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Persistent immune dysregulation and metabolic alterations following SARS-CoV-2 infection
SARS-CoV-2 can cause a variety of post-acute sequelae including Long COVID19 (LC), a complex, multisystem disease characterized by a broad range of symptoms including fatigue, cognitive impairment, and post-exertional malaise. The pathogenesis of LC is incompletely understood. In this study, we performed comprehensive cellular and transcriptional immunometabolic profiling within a cohort that included SARS-CoV-2-naïve controls (NC, N=30) and individuals with prior COVID-19 (∼4-months) who fully recovered (RC, N=38) or went on to experience Long COVID symptoms (N=58). Compared to the naïve controls, those with prior COVID-19 demonstrated profound metabolic and immune alterations at the proteomic, cellular, and epigenetic level. Specifically, there was an enrichment in immature monocytes with sustained inflammasome activation and oxidative stress, elevated arachidonic acid levels, decreased tryptophan, and variation in the frequency and phenotype of peripheral T-cells. Those with LC had increased CD8 T-cell senescence and a distinct transcriptional profile within CD4 and CD8 T-cells and monocytes by single cell RNA sequencing. Our findings support a profound and persistent immunometabolic dysfunction that follows SARS-CoV-2 which may form the pathophysiologic substrate for LC. Our findings suggest that trials of therapeutics that help restore immune and metabolic homeostasis may be warranted to prevent, reduce, or resolve LC symptoms.
### Competing Interest Statement
SGD reports consulting for Enanta Pharmaceuticals and Pfizer and reports research support from Aerium Therapeutics outside the submitted work. MJP has received consulting fees from Gilead Sciences, AstraZeneca, BioVie, Apellis Pharmaceuticals, and BioNTech and research support from Aerium Therapeutics, outside the submitted work.
### Funding Statement
This research was supported [in part] by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID) as well as funded in part with federal funds from the NIAID, National Institutes of Health, Department of Health and Human Services under BCBB Support Services Contract HHSN316201300006W/75N93022F00001 to Guidehouse Digital. Funding: National Institutes of Health grant (HHSN261200800001E) National Institutes of Health grant (HHSN2612015000031) National Institutes of Health grant (75N910D00024) MJP is supported on K23AI157875 PolyBioResearch Foundation NIAID (R01AI141003/HHSN316201300006W/75N93022F00001) NINDS (1R01NS136197)
### Author Declarations
I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.
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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:
Ethics committee/IRB of the University of California and the National Institute of Allergy and Infectious Diseases (NIH) gave ethical approval for this work.
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I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.
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All data produced in the present study are available upon reasonable request to the authors.
