Longitudinal immune dynamics of mild COVID-19 define signatures of recovery and persistence

Abstract

SARS-CoV-2 has infected over 160 million and caused more than 3 million deaths to date. Most individuals (>80%) have mild symptoms and recover in the outpatient setting, but detailed studies of immune responses have focused primarily on moderate to severe COVID-19. We deeply profiled the longitudinal immune response in individuals with mild COVID beginning with early time points post-infection (1-15 days) and proceeding through convalescence to >100 days after symptom onset. We correlated data from single cell analyses of peripheral blood cells, serum proteomics, virus-specific cellular and humoral immune responses, and clinical metadata. Acute infection was characterized by vigorous coordinated innate and adaptive activation, including an early cellular and proteomic signature that correlated with the amplitude of virus-specific humoral responses after day 30. We characterized signals associated with recovery and convalescence to define a new signature of inflammatory cytokines, gene expression, and chromatin accessibility that persists in individuals with post-acute sequelae of SARS-CoV-2 infection (PASC).

Optimized workflow for human PBMC multiomic immunosurveillance studies

“…To this end, the high rigor of this protocol minimizes batch variance. For example, cell hashing in scRNA-seq mitigates well and chip variance, resulting in a low 0.1% batch variance based on measurements of technical reproducibility of the batch control ( Talla et al., 2021 ).…”

“…Data analysis for the scRNA-seq and integration of data sets are not encompassed within this protocol but are described in Savage et al. (2021) , Swanson et al (2021) and Talla et al. (2021) .…”

Early immune responses have long-term associations with clinical, virologic, and immunologic outcomes in patients with COVID-19

“…We identified 36 plasma proteins significantly associated with oropharyngeal viral load (top 10 significant proteins shown in Figure 5A, Supplemental table 3). Higher levels of several of these proteins were inversely correlated with viral load, including the cytosolic RNA sensor RIG-I (gene symbol DDX58), chemokines (CCL20 and CCL25), and other proteins (Keratin 19 {KRT19}, amphiregulin{AREG}) previously shown to be upregulated in COVID-19 patients 14,25 . Several immune transcriptomic pathways were also associated with viral control, including complement and B cell activation and the humoral immune response pathway (top 10 significant pathways shown in Figure 5B, Supplemental Table 3).…”

“…Importantly, SARS-CoV-2 proteins interfere with induction of these IFNs [2][3][4] , and deficient IFN production has been associated with increased disease severity and poor outcomes 5,6 . Most studies evaluating the early host immune response have been performed in patients with severe disease 5,[7][8][9][10][11][12][13] ; signatures associated with patient outcomes among those with more mild to moderate disease remain less well defined 14 .…”

Broken Connections: The Evidence for Neuroglial Failure in ME/CFS

“…For one, elevated IL-1beta seems to be a consistent signal in studies of PASC. 426,427 Also SARS-CoV-2 vaccination seems to have given (if only temporarily) respite to up to 57% of Long Covid sufferers 428 -somewhat reminiscent of the very marked success of the staphylococcal vaccine Staphypan in ME/CFS (unfortunately withdrawn from the market by the company many years ago). 239,240  Autoimmunity seems to be a big theme in Covid, with more than 100 autoantibodies detected in Covid patients, 253 some of which are to be found in the cerebrospinal fluid and pertain to neuronal targets.…”