The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease (COVID-19) pandemic has attracted interest because of its global rapid spread, clinical severity, high mortality rate and capacity to overwhelm healthcare systems [1, 2]. SARS-CoV-2 transmission occurs mainly through droplets, although surface contamination contributes and debate continues on aerosol transmission [3-5]. The disease is usually characterised by initial signs and symptoms [4-9] similar to those of related viral infections (e.g. influenza, SARS, Middle East respiratory syndrome) and tuberculosis (TB), although prognosis and complications sometimes differ. Experience with concomitant TB and COVID-19 is extremely limited. One case-control study of COVID-19 patients with interferon-γ release assay-confirmed TB infection [10] and a single case of TB with COVID-19 have been submitted to, but not yet published in, peer-reviewed journals [11]. In a recent analysis of 1217 consecutive respiratory specimens collected from COVID-19 patients (Mycobacterium tuberculosis was not tested), the authors concluded that higher rates of co-infection between SARS-CoV-2 and other respiratory pathogens can be expected [12]. The present study describes the first-ever global cohort of current or former TB patients (post-TB treatment sequelae) with COVID-19, recruited by the Global Tuberculosis Network (GTN) in eight countries and three continents. No analysis for determinants of outcome was attempted. The study is nested within the GTN project monitoring adverse drug reactions [13, 14] for which the coordinating centre has an ethics committee approval, alongside ethics clearance from participating centres according to respective national regulation [13, 14]. A specific nested database was created in collaboration with the eight countries reporting patients with TB and COVID-19; the remaining countries had not yet observed COVID-19 in their patients at the time this manuscript was written. Continuous variables, if not otherwise specified, are presented as medians with interquartile ranges. Overall, 49 consecutive patients with current or former TB and COVID-19 from 26 centres in Belgium (n=1), Brazil (Porto Alegre, Rio Grande do Sul State; n=1), France (n=12), Italy (n=17), Russia (Moscow Region; n=6), Singapore (n=1), Spain (n=10) and Switzerland (Vaud Canton; n=1) were recruited (dataset updated as of

Advances in flow cytometry and other single-cell technologies have enabled high-dimensional, high-throughput measurements of individual cells and allowed interrogation of cell population heterogeneity. Computational tools to take full advantage of these technologies are lacking. Here, we present COMPASS, a computational framework for unbiased polyfunctionality analysis of antigen-specific T-cell subsets. COMPASS uses a Bayesian hierarchical framework to model all observed functional cell subsets and select those most likely to exhibit antigen-specific responses. Cell-subset responses are quantified by posterior probabilities, while subject-level responses are quantified by two novel summary statistics that can be correlated directly with clinical outcome, and describe the quality of an individual’s (poly)functional response. Using three clinical datasets of cytokine production we demonstrate how COMPASS improves characterization of antigen-specific T cells and reveals novel cellular correlates of protection in the RV144 HIV vaccine efficacy trial that are missed by other methods. COMPASS is available as open-source software.

Protective immunity to Mycobacterium tuberculosis (Mtb) remains poorly understood and the role of Mtb-specific CD8 + T cells is controversial. Here we performed a broad phenotypic and functional characterization of Mtb-specific CD8 + T cells in 326 subjects with latent Mtb infection (LTBI) or active TB disease (TB). Mtb-specific CD8 + T cells were detected in most (60%) TB patients and few (15%) LTBI subjects but were of similar magnitude. Mtb-specific CD8 + T cells in LTBI subjects were mostly T EMRA cells (CD45RA + CCR7 − ), coexpressing 2B4 and CD160, and in TB patients were mostly T EM cells (CD45RA − CCR7 − ), expressing 2B4 but lacking PD-1 and CD160. The cytokine profile was not significantly different in both groups. Furthermore, Mtb-specific CD8 + T cells expressed low levels of perforin and granulysin but contained granzymes A and B. However, in vitro-expanded Mtb-specific CD8 + T cells expressed perforin and granulysin. Finally, Mtb-specific CD8 + T-cell responses were less frequently detected in extrapulmonary TB compared with pulmonary TB patients. Mtb-specific CD8 + T-cell proliferation was also greater in patients with extrapulmonary compared with pulmonary TB. Thus, the activity of Mtb infection and clinical presentation are associated with distinct profiles of Mtb-specific CD8 + T-cell responses. These results provide new insights in the interaction between Mtb and the host immune response.Keywords: Active TB disease r Cytotoxicity r Functional profile r Latent Mtb infection r Mtb-specific CD8 + T cells Additional supporting information may be found in the online version of this article at the publisher's web-site Eur. J. Immunol. 2013Immunol. . 43: 1568Immunol. -1577 Immunity to infection 1569 IntroductionOne-third of the world's population is believed to be latently infected with Mycobacterium tuberculosis (Mtb) and two million people die of tuberculosis (TB) every year [1], thus underscoring the tremendous need for protective vaccines, new diagnostic tools, and medications. T lymphocytes are thought to play an important role in the control of TB and Mtb may reactivate under certain conditions of immunodeficiency such as in elderly or secondary to coinfection with HIV or to immunosuppressive therapy [2,3]. Several studies have underscored the essential role of CD4 + T cells in protection against Mtb, since CD4 + T-cell depletion is also associated with Mtb reactivation in HIV-infected individuals [4] and uncontrolled bacilli growth [5,6]. The protective Mtb-specific CD4 + T-cell response is considered to be a typical T H 1 response with CD4 + T cells producing cytokines such as IFN-γ or TNF-α that contribute to the recruitment of monocytes and granulocytes and activate the antimicrobial activity of macrophages [7,8]. Of interest, we recently demonstrated that Mtb-specific CD4 + T-cell responses were functionally different in patients with active TB disease as compared with those in subjects with latent Mtb infection (LTBI) [9]. Several studies also suggested a role of T H 17 cells in the con...

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