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Tissue-specific tolerance in fatal Covid-19

Successful host defence against a pathogen can involve resistance or tolerance, with implications for prioritising either antimicrobial or immunomodulatory therapeutic approaches. Hyper-inflammation occurs in Covid-19 and is associated with worse outcomes. The efficacy of dexamethasone in preventing mortality in critical Covid-19 suggests that inflammation has a causal role in death. Whether this deleterious inflammation is primarily a direct response to the presence of SARS-CoV-2 requiring enhanced resistance, or an independent immunopathologic process necessitating enhanced tolerance, is unknown. Here we report an aberrant immune response in fatal Covid-19, principally involving the lung and reticuloendothelial system, that is not clearly topologically associated with the virus, indicating tissue-specific tolerance of SARS-CoV-2. We found that inflammation and organ dysfunction in fatal Covid-19 did not map to the widespread tissue and cellular distribution of SARS-CoV-2 RNA and protein, both between and within tissues. A monocyte/myeloid-rich vasculitis was identified in the lung, along with an influx of macrophages/monocytes into the parenchyma. In addition, stereotyped abnormal reticulo-endothelial responses (reactive plasmacytosis and iron-laden macrophages) were present and dissociated from the presence of virus in lymphoid tissues. Our results support virus-independent immunopathology being one of the primary mechanisms underlying fatal Covid-19. This supports prioritising pathogen tolerance as a therapeutic strategy in Covid-19, by better understanding non-injurious organ-specific viral tolerance mechanisms and targeting aberrant macrophage and plasma cell responses.

Fig : Distribution of SARS-CoV-2 RNA for all patients was determined by multiplex PCR (A; colour intensity denotes frequency of detectable RNA, dotted line on legend denotes maximal frequency within the patient cohort) (n=11). Distribution of individual patient viral RNA presence within organs plotted against time interval between illness onset and death comparedwith semi-quantitative score of organ specific inflammation for each patient (B). Severity of acute organ injury was assessed semi-quantitatively (0-3; no acute change (0) to severe organ injury/histological abnormality (3)) with aggregate scores visualised (C; n=10-11 per organ/tissue site). Cellular distribution of SARS-CoV-2 S protein was evaluated by immunohistochemistry and multiplex immunofluorescence on FFPE tissue demonstrating its presence within alveolar epithelium and rarely in macrophages and endothelium within the lung parenchyma (D) nasal mucosal and bronchial epithelium (E), as well as small bowel enterocytes (F), distal biliary epithelium within the liver (G) and distal renal tubular epithelium (H). Representative images from n=4 PCR-positive patients.

Mapping SARS-CoV-2 to local inflammation for the first time --

Hyper-inflammation is associated with death in COVID. In this study, researchers performed detailed autopsies of organ injury throughout the body and present a multi-parameter tissue survey of fatal COVID. This study highlights for the first time the discrepancy between the presence of SARS-CoV-2 and tissue inflammation.

1) created a detailed tissue atlas of fatal COVID

2) sampled 37 distinct anatomical tissue sites to identify viral RNA distribution and host inflammatory responses.

3) detected SARS- CoV-2 RNA across all sampled organs and tissue sites, most frequently in respiratory tract, but also in the GI tract, heart, liver, and kidney

4) found that tissue inflammation and organ dysfunction do not map to the tissue and cellular distribution of SARS-CoV-2, demonstrating tissue-specific tolerance.

5) conclude that death in COVID is primarily a consequence of immune-mediated, rather than pathogen-mediated, organ inflammation and injury.

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