Variation in gamma interferon responses to different infecting strains of Mycobacterium tuberculosis in acid-fast bacillus smear-positive patients and household contacts in Antananarivo, Madagascar

Abstract

The majority of healthy individuals exposed to Mycobacterium tuberculosis will not develop tuberculosis (TB), though many may become latently infected. More precise measurement of the human immune response to M. tuberculosis infection may help us understand this difference and potentially identify those subjects most at risk of developing active disease. Gamma interferon (IFN-gamma) production has been widely used as a proxy marker to study infection and to examine the human immune response to specific M. tuberculosis antigens. It has been suggested that genetically distinct M. tuberculosis strains may invoke different immune responses, although how these differences influence the immune responses and clinical outcome in human tuberculosis is still poorly understood. We therefore evaluated the antigen-specific IFN-gamma production responses in peripheral blood mononuclear cells from two cohorts of subjects recruited in Antananarivo, Madagascar, from 2004 to 2006 and examined the influence of the infecting M. tuberculosis strains on this response. The cohorts were sputum-positive index cases and their household contacts. Clinical strains isolated from the TB patients were typed by spoligotyping. Comparison of the IFN-gamma responses with the spoligotype of the infecting clinical strains showed that "modern" M. tuberculosis strains, like Beijing and Central Asian (CAS) strains, tended to induce lower IFN-gamma responses than "ancient" strains, like East African-Indian (EAI) strains, in index cases and their household contacts. These results suggest that new strains may have evolved to induce a host response different from that of ancient strains. These findings could have important implications in the development of therapeutic and diagnostic strategies.

Figures

FIG. 1.

Distribution of the spoligotype families found among the M. tuberculosis strains isolated from the index cases. (A) Spoligotype family according to data in the SpolDB4 database (CAS, Central Asian; EAI, East African Indian; LAM, Latin American-Mediterranean; H, Haarlem; T, undefined family) (10); ND, not described in SpolDB4 database. (B) Groups according to Arnold (5).

FIG. 2.

In vitro IFN-γ responses of PBMCs from ICs to restimulation with M. tuberculosis ESAT-6, PPD, and CFP7 antigens at the inclusion period (A) and after treatment (B), according to the spoligotypes of the infecting M. tuberculosis strains. The levels of IFN-γ which were significantly different between groups (Mann-Whitney test) are indicated. The horizontal bars indicate the median number of spots per 106 PBMCs.

FIG. 3.

In vitro IFN-γ responses of PBMCs from household contacts to restimulation with the ESAT-6, PPD, and CFP7 antigens at the inclusion period (A) and 3 months after the inclusion period (B), according to the spoligotypes of the infecting M. tuberculosis strains isolated from their respective IC patients. The levels of IFN-γ which were significantly different between groups (Mann-Whitney test) are indicated. The horizontal bars indicate the median number of spots per 106 PBMCs. ⧫, HHCs; ⋄, TBHCs.

FIG. 4.

TST results for household contacts, according to the genotype of the M. tuberculosis isolates from the index case patients.