Time-resolved systems immunology reveals a late juncture linked to fatal COVID-19

Abstract

COVID-19 exhibits extensive patient-to-patient heterogeneity. To link immune response variation to disease severity and outcome over time, we longitudinally assessed circulating proteins as well as 188 surface protein markers, transcriptome, and T-cell receptor sequence simultaneously in single peripheral immune cells from COVID-19 patients. Conditional-independence network analysis revealed primary correlates of disease severity, including gene expression signatures of apoptosis in plasmacytoid dendritic cells and attenuated inflammation but increased fatty acid metabolism in CD56 dim CD16 hi NK cells linked positively to circulating IL-15. CD8 + T cell activation was apparent without signs of exhaustion. While cellular inflammation was depressed in severe patients early after hospitalization, it became elevated by days 17-23 post symptom onset, suggestive of a late wave of inflammatory responses. Furthermore, circulating protein trajectories at this time were divergent between and predictive of recovery-fatal outcomes. Our findings stress the importance of timing in the analysis, clinical monitoring, and therapeutic intervention of COVID-19.

What we know and still ignore on COVID-19 immune pathogenesis and a proposal based on experience of allergic disorders.

“…This agrees with reports in which innate cytokine/chemokine signatures of immunopathology [7] have been associated with end-stage COVID-19 disease [16]. The lack of temporal coordination between innate and adaptive responses allows the persistence of a high viral load, which can trigger a second wave of inflammation, occurring during the third week from infection, which is crucial for the worst clinical outcomes [8].Pre-existing immunity to the virus in unexposed individuals.SARS-CoV-2-specific T cells have been detected in about 50% of unexposed individuals, suggesting T cell cross-reactivity between SARS-CoV-2 and common cold coronaviruses (CCC), which affect >75% of general young population [17]. High level of pre-existing memory CD4+ and CD8+ T cells could allow to favor a faster and stronger adaptive immune response upon exposure to SARS-CoV-2, limiting disease severity.…”

“…to recruitment into tissues and apoptosis and their number is negatively related to disease severity [7]. Low numbers of pDCs can be responsible for the reduced presentation of viral epitopes to T cells and for defective activation of natural killer (NK) cells [8]. NK cells may be impaired early due to: i. the over production of cytokines (mainly IL-6) by infected APC [9], ii.…”

“…Since Treg cells limit antiviral responses and tissue immunopathology [21], their reduction may favor a vigorous amplification of any (specific or non-specific) T cell response including autoreactive T cells triggering autoimmunity. The direct interaction of CD147 (mainly expressed on Treg cells) and Spike 1 (S1) protein of SARS-CoV-2, which mediates infection of host cells, has been suggested to be responsible for Treg cell dysfunction observed in severe COVID-19 [8,15,21]. Indeed, CD147, also called Basigin (an inducer of matrix metalloproteases), is highly expressed by the early activated memory Foxp3+ Treg cells displaying the strongest suppressive activity [22].Super-antigen hypothesis.…”

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“…A longitudinal study of CD8 + T cells during SARS-CoV-2 infections revealed an exhausted phenotype of CD8 + T cells, based on the presence of exhaustion markers including PD-1, CTLA-4, and TIGIT, which, together with reduced poly-functionality according to markers such as IFN-γ, TNF-α, and IL-2 predicted disease severity [396]. However, other studies showed that CD8 + T cells are not exhausted but remain functional [397,398] and a significant proportion of SARS-CoV-2 reactive T cells with "exhausted" phenotype are also found in patients with mild COVID-19 [399]. Interestingly these cells exhibited lesser cytotoxic and inflammatory features and could maintain their exhausted state even after viral clearance.…”

“…Among the heavily distorted innate immune response typical of COVID-19, the latewave inflammatory response in particular is linked to COVID-19 disease severity [398,456,457]. The major differences in immune phenotype between moderate and severe cases are apparent after day 10 of infection.…”