ABSTRACT
The biology driving individual patient responses to SARS-CoV-2 infection remains ill understood. Here, we developed a patient-centric framework leveraging detailed longitudinal phenotyping data, covering a year post disease onset, from 215 SARS-CoV-2 infected subjects with differing disease severities. Our analyses revealed distinct "systemic recovery" profiles with specific progression and resolution of the inflammatory, immune, metabolic and clinical responses, over weeks to several months after infection. In particular, we found a strong intra-patient temporal covariation of innate immune cell numbers, kynurenine- and host lipid-metabolites, which suggested candidate immunometabolic pathways putatively influencing restoration of homeostasis, the risk of death and of long COVID. Based on these data, we identified a composite signature predictive of systemic recovery on the patient level, using a joint model on cellular and molecular parameters measured soon after disease onset. New predictions can be generated using the online tool http://shiny.mrc-bsu.cam.ac.uk/apps/covid-systemic-recovery-prediction-app, designed to test our findings prospectively. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=122 SRC="FIGDIR/small/22276437v1_ufig1.gif" ALT="Figure 1"> View larger version (38K): org.highwire.dtl.DTLVardef@e410cforg.highwire.dtl.DTLVardef@10bad79org.highwire.dtl.DTLVardef@1a9ebadorg.highwire.dtl.DTLVardef@afb5f7_HPS_FORMAT_FIGEXP M_FIG C_FIG
ABSTRACT
Prominent early features of COVID-19 include severe, often clinically silent, hypoxia and a pronounced reduction in B cells, the latter important in defence against SARS-CoV-2. This brought to mind the phenotype of mice with VHL-deficient B cells, in which Hypoxia-Inducible Factors are constitutively active, suggesting hypoxia might drive B cell abnormalities in COVID-19. We demonstrated the breadth of early and persistent defects in B cell subsets in moderate/severe COVID-19, including reduced marginal zone-like, memory and transitional B cells, changes we also observed in B cell VHL-deficient mice. This was corroborated by hypoxia-related transcriptional changes in COVID-19 patients, and by similar B cell abnormalities in mice kept in hypoxic conditions, including reduced marginal zone and germinal center B cells. Thus hypoxia might contribute to B cell pathology in COVID-19, and in other hypoxic states. Through this mechanism it may impact on COVID-19 outcome, and be remediable through early oxygen therapy.
ABSTRACT
In a study of 207 SARS-CoV2-infected individuals with a range of severities followed over 12 weeks from symptom onset, we demonstrate that an early robust bystander CD8 T cell immune response, without systemic inflammation, is characteristic of asymptomatic or mild disease. Those presenting to hospital had delayed bystander responses and systemic inflammation already evident at around symptom onset. Such early evidence of inflammation suggests immunopathology may be inevitable in some individuals, or that preventative intervention might be needed before symptom onset. Viral load does not correlate with the development of this pathological response, but does with its subsequent severity. Immune recovery is complex, with profound persistent cellular abnormalities correlating with a change in the nature of the inflammatory response, where signatures characteristic of increased oxidative phosphorylation and reactive-oxygen species-associated inflammation replace those driven by TNF and IL-6. These late immunometabolic inflammatory changes and unresolved immune defects may have clinical implications.
