Downregulation of MHC Class I Expression by Influenza A and B Viruses

Abstract

Manipulation of the MHC-I presentation pathway, and thus limiting MHC-I cell surface expression, is used by many viruses to evade immune recognition. In particular, downregulation of MHC-I molecules at the cell surface can reduce the ability of CD8 + T cells to recognize viral peptides presented by MHC-I molecules and thereby delay viral clearance by CD8 + T cells. To date, MHC-I downregulation by influenza viruses has not been reported. Given that influenza virus infections are a global health concern and that CD8 + T cells play an important role in promoting influenza virus clearance and recovery from influenza disease, we investigated whether influenza A and B viruses (IAV, IBV) downregulated MHC-I as a novel mechanism to evade cellular immunity. Here, we showed that infection of several cell types, including epithelial A549 cells, with a panel of IAV and IBV viruses downregulated the surface MHC-I expression on IAV/IBV-infected cells during the late stages of influenza virus infection in vitro . This observation was consistent across a panel of class I-reduced (C1R) cell lines expressing 14 different HLA-A or -B alleles and a panel of 721.221 cell lines expressing 11 HLA-C alleles. Interestingly, IBV infection caused more pronounced reduction in surface MHC-I expression compared to IAV. Importantly, the two viruses utilized two distinct mechanisms for MHC-I downregulation. Our data demonstrated that while IAV caused a global loss of MHC-I within influenza-infected cells, IBV infection resulted in the preferential loss of MHC-I molecules from the cell surface, consequent of delayed MHC-I trafficking to the cell surface, resulting from retaining MHC-I intracellularly during IBV infection. Overall, our study suggests that influenza viruses across both IAV and IBV subtypes have the potential to downregulate MHC-I surface expression levels. Our findings provide new insights into the host-pathogen interaction of influenza A and B viruses and inform the design of novel vaccine strategies against influenza viruses.

Co-Expression Network Analysis of Spleen Transcriptome in Rock Bream (Oplegnathus fasciatus) Naturally Infected with Rock Bream Iridovirus (RBIV)

“…This suggests that RBIV is recognized by TLR9 to induce MHC class I expression for antigen processing and presentation during the early stage of infection, although RBIV might downregulate MHC-I and -II expression on RBIV-infected cells during the late phase of RBIV infection in rock bream. This is consistent with previous data demonstrating that influenza A and B viruses can downregulate MHC class I expression on IAV/IBV-infected cells in vitro [66].…”

Severity and outcomes of influenza-related pneumonia in type A and B strains in China, 2013–2019

“…In vivo, both influenza A and B viruses downregulate the surface expression of major histocompatibility complex-I (MHC-I). A more pronounced reduction in surface MHC-I expression was observed in influenza B patients, leading to milder immunologic reactions, followed by significantly lower levels of inflammatory cytokines and lung tissue injury [28].…”

Alterations of multiple alveolar macrophage states in chronic obstructive pulmonary disease

“…First, we did not identify single markers that are specific for COPD GOLD 2, suggesting that signatures rather than individual markers will have to be developed. For 25 example, the loss of MHC class I molecules on myeloid cells is not only seen in COPD, it is also described in cancer (Noy and Pollard, 2014) and in influenza (Koutsakos et al, 2019). Similarly, the increase of the mono-like macrophage cell state as a hallmark for cell influx from the systemic circulation will also be seen in other pathophysiological situations of the lung, for example, acute infections such as pneumonia (Goto et al, 2004) or influenza infection (Aegerter et al, 2020).…”