Pathogenesis of influenza and SARS-CoV-2 co-infection at the extremes of age: decipher the ominous tales of immune vulnerability
Kai-lin Mai , Wei-qi Pan , Zheng-shi Lin , Yang Wang , Zi-feng Yang
Advanced Biotechnology ›› 2025, Vol. 3 ›› Issue (1) : 5
Pathogenesis of influenza and SARS-CoV-2 co-infection at the extremes of age: decipher the ominous tales of immune vulnerability
The co-circulation of influenza and SARS-CoV-2 has led to co-infection events, primarily affecting children and older adults, who are at higher risk for severe disease. Although co-infection prevalence is relatively low, it is associated with worse outcomes compared to mono-infections. Previous studies have shown that the outcomes of co-infection depend on multiple factors, including viral interference, virus-host interaction and host response. Children and the elderly exhibit distinct patterns of antiviral response, which involve airway epithelium, mucociliary clearance, innate and adaptive immune cells, and inflammatory mediators. This review explores the pathogeneses of SARS-CoV-2 and influenza co-infection, focusing on the antiviral responses in children and the elderly. By comparing immature immunity in children and immune senescence in older adults, we aim to provide insights for the clinical management of severe co-infection cases.
| [1] |
|
| [2] |
|
| [3] |
|
| [4] |
|
| [5] |
|
| [6] |
Almanan M, Raynor J, Ogunsulire I, Malyshkina A, Mukherjee S, Hummel SA et al. IL-10-producing Tfh cells accumulate with age and link inflammation with age-related immune suppression. Sci Adv. 2020;6(31):eabb0806. https://doi.org/10.1126/sciadv.abb0806. |
| [7] |
|
| [8] |
Baker PJ, Bohrer AC, Castro E, Amaral EP, Snow-Smith M, Torres-Juárez F, et al. The inflammatory microenvironment of the lung at the time of infection governs innate control of SARS-CoV-2 replication. BioRxiv . 2024. https://doi.org/10.1101/2024.03.27.586885. |
| [9] |
|
| [10] |
|
| [11] |
Bolouri H, Speake C, Skibinski D, Long SA, Hocking AM, Campbell DJ, et al. The COVID-19 immune landscape is dynamically and reversibly correlated with disease severity. J Clin Invest. 2021;131(3). https://doi.org/10.1172/JCI143648. |
| [12] |
Bonfante F, Costenaro P, Cantarutti A, Di Chiara C, Bortolami A, Petrara MR, et al. Mild SARS-CoV-2 infections and neutralizing antibody titers. Pediatrics. 2021;148(3). https://doi.org/10.1542/peds.2021-052173. |
| [13] |
Brauning A, Rae M, Zhu G, Fulton E, Admasu TD, Stolzing A, et al. Aging of the immune system: focus on natural killer cells phenotype and functions. Cells. 2022;11(6). https://doi.org/10.3390/cells11061017. |
| [14] |
|
| [15] |
|
| [16] |
|
| [17] |
Chason KD, Jaspers I, Parker J, Sellers S, Brighton LE, Hunsucker, SA, et al. Age-associated changes in the respiratory epithelial response to influenza infection. J Gerontol: Series A. 2018;73(12):1643–1650. https://doi.org/10.1093/gerona/gly126. |
| [18] |
|
| [19] |
|
| [20] |
|
| [21] |
|
| [22] |
|
| [23] |
|
| [24] |
|
| [25] |
Costa, V.G.d., Gomes, A.J.C., Bittar, C., Geraldini, D.B., Previdelli da Conceição, P.J., Cabral, Á.S., et al. Burden of influenza and respiratory syncytial viruses in suspected COVID-19 patients: a cross-sectional and meta-analysis study. Viruses. 2023;15(3). https://doi.org/10.3390/v15030665. |
| [26] |
|
| [27] |
|
| [28] |
|
| [29] |
|
| [30] |
|
| [31] |
De Leeuw E, Hammad H. The role of dendritic cells in respiratory viral infection. Eur Respir Rev. 2024;33(172). https://doi.org/10.1183/16000617.0250-2023. |
| [32] |
De Maeyer RPH, Chambers ES. The impact of ageing on monocytes and macrophages. Immunol Lett. 2021;230. https://doi.org/10.1016/j.imlet.2020.12.003. |
| [33] |
|
| [34] |
|
| [35] |
|
| [36] |
|
| [37] |
|
| [38] |
|
| [39] |
|
| [40] |
|
| [41] |
|
| [42] |
|
| [43] |
Fage C, Hénaut M, Carbonneau J, Piret J, Boivin G. Influenza A(H1N1)pdm09 virus but not respiratory syncytial virus interferes with SARS-CoV-2 replication during sequential infections in human nasal epithelial cells. Viruses. 2022;14(2). https://doi.org/10.3390/v14020395. |
| [44] |
|
| [45] |
Garg I, Gangu K, Shuja H, Agahi A, Sharma H, Bobba A, et al. COVID-19 and influenza coinfection outcomes among hospitalized patients in the United States: a propensity matched analysis of national inpatient sample. Vaccines. 2022;10(12). https://doi.org/10.3390/vaccines10122159. |
| [46] |
|
| [47] |
|
| [48] |
|
| [49] |
|
| [50] |
|
| [51] |
|
| [52] |
|
| [53] |
|
| [54] |
|
| [55] |
Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell. 2020;181(2). https://doi.org/10.1016/j.cell.2020.02.052. |
| [56] |
|
| [57] |
|
| [58] |
Jeican II, Gheban D, Mariș A, Albu S, Aluaș M, Siserman CV, et al. Flurona: the first autopsied case. Medicina (Kaunas, Lithuania). 2023;59(9). https://doi.org/10.3390/medicina59091616. |
| [59] |
|
| [60] |
|
| [61] |
Karron RA, Garcia Quesada M, Schappell EA, Schmidt SD, Deloria Knoll M, Hetrich MK, et al. Binding and neutralizing antibody responses to SARS-CoV-2 in very young children exceed those in adults. JCI Insight 2022;7(8). https://doi.org/10.1172/jci.insight.157963. |
| [62] |
|
| [63] |
|
| [64] |
|
| [65] |
Kollmann TR, Crabtree J, Rein-Weston A, Blimkie D, Thommai F, Wang XY, et al. Neonatal innate TLR-mediated responses are distinct from those of adults. J Immunol (Baltimore, Md. : 1950). 2009;183(11):7150–7160. https://doi.org/10.4049/jimmunol.0901481. |
| [66] |
|
| [67] |
|
| [68] |
Kumar N, Sharma S, Barua S, Tripathi BN, Rouse BT. Virological and immunological outcomes of coinfections. Clin Microbiol Rev. 2018;31(4). https://doi.org/10.1128/CMR.00111-17. |
| [69] |
|
| [70] |
|
| [71] |
|
| [72] |
|
| [73] |
|
| [74] |
|
| [75] |
Maddux AB, Douglas IS. Is the developmentally immature immune response in paediatric sepsis a recapitulation of immune tolerance? Immunology. 2015;145(1). https://doi.org/10.1111/imm.12454. |
| [76] |
Maltezou HC, Papanikolopoulou A, Vassiliu S, Theodoridou K, Nikolopoulou G, Sipsas NV. COVID-19 and respiratory virus co-infections: a systematic review of the literature. Viruses. 2023;15(4). https://doi.org/10.3390/v15040865. |
| [77] |
|
| [78] |
|
| [79] |
Meade P, Kuan G, Strohmeier S, Maier HE, Amanat F, Balmaseda A, et al. Influenza virus infection induces a narrow antibody response in children but a broad recall response in adults. MBio. 2020;11(1). https://doi.org/10.1128/mBio.03243-19. |
| [80] |
|
| [81] |
Mifsud EJ, Kuba M, Barr IG. Innate immune responses to influenza virus infections in the upper respiratory tract. Viruses. 2021;13(10). https://doi.org/10.3390/v13102090. |
| [82] |
|
| [83] |
|
| [84] |
|
| [85] |
|
| [86] |
|
| [87] |
|
| [88] |
|
| [89] |
|
| [90] |
|
| [91] |
|
| [92] |
|
| [93] |
|
| [94] |
Pinky L, DeAguero JR, Remien CH, Smith AM. How interactions during viral-viral coinfection can shape infection kinetics. Viruses. 2023;15(6). https://doi.org/10.3390/v15061303. |
| [95] |
|
| [96] |
|
| [97] |
|
| [98] |
Romero Starke K, Reissig D, Petereit-Haack G, Schmauder S, Nienhaus A, Seidler A. The isolated effect of age on the risk of COVID-19 severe outcomes: a systematic review with meta-analysis. BMJ Glob Health 2021;6(12). https://doi.org/10.1136/bmjgh-2021-006434. |
| [99] |
|
| [100] |
|
| [101] |
|
| [102] |
|
| [103] |
|
| [104] |
|
| [105] |
|
| [106] |
|
| [107] |
Svyatchenko VA, Ternovoi VA, Lutkovskiy RY, Protopopova EV, Gudymo AS, Danilchenko NV, et al. Human adenovirus and influenza A virus exacerbate SARS-CoV-2 infection in animal models. Microorganisms. 2023;11(1). https://doi.org/10.3390/microorganisms11010180. |
| [108] |
Thevaranjan N, Puchta A, Schulz C, Naidoo A, Szamosi JC, Verschoor CP, et al. Age-associated microbial dysbiosis promotes intestinal permeability, systemic inflammation, and macrophage dysfunction. Cell Host Microbe. 2017;21(4). https://doi.org/10.1016/j.chom.2017.03.002. |
| [109] |
|
| [110] |
Unione L, Moure MJ, Lenza MP, Oyenarte I, Ereño-Orbea J, Ardá A, et al. The SARS-CoV-2 spike glycoprotein directly binds exogeneous sialic acids: a NMR view. Angewandte Chemie (International Ed. In English). 2022;61(18):e202201432. https://doi.org/10.1002/anie.202201432. |
| [111] |
Uyeki TM. Global epidemiology of human infections with highly pathogenic avian influenza A (H5N1) viruses. Respirology (Carlton, Vic.) 2008;13 Suppl 1:S2-S9. https://doi.org/10.1111/j.1440-1843.2008.01246.x. |
| [112] |
|
| [113] |
|
| [114] |
|
| [115] |
Wang S, Wang D. Co-circulation, Co-infection of SARS-CoV-2 and influenza virus, where will it go? Zoonoses. 2023;3(1). https://doi.org/10.15212/ZOONOSES-2023-0006. |
| [116] |
|
| [117] |
|
| [118] |
|
| [119] |
Wlodarczyk MF, Kraft AR, Chen HD, Kenney LL, Selin LK. Anti-IFN-γ and peptide-tolerization therapies inhibit acute lung injury induced by cross-reactive influenza A-specific memory T cells. J Immunol (Baltimore, Md. : 1950). 2013;190(6):2736–2746. https://doi.org/10.4049/jimmunol.1201936. |
| [120] |
|
| [121] |
|
| [122] |
Yang J, Gong Y, Zhang C, Sun J, Wong G, Shi W, et al. Co-existence and co-infection of influenza A viruses and coronaviruses: public health challenges. Innovation (Cambridge (Mass.)). 2022;3(5):100306. https://doi.org/10.1016/j.xinn.2022.100306. |
| [123] |
You D, Ripple M, Balakrishna S, Troxclair D, Sandquist D, Ding L, et al. Inchoate CD8+ T cell responses in neonatal mice permit influenza-induced persistent pulmonary dysfunction. J Immunol (Baltimore, Md. : 1950). 2008;181(5):3486–3494. |
| [124] |
|
| [125] |
|
| [126] |
|
| [127] |
|
| [128] |
|
| [129] |
|
| [130] |
|
| [131] |
|
| [132] |
|
| [133] |
|
| [134] |
|
National Natural Science Foundation of China(82361168672)
National Natural Science Foundation of China(82174053)
National Natural Science Foundation of China(82341099)
Science and Technology Development Fund of Macau SAR, China(FDCT0111/2023/AFJ)
Science and Technology Development Fund of Macau SAR, China(005/2022/ALC)
Science and Technology Development Fund of Macau SAR, China(0045/2021/A)
Open Project of State Key Laboratory of Respiratory Disease(SKLRD-OP-202209)
Self-supporting Program of Guangzhou Laboratory(SRPG22-007)
The Author(s)
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