Asymptomatic COVID‐19: disease tolerance with efficient anti‐viral immunity against SARS‐CoV‐2

Abstract

The immune responses and mechanisms limiting symptom progression in asymptomatic cases of SARS-CoV-2 infection remain unclear. We comprehensively characterized transcriptomic profiles, cytokine responses, neutralization capacity of antibodies, and cellular immune phenotypes of asymptomatic patients with acute SARS-CoV-2 infection to identify potential protective mechanisms. Compared to symptomatic patients, asymptomatic patients had higher counts of mature neutrophils and lower proportion of CD169 + expressing monocytes in the peripheral blood. Systemic levels of pro-inflammatory cytokines were also lower in asymptomatic patients, accompanied by milder pro-inflammatory gene signatures. Mechanistically, a more robust systemic Th2 cell signature with a higher level of virus-specific Th17 cells and a weaker yet sufficient neutralizing antibody profile against SARS-CoV-2 was observed in asymptomatic patients. In addition, asymptomatic COVID-19 patients had higher systemic levels of growth factors that are associated with cellular repair. Together, the data suggest that asymptomatic patients mount less pro-inflammatory and more protective immune responses against SARS-CoV-2 indicative of disease tolerance. Insights from this study highlight key immune pathways that could serve as therapeutic targets to prevent disease progression in COVID-19.

Blood Transcriptomes of Anti-SARS-CoV-2 Antibody-Positive Healthy Individuals Who Experienced Asymptomatic Versus Clinical Infection

“…For example, IFIT3, IFI44L and RSAD3 expression can be induced by viruses which in turn enhances the progress of the viral infection ( 62 – 64 ), whereas higher intrinsic expression of IFIT3, FOLR3, PI3 and ALOX-15 have all been associated with immune-mediated chronic diseases ( 65 – 68 ) In contrast, a protective effect of GZMH, CLEC1B, CLEC12A , that have a higher expression in asymptomatic individuals, may be associated with the effectiveness of GZMH in viral eradication ( 69 ) and the ability of CLEC1B and CLEC12A to enhance neutrophil extracellular trap formation, thus presenting an antiviral effect that helps to control systemic virus levels ( 70 ). Despite the fact that our findings have to be validated in a larger independent cohort of prior SARS-CoV-2 infected individuals, taken together with those of the literature support the hypothesis that there are differences in the innate immune responses between clinical and asymptomatic individuals during SARS-CoV-2 infections ( 15 , 16 ).…”

“…More recently, Chan et al. also showed in a whole blood transcriptomic analyses that asymptomatic patients display a less robust response to type-I interferon than symptomatic patients, whereas differences between asymptomatic and symptomatic patients may be present at the cellular, innate, and adaptive immune response levels ( 16 )…”

Asymptomatic COVID-19 Individuals Tend to Establish Relatively Balanced Innate and Adaptive Immune Responses

“…A study of RNA sequencing recently explored differentially expressed genes of symptomatic and asymptomatic patients with COVID-19. The results showed a higher expression of the genes involved in the Th2 pathway, together with the down-regulation of the genes in Th1 and Th17 pathways in asymptomatic individuals [ 35 ]. Our results are consistent with theirs.…”

Biomarkers of ageing and frailty may predict COVID-19 severity

“…Disease tolerance declines with increased age, and as a result of deteriorated immunity ( Medzhitov et al, 2012 ) and may differentially affect older or frail individuals infected by SARS-CoV-2. For example, a recent study found that significantly different molecular and cellular responses are mounted in response to SARS-CoV-2 infection by symptomatic patients, compared to asymptomatic patients ( Chan et al, 2021 ) The study, which involved 178 symptomatic patients (age range: 39.4± 12.5 years) and 48 asymptomatic patients (48.2± 15.9), was not designed to test aging or frailty; however, it identified potentially new biomarkers predictive of disease trajectory which may be differentially expressed in older and frail individuals ( Chan et al, 2021 ). The authors found that symptomatic patients had higher counts of mature neutrophils and lower proportion of CD169+ expressing monocytes in the peripheral blood tolerance ( Chan et al, 2021 ).…”