Gene Expression Study of Host and Mycobacterium tuberculosis Interactions in the Manifestation of Acute Tuberculosis.

Mycobacterium tuberculosis (M.tb) could induce type IV hypersensitivity. The chemotaxis of the leukocytes toward the site of infection and producing matrix metalloproteinases (MMPs) are key factors in the immune pathogenesis of tuberculosis (TB). Mononuclear cells were isolated from bronchoalveolar lavage (BAL) specimens, and the target from genomic DNA was used for qPCR TB diagnosis and cDNA for specific RT-qPCR gene expression. The subjects were then classified into TB+ and TB- groups, and the expression levels of CFP-10, ESAT-6, CCR1, CCR12 and MMP3,9 were evaluated. The mean level of CCR1 expression in TB+ and TB- patients' BAL was 1.71 ± 0.78 and 0.5 ± 0.22, respectively, which was statistically different (p = 0.01). The CCR2 level, in TB+ (2.07 ± 1.4), was higher than in TB- patients (1.42 ± 0.89, p = 0.01). The MMP9 expression in TB+ was 2.56 ± 0.68, also higher than in TB- patients (1.13 ± 0.35), while MMP3 was lower in TB+ (0.22 ± 0.09) than in TB- (0.64 ± 0.230, p = 0.05). The CCR2/CCR1 and MMP3/MMP9 balance in TB+ were reduced, compared to the TB-. The CFP-10 and ESAT-6 were highly expressed in TB+ patients. The CFP-10 expression had a strong negative correlation with albumin (r = - 0.93, p = 0.001), and a negative correlation with neutrophil (r = - 0.444, p = 0.1 with 90% CI). The MMP-9 expression showed a positive correlation with WBC count (r = 0.61, p = 0.02), in TB+, and had a negative correlation with BMI (r = 0.59, p = 0.02) in TB-. The M.tb CFP-10 might be implicated in lowering CCR2 and MMP3 expression in favour of M.tb dissemination. Moreover, the balance of CCR2/CCR1 and MMP3/MMP9 can be used as prognostic factors in the severity of TB.

Game theory applications in host-microbe interactions toward disease manifestation: Mycobacterium tuberculosis infection as an example.

OBJECTIVES: Game theory describes the interactions between two players and the pay-off from winning, losing, or compromising. In the present study, Mycobacterium tuberculosis (Mtb)-host interactions were used as an example for the application of game theory to describe and predict the different outcomes of Mtb-infection and introducing target molecules for use in protection or therapy. MATERIALS AND METHODS: The gene expression for eight main markers (CCR1, CCR2, IDO, Tbet, TGFß, iNOS, MMP3, MMP9) of host response and three Mtb virulence factors (Ag85B, CFP-10, ESAT-6) were assessed in broncho-alveolar lavage of TB+ and TB- patients. RESULTS: The players' strategies in the "Nash equilibrium", showed that Ag85B is the main virulence factor for Mtb in active phase, and also the most immunogenic factor, if the host can respond by high expression of T-bet and iNOS toward a Th1 response. In this situation, Mtb can express high levels of ESAT-6 and CFP10 and change the game to the latency, in which host responses by medium expression of T-bet and iNOS and medium level of TGF-ß and IDO. Consistently, the IDO expression was 134-times higher in TB+s than the TB-s,and the T-bet expression,~200-times higher in the TB-s than the TB+s. Furthermore, Mtb-Ag85B had a strong positive association with CCR2, T-bet and iNOS, but had a negative correlation with IDO. CONCLUSION: Ag85B and maybe ESAT6 (without its suppressive C-terminal) should be considered for making subunit vaccines. And, preventing IDO formation in dendritic cells might be a novel target for immunotherapy of tuberculosis, to reduce the pressure of immune-suppression on Th1 responses.