Innovative perspectives on pulmonary immune responses: Pathogens versus protectors

Abstract

The pulmonary immune system serves as a critical frontline in the host’s defense against invading pathogens. Understanding the dynamic interplay between invading pathogens and the host’s immune defenses is essential for the development of innovative therapeutic strategies. This review explores the complex mechanisms underlying pulmonary immune responses, with a focus on the balance between pathogen virulence and host immunity. Relevant publications - including peer-reviewed articles, clinical studies, and technological advancements published between 2020 and 2025 - were identified through searches of electronic databases such as Google Scholar, PubMed, Scopus, and Web of Science. The findings reveal that pathogens employ sophisticated strategies to evade immune detection, such as modulation of host cell signaling pathways and the secretion of virulence factors. Conversely, the host mounts protective immune responses characterized by rapid activation of innate immunity, cytokine-mediated signaling, and the development of adaptive immune memory. Notably, recent studies have reported several novel biomarkers associated with enhanced pathogen clearance and tissue repair, highlighting their potential as therapeutic targets. This review provides new insights into pulmonary immune responses, highlighting the delicate balance between pathogen evasion and host defense mechanisms. By identifying key immune regulators and pathogen-specific vulnerabilities, it highlights potential targets for innovative treatments to enhance pulmonary immunity. These findings underscore the importance of interdisciplinary approaches in advancing knowledge of respiratory infections and immune defense.

Keywords

Host defense / Immune regulation / Pathogen evasion / Respiratory infections / Pulmonary immunity / Therapeutic targets

References

[1] Dondi A, Carbone C, Manieri E, et al. Outdoor air pollution and childhood respiratory disease: The role of oxidative stress. Int J Mol Sci. 2023; 24(5):4345. doi: 10.3390/ijms24054345

[2] Besharati S. The expanding antibiotic resistance: The requirement of new therapeutic strategy for the development of new anti-infective. In: Innate Immunity - New Perspectives and Therapeutic Opportunities. London: IntechOpen. 2025. p. 49. doi: 10.5772/intechopen.1006935

[3] Besharati S, Kalaleh AR. Personalized nursing and precision nursing: A concept of the future of the health model. J Prev Diagn Treat Strategies Med. 2024; 3(4):227-234. doi: 10.4103/jpdtsm.jpdtsm_48_24

[4] Block H, Zarbock A. A fragile balance: Does neutrophil extracellular trap formation drive pulmonary disease progression? Cells. 2021; 10(8):1932. doi: 10.3390/cells10081932

[5] Besharati S. The expanding antibiotic resistance: The requirement of new therapeutic strategy for the development of new anti-infective. In: Innate Immunity - New Perspectives and Therapeutic Opportunities. London: IntechOpen. 2024. doi: 10.5772/intechopen.1006935

[6] Mojahed M, Besharati S, Farzanegan B, et al. Identification of operational errors in the stages of the hemovigilance program with the guidance of the Global Trigger Tool and comparing it with the reported errors. Sci J Iran Blood Transfus Organ. 2024; 21(4):320-332.

[7] Li R, Li J, Zhou X. Lung microbiome: New insights into the pathogenesis of respiratory diseases. Signal Transduct Target Ther. 2024; 9(1):19. doi: 10.1038/s41392-023-01722-y

[8] Fröhlich E. Non-cellular layers of the respiratory tract: Protection against pathogens and target for drug delivery. Pharmaceutics. 2022; 14(5):992. doi: 10.3390/pharmaceutics14050992

[9] Zhang H, He F, Li P, Hardwidge PR, Li N, Peng Y. The role of innate immunity in pulmonary infections. BioMed Res Int. 2021; 2021(1): 6646071. doi: 10.1155/2021/6646071

[10] Bizimana Rukundo T. Cross-reactivity in adaptive immunity: An overview. Appl Sci (NIJBAS). 2024; 5(3):39-43. doi: 10.59298/NIJBAS/2024/5.3.394311

[11] Whiteside SA, McGinniss JE, Collman RG. The lung microbiome: Progress and promise. J Clin Investig. 2021; 131(15):e150473. doi: 10.1172/JCI150473

[12] Gillissen A, Paparoupa M. Inflammation and infections in asthma. Clin Respir J. 2015; 9(3):257-269. doi: 10.1111/crj.12135

[13] Muyayalo KP, Gong GS, Kiyonga Aimeé K, Liao AH. Impaired immune response against SARS-CoV-2 infection is the major factor indirectly altering reproductive function in COVID-19 patients: A narrative review. Hum Fertil (Camb). 2023; 26(4):778-796. doi: 10.1080/14647273.2023.2262757

[14] Saeid AB, De Rubis G, Williams KA, et al. Revolutionising lung health: Exploring the latest breakthroughs and future prospects of synbiotic nanostructures in lung diseases. Chem Biol Interact. 2024;395:111009. doi: 10.1016/j.cbi.2024.111009

[15] FarniaTP, Ghanavi J, Besharati S, Farnia P, Velayati AA. The pili at genomic level. Pili in Mycobacterium Tuberculosis: Structure, Function, and Therapeutic Advances. Netherlands: Elsevier; 2024. p. 161.

[16] Fouladi MD, Besharati S, Farnia P, Khosravi A. A concise review of the effect of efflux pump on biofilm intensity in bacteria with a special view to mycobacterium. J Prev Diagn Treat Strategies Med. 2024; 3(1):1-5. doi: 10.4103/jpdtsm.jpdtsm_119_23

[17] Mu P, Zhou S, Lv T, et al. Newly developed 3D in vitro models to study tumor-immune interaction. J Exp Clin Cancer Res. 2023; 42(1):81. doi: 10.1186/s13046-023-02653-w

[18] Zong Y, Li H, Liao P, et al. Mitochondrial dysfunction: Mechanisms and advances in therapy. Signal Transduct Target Ther. 2024; 9(1):124. doi: 10.1038/s41392-024-01839-8

[19] Zhou X, Wu Y, Zhu Z, et al. Mucosal immune response in biology, disease prevention and treatment. Signal Transduct Target Ther. 2025; 10(1):7. doi: 10.1038/s41392-024-02043-4

[20] Mochan E, Sego T. Mathematical modeling of the lethal synergism of coinfecting pathogens in respiratory viral infections: A review. Microorganisms. 2023; 11(12):2974. doi: 10.3390/microorganisms11122974

[21] Qadri H, Shah AH, Almilaibary A, Mir MA. Microbiota, natural products, and human health: Exploring interactions for therapeutic insights. Front Cell Infect Microbiol. 2024;14:1371312. doi: 10.1038/s41392-024-02043-4

[22] Chiu CW, Tsai PJ, Lee CC, Ko WC, Hung YP. Application of microbiome management in therapy for Clostridioides difficile Infections: From fecal microbiota transplantation to probiotics to microbiota-preserving antimicrobial agents. Pathogens. 2021; 10(6):649.

[23] Land WG. The DAMP-driven host immune defense program against pathogens. In: Damage-Associated Molecular Patterns in Human Diseases: Antigen-Related Disorders. Vol. 3. Germany: Springer; 2023. p. 203-284. doi: 10.1007/978-3-031-21776-0_4

[24] Meng X, Layhadi JA, Keane ST, Cartwright NJ, Durham SR, Shamji MH. Immunological mechanisms of tolerance: Central, peripheral and the role of T and B cells. Asia Pac Allergy. 2023; 13(4):175-186. doi: 10.5415/apallergy.0000000000000128

[25] Besharati S, Aghajani J, Farnia P, et al. Association between the Vitamin D Receptor Gene (FokI, BsmI. ApaI, and TaqI) polymorphism in health-care workers and susceptibility to COVID-19. Biomed Biotechnol Res J (BBRJ). 2023; 7(3):404-410. doi: 10.4103/bbrj.bbrj_133_23

[26] Farnia P, Besharati S, Farina P, et al. The role of efflux pumps transporter in multi-drug resistant tuberculosis: Mycobacterial memberane protein (MmpL5). Int J Mycobacteriol. 2024; 13(1):7-14. doi: 10.4103/ijmy.ijmy_37_24

[27] Farnia P, Farnia P, Ghanavi J, Ayoubi S, Besharati S, Velayati AA. Comparison of proline-glutamate-proline-glutamate-polymorphic GC-rich sequences family protein Wag22 (Rv1759c), PE_PGRS 31 (Rv1768), PE_PGRS32 ( Rv1803), and PE_PGRS33gene (Rv1818c) in exponential state and under in vitro model of latency in same clinical isolates of Mycobacterium tuberculosis: Frameshift mutation in extensively drug-resistant and totally drug-resistant Tuberculosis bacilli. Biomed Biotechnol Res J (BBRJ). 2023; 7(4):621-632. doi: 10.4103/bbrj.bbrj_271_23

[28] Wang Y, Pruitt RN, Nürnberger T, Wang Y. Evasion of plant immunity by microbial pathogens. Nat Rev Microbiol. 2022; 20(8):449-464. doi: 10.1038/s41579-022-00710-3

[29] Tanaka Y, Luo Y, O’Shea JJ, Nakayamada S. Janus kinase-targeting therapies in rheumatology: A mechanisms-based approach. Nat Rev Rheumatol. 2022; 18(3):133-145. doi: 10.1038/s41584-021-00726-8

[30] Varahram M, Besharati S, Farnia P, et al. Correlation of single-nucleotide polymorphism at interferon-gamma R1 (at position- 56) in positive purified protein derivative health workers with COVID-19 infection. Int J Mycobacteriol. 2022; 11(3):318-322. doi: 10.4103/ijmy.ijmy_133_22

[31] Lei L, Pan W, Shou X, et al. Nanomaterials-assisted gene editing and synthetic biology for optimizing the treatment of pulmonary diseases. J Nanobiotechnol. 2024; 22(1):343. doi: 10.1186/s12951-024-02627-w

[32] Adivitiya, Kaushik MS, Chakraborty S, Veleri S, Kateriya S. Mucociliary respiratory epithelium integrity in molecular defense and susceptibility to pulmonary viral infections. Biology (Basel). 2021; 10(2):95. doi: 10.3390/biology10020095

[33] Dransfield M, Rowe S, Vogelmeier CF, et al. Cystic fibrosis transmembrane conductance regulator: Roles in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2022; 205(6):631-640. doi: 10.1164/rccm.202109-2064TR

[34] Besharati S, Owlia P. Evaluation of biofilm production capacity in Salmonella isolated from chicken meat in Tehran municipally daily fruit and vegetable markets. Daneshvar Med. 2020; 28(1):62-72.

[35] Besharati S, Farnia P, Farnia P, Ghanavi J, Velayati AA. Investigation of the hypothesis of biofilm formation in coronavirus (COVID-19). Biomed Biotechnol Res J (BBRJ). 2020; 4(Suppl 1):S99-S100. doi: 10.4103/bbrj.bbrj_126_20

[36] Besharati S, Soleimani N, Rahbar M.Evaluation of the prevalence of Integron 1, 2 and biofilm formation in clinical isolates of Pseudomonas aeruginosa in Tehran, 2024. J Isfahan Med Sch. 2025; 43:125-134. doi: 10.48305/jims.v43.i805.0125

[37] Besharati S, Owlia P, Sadeghi A, et al. Frequency, antibiotic resistance and serogroups of Salmonella among chicken meat specimens in Tehran, Iran. Daneshvar Med. 2020; 27(4):1-10. doi: 10.1007/s11032-023-01398-w

[38] Yang R, Fu D, Liao A. The role of complement in tumor immune tolerance and drug resistance: A double-edged sword. Front Immunol. 2025;16:1529184. doi: 10.3389/fimmu.2025.1529184

[39] Chow A, Perica K, Klebanoff CA, Wolchok JD. Clinical implications of T cell exhaustion for cancer immunotherapy. Nat Rev Clin Oncol. 2022; 19(12):775-790. doi: 10.1038/s41571-022-00689-z

[40] Zhang G, Wang J, Zhao Z, et al. Regulated necrosis, a proinflammatory cell death, potentially counteracts pathogenic infections. Cell Death Dis. 2022; 13(7):637. doi: 10.1038/s41419-022-05066-3

[41] Gao D, Gao W, Zhai Z, Zhu W. Immune mechanisms and novel therapies for idiopathic pulmonary fibrosis. Pharm Sci Adv. 2024;2:100030. doi: 10.1016/j.pscia.2023.100030

[42] Ahmed R, Zaman T, Chowdhury F, et al. Single-cell RNA sequencing with spatial transcriptomics of cancer tissues. Int J Mol Sci. 2022; 23(6):3042. doi: 10.3390/ijms23063042

[43] Pelaia C, Tinello C, Vatrella A, De Sarro G, Pelaia G. Lung under attack by COVID-19-induced cytokine storm: Pathogenic mechanisms and therapeutic implications. Ther Adv Respir Dis. 2020;14:1-9. doi: 10.1177/1753466620933508

[44] Hsu RJ, Yu WC, Peng GR, et al. The role of cytokines and chemokines in severe acute respiratory syndrome coronavirus 2 infections. Front Immunol. 2022;13:832394. doi: 10.3389/fimmu.2022.832394

[45] Stegeman SK, Kourko O, Amsden H, et al. RNA viruses, toll-like receptors, and cytokines: The perfect storm? J Innate Immun. 2025;17:126-153. doi: 10.1159/000543608

[46] Lu T, Yan H, Luo J, Wang S, Xia Y, Xu X. Elevated thrombosis-related biomarkers as predictors of disease severity and mortality in patients with severe fever with thrombocytopenia syndrome. BMC Infect Dis. 2025;25:235. doi: 10.1186/s12879-025-10574-6

[47] Krishnamachary B, Cook C, Kumar A, Spikes L, Chalise P, Dhillon NK. Extracellular vesicletors of disease severity and mortality in patients with severe fever with thrombocytopenia syndrome. J Extracell Vesicles. 2021; 10(9):e12117. doi: 10.1002/jev2.12117

[48] Ramaswamy A, Brodsky NN, Sumida TS, et al. Immune dysregulation and autoreactivity correlate with disease severity in SARS-CoV-2-associated multisystem inflammatory syndrome in children. Immunity. 2021; 54(5):1083-1095.e7. doi: 10.1016/j.immuni.2021.04.003

[49] Mohite P, Yadav V, Pandhare R, et al. Revolutionizing cancer treatment: Unleashing the power of viral vaccines, monoclonal antibodies, and proteolysis-targeting chimeras in the new era of immunotherapy. ACS Omega. 2024; 9(7):7277-7295. doi: 10.1021/acsomega.3c06501

[50] Paudyal B, McNee A, Rijal P, et al. Low dose pig anti-influenza virus monoclonal antibodies reduce lung pathology but do not prevent virus shedding. Front Immunol. 2021;12:790918. doi: 10.3389/fimmu.2021.790918

[51] Li N, Parkes JE, Spathis R, et al. The effect of immunomodulatory treatments on anti-dystrophin immune response after AAV gene therapy in dystrophin deficient mdx mice. J Neuromuscul Dis. 2021; 8(s2):S325-S340. doi: 10.3233/JND-210706

[52] Xu C, Hao M, Zai X, et al. A new perspective on gut-lung axis affected through resident microbiome and their implications on immune response in respiratory diseases. Arch Microbiol. 2024; 206(3):107. doi: 10.1007/s00203-024-03843-6

[53] Song Z, Meng Y, Fricker M, Tian H, Tan Y, Qin L. The role of gut-lung axis in COPD: Pathogenesis, immune response, and prospective treatment. Heliyon. 2024; 10(9):e30612. doi: 10.1016/j.heliyon.2024.e3061

[54] De Oliveira GLV, Oliveira CNS, Pinzan CF, De Salis LVV, Cardoso CRB. Microbiota modulation of the gut-lung axis in COVID-19. Front Immunol. 2021;12:635471. doi: 10.3389/fimmu.2021.635471

[55] Loera-Muro A, Guerrero-Barrera A, Tremblay DNY, Hathroubi S, Angulo C. Bacterial biofilm-derived antigens: A new strategy for vaccine development against infectious diseases. Expert Rev Vaccines. 2021; 20(4):385-396. doi: 10.1080/14760584.2021.1892492

[56] Worley MJ. Immune evasion and persistence in enteric bacterial pathogens. Gut Microbes. 2023; 15(1):2163839. doi: 10.1080/19490976.2022.2163839

[57] Johnston SL, Goldblatt DL, Evans SE, Tuvim MJ, Dickey BF. Airway epithelial innate immunity. Front Physiol. 2021;12:749077. doi: 10.3389/fphys.2021.749077

[58] Paradis T, Bègue H, Basmaciyan L, Dalle F, Bon F. Tight junctions as a key for pathogens invasion in intestinal epithelial cells. Int J Mol Sci. 2021; 22(5):2506. doi: 10.3390/ijms22052506

[59] Ishihara N, Tanaka M, Namba K, et al. Long-term exposure to urban particulate matter exacerbates mortality after ischemic stroke in mice. J Toxicol Sci. 2025; 50(3):147-159. doi: 10.2131/jts.50.147

[60] Hu D, Jia X, Cui L, et al. Exposure to fine particulate matter promotes platelet activation and thrombosis via obesity-related inflammation. J Hazard Mater. 2021;413:125341. doi: 10.1016/j.jhazmat.2021.125341

[61] Koul A, Bawa RK, Kumar Y. Artificial intelligence techniques to predict the airway disorders illness: A systematic review. Arch Computat Methods Eng. 2023; 30(2):831-864. doi: 10.1007/s11831-022-09818-4

[62] Yan C, Wang L, Lin J, et al. A fully automatic artificial intelligence-based CT image analysis system for accurate detection, diagnosis, and quantitative severity evaluation of pulmonary tuberculosis. Eur Radiol. 2022; 32:2188-2199. doi: 10.1007/s00330-021-08365-z

[63] Mettelman RC, Allen EK, Thomas PG. Mucosal immune responses to infection and vaccination in the respiratory tract. Immunity. 2022; 55(5):749-780. doi: 10.1016/j.immuni.2022.04.013

[64] Fraser R, Orta-Resendiz A, Mazein A, Dockrell DH. Upper respiratory tract mucosal immunity for SARS-CoV-2 vaccines. Trends Mol Med. 2023; 29(4):255-267. doi: 10.1016/j.molmed.2023.01.003

[65] Jung M, Dourado M, Maksymetz J, et al. Cross-species transcriptomic atlas of dorsal root ganglia reveals species-specific programs for sensory function. Nat Commun. 2023; 14(1):366. doi: 10.1038/s41467-023-36014-0

[66] Mogilenko DA, Shpynov O, Andhey PS, et al. Comprehensive profiling of an aging immune system reveals clonal GZMK+ CD8+ T cells as conserved hallmark of inflammaging. Immunity. 2021; 54(1):99-115.e12. doi: 10.1016/j.immuni.2020.11.005