Influenza viral matrix 1 protein aggravates viral pathogenicity by inducing TLR4-mediated reactive oxygen species production and apoptotic cell death

Abstract

Influenza virus is one of the most challenging viruses threating human health. Since infection with influenza virus triggers inflammatory responses and induces cell death, the molecular and cellular mechanisms by which the virus-infected cells undergo apoptotic and necrotic cell death have been widely studied. However, most of the studies have focused on the molecular events occurring in the cytosol and there is limited information on the physiological correlation between virus-induced cell death and the viral pathogenesis in vivo. In this study, we demonstrate that the influenza virus matrix 1 (M1) protein is released from virus-infected cells and triggers apoptotic cell death of lung epithelial and pulmonary immune cells, through the activation of Toll-like receptor 4 (TLR4) signaling. Treatment with M1 protein led to robust cellular inflammatory responses, such as the production of proinflammatory cytokines and cellular reactive oxygen species (ROS), and induction of cell death. When M1 protein was administered in vivo, it induced the activation of inflammatory responses and cell death in the lungs. Furthermore, the administration of M1 aggravated lung pathology and mortality of the virus-infected mice in a TLR4-dependent manner. These results demonstrate that M1 is an important pathogenic factor contributing to influenza virus pathogenicity by enhancing cell death in the lungs, thereby expanding our understanding of the molecular mechanism of influenza virus-induced cell death through the interaction with an innate immune receptor.

H9N2 Avian Influenza Virus Downregulates FcRY Expression in Chicken Macrophage Cell Line HD11 by Activating the JNK MAPK Pathway

“…NS1 overexpression activates the JNK MAPK signaling pathway in certain influenza virus subtypes [ 41 ]. The M1 protein of the influenza virus induces apoptosis by activating the TLR4 signaling pathway [ 14 ]. Similarly, we found that the overexpression of either influenza NS1 or M1 proteins activated the JNK MAPK signaling pathway, causing a decrease in FcRY expression.…”

“…PB2 protein blocks JAK1/STAT signaling by degrading JAK1, thereby impeding the production of interferon-stimulated genes (ISGs) [ 13 ]. The M1 protein of influenza viruses enhances viral pathogenicity by activating the Toll-like receptor 4 (TLR4) signaling pathway [ 14 ]. These studies suggest that the influenza virus suppresses host antiviral responses by modulating immune signaling through its core proteins.…”

Mitochondrial Reactive Oxygen Species in TRIF-Dependent Toll-like Receptor 3 Signaling in Bronchial Epithelial Cells against Viral Infection

“…Viral infection increases ROS production in immune and infected host cells [ 43 ]. For instance, the influenza virus stimulates intracellular ROS overproduction via TLR4 signaling pathway activation, leading to enhanced apoptotic cell death in the lungs [ 44 ]. Innate immune cells produce mtROS for use as antimicrobial agents in the host defense against infectious microorganisms [ 29 ].…”