Human Properdin Released By Infiltrating Neutrophils Can Modulate Influenza A Virus Infection

Frontiers in Immunology

Shuvechha Mukherjee¹  Susan Idicula-Thomas¹  Uday Kishore²  Nazar Beirag²  Valarmathy Murugaiah²  Robert B. Sim³  Fahad N. Almajhdi⁴  Souad M. Saleh⁵  Futwan A. Al-Mohanna⁵  Taruna Madan⁶  Saad H. Alkahtani⁷  Beatrice Nal Rogier⁸  Reena Rajkumari⁹  Praveen M. Varghese⁹ 

[1] Biomedical Informatics Centre, Indian Council of Medical Research (ICMR)-National Institute for Research in Reproductive Health, Mumbai, India;Biosciences, College of Health, Medicine and Life Sciences, Brunel University London, Uxbridge, United Kingdom;Department of Biochemistry, University of Oxford, Oxford, United Kingdom;Department of Botany and Microbiology, College of Science, King Saud University, Riyadh, Saudi Arabia;Department of Cell Biology, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia;Department of Innate Immunity, Indian Council of Medical Research (ICMR)-National Institute for Research in Reproductive Health, Mumbai, India;Department of Zoology, College of Sciences, King Saud University, Riyadh, Saudi Arabia;INSERM U1104 Centre d’immunologie de Marseille-Luminy (CIML), Marseille, France;School of Biosciences and Technology, Vellore Institute of Technology, Vellore, India;

关键词: innate immune system;    complement system;    complement evasion;    human properdin;    RNA viruses;    influenza A virus;   

DOI  :  10.3389/fimmu.2021.747654

来源: DOAJ

【 摘 要 】

The complement system is designed to recognise and eliminate invading pathogens via activation of classical, alternative and lectin pathways. Human properdin stabilises the alternative pathway C3 convertase, resulting in an amplification loop that leads to the formation of C5 convertase, thereby acting as a positive regulator of the alternative pathway. It has been noted that human properdin on its own can operate as a pattern recognition receptor and exert immune functions outside its involvement in complement activation. Properdin can bind directly to microbial targets via DNA, sulfatides and glycosaminoglycans, apoptotic cells, nanoparticles, and well-known viral virulence factors. This study was aimed at investigating the complement-independent role of properdin against Influenza A virus infection. As one of the first immune cells to arrive at the site of IAV infection, we show here that IAV challenged neutrophils released properdin in a time-dependent manner. Properdin was found to directly interact with haemagglutinin, neuraminidase and matrix 1 protein Influenza A virus proteins in ELISA and western blot. Furthermore, modelling studies revealed that properdin could bind HA and NA of the H1N1 subtype with higher affinity compared to that of H3N2 due to the presence of an HA cleavage site in H1N1. In an infection assay using A549 cells, properdin suppressed viral replication in pH1N1 subtype while promoting replication of H3N2 subtype, as revealed by qPCR analysis of M1 transcripts. Properdin treatment triggered an anti-inflammatory response in H1N1-challenged A549 cells and a pro-inflammatory response in H3N2-infected cells, as evident from differential mRNA expression of TNF-α, NF-κB, IFN-α, IFN-β, IL-6, IL-12 and RANTES. Properdin treatment also reduced luciferase reporter activity in MDCK cells transduced with H1N1 pseudotyped lentiviral particles; however, it was increased in the case of pseudotyped H3N2 particles. Collectively, we conclude that infiltrating neutrophils at the site of IAV infection can release properdin, which then acts as an entry inhibitor for pandemic H1N1 subtype while suppressing viral replication and inducing an anti-inflammatory response. H3N2 subtype can escape this immune restriction due to altered haemagglutinin and neuraminindase, leading to enhanced viral entry, replication and pro-inflammatory response. Thus, depending on the subtype, properdin can either limit or aggravate IAV infection in the host.

【 授权许可】

Unknown