Differences in T‐cell responses between Mycobacterium tuberculosis and Mycobacterium africanum‐infected patients

Abstract

In The Gambia, Mycobacterium tuberculosis (Mtb) and Mycobacterium africanum (Maf) are major causes of tuberculosis (TB). Maf is more likely to cause TB in immune suppressed individuals, implying differences in virulence. Despite this, few studies have assessed the underlying immunity to the two pathogens in human. In this study, we analyzed T-cell responses from 19 Maf-and 29 Mtb-infected HIV-negative patients before and after TB chemotherapy following overnight stimulation of whole blood with TB-specific antigens. Before treatment, percentages of early secreted antigenic target-6(ESAT-6)/culture filtrate protein-10(CFP-10) and purified protein derivative-specific single-TNF-α-producing CD4 + and CD8 + T cells were significantly higher while single-IL-2-producing T cells were significantly lower in Maf-compared with Mtb-infected patients. Purified protein derivativespecific polyfunctional CD4 + T cells frequencies were significantly higher before than after treatment, but there was no difference between the groups at both time points. Furthermore, the proportion of CD3 + CD11b + T cells was similar in both groups pretreatment, but was significantly lower with higher TNF-α, IL-2, and IFN-γ production in Mtbcompared with that of Maf-infected patients posttreatment. Our data provide evidence of differences in T-cell responses to two mycobacterial strains with differing virulence, providing some insight into TB pathogenesis with different Mtb strains that could be prospectively explored as biomarkers for TB protection or susceptibility. Keywords: Cytokines r Mycobacterium africanum r Mycobacterium tuberculosis r T cells r TuberculosisAdditional supporting information may be found in the online version of this article at the publisher's web-site 1388 Leopold D. Tientcheu et al. Eur. J. Immunol. 2014. 44: 1387-1398 TB is caused by two distinct strains Mycobacterium africanum (Maf) and Mycobacterium tuberculosis (Mtb), with Maf causing up to half of all TB [2]. In The Gambia, TB patients infected with Maf West African type 2 are more likely to be older, HIV coinfected, and/or severely malnourished [3]. In addition, their exposed household contacts have a slower rate of progression to active disease compared with their Mtb-exposed counterparts [4], suggesting that Maf might be the less virulent of the two prevalent strains [5,6]. The heterogeneity in chest x-rays, bacillary load in sputum and clinical symptoms, likely reflects the variation in host immune response to the invading pathogen, and/or the differences between the lineages within the MTBC. For instance, Maf has slower growth in culture medium compared with Mtb [6,7], which may influence progression to active disease [4].The recently published genome of Maf reveals a high content of pseudogenes and the presence of a unique sequence -the region of difference 900 "RD900" that has been deleted evolutionarily from Mtb and M. bovis strains [8]. Many studies have concentrated on the pathogen strain differences in various geographical locations, with only a few anal...

M. tuberculosis T Cell Epitope Analysis Reveals Paucity of Antigenic Variation and Identifies Rare Variable TB Antigens

“…Samples without stimulus were used as negative controls to allow calculation of the magnitude of the induced responses. Phytohemagglutinin (PHA; 5 µg/mL), purified protein derivative (PPD; Staten Serum Institute, Denmark) and a pool of 35 overlapping 15 mer peptides (2.5 µg/mL) derived from the 6 kDa Early Secreted Antigenic Target and the Culture Filtrate Protein-10 protein (ESAT-6/CFP-10) were used as positive controls (Tientcheu et al, 2014). Antigens were stimulated in triplicate and after seven days incubation at 37°C in a humidified CO 2 incubator, supernatants were removed for assay of IFN-γ.…”

Transmissible Mycobacterium tuberculosis Strains Share Genetic Markers and Immune Phenotypes

“…Further support for our findings stems from other genomic epidemiological studies. Nonsynonymous SNPs (albeit different from the ones identified in this study) and a frameshift mutation in espE were found to be more common in Mycobacterium africanum strains relative to H37Rv (28) and to be implied in their reduced ability to induce a CD4-cell ESAT-6-induced IFN-g host response (29,30). Similarly, in a previous study, researchers identified a large sequence polymorphism associated with clustering in a gene (MT1801) encoding molybdopterin oxidoreductase, which is also encoded by Rv0197 (31).…”

Comparative genomics ofMycobacterium africanumLineage 5 and Lineage 6 from Ghana suggests different ecological niches

“…This result is comparable to an earlier report comparing mutations within regulatory proteins between Mtbss and M. bovis , which found most of the M. bovis to harbor majority of the mutations 36 . As mutations within some regulatory proteins have been associated with attenuated virulence 38–40 , our observation could account for the reported attenuated virulence of Maf relative to Mtbss 14,15,17,41 . This calls for further comparative studies of regulatory proteins between L5, L6 and other MTBC lineages to ascertain the role of regulatory proteins.…”

“…Some evidence in support of the first hypothesis is the reported association of Maf (L6) with HIV co-infection, attenuated ESAT-6 responses and delayed progression to active disease relative to Mtbss 9,13–16 . In addition, both Maf lineages as well as Mtbss L1, together described as “ancestral” MTBC lineages, have been shown to elicit a stronger early production of pro-inflammatory cytokines compared to the “modern” MTBBC L2, L3 and L4 17 .…”