ABSTRACT
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.
Subject(s)
COVID-19ABSTRACT
Critical illness in COVID-19 is caused by inflammatory lung injury, mediated by the host immune system. We and others have shown that host genetic variation influences the development of illness requiring critical care1 or hospitalisation2;3;4 following SARS-Co-V2 infection. The GenOMICC (Genetics of Mortality in Critical Care) study is designed to compare genetic variants in critically-ill cases with population controls in order to find underlying disease mechanisms. Here, we use whole genome sequencing and statistical fine mapping in 7,491 critically-ill cases compared with 48,400 population controls to discover and replicate 22 independent variants that significantly predispose to life-threatening COVID-19. We identify 15 new independent associations with critical COVID-19, including variants within genes involved in interferon signalling (IL10RB, PLSCR1), leucocyte differentiation (BCL11A), and blood type antigen secretor status (FUT2). Using transcriptome-wide association and colocalisation to infer the effect of gene expression on disease severity, we find evidence implicating expression of multiple genes, including reduced expression of a membrane flippase (ATP11A), and increased mucin expression (MUC1), in critical disease. We show that comparison between critically-ill cases and population controls is highly efficient for genetic association analysis and enables detection of therapeutically-relevant mechanisms of disease. Therapeutic predictions arising from these findings require testing in clinical trials.
Subject(s)
Lung Diseases , Critical Illness , COVID-19 , Nijmegen Breakage SyndromeABSTRACT
New variants of SARS-CoV-2 are continuing to emerge and dominate the regional and global sequence landscapes. Several variants have been labelled as Variants of Concern (VOCs) because of perceptions or evidence that these may have a transmission advantage, increased risk of morbidly and/or mortality or immune evasion in the context of prior infection or vaccination. Placing the VOCs in context and also the underlying variability of SARS-CoV-2 is essential in understanding virus evolution and selection pressures. Sequences of SARS-CoV-2 in nasopharyngeal swabs from hospitalised patients in the UK were determined and virus isolated. The data indicated the virus existed as a population with a consensus level and non-synonymous changes at a minor variant. For example, viruses containing the nsp12 P323L variation from the Wuhan reference sequence, contained minor variants at the position including P and F and other amino acids. These populations were generally preserved when isolates were amplified in cell culture. In order to place VOCs B.1.1.7 (the UK Kent variant) and B.1.351 (the South African variant) in context their growth was compared to a spread of other clinical isolates. The data indicated that the growth in cell culture of the B.1.1.7 VOC was no different from other variants, suggesting that its apparent transmission advantage was not down to replicating more quickly. Growth of B.1.351 was towards the higher end of the variants. Overall, the study suggested that studying the biology of SARS-CoV-2 is complicated by population dynamics and that these need to be considered with new variants.