Pneumocytes are distinguished by highly elevated expression of the ER stress biomarker GRP78, a co-receptor for SARS-CoV-2, in COVID-19 autopsies

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 to 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 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 might afford an alternative therapeutic strategy to modulate host-viral interactions during SARS-CoV-2 infections.

The stress-inducible ER chaperone GRP78/BiP is upregulated during SARS-CoV-2 infection and acts as a pro-viral protein

“…In conclusion, GRP78 is a pro-viral protein that is upregulated during SARS-CoV-2 infection, as observed here and in other studies in vitro [10][11][12] and in patient tissues and serum 13,14 . Thus, we hypothesize that anti-GRP78 agents in combination with anti-SARS-CoV-2 therapeutics, could further suppress SARS-CoV-2 infection since GRP78 inhibition can deprive the virus of an essential chaperone for their entry and viral protein production.…”

“…In primary human lung microvascular endothelial cells, MERS-CoV infection led to a substantial increase in GRP78 protein level at 24 hpi 12 . Importantly, autopsy analysis of lungs from COVID-19 patients and non-COVID-19 controls showed that pneumocytes from SARS-CoV-2-infected lungs exhibited robust in situ GRP78 immunostaining compared with that from uninfected controls 13 . Serum GRP78 levels were also reported to be significantly higher in patients during COVID-19 infection compared to control groups 14 .…”

Cellular stress modulates severity of the acute respiratory distress syndrome in COVID-19

“…Until recently, BiP has been defined as a chaperone assisting protein folding and UPR signaling within the ER compartment, however, this multifunctional protein has also been found to translocate to other cell locations expanding its role from an ER stress regulator to a general cellular stress transducer in the cytoplasm, mitochondria, and cell surface 28, 29 . Evidence that cell surface BiP influences ligand and antigen recognition is well documented 30, 70 , especially in COVID19, where BiP recognition by SARS-CoV-2 has been recently demonstrated 32, 71, 72 . This role, together with the fact that BiP reaches the cell surface upon stress stimulus, makes it a strong candidate to link inflammatory extracellular signals and stress in immune cells.…”

Insights into the Activation of Unfolded Protein Response Mechanism during Coronavirus Infection

“…Also, Shin et al observed reduced viral replication when Grp78 was inhibited, indicating the significance of ER stress regarding the SARS-CoV-2 pathogenesis [90]. The importance of Grp78 and its upregulation during COVID-19 was further indicated in vivo as its expression was found to be abundant in autopsied lung tissues from COVID-19 patients [91], as well as in hamster lung tissues and human lung organoids infected with SARS-CoV-2 [92]. These findings were also consistent with the protein-protein interaction (PPI) network analysis from Sinha et al, who highlighted that ER stress is a major response for the emergence of post-COVID-19 lung disease [92].…”