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Little is known about T-cell responses during acute coronavirus disease-2019 (COVID-19). We measured T-cell interferon gamma (IFN-γ) responses to spike 1 (S1), spike 2 (S2), nucleocapsid (N) and membrane (M) SARS-CoV-2 antigens using the T-SPOT® Discovery SARS-CoV-2 assay, a proven EliSPOT technology, in 114 hospitalised adult COVID-19 patients and assessed their association with clinical disease phenotype. T-SPOT® Discovery SARS-CoV-2 responses were detectable within 2 days of a positive PCR and did not correlate with vaccination status or symptom duration. Higher responses to S1 protein associated with a higher symptom burden, and serum IL-6 levels. Despite treatment with dexamethasone this subgroup was also at greater risk of requiring continuous positive airway pressure (CPAP) in the days following sampling. Higher T-cell responses measured using T-SPOT® Discovery SARS-CoV-2 associate with progressive disease in acute COVID-19 disease and may have utility as a prognostic biomarker that should be evaluated in larger cohorts.

Experimental mouse models of TB suggest that early events in the lung impact immunity. Early events in the human lung in response to TB are difficult to probe and their impact on disease outcome is unknown. We have shown in mouse that a secreted alternatively-spliced variant of IL-12Rβ1, lacking the transmembrane domain and termed ΔTM-IL-12Rβ1, promotes dendritic cell migration to the draining lymph node, augments T cell activation and limits dissemination ofM. tuberculosis(Mtb). We show here that CBA/J and C3H/HeJ mice (both highly susceptible to Mtb) express higher levels of ΔTM-IL-12Rβ1 than resistant C57BL6 mice and limit early dissemination of Mtb from the lungs. Both CD11c+ cells and T cells express ΔTM-IL-12Rβ1 in humans, and mice unable to make ΔTM-IL-12Rβ1 in either CD4 or CD11c expressing cells permit early dissemination from the lung. Analysis of publically available blood transcriptomes indicates that pulmonary TB is associated with high ΔTM-IL-12Rβ1 expression and that of all IL-12 related signals, the ΔTM-IL-12Rβ1 signal best predicts active disease. ΔTM-IL-12Rβ1 expression reflects the heterogeneity of latent TB infection and has the capacity to discriminate between latent and active disease. In a new Chinese TB patient cohort, ΔTM-IL-12Rβ1 effectively differentiates TB from latent TB, healthy controls and pneumonia patients. Finally, ΔTM-IL-12Rβ1 expression drops in drug-treated individuals in the UK and China where infection pressure is low. We propose that ΔTM-IL-12Rβ1 regulates early dissemination from the lung and that it has diagnostic potential and provides mechanistic insights into human TB.

The mouse provides a tool with which to probe the complex interaction between the mammalian immune system and the slow-growing, inflammatory, and persistent bacterium, Mycobacterium tuberculosis (Mtb). Simple mouse models using genetic deletion or antibody inhibition have identified causal connections between specific components of the immune response and survival upon challenge with Mtb, and these studies have corresponded with observations made in humans. To improve on current intervention strategies, it is essential that the complex interactions between the components of the immune response that mediate and regulate the protective response to Mtb infection be dissected; furthermore, the pathways by which specific molecules and cells act must be delineated. The mouse model provides a tool with which to achieve this goal; however, experimental design and data interpretation must be made in the context of data sets generated from the entire tuberculosis field.