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Pneumocytes are distinguished by highly elevated expression of the ER stress biomarker GRP78, a co-receptor for SARS-CoV-2, in COVID-19 autopsies. Cell Stress Chaperones 2021 Sep;26(5):859-868

Date

08/13/2021

Pubmed ID

34382151

Pubmed Central ID

PMC8357488

DOI

10.1007/s12192-021-01230-4

Scopus ID

2-s2.0-85112285201   5 Citations

Abstract

Vaccinations are widely credited with reducing death rates from COVID-19, but the underlying host-viral mechanisms/interactions for morbidity and mortality of SARS-CoV-2 infection remain poorly understood. Acute respiratory distress syndrome (ARDS) describes the severe lung injury, which is pathologically associated with alveolar damage, inflammation, non-cardiogenic edema, and hyaline membrane formation. Because proteostatic pathways play central roles in cellular protection, immune modulation, protein degradation, and tissue repair, we examined the pathological features for the unfolded protein response (UPR) using the surrogate biomarker glucose-regulated protein 78 (GRP78) and co-receptor for SARS-CoV-2. At autopsy, immunostaining of COVID-19 lungs showed highly elevated expression of GRP78 in both pneumocytes and macrophages compared with that of non-COVID control lungs. GRP78 expression was detected in both SARS-CoV-2-infected and un-infected pneumocytes as determined by multiplexed immunostaining for nucleocapsid protein. In macrophages, immunohistochemical staining for GRP78 from deceased COVID-19 patients was increased but overlapped with GRP78 expression taken from surgical resections of non-COVID-19 controls. In contrast, the robust in situ GRP78 immunostaining of pneumocytes from COVID-19 autopsies exhibited no overlap and was independent of age, race/ethnicity, and gender compared with that from non-COVID-19 controls. Our findings bring new insights for stress-response pathways involving the proteostatic network implicated for host resilience and suggest that targeting of GRP78 expression with existing therapeutics might afford an alternative therapeutic strategy to modulate host-viral interactions during SARS-CoV-2 infections.

Author List

Puzyrenko A, Jacobs ER, Sun Y, Felix JC, Sheinin Y, Ge L, Lai S, Dai Q, Gantner BN, Nanchal R, North PE, Simpson PM, Rui H, Benjamin IJ

Authors

Ivor J. Benjamin MD Center Director, Professor in the Medicine department at Medical College of Wisconsin
Juan Felix MD Vice Chair, Director, Professor in the Pathology department at Medical College of Wisconsin
Benjamin N. Gantner PhD Assistant Professor in the Medicine department at Medical College of Wisconsin
Rahul Sudhir Nanchal MD Professor in the Medicine department at Medical College of Wisconsin
Paula E. North MD, PhD Professor in the Pathology department at Medical College of Wisconsin
Hallgeir Rui MD, PhD Vice Chair, Professor in the Pathology department at Medical College of Wisconsin
Yuri M. Sheinin MD, PhD Assistant Professor in the Pathology department at Medical College of Wisconsin
Yunguang Sun MD, PhD Assistant Professor in the Pathology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Adult
Aged
Aged, 80 and over
Alveolar Epithelial Cells
Autopsy
Case-Control Studies
Endoplasmic Reticulum Stress
Female
Heat-Shock Proteins
Host-Pathogen Interactions
Humans
Macrophages, Alveolar
Male
Middle Aged
Proteostasis
Up-Regulation
Young Adult