F, Kröger A, Schols D, Pietschmann T, Brönstrup M. Labyrinthopeptins exert broad-spectrum antiviral activity through lipid-binding-mediated virolysis. Journal of Virology, 2020, 94(2): e01471–19

[130] Jain N, Lodha R, Kabra S K. Upper respiratory tract infections. Indian Journal of Pediatrics, 2001, 68(12): 1135–1138

[131] Shan C, Yao Y F, Yang X L, Zhou Y W, Gao G, Peng Y, Yang L, Hu X, Xiong J, Jiang R D, Zhang H J, Gao X X, Peng C, Min J, Chen Y, Si H R, Wu J, Zhou P, Wang Y Y, Wei H P, Pang W, Hu Z F, Lv L B, Zheng Y T, Shi Z L, Yuan Z M. Infection with novel coronavirus (SARS-CoV-2) causes pneumonia in Rhesus macaques. Cell Research, 2020, 30(8): 670–677

[132] Serkedjieva J, Danova S, Ivanova I. Antiinfluenza virus activity of a bacteriocin produced by Lactobacillus delbrueckii. Applied Biochemistry and Biotechnology, 2012, 88(1): 285–298

[133] Salman J, Mahmood N N, Abdulsattar B O, Abid H A. The effectiveness of probiotics against viral infections: a rapid review with focus on SARS-CoV-2 infection. Open Access Macedonian Journal of Medical Sciences, 2020, 8(T1): 496–508

[134] Anwar F, Altayb H N, Al-Abbasi F A, Al-Malki A L, Kamal M A, Kumar V. Antiviral effects of probiotic metabolites on COVID-19. Journal of Biomolecular Structure & Dynamics, 2020

[135] Thanh Le T, Andreadakis Z, Kumar A, Gómez Román R, Tollefsen S, Saville M, Mayhew S. The COVID-19 vaccine development landscape. Nature Reviews: Drug Discovery, 2020, 19(5): 305–306

[136] Jackson L A, Anderson E J, Rouphael N G, Roberts P C, Makhene M, Coler R N, McCullough M P, Chappell J D, Denison M R, Stevens L J, Pruijssers A J, McDermott A, Flach B, Doria-Rose N A, Corbett K S, Morabito K M, O’Dell S, Schmidt S D, Swanson P A II, Padilla M, Mascola J R, Neuzil K M, Bennett H, Sun W, Peters E, Makowski M, Albert J, Cross K, Buchanan W, Pikaart-Tautges R, Ledgerwood J E, Graham B S, Beigel J H, for the mRNA-1273 Study Group. An mRNA vaccine against SARS-CoV-2—preliminary report. New England Journal of Medicine, 2020, 383(20): 1920–1931

[137] Peeples L. News Feature: avoiding pitfalls in the pursuit of a COVID-19 vaccine. Proceedings of the National Academy of Sciences of the United States of America, 2020, 117(15): 8218–8221

[138] Calvo Fernández E, Zhu L Y. Racing to immunity: journey to a COVID-19 vaccine and lessons for the future. British Journal of Clinical Pharmacology, 2020

[139] Shoenfeld Y. Corona (COVID-19) time musings: our involvement in COVID-19 pathogenesis, diagnosis, treatment and vaccine planning. Autoimmunity Reviews, 2020, 19(6): 102538

[140] Abdelmageed M I, Abdelmoneim A H, Mustafa M I, Elfadol N M, Murshed N S, Shantier S W, Makhawi A M. Design of a multiepitope-based peptide vaccine against the E protein of human COVID-19: an immunoinformatics approach. BioMed Research International, 2020: 2683286

[141] Yadav D K, Yadav N, Khurana S M P. Vaccines: present status and applications. In: Verma A S, Singh A, eds. Animal Biotechnology (Second Edition). Academic Press, 2020, 523–542

[142] Raska M, Turanek J. DNA vaccines for the induction of immune responses in mucosal tissues. In: Mestecky J, Strober W, Russell M W, Kelsall B L, Cheroutre H, Lambrecht B N, eds. Mucosal Immunology (Fourth Edition). Academic Press, 2015, 1307–1335

[143] Yoon S K, Seo Y B, Im S J, Bae S H, Song M J, You C R, Jang J W, Yang S H, Suh Y S, Song J S, Kim B M, Kim C Y, Jeong S H, Sung Y C. Safety and immunogenicity of therapeutic DNA vaccine with antiviral drug in chronic HBV patients and its immunogenicity in mice. Liver International, 2015, 35(3): 805–815

[144] Zajac B A, West D J, McAleer W J, Scolnick E M. Overview of clinical studies with hepatitis B vaccine made by recombinant DNA. Journal of Infection, 1986, 13(Suppl A): 39–45

[145] Zhu L, Yang Q, Huang L, Wang K, Wang X, Chen D, Geng Y, Huang X, Ouyang P, Lai W. Effectivity of oral recombinant DNA vaccine against Streptococcus agalactiae in Nile tilapia. Developmental and Comparative Immunology, 2017, 77: 77–87

[146] Adamczyk-Poplawska M, Markowicz S, Jagusztyn-Krynicka E K. Proteomics for development of vaccine. Journal of Proteomics, 2011, 74(12): 2596–2616

[147] Galassie A C, Link A J. Proteomic contributions to our understanding of vaccine and immune responses. Proteomics: Clinical Applications, 2015, 9(11–12): 972–989

[148] Charlton Hume H K, Vidigal J, Carrondo M J T, Middelberg A P J, Roldão A, Lua L H L. Synthetic biology for bioengineering virus-like particle vaccines. Biotechnology and Bioengineering, 2019, 116(4): 919–935

[149] Kitney R I, Bell J, Philp J.Build a Sustainable Vaccines Industry with Synthetic Biology. Trends in Biotechnology, 2021 doi: 10.1016/j.tibtech.2020.12.006

[150] Mamo T, Poland G A. Nanovaccinology: the next generation of vaccines meets 21st century materials science and engineering. Vaccine, 2012, 30(47): 6609–6611

[151] Yadav H K S, Dibi M, Mohammad A, Srouji A E. Nanovaccines formulation and applications—a review. Journal of Drug Delivery Science and Technology, 2018, 44: 380–387

[152] Raffatellu M, Chessa D, Wilson R P, Dusold R, Rubino S, Bäumler A J. The Vi capsular antigen of Salmonella enterica serotype Typhi reduces Toll-like receptor-dependent interleukin-8 expression in the intestinal mucosa. Infection and Immunity, 2005, 73(6): 3367–3374

[153] Choy W Y, Lin S G, Chan P K S, Tam J S L, Lo Y M D, Chu I M T, Tsai S N, Zhong M Q, Fung K P, Waye M M Y, Tsui S K W, Ng K O, Shan Z X, Yang M, Wu Y L, Lin Z Y, Ngai S M. Synthetic peptide studies on the severe acute respiratory syndrome (SARS) coronavirus spike glycoprotein: perspective for SARS vaccine development. Clinical Chemistry, 2004, 50(6): 1036–1042

[154] McNeil S E. Unique benefits of nanotechnology to drug delivery and diagnostics. In: McNeil S, ed. Characterization of nanoparticles intended for drug delivery. Methods in Molecular Biology (Methods and Protocols). USA: Humana Press, 2011, 3–8

[155] Li Y, Lin Z, Guo M, Xia Y, Zhao M, Wang C, Xu T, Chen T, Zhu B. Inhibitory activity of selenium nanoparticles functionalized with oseltamivir on H1N1 influenza virus. International Journal of Nanomedicine, 2017, 12: 5733–5743

[156] Stone J W, Thornburg N J, Blum D L, Kuhn S J, Wright D W, Crowe J E Jr. Gold nanorod vaccine for respiratory syncytial virus. Nanotechnology, 2013, 24(29): 295102

[157] Fujimori Y, Sato T, Hayata T, Nagao T, Nakayama M, Nakayama T, Sugamata R, Suzuki K. Novel antiviral characteristics of nanosized copper(I) iodide particles showing inactivation activity against 2009 pandemic H1N1 influenza virus. Applied and Environmental Microbiology, 2012, 78(4): 951–955

[158] Vemula S V, Zhao J, Liu J, Wang X, Biswas S, Hewlett I. Current approaches for diagnosis of influenza virus infections in humans. Viruses, 2016, 8(4): 96

[159] Elechiguerra J L, Burt J L, Morones J R, Camacho-Bragado A, Gao X, Lara H H, Yacaman M J. Interaction of silver nanoparticles with HIV-1. Journal of Nanobiotechnology, 2005, 3(1): 6

[160] Łoczechin A, Séron K, Barras A, Giovanelli E, Belouzard S, Chen Y T, Metzler-Nolte N, Boukherroub R, Dubuisson J, Szunerits S. Functional carbon quantum dots as medical countermeasures to human coronavirus. ACS Applied Materials & Interfaces, 2019, 11(46): 42964–42974

[161] Zehbe I, Hacker G W, Su H, Hauser-Kronberger C, Hainfeld J F, Tubbs R. Sensitive in situ hybridization with catalyzed reporter deposition, streptavidin-Nanogold, and silver acetate autometallography: detection of single-copy human papillomavirus. American Journal of Pathology, 1997, 150(5): 1553–1561

[162] Martínez G‐ M BParedes A, González‐García , Costa‐García . Genosensor for SARS virus detection based on gold nanostructured screen‐printed carbon electrodes. Electroanalysis, 2009, 21(3–5): 379–385

[163] Babamiri B, Salimi A, Hallaj R. A molecularly imprinted electrochemiluminescence sensor for ultrasensitive HIV-1 gene detection using EuS nanocrystals as luminophore. Biosensors & Bioelectronics, 2018, 117: 332–339

[164] Afsahi S, Lerner M B, Goldstein J M, Lee J, Tang X, Bagarozzi D A Jr, Pan D, Locascio L, Walker A, Barron F, Goldsmith B R. Novel graphene-based biosensor for early detection of Zika virus infection. Biosensors & Bioelectronics, 2018, 100: 85–88

[165] Shahrajabian M H, Sun W, Shen H, Cheng Q. Chinese herbal medicine for SARS and SARS-CoV-2 treatment and prevention, encouraging using herbal medicine for COVID-19 outbreak. Acta Agriculturæ Scandinavica. Section B: Soil and Plant Science, 2020, 70(5): 437–443

[166] Guan W, Lan W, Zhang J, Zhao S, Ou J, Wu X, Yan Y, Wu J, Zhang Q. COVID-19: antiviral agents, antibody development and traditional Chinese medicine. Virologica Sinica, 2020, 35(6): 685–698

[167] Li Y, Li J, Zhong D, Zhang Y, Zhang Y, Guo Y, Clarke M, Jin R. Clinical practice guidelines and experts’ consensuses of traditional Chinese herbal medicine for novel coronavirus (COVID-19): protocol of a systematic review. Systematic Reviews, 2020, 9(1): 170

[168] Leung E L H, Pan H D, Huang Y F, Fan X X, Wang W Y, He F, Cai J, Zhou H, Liu L. The scientific foundation of Chinese herbal medicine against COVID-19. Engineering, 2020, 6(10): 1099–1107

[169] Wang S X, Wang Y, Lu Y B, Li J Y, Song Y J, Nyamgerelt M, Wang X X. Diagnosis and treatment of novel coronavirus pneumonia based on the theory of traditional Chinese medicine. Journal of Integrative Medicine, 2020, 18(4): 275–283

[170] Li J G, Xu H. Chinese medicine in fighting against COVID-19: role and inspiration. Chinese Journal of Integrative Medicine, 2021, 27(1): 3–6

[171] Tong T, Wu Y Q, Ni W J, Shen A Z, Liu S. The potential insights of Traditional Chinese Medicine on treatment of COVID-19. Chinese Medicine, 2020, 15(1): 51

[172] Pan B, Fang S, Zhang J, Pan Y, Liu H, Wang Y, Li M, Liu L. Chinese herbal compounds against SARS-CoV-2: puerarin and quercetin impair the binding of viral S-protein to ACE2 receptor. Computational and Structural Biotechnology Journal, 2020, 18: 3518–3527

[173] Zhao Z, Li Y, Zhou L, Zhou X, Xie B, Zhang W, Sun J. Prevention and treatment of COVID-19 using Traditional Chinese Medicine: a review. Phytomedicine, 2021, 85: 153308

[174] Li Q, Wang H, Li X, Zheng Y, Wei Y, Zhang P, Ding Q, Lin J, Tang S, Zhao Y, Zhao L, Tong X. The role played by traditional Chinese medicine in preventing and treating COVID-19 in China. Frontiers of Medicine, 2020, 14(5): 681–688

RIGHTS & PERMISSIONS

The Author(s) 2021. Published by Higher Education Press. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0)