Abstract
The upcoming flu season in the Northern Hemisphere merging with the current COVID-19 pandemic raises a potentially severe threat to public health. Through experimental coinfection with influenza A virus (IAV) and either pseudotyped or live SARS-CoV-2 virus, we found that IAV preinfection significantly promoted the infectivity of SARS-CoV-2 in a broad range of cell types. Remarkably, in vivo, increased SARS-CoV-2 viral load and more severe lung damage were observed in mice coinfected with IAV. Moreover, such enhancement of SARS-CoV-2 infectivity was not observed with several other respiratory viruses, likely due to a unique feature of IAV to elevate ACE2 expression. This study illustrates that IAV has a unique ability to aggravate SARS-CoV-2 infection, and thus, prevention of IAV infection is of great significance during the COVID-19 pandemic.
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References
Huang, C. et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 395, 497–506 (2020).
Wang, C., Horby, P. W., Hayden, F. G. & Gao, G. F. A novel coronavirus outbreak of global health concern. Lancet 395, 470–473 (2020).
Van Riel, D. et al. Human and avian influenza viruses target different cells in the lower respiratory tract of humans and other mammals. Am. J. Pathol. 171, 1215–1223 (2007).
St. John, A. L. & Rathore, A. P. S. Early insights into immune responses during COVID-19. J. Immunol. 205, 555 (2020).
Traylor, Z. P., Aeffner, F. & Davis, I. C. Influenza A H1N1 induces declines in alveolar gas exchange in mice consistent with rapid post-infection progression from acute lung injury to ARDS. Influenza and other respiratory. Viruses 7, 472–479 (2013).
Hou, Y. et al. SARS-CoV-2 reverse genetics reveals a variable infection gradient in the respiratory tract. Cell 182, 429–446 (2020).
Belongia, E. & Osterholm, M. COVID-19 and flu, a perfect storm. Science 368, 1163 (2020).
Olsen, S. et al. Decreased influenza activity during the COVID-19 Pandemic - United States, Australia, Chile, and South Africa, 2020. MMWR Morb. Mortal Wkly. Rep. 69, 1305–1309 (2020).
Cuadrado-Payán, E. et al. SARS-CoV-2 and influenza virus co-infection. Lancet 395, e84 (2020).
Zheng, X. et al. Co-infection of SARS-CoV-2 and influenza virus in early stage of the COVID-19 epidemic in Wuhan, China. J. Infect. 81, e128–e129 (2020).
Yue, H. et al. The epidemiology and clinical characteristics of co-infection of SARS-CoV-2 and influenza viruses in patients during COVID-19 outbreak. J. Med. Virology 92, 2870–2873 (2020).
Xiong, H.L. et al. Robust neutralization assay based on SARS-CoV-2 S-protein-bearing vesicular stomatitis virus (VSV) pseudovirus and ACE2-overexpressing BHK21 cells. Emerg. Microbes Infect. 9, 2105–2113 (2020).
Zhou, P. et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 579, 270–273 (2020).
Wang, Q. et al. Structural and functional basis of SARS-CoV-2 entry by using human ACE2. Cell 181, 894–904.e9 (2020).
Lan, J. et al. Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor. Nature 581, 215–220 (2020).
Hoffmann, M. et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 181, 271–280.e278 (2020).
Wu, C. et al. Furin, a potential therapeutic target for COVID-19. iScience 23, 101642 (2020).
Grimm, C. & Tang, R. Could an endo-lysosomal ion channel be the achilles heel of SARS-CoV2? Cell Calcium 88, 102212 (2020).
Walls, A. C. et al. Structure, function, and antigenicity of the SARS-CoV-2 spike glycoprotein. Cell 181, 281–292.e286 (2020).
Ziegler, C. G. K. et al. SARS-CoV-2 receptor ACE2 is an interferon-stimulated gene in human airway epithelial cells and is detected in specific cell subsets across tissues. Cell 181, 1016–1035.e1019 (2020).
Priyamvada, L. et al. Human antibody responses after dengue virus infection are highly cross-reactive to Zika virus. Proc. Natl. Acad. Sci. USA 113, 7852 (2016).
Mateus, J. et al. Selective and cross-reactive SARS-CoV-2 T cell epitopes in unexposed humans. Science 370, 89–94 (2020).
Shi, G. et al. Opposing activities of IFITM proteins in SARS-CoV-2 infection. EMBO J. 0, e106501 (2020).
Vanderheiden, A. et al. Type I and Type III interferons restrict SARS-CoV-2 infection of human airway epithelial cultures. J. Virol. 94, e00985–00920 (2020).
Lokugamage, K. G. et al. Type I interferon susceptibility distinguishes SARS-CoV-2 from SARS-CoV. J. Virol. 94, e01410–e01420 (2020).
Wise, H. M. et al. A complicated message: Identification of a novel PB1-related protein translated from influenza A virus segment 2 mRNA. J. Virol. 83, 8021–8031 (2009).
Wang, R. et al. Influenza A virus protein PB1-F2 impairs innate immunity by inducing mitophagy. Autophagy https://doi.org/10.1080/15548627.2020.1725375 (2020).
Wise, H. et al. Overlapping signals for translational regulation and packaging of influenza A virus segment 2. Nucleic Acids Res. 39, 7775–7790 (2011).
Han, Q. et al. Sumoylation of influenza A virus nucleoprotein is essential for intracellular trafficking and virus growth. J. Virology 88, 9379–9390 (2014).
McCray, P. B. Jr et al. Lethal infection of K18-hACE2 mice infected with severe acute respiratory syndrome coronavirus. J. Virology 81, 813–821 (2007).
Zheng, J. et al. COVID-19 treatments and pathogenesis including anosmia in K18-hACE2 mice. Nature 589, 603–607 (2021).
Winkler, E. S. et al. SARS-CoV-2 infection of human ACE2-transgenic mice causes severe lung inflammation and impaired function. Nat. Immunol. 21, 1327–1335 (2020).
Acknowledgements
This work was supported in part by the National Key R&D Program (2018FYA0900801 to K.X. and 2016YFA0502103 to K.L.), the National Natural Science Foundation of China (grants 31922004 and 81772202 to K.X.), Application & Frontier Research Program of the Wuhan Government (2019020701011463 to K.X.), and Hubei Innovation Team Foundation (2020CFA015 to K.X. and K.L.).
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K.X. and K.L. conceived the project and designed the experiments. L.B., J.D., M.G., X.W., Z.H., Z.Z., and YC. Z. coordinated the live SARS-CoV-2 study and performed animal infection experiments. YL. Z. and S. L. conducted pseudotyped virus infection experiments, IFN treatment experiments, and data analysis. L.B. and J.D. evaluated the immunofluorescence, histopathological and immunohistochemical studies. X.L. performed HRV3, HPIV, and HRSV infection experiments. YL. Z and X. L. generated the mutant virus and performed the related tests. L.B., S.L., J.D., and X.L. repeated the key experiments in infected cells. X.S., Q.L., D.N., M.X., K.S., J.Y., W.Z., Z.T., M.T., Y.Z., C.S., M.D., L.Z., Y.C., and H.Y. provided technical support and materials. L. D. constructed ACE2 knockout cells and conducted related analysis. K.X., K.L., S.L., and YL. Z. wrote the manuscript with input from all the other authors. For their research spirit and courage, we also thank our group members of the SARS-CoV-2 working group in the State Key Laboratory of Virology, Wuhan University, who are working closely together during this new virus pandemic. We are grateful to Taikang Insurance Group Co., Ltd; Beijing Taikang Yicai Foundation; and Special Fund for COVID-19 Research of Wuhan University for their great supports of this work.
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Bai, L., Zhao, Y., Dong, J. et al. Coinfection with influenza A virus enhances SARS-CoV-2 infectivity. Cell Res 31, 395–403 (2021). https://doi.org/10.1038/s41422-021-00473-1
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DOI: https://doi.org/10.1038/s41422-021-00473-1
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