Mitochondrial regulation of acute extrafollicular B-cell responses to COVID-19 severity

Background Patients with COVID-19 display a broad spectrum of manifestations from asymptomatic to life-threatening disease with dysregulated immune responses. Mechanisms underlying the detrimental immune responses and disease severity remain elusive. Methods We investigated a total of 137 APs infected with SARS-CoV-2. Patients were divided into mild and severe patient groups based on their requirement of oxygen supplementation. All blood samples from APs were collected within three weeks after symptom onset. Freshly isolated PBMCs were investigated for B cell subsets, their homing potential, activation state, mitochondrial functionality and proliferative response. Plasma samples were tested for cytokine concentration, and titer of Nabs, RBD-, S1-, SSA/Ro- and dsDNA-specific IgG. Results While critically ill patients displayed predominantly extrafollicular B cell activation with elevated inflammation, mild patients counteracted the disease through the timely induction of mitochondrial dysfunction in B cells within the first week post symptom onset. Rapidly increased mitochondrial dysfunction, which was caused by infection-induced excessive intracellular calcium accumulation, suppressed excessive extrafollicular responses, leading to increased neutralizing potency index and decreased inflammatory cytokine production. Patients who received prior COVID-19 vaccines before infection displayed significantly decreased extrafollicular B cell responses and mild disease. Conclusion Our results reveal an immune mechanism that controls SARS-CoV-2-induced detrimental B cell responses and COVID-19 severity, which may have implications for viral pathogenesis, therapeutic interventions and vaccine development.

Automated summary

Background: Patients with COVID-19 display a wide range of disease severity and immune responses, and the mechanisms are unclear. Methods: We studied 137 patients infected with SARS-CoV-2, divided into mild and severe groups, and analyzed their immune and mitochondrial functions. Results: Severe patients showed increased activation of extrafollicular B cells and inflammation, while mild patients countered the disease through modulation of B cell mitochondrial function. Patients who received prior vaccination showed reduced B cell responses and milder disease. Conclusion: We identified an immune mechanism that controls disease severity, with implications for virus research, treatment, and vaccine development.