Endoplasmic Reticulum (ER)-phagy in Influenza Infection

Project Summary
Influenza infection in susceptible patients results in a higher viral load, cytokine storm, tissue
damage, lung function decline, and mortality. It is well known that interferons control influenza
burden and inflammatory responses. However, mechanistic understandings of IFN-mediated
regulation of influenza burden in the lung epithelial cells is unclear. We have identified a novel
association between Endoplasmic Reticulum (ER)-specific-autophagy response, termed ER-
phagy, as regulators of the influenza burden in lung epithelial cells. Characterizing the epithelial
ER-Phagy-IFN axis in influenza infection will be the focus of the current application. Unraveling
this axis in lung epithelial cells provides much-needed mechanistic insights into controlling viral
burden and mitigating virus-induced lung injury. Our preliminary data suggest that levels of ER-
phagy receptors in lung epithelial cells regulate viral burden in an IFNβ dependent manner.
Based on these novel data, we hypothesize that lung epithelial cells upregulate IFNβ- and IRE1-
dependent ER-phagy to diminish viral burden. We will test this hypothesis in the following
specific aims: In specific aim 1, we will determine that specific ER-phagy receptors are required
to decrease influenza burden in epithelial cells and subsequent lung injury. Aim 2 will use
epithelial-specific knockouts of IFNAR1 receptor and recombinant interferons to determine that
the type-I IFNs regulate ER-phagy activity post-IAV infection to control IAV burden and lung
injury. These studies will determine that the ER-Phagy-IFN axis acts as a first line of defense in
the primary site of influenza infection (epithelial cells) to decrease the IAV burden and
subsequent lung injury.

Grant Number: 1R21AI183025-01A1
NIH Institute/Center: NIH
Principal Investigator: Vikas Anathy