Analysis of Host Responses to Mycobacterium tuberculosis Antigens in a Multi-Site Study of Subjects with Different TB and HIV Infection States in Sub-Saharan Africa

Abstract

BackgroundTuberculosis (TB) remains a global health threat with 9 million new cases and 1.4 million deaths per year. In order to develop a protective vaccine, we need to define the antigens expressed by Mycobacterium tuberculosis (Mtb), which are relevant to protective immunity in high-endemic areas.MethodsWe analysed responses to 23 Mtb antigens in a total of 1247 subjects with different HIV and TB status across 5 geographically diverse sites in Africa (South Africa, The Gambia, Ethiopia, Malawi and Uganda). We used a 7-day whole blood assay followed by IFN-γ ELISA on the supernatants. Antigens included PPD, ESAT-6 and Ag85B (dominant antigens) together with novel resuscitation-promoting factors (rpf), reactivation proteins, latency (Mtb DosR regulon-encoded) antigens, starvation-induced antigens and secreted antigens.ResultsThere was variation between sites in responses to the antigens, presumably due to underlying genetic and environmental differences. When results from all sites were combined, HIV- subjects with active TB showed significantly lower responses compared to both TST- and TST+ contacts to latency antigens (Rv0569, Rv1733, Rv1735, Rv1737) and the rpf Rv0867; whilst responses to ESAT-6/CFP-10 fusion protein (EC), PPD, Rv2029, TB10.3, and TB10.4 were significantly higher in TST+ contacts (LTBI) compared to TB and TST- contacts fewer differences were seen in subjects with HIV co-infection, with responses to the mitogen PHA significantly lower in subjects with active TB compared to those with LTBI and no difference with any antigen.ConclusionsOur multi-site study design for testing novel Mtb antigens revealed promising antigens for future vaccine development. The IFN-γ ELISA is a cheap and useful tool for screening potential antigenicity in subjects with different ethnic backgrounds and across a spectrum of TB and HIV infection states. Analysis of cytokines other than IFN-γ is currently on-going to determine correlates of protection, which may be useful for vaccine efficacy trials.

New Genome-Wide Algorithm Identifies Novel In-Vivo Expressed Mycobacterium Tuberculosis Antigens Inducing Human T-Cell Responses with Classical and Unconventional Cytokine Profiles

“…For comparative purposes we also included ten additional Mtb antigens identified previously (Rv0867, Rv1009, Rv1733, Rv1737, Rv2029, Rv2032, Rv2034, Rv2389, Rv2450, and Rv3353)2324414748495051525354. Diluted whole blood samples were stimulated for six days and the cytokine levels were assessed by a seven-plex assay (data shown only for IFN-γ, IL-17, TNF-α and IP-10 Fig.…”

Mannose-Capped Lipoarabinomannan from Mycobacterium tuberculosis Induces CD4+ T Cell Anergy via GRAIL

“…Recent studies have demonstrated that CD4 + T cells from persons who have controlled Mtb infection recognize a very diverse range of antigens (1–4). Antigenic variation among Mtb strains for CD4 + T cells is minimal and an unlikely mechanism of immune evasion (5).…”

Resuscitation-promoting factors are important determinants of the pathophysiology inMycobacterium tuberculosisinfection

“…This is an important finding as household contacts are at high risk, particularly within the first year of developing active Mtb (Fox et al, 2013). Collectively these studies indicate that Rpf IGRAs may overcome the limitations of current commercial IGRAs although as the response to Rpf antigens can vary by location (Sutherland et al, 2013), these studies should be replicated in different settings. Furthermore, given the exposure of individuals to Rpf through, for example, BCG vaccination or nontuberculous mycobacterial disease, the diagnostic performance of Rpf IGRAs should be verified in these populations.…”