Mx1 reveals innate pathways to antiviral resistance and lethal influenza disease

Abstract

Influenza A virus (IAV) causes up to half a million deaths worldwide annually, 90% of which occur in older adults. We show that IAV-infected monocytes from older humans have impaired antiviral interferon production but retain intact inflammasome responses. To understand the in vivo consequence, we used mice expressing a functional Mx gene encoding a major interferon-induced effector against IAV in humans. In Mx1-intact mice with weakened resistance due to deficiencies in Mavs and Tlr7, we found an elevated respiratory bacterial burden. Notably, mortality in the absence of Mavs and Tlr7 was independent of viral load or MyD88-dependent signaling but dependent on bacterial burden, caspase-1/11, and neutrophil-dependent tissue damage. Therefore, in the context of weakened antiviral resistance, vulnerability to IAV disease is a function of caspase-dependent pathology.

Early local immune defences in the respiratory tract

“…In addition, neutrophils release neutrophil extracellular traps (NETs) 94 , which contain DNA, histones, proteases and antimicrobial proteins. NET production is evident in the lungs of virally infected mice 95 and is associated with optimal clearance of bacterial infections during septicaemia 94 and fungal infections in lung tissue 96 . However, the toxic substances released by neutrophils can lead to irreparable damage and even death.…”

“…For example, reducing the magnitude of inflammatory responses can improve survival without compromising antimicrobial host defenses. In mice lacking the TLR and RLR signaling machinery necessary for IAV detection, disruption of caspase-1/11 activation can reverse IAV-associated lung tissue damage and mortality without altering pathogen burden 95 . Caspase-1 is also deleterious during later stages of pneumonic plague without offering an advantage in bacterial clearance 114 , and is responsible for causing CD4 + T cell loss in HIV-1 infection without affecting viral load 115 .…”

Checks and Balances between Autophagy and Inflammasomes during Infection

“…In addition, a minor role for the RNA sensor Melanoma Differentiation-Associated protein 5 (MDA5), which also signals through MAVS, has been reported recently [195], and TLR7 is the primary sensor for influenza virus leading to IFN production specifically in plasmacytoid DCs [190,196]. Double knockout of MAVS and TLR7 thus results in increased mortality during infection due to loss of type I IFN production [197]. In addition to IFNs, DCs and macrophages also secrete IL-1β when infected with influenza virus in vitro , indicating that inflammasome activation also occurs during infection [198,199].…”

Molecular mechanisms and functions of pyroptosis, inflammatory caspases and inflammasomes in infectious diseases

“…Indeed, Casp1 −/− Casp11 −/− mice are more susceptible to infection by influenza A virus (143, 144, 147), and produce less IL-1β and IL-18 in the lungs, and have diminished lung functions and increased viral titers compared to wild-type mice (143, 147). However, Casp1 −/− Casp11 −/− mice are as resistant as Mx1 congenic mice on the C57BL/6 background after infection with influenza A virus but the absence of Casp1 and Casp11 provides protection from lethality in Tlr7 −/− Mavs −/− mice (148). Individual roles for caspase-1 and caspase-11 have not been deciphered in vivo.…”