Mucosal and Systemic Immune Correlates of Viral Control following SARS-CoV-2 Infection Challenge in Seronegative Adults (preprint)

Human infection challenge permits characterisation of the associated immune response in unparalleled depth, enabling evaluation of early pre-symptomatic immune changes and the dynamic immune factors important for viral clearance. Here, 34 healthy young adult volunteers, seronegative to SARS-CoV-2, were inoculated with a D614G-containing pre-Alpha SARS-CoV-2 strain. Nasal and systemic soluble mediator and antibody responses, and peripheral blood T cell and B cell responses were measured by MesoScale Discovery and flow cytometry just before and up to 1 year after intra-nasal inoculation. In the 18 (53%) participants who became infected, both nasal and systemic mediator responses were dominated by interferons (IFN) but with divergent kinetics. T cell activation and proliferation in blood peaked at day 10 in CD4+ T cells and day 14 in CD8+ T cells, returning to baseline by day 28. Following infection, antigen-specific T cells were largely CD38+Ki67+ and displayed central and effector memory phenotypes. T cells contracted after viral clearance with expanded antigen-specific memory T cell populations persisting past day 28. Both mucosal and systemic antibodies became detectable around day 10 but nasal antibodies plateaued after day 14 while circulating antibodies continued to rise. Using piecewise linear regression modelling, viral load related closely to the induction of type I IFN responses, moreover, CD8+ T cell responses and early IgA responses were strongly associated with viral clearance. Detailed analysis of innate and adaptive immune responses to primary SARS-CoV-2 infection following human challenge thus revealed the relationship between immune kinetics and viral load as factors associated with resolution of infection.

Large scale phenotyping of long COVID inflammation reveals mechanistic subtypes of disease (preprint)

One in ten SARS-CoV-2 infections result in prolonged symptoms termed "long COVID", yet disease phenotypes and mechanisms are poorly understood. We studied the blood proteome of 719 adults, grouped by long COVID symptoms. Elevated markers of monocytic inflammation and complement activation were associated with increased likelihood of all symptoms. Elevated IL1R2, MATN2 and COLEC12 associated with cardiorespiratory symptoms, fatigue, and anxiety/depression, while elevated MATN2 and DPP10 associated with gastrointestinal (GI) symptoms, and elevated C1QA was associated with cognitive impairment (the proteome of those with cognitive impairment and GI symptoms being most distinct). Markers of neuroinflammation distinguished cognitive impairment whilst elevated SCG3, indicative of brain-gut axis disturbance, distinguished those with GI symptoms. Women had a higher incidence of long COVID and higher inflammatory markers. Symptoms did not associate with respiratory inflammation or persistent virus in sputum. Thus, persistent inflammation is evident in long COVID, distinct profiles being associated with specific symptoms.

Elevated antiviral, myeloid and endothelial inflammatory markers in severe COVID-19 (preprint)

The mechanisms that underpin COVID-19 disease severity, and determine the outcome of infection, are only beginning to be unraveled. The host inflammatory response contributes to lung injury, but circulating mediators levels fall below those in classical cytokine storms. We analyzed serial plasma samples from 619 patients hospitalized with COVID-19 recruited through the prospective multicenter ISARIC clinical characterization protocol U.K. study and 39 milder community cases not requiring hospitalization. Elevated levels of numerous mediators including angiopoietin-2, CXCL10, and GM-CSF were seen at recruitment in patients who later died. Markers of endothelial injury (angiopoietin-2 and von-Willebrand factor A2) were detected early in some patients, while inflammatory cytokines and markers of lung injury persisted for several weeks in fatal COVID-19 despite decreasing antiviral cytokine levels. Overall, markers of myeloid or endothelial cell activation were associated with severe, progressive, and fatal disease indicating a central role for innate immune activation and vascular inflammation in COVID-19.