Acute Lung Injury Results from Innate Sensing of Viruses by an ER Stress Pathway

Abstract

SUMMARY Incursions of new pathogenic viruses into humans from animal reservoirs are occurring with alarming frequency. The molecular underpinnings of immune recognition, host responses, and pathogenesis in this setting are poorly understood. We studied pandemic influenza viruses to determine the mechanism by which increasing glycosylation during evolution of surface proteins facilitates diminished pathogenicity in adapted viruses. ER stress during infection with poorly glycosylated pandemic strains activated the unfolded protein response, leading to inflammation, acute lung injury, and mortality. Seasonal strains or viruses engineered to mimic adapted viruses displaying excess glycans on the hemagglutinin did not cause ER stress, allowing preservation of the lungs and survival. We propose that ER stress resulting from recognition of non-adapted viruses is utilized to discriminate “non-self” at the level of protein processing and to activate immune responses, with unintended consequences on pathogenesis. Understanding this mechanism should improve strategies for treating acute lung injury from zoonotic viral infections.

Glycosylation changes in the globular head of H3N2 influenza hemagglutinin modulate receptor binding without affecting virus virulence

“…The virulence of these viruses in mice has previously been studied, but only at high infectious dose of 10 6 plaque forming unit (PFU) per mouse1112. At this high virus dose, there was no correlation between H3N2 virulence and receptor binding.…”

“…We have previously shown that increasing HA glycosylation can reduce H3N2 virulence in mice through virus neutralization by respiratory tract collectin SP-D11 and through abrogation of the inflammation associated with activation of ER stress pathways12. Glycans on HA can also reduce receptor binding91022232635, which in turn may affect viral virulence.…”

“…Consistent with observations in humans, a progressive reduction of morbidity, mortality, and viral lung titers in mice was observed as HA glycosylation increased. Virus neutralization by lung-resident surfactant protein D (SP-D)11, the respiratory tract collectin, and attenuation of H3N2 IAV infection through ER stress pathways12, has at least in part contributed to the observed effects. However, it is likely that this increasing glycosylation can diminish virulence by other mechanisms as well.…”

Addition of N-glycosylation sites on the globular head of the H5 hemagglutinin induces the escape of highly pathogenic avian influenza A H5N1 viruses from vaccine-induced immunity

“…Alternatively or additionally, the decrease in virulence of glyV G virus in mice despite its full capacity to replicate in the lungs could be explained by an avoidance of endoplasmic reticulum (ER) stress during transport of the HA to the plasma membrane. Indeed, Hrincius et al recently demonstrated that the recognition of poorly glycosylated HA by an ER stress pathway result in acute lung inflammation in mice (Hrincius et al, 2015). Conversely, highly glycosylated HA are not recognized by ER stress, resulting in a decrease of lung inflammation and associated pathology.…”

Tauroursodeoxycholic acid (TUDCA) inhibits influenza A viral infection by disrupting viral proton channel M2

“…Recently, TUDCA is implicated as a therapy for hepatitis B virus infection [21]. TUDCA also inhibits IAV replication [22] by suppressing the inositol-requiring enzyme 1 (IRE1) branch of the unfolded protein response (UPR) [22,23], a conserved molecular network orchestrating ER pathology.…”