ER stress protein PERK promotes inappropriate innate immune responses and pathogenesis during RSV infection

Abstract

The activation of dendritic cells (DC) during respiratory viral infections is central to directing the immune response and the pathologic outcome. In these studies, the effect of RSV infection on development of ER stress responses and the impact on innate immunity was examined. The upregulation of ER stress was closely associated with the PERK pathway through the upregulation of CHOP in RSV infected DC. The inhibition of PERK corresponded with decreased EIF2a phosphorylation but had no significant effect on Nrf2 in DC, two primary pathways regulated by PERK. Subsequent studies identified that by blocking PERK activity in infected DC an altered ER stress response and innate cytokine profile was observed with the upregulation of IFNβ and IL-12, coincident to the down regulation of IL-1β. When mitochondria respiration was assessed in PERK deficient DC there were increased dysfunctional mitochondria after RSV infection that resulted in reduced oxygen consumption rates (OCR) and ATP production indicating altered cellular metabolism. Use of a CD11c targeted genetic deleted murine model, RSV infection was characterized by reduced inflammation and diminished mucus staining as well as reduced mucus-associated gene gob5 expression. The assessment of the cytokine responses showed decreased IL-13 and IL-17 along with diminished IL-1β in the lungs of PERK deficient infected mice. When PERK-deficient animals were assessed in parallel for lung leukocyte numbers, animals displayed significantly reduced myeloid and activated CD4 and CD8 T cell numbers. Thus, the PERK activation pathway may provide a rational target for altering the severe outcome of an RSV infection through modifying immune responses.

A steroid‐resistant cockroach allergen model is associated with lung and cecal microbiome changes

“…Slides from PAS‐stained lungs were coded and scored by a blinded observer. Mucus was quantified on a score of 1–4, with 1 = minimal/no mucus; 2 = slight: multiple airways with goblet cell hyperplasia and mucus; 3 = moderate: multiple airways with significant mucus and some plugging; 4 = severe: significant mucus plugging, as previously described (Narayanan et al, 2022 ).…”

Modulation of Endoplasmic Reticulum Stress Response Pathways by Respiratory Viruses

“…UPR activation by respiratory viruses is likely somewhat cell-type specific. An example of this is observed in the atypical activation of PERK in RSV infected dendritic cells [63]. Non-canonical UPR activation strongly suggests that the UPR is specifically modulated by viruses.…”

“…Although IRE1 and ATF6 activation are typical of RSV infection, in PERK-deficient mice RSV infection results in lower counts of myeloid and activated CD4 and CD8 T cells, mucous production, and cytokine responses [63]. This suggests PERK activation is associated with increased immune recognition in RSV infection.…”

Respiratory Virus-Induced PARP1 Alters DC Metabolism and Antiviral Immunity Inducing Pulmonary Immunopathology

“…Previous studies from our laboratory have established the myeloid dendritic cell (DC), a significant contributor to host acquired immunity, as a key innate cell during RSV that drives infection-induced pathology [ 8 , 9 ]. A significant body of research points to RSV manipulating the host cell immune responses, especially DC function [ 10 , 11 , 12 ]. This creates a particularly important paradigm with DC, with evidence from our studies suggesting that the latter play a role in driving changes in cell metabolism that regulates cell immune function through multiple pathways that now include PARP1.…”