Tissue-specific tolerance in fatal Covid-19

Dorward, D. A.; Russell, C. D.; Um, I. H.; Elshani, M.; Armstrong, S. D.; Penrice-Randal, R.; Millar, T.; Lerpiniere, C. E.; Tagliavini, G.; Hartley, C. S.; Randall, N. P.; Gachanja, N. N.; Potey, P. M.; Anderson, A. M.; Campbell, V. L.; Duguid, A. J.; Al Qsous, W.; BouHaidar, R.; Baillie, J. K.; Dhaliwal, K.; Wallace, W. A.; Bellamy, C. O.; Prost, S.; Smith, C.; Hiscox, J. A.; Harrison, D. J.; Lucas, C. D.; ICECAP,

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.