Clinical efficacies of immune-cell-targeted interventions a revolutionary era in host immune gene expression in MRSA infections

Abstract

Background and aims: Methicillin-resistant Staphylococcus aureus (MRSA) remains a major cause of healthcare-associated infections worldwide, frequently progressing to bacteremia, and with high mortality rates, particularly in patients with recurrent or persistent infections involving skin/soft tissue and the bloodstream. Traditional antibiotic therapies are increasingly limited by MDR and immune evasion mechanisms. This review synthesized host immune transcriptomic changes during MRSA infections and evaluated the clinical translational potential of next-generation vaccines developed after 2020. Methods: Relevant searches were conducted in PubMed, Embase, and Web of Science (2020–2025) using combinations of terms related to MRSA, host immune gene expression, transcriptomics, scRNA-seq, and next-generation vaccines. Eligible studies included original research and reviews reporting primary data on immune transcriptomics or vaccine immunogenicity/protective efficacy in MRSA infections. Results: MRSA infection triggers strong innate immune activation (TLR2/NOD2 signaling, IL-1β/IL-6/TNF-α upregulation) and heterogeneous macrophage polarization (M1 proinflammatory vs. M2 immunosuppressive phenotypes), alongside adaptive Th1/Th17 responses that are undermined by superantigens, IL-10 hypersecretion, and PD-1-mediated exhaustion. Multivalent mRNA-LNP vaccines encoding ClfA- Hla- IsdB fusions induce strong Th1/Th17 immunity, ~80% opsonophagocytic killing activity, 90% reduction in bacterial load, and 75% survival in murine sepsis models. Conclusion: This review demonstrated that integrating scRNA-seq-derived macrophage polarization biomarkers with next-generation mRNA and nanoparticle vaccine platforms offers a promising precision medicine strategy to counter MRSA immune evasion. These approaches may substantially reduce infection recurrence and complications in high-risk patients, paving the way for clinically effective vaccines in the era of antimicrobial resistance.

Keywords

mRNA vaccine / methicillin-resistant Staphylococcus aureus / nano-particle vaccine / macrophage activations

References

[1] Liu Y, Lu H, Hu G, et al. (2025) Unmasking MRSA’s armor: Molecular mechanisms of resistance and pioneering therapeutic countermeasures. Microorganisms 13: 1928. https://doi.org/10.3390/microorganisms13081928

[2] Guo Y, Song G, Sun M, et al. (2020) Prevalence and therapies of antibiotic—resistance in Staphylococcus aureus. Front Cell Infect Microbiol 10: 107. https://doi.org/10.3389/fcimb.2020.00107

[3] Tabassum F, Munir A, Shakeel F, et al. (2025) Methicillin resistance in Staphylococcus aureus: A review of the mecA gene and its role in antibiotic resistance. IJBR 3. https://doi.org/10.70749/ijbr.v3i9.2302

[4] Touaitia R, Mairi A, Ibrahim NA, et al. (2025) Staphylococcus aureus: A review of the pathogenesis and virulence mechanisms. Antibiotics 14: 470. https://doi.org/10.3390/antibiotics14050470

[5] Vieira G, Leal N, Rodrigues A, et al. (2020) MRSA/MSSA causing infections: Prevalence of mecA gene. Eur J Public Health 30: ckaa040.052. https://doi.org/10.1093/eurpub/ckaa040.052

[6] Bahmaie N, Esmaeilzadeh A (2016) Sepsis biomarkers; A new approach in the diagnosis and follow up treatment of infectious diseases. Lab Diagn 7: 53-64.

[7] Borcak D, Ozdemir YE, Yesilbag Z, et al. (2025) Clinical and laboratory predictors of mortality in Staphylococcus aureus bacteremia. Sci Rep 15: 30709. https://doi.org/10.1038/s41598—025—16137—8

[8] Kadmiri IM, Ouhssain A, Bennis I, et al. (2025) Nanomaterials in antimicrobial therapy: Unlocking solutions for multidrug—resistant pathogenic bacteria, In: Nanotechnology For Medicine, Florida: CRC Press, 294-317. https://doi.org/10.1201/9781003562917—16

[9] Fiore M, Alfieri A, Fiore D, et al. (2025) Use of Daptomycin to manage severe MRSA infections in humans. Antibiotics 14: 617. https://doi.org/10.3390/antibiotics14060617

[10] Abebe AA, Birhanu AG (2023) Methicillin resistant Staphylococcus aureus: Molecular mechanisms underlying drug resistance development and novel strategies to combat. Infect Drug Resist 2023: 7641-7662. https://doi.org/10.2147/IDR.S428103

[11] Li J, Cheng F, Wei X, et al. (2025) Methicillin—resistant Staphylococcus aureus (MRSA): Resistance, prevalence, and coping strategies. Antibiotics 14: 771. https://doi.org/10.3390/antibiotics14080771

[12] Karimbakhsh M, Eramian M, Gholami M (2025) Staphylococcus haemolyticus: Tackling multidrug resistance and biofilm hurdles—advances in antimicrobial strategies (mini—review). Res Mol Med 13: 1-8. https://doi.org/10.32598/rmm.13.1.1365.3

[13] Lade H, Kim JS (2023) Molecular determinants of β—Lactam resistance in methicillin—resistant Staphylococcus aureus (MRSA): An updated review. Antibiotics (Basel) 12: 1362. https://doi.org/10.3390/antibiotics12091362

[14] Naik P, Joseph J (2022) Difference in host immune response to methicillin—resistant and methicillin sensitive staphylococcus aureus (MRSA and MSSA) endophthalmitis. Ocul Immunol Inflamm 30: 1044-1054. https://doi.org/10.1080/09273948.2020.1859551

[15] Bisola M—AI, Olatunji G, Kokori E, et al. (2024) Emerging challenges in innate immunity: Staphylococcus aureus and healthcare—associated infection. J Med Surg Public Health 3: 100103. https://doi.org/10.1016/j.glmedi.2024.100103

[16] Tuffs SW, Goncheva MI, Xu SX, et al. (2022) Superantigens promote Staphylococcus aureus bloodstream infection by eliciting pathogenic interferon—gamma production. Proc Natl Acad Sci USA 119: e2115987119. https://doi.org/10.1073/pnas.2115987119

[17] Oliveira CS, Negut I (2025) Precision medicine and omics approaches for managing infectious diseases: Technologies, applications, and current achievements, In: AI and Precision Medicine in Infectious Disease Management, Florida: CRC Press, 71-97. https://doi.org/10.1201/9781003615699—4

[18] Fan YN, Zhao G, Zhang Y, et al. (2023) Progress in nanoparticle—based regulation of immune cells. Med Rev 3: 152179. https://doi.org/10.1515/mr—2022—0047

[19] Chen H, Zhang J, He Y, et al. (2022) Exploring the role of Staphylococcus aureus in inflammatory diseases. Toxins (Basel) 14: 464. https://doi.org/10.3390/toxins14070464

[20] Niu L, Duan H, Wang J, et al. (2025) Probiotic peptidoglycan skeleton enhances vaccine efficacy against MRSA by inducing trained immunity via the TLR2/JAK—STAT3 pathway. Front Immunol 16: 1606626. https://doi.org/10.3389/fimmu.2025.1606626

[21] Nikolic P, Mudgil P (2023) The cell wall, cell membrane and virulence factors of Staphylococcus aureus and their role in antibiotic resistance. Microorganisms 11: 259. https://doi.org/10.3390/microorganisms11020259

[22] Rasquel—Oliveira FS, Ribeiro JM, Martelossi—Cebinelli G, et al. (2025) Staphylococcus aureus in inflammation and pain: Update on pathologic mechanisms. Pathogens 14: 185. https://doi.org/10.3390/pathogens14020185

[23] Esmaeilzadeh A, Bahmaie N, Nouri E, et al. (2021) Immunobiological properties and clinical applications of interleukin—38 for immune—mediated disorders: A systematic review study. Int J Mol Sci 22: 12552. https://doi.org/10.3390/ijms222312552

[24] Eld HMS, Johnsen PR, Nielsen EM, et al. (2022) Soluble C—type lectin—receptor ligands stimulate ROS production in dendritic cells and potentiate killing of MRSA as well as the MRSA induced IL—12 production. Front Immunol 13: 845881. https://doi.org/10.3389/fimmu.2022.845881

[25] Xu W, Tian K, Hu S, et al. (2023) IL—9 promotes methicillin—resistant Staphylococcus aureus pneumonia by regulating the polarization and phagocytosis of macrophages. Infect Immun 91: e0016623. https://doi.org/10.1128/iai.00166—23

[26] Wong Fok Lung T, Chan LC, Prince A, et al. (2022) Staphylococcus aureus adaptive evolution: Recent insights on how immune evasion, immunometabolic subversion and host genetics impact vaccine development. Front Cell Infect Microbiol 12: 1060810. https://doi.org/10.3389/fcimb.2022.1060810

[27] Jahan N, Patton T, O’keeffe M (2022) The influence of antibiotic resistance on innate immune responses to Staphylococcus aureus infection. Antibiotics 11: 542. https://doi.org/10.3390/antibiotics11050542

[28] Zhao Y, Zhai L, Qin T, et al. (2023) Time—course transcriptome analysis of the lungs of mice challenged with aerosols of methicillin—resistant Staphylococcus aureus USA300 clone reveals inflammatory balance. Biomolecules 13: 347. https://doi.org/10.3390/biom13020347

[29] Parmar R, Pickering H, Ahn R, et al. (2024) Integrated transcriptomic analysis reveals immune signatures distinguishing persistent versus resolving outcomes in MRSA bacteremia. Front Immunol 15: 1373553. https://doi.org/10.3389/fimmu.2024.1373553

[30] Parsons JB, Westgeest AC, Conlon BP, et al. (2023) Persistent methicillin—resistant Staphylococcus aureus bacteremia: Host, pathogen, and treatment. Antibiotics (Basel) 12: 455. https://doi.org/10.3390/antibiotics12030455

[31] Zhou P, Shi X, Xia J, et al. (2024) Innovative epitopes in Staphylococcal Protein—A an immuno—informatics approach to combat MDR—MRSA infections. Front Cell Infect Microbiol 14: 1503944. https://doi.org/10.3389/fcimb.2024.1503944

[32] Mellergaard M, Skovbakke SL, Jepsen SD, et al. (2023) Clinical Staphylococcus aureus inhibits human T—cell activity through interaction with the PD—1 receptor. mBio 14: e0134923. https://doi.org/10.1128/mbio.01349—23

[33] Scully J, Mustafa AS, Hanif A, et al. (2024) Immune responses to methicillin—resistant Staphylococcus aureus infections and advances in the development of vaccines and immunotherapies. Vaccines (Basel) 12: 1106. https://doi.org/10.3390/vaccines12101106

[34] Cahill SC, Soldaini E, McLoughlin RM (2025) Pathobiont immune tuning: The untold consequences of Staphylococcus aureus exposure on host immunity. Trends Microbiol 34: 159-170. https://doi.org/10.1016/j.tim.2025.07.008

[35] Kak G, Van Roy Z, Heim CE, et al. (2023) IL—10 production by granulocytes promotes Staphylococcus aureus craniotomy infection. J Neuroinflammation 20: 114. https://doi.org/10.1186/s12974—023—02798—7

[36] Bergersen KV, Zheng Y, Rossetti M, et al. (2025) Early cytokine signatures and clinical phenotypes discriminate persistent from resolving MRSA bacteremia. BMC Infect Dis 25: 231. https://doi.org/10.1186/s12879—025—10620—3

[37] Hajam IA, Liu GY (2024) Linking S. aureus immune evasion mechanisms to staphylococcal vaccine failures. Antibiotics (Basel) 13: 410. https://doi.org/10.3390/antibiotics13050410

[38] Fu Y, Yang Z, Zhang H, et al. (2021) 14—O—[(4,6—Diamino—pyrimidine—2—yl) thioacetyl] mutilin inhibits α—hemolysin and protects Raw264.7 cells from injury induced by methicillin—resistant S. aureus. Microb Pathog 161: 105229. https://doi.org/10.1016/j.micpath.2021.105229

[39] Ridder MJ, McReynolds AKG, Dai H, et al. (2022) Kinetic characterization of the immune response to methicillin—resistant Staphylococcus aureus subcutaneous skin infection. Infect Immun 90: e0006522. https://doi.org/10.1128/iai.00065—22

[40] Linz MS, Mattappallil A, Finkel D, et al. (2023) Clinical impact of Staphylococcus aureus skin and soft tissue infections. Antibiotics (Basel) 12: 557. https://doi.org/10.3390/antibiotics12030557

[41] Fu Y, Leng C, Fan Y, et al. (2021) In Vitro and In Vivo Activity of 14—O—[(4,6—Diamino—pyrimidine—2—yl) thioacetyl] Mutilin against methicillin—resistant Staphylococcus aureus . Molecules 26: 3277. https://doi.org/10.3390/molecules26113277

[42] Theodorakis N, Feretzakis G, Hitas C, et al. (2024) Immunosenescence: How aging increases susceptibility to bacterial infections and virulence factors. Microorganisms 12: 2052. https://doi.org/10.3390/microorganisms12102052

[43] Jang K, Kim H, Choi D, et al. (2025) Staphylococcus aureus utilizes vimentin to internalize human keratinocytes. Front Cell Infect Microbiol 15: 1543186. https://doi.org/10.3389/fcimb.2025.1543186

[44] Pidwill GR, Gibson JF, Cole J, et al. (2021) The role of macrophages in Staphylococcus aureus infection. Front Immunol 11: 620339. https://doi.org/10.3389/fimmu.2020.620339

[45] Kolla HB, Tirumalasetty C, Sreerama K, et al. (2021) An immunoinformatics approach for the design of a multi—epitope vaccine targeting super antigen TSST—1 of Staphylococcus aureus . J Genet Eng Biotechnol 19: 69. https://doi.org/10.1186/s43141—021—00160—z

[46] Li J, Ju Y, Jiang M, et al. (2025) Epitope—based vaccines: The next generation of promising vaccines against bacterial infection. Vaccines (Basel) 13: 248. https://doi.org/10.3390/vaccines13030248

[47] Kbah N, Shkir F, Hashim S, et al. (2025) Design and preclinical evaluation of a multi—epitope mRNA vaccine against methicillin—Resistant Staphylococcus Aureus (MRSA). Trends Biotechnol 3: 16-35. https://doi.org/10.57238/tpb.2025.153196.1025

[48] Rajangam SL, Narasimhan MK (2024) Current treatment strategies for targeting virulence factors and biofilm formation in Acinetobacter baumannii . Future Microbiol 19: 941-961. https://doi.org/10.2217/fmb—2023—0263

[49] Hulme J (2022) Application of nanomaterials in the prevention, detection, and treatment of methicillin—resistant Staphylococcus aureus (MRSA) . Pharmaceutics 14: 805. https://doi.org/10.3390/pharmaceutics14040805

[50] Gao X, Zheng Y, Wang X, et al. (2025) A multivalent mRNA—LNP cocktail vaccine confers superior efficacy against Staphylococcus aureus infection in murine models. NPJ Vaccines 10: 210. https://doi.org/10.1038/s41541—025—01244—4

[51] Pardi N, Hogan MJ, Weissman D (2020) Recent advances in mRNA vaccine technology. Curr Opin Immunol 65: 14-20. https://doi.org/10.1016/j.coi.2020.01.008

[52] Balanca CC, Capietto AH, Carbone C, et al. (2024) Abstract A030: CD4 neoantigen mRNA vaccine enhances endogenous CD8 responses and tumor control. Cancer Immunol Res 12: A030. https://doi.org/10.1158/2326—6074.TUMIMM24—A030

[53] Clegg J, Soldaini E, McLoughlin RM, et al. (2021) Staphylococcus aureus vaccine research and development: The past, present and future, including novel therapeutic strategies. Front Immunol 12: 705360. https://doi.org/10.3389/fimmu.2021.705360

[54] Bahmaie N, Nouri E, Ghotbi D, et al. (2020) Immune gene and cell therapy: A novel and promising approach for immunotherapy of sepsis management. J Emerging Dis Prev Med 1.

[55] Luo JR, Qi XX, Tian TT, et al. (2025) Design of a multi—Epitope mRNA vaccine against Brucella type IV secretion system using reverse vaccinology and immunogenicity approaches. Sci Rep 15: 30698. https://doi.org/10.1038/s41598—025—09509—7

[56] Haghighat S, Siadat SD, Akhavan Sepahi A, et al. (2022) Recombinant PBP2a/autolysin conjugate as PLGA—based nanovaccine induced humoral responses with opsonophagocytosis activity, and protection versus methicillin—resistant Staphylococcus aureus infection. Iran J Basic Med Sci 25: 442-450. https://doi.org/10.22038/IJBMS.2022.59992.13303

[57] de Vor L, Rooijakkers SHM, van Strijp JAG (2020) Staphylococci evade the innate immune response by disarming neutrophils and forming biofilms. FEBS Lett 594: 2556-2569. https://doi.org/10.1002/1873—3468.13767

[58] Tsai CM, Caldera JR, Hajam IA, et al. (2022) Non—protective immune imprint underlies failure of Staphylococcus aureus IsdB vaccine. Cell Host Microbe 30: 1163-1172.e1166. https://doi.org/10.1016/j.chom.2022.06.006

[59] Roßmann L, Bagola K, Stephen T, et al. (2021) Distinct single—component adjuvants steer human DC—mediated T—cell polarization via Toll—like receptor signaling toward a potent antiviral immune response. Proc Natl Acad Sci USA 118: e2103651118. https://doi.org/10.1073/pnas.2103651118

[60] Tan Z, Yang W, O'Brien NA, et al. (2024) A comprehensive synthetic library of poly—N—acetyl glucosamines enabled vaccine against lethal challenges of Staphylococcus aureus . Nat Commun 15: 3420. https://doi.org/10.1038/s41467—024—47457—4

[61] Venkatasubramaniam A, Liao G, Cho E, et al. (2021) Safety and Immunogenicity of a 4—Component Toxoid—Based Staphylococcus aureus Vaccine in Rhesus Macaques. Front Immunol 12: 621754. https://doi.org/10.3389/fimmu.2021.621754

[62] Zian Z, Berry SD—G, Bahmaie N, et al. (2021) The clinical efficacy of Rituximab administration in autoimmunity disorders, primary immunodeficiency diseases and malignancies. Int Immunopharmacol 95: 107565. https://doi.org/10.1016/j.intimp.2021.107565

[63] Pan N, Liu Y, Zhang H, et al. (2023) Oral vaccination with engineered probiotic Limosilactobacillus reuteri has protective effects against localized and systemic Staphylococcus aureus infection. Microbiol Spectr 11: e0367322. https://doi.org/10.1128/spectrum.03673—22

[64] Ranjbariyan A, Haghighat S, Yazdi MH, et al. (2022) Synthetic selenium nanoparticles as co—adjuvant improved immune responses against methicillin—resistant Staphylococcus aureus . World J Microbiol Biotechnol 39: 16. https://doi.org/10.1007/s11274—022—03455—6

[65] Ramalingam K (2021) Handbook of Research on Nanoemulsion Applications in Agriculture, Food, Health, and Biomedical Sciences , Pennsylvania: IGI Global, 671. https://doi.org/10.4018/978—1—7998—8378—4