The complement system is an ancient innate immune defense mechanism that can recognize molecular patterns on the invading pathogens. Factor H, as an inhibitor of the alternative pathway, down-regulates complement activation on the host cell surface. Locally synthesized factor H at the site of infection/injury, including lungs, can act as a pattern recognition molecule without involving complement activation. Here, we report that factor H, a sialic acid binder, interacts with influenza A virus (IAV) and modulates IAV entry, as evident from down-regulation of matrix protein 1 (M1) in H1N1 subtype-infected cells and up-regulation of M1 expression in H3N2-infected A549 cells. Far-western blot revealed that factor H binds hemagglutinin (HA, ~70 kDa), neuraminidase (NA, ~60 kDa), and M1 (~25 kDa). IAV-induced transcriptional levels of IFN-α, TNF-α, IL-12, IL-6, IFN-α, and RANTES were reduced following factor H treatment for the H1N1 subtype at 6 h post-infection. However, for the H3N2 subtype, mRNA levels of these pro-inflammatory cytokines were enhanced. A recombinant form of vaccinia virus complement control protein (VCP), which like factor H, contains CCP modules and has complement-regulatory activity, mirrored the results obtained with factor H. Both factor H (25%), and VCP (45%) were found to reduce luciferase reporter activity in MDCK cells transduced with H1N1 pseudotyped lentiviral particles. Factor H (50%) and VCP (30%) enhanced the luciferase reporter activity for H3N2, suggesting an entry inhibitory role of factor H and VCP against H1N1, but not H3N2. Thus, factor H can modulate IAV infection and inflammatory responses, independent of its complement-related functions.
Keywords: complement; cytokine storm; factor H; influenza A virus; innate immunity; pseudotyped lentiviral particles; vaccinia virus complement control protein.
Copyright © 2020 Murugaiah, Varghese, Saleh, Tsolaki, Alrokayan, Khan, Collison, Sim, Nal, Al-Mohanna and Kishore.
Entry Inhibition and Modulation of Pro-Inflammatory Immune Response Against Influenza A Virus by a Recombinant Truncated Surfactant Protein D.Front Immunol. 2018 Jul 30;9:1586. doi: 10.3389/fimmu.2018.01586. eCollection 2018. Front Immunol. 2018. PMID: 30105014 Free PMC article.
Full-length human surfactant protein A inhibits influenza A virus infection of A549 lung epithelial cells: A recombinant form containing neck and lectin domains promotes infectivity.Immunobiology. 2019 May;224(3):408-418. doi: 10.1016/j.imbio.2019.02.006. Epub 2019 Feb 11. Immunobiology. 2019. PMID: 30954271
Key role of regulated upon activation normal T-cell expressed and secreted, nonstructural protein1 and myeloperoxidase in cytokine storm induced by influenza virus PR-8 (A/H1N1) infection in A549 bronchial epithelial cells.Microbiol Immunol. 2011 Dec;55(12):874-84. doi: 10.1111/j.1348-0421.2011.00396.x. Microbiol Immunol. 2011. PMID: 22039999 Free PMC article.
In vivo effect of quantified flavonoids-enriched extract of Scutellaria baicalensis root on acute lung injury induced by influenza A virus.Phytomedicine. 2019 Apr;57:105-116. doi: 10.1016/j.phymed.2018.12.009. Epub 2018 Dec 10. Phytomedicine. 2019. PMID: 30668313
[Cytokine storm in avian influenza].Mikrobiyol Bul. 2008 Apr;42(2):365-80. Mikrobiyol Bul. 2008. PMID: 18697437 Review. Turkish.