Defining resistance & tolerance traits in Covid-19: towards a stratified medicine approach

Successful host defence against infectious disease involves resistance (reduce pathogen load) and tolerance (reduce tissue damage associated with pathogen presence). Integration of clinical, immunologic, genetic and therapeutic discoveries has identified defects in both of these responses in the progression from SARS-CoV-2 infection to life-threatening Covid-19 lung injury. Early after infection with SARS-CoV-2, resistance can be compromised by a failed type 1 interferon (IFN-I) response, due to direct viral antagonism of induction and signalling, deleterious host genetic variants (IFNAR2, IFNA10, TYK2, PLSCR1), and neutralising auto-antibodies directed against IFN-I (predominantly IFN-α). Later in disease, after pathogen sensing has activated a pro-inflammatory response, a failure to appropriately regulate this response compromises tolerance resulting in virus-independent immunopathology involving the lung and reticuloendothelial system. Monocytes are activated in the periphery (involving M-CSF, GM-CSF, IL-6, NLRP1 inflammasomes, TYK2 and afucosylated anti-spike IgG) then recruited to the lung (involving CCR2::MCP-3/MCP-1 and C5a::C5aR1 axes) as pro-inflammatory monocyte-derived macrophages, resulting in inflammatory lung injury. Phenotypic and genotypic heterogeneity is apparent in all these responses, identifying 'treatable traits' (therapeutically-relevant components of inter-individual variation) which could be exploited to achieve a stratified medicine approach to Covid-19. Overall, Covid-19 pathogenesis re-affirms the importance of resistance in surviving an infectious disease, and highlights that tolerance is also a central pillar of host defence in humans and can be beneficially modified using host-directed therapies.