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ER stress protein PERK promotes inappropriate innate immune responses and pathogenesis during RSV infection.
Narayanan, Samanthi; Elesela, Srikanth; Rasky, Andrew J; Morris, Susan H; Kumar, Surinder; Lombard, David; Lukacs, Nicholas W.
Afiliação
  • Narayanan S; Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA.
  • Elesela S; Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA.
  • Rasky AJ; Mary H. Weiser Food Allergy Center, University of Michigan, Ann Arbor, Michigan, USA.
  • Morris SH; Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA.
  • Kumar S; Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA.
  • Lombard D; Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA.
  • Lukacs NW; Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA.
J Leukoc Biol ; 111(2): 379-389, 2022 02.
Article em En | MEDLINE | ID: mdl-33866604
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 IFNß and IL-12, coincident to the down regulation of IL-1ß. 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-1ß 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.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Vírus Sinciciais Respiratórios / Células Dendríticas / Infecções por Vírus Respiratório Sincicial / EIF-2 Quinase / Estresse do Retículo Endoplasmático / Imunidade Inata / Inflamação Idioma: En Ano de publicação: 2022 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Vírus Sinciciais Respiratórios / Células Dendríticas / Infecções por Vírus Respiratório Sincicial / EIF-2 Quinase / Estresse do Retículo Endoplasmático / Imunidade Inata / Inflamação Idioma: En Ano de publicação: 2022 Tipo de documento: Article