Micro RNAs, new players in the Immunopathogenesis of Tuberculosis

Whereas a third of the world‟s population is infected with Mycobacterium tuberculosis (M. tuberculosis), there is still a lot to learn about the specific role of cellular immune system in particular the role that is played by CD4+ T cell derived IFN-γ and micro RNAs in immune modulation during active tuberculosis. Although IFN-γ remains a very important mediator of host immune response to M. tuberculosis infection, there has been documented speculations about IFN-γ independent mechanism of mtb control by CD4+ T cells emphasizing on IFN-γ as a measure of inflammatory status other than an appropriate immune response. Although miRNAs had been documented to be implicated in autoimmunity and cancer, it was not until recently that investigators have suggested a role for them in host pathogen interaction especially in modulating several processes in humoral and cell mediated immunity. This study investigated the dynamics of IFN-γ production during acute pulmonary tuberculosis in a tuberculosis endemic region of Ghana. Again pathogen induced immune modulation in CD4+ T cells via miRNAs was investigated in tuberculosis patients and their exposed but healthy household contacts. This case control study nested with a cohort design recruited a total of 32 clinically confirmed Tuberculosis patients and 56 exposed but healthy household contacts otherwise referred to as Latent tuberculosis infected persons (LTBIs) consecutively from three hospitals in Kumasi, Ghana (Komfo Anokye Teaching Hospital, Kwame Nkrumah University of science and Technology Hospital and Kumasi South Hospital). PBMCs were isolated from whole blood for stimulation using PPD and ESAT-6 as Tuberculosis specific antigen and PMA/Io, PHA and SEB as positive control for 5 days. IFN-γ from culture supernatants were quantified using ELISA. CD4+ T cells were isolated from PBMCs using the Imag system and its purity determined using FACS analysis. MiRNAs were extracted from CD4+ T cells and the differential expression of candidate miRNAs were quantified using qRT-PCR. vi It is shown in this study that IFN-γ response is higher in LTBIs than tuberculosis patients. IFN-γ response pattern does not change significantly during antituberculous chemotherapy. Again, concomitant diseases, age, sex and prior BCG vaccination does not influence IFN-γ response during acute pulmonary tuberculosis. Moreover, study findings reveal that 7 different miRNAs may be involved in the T cell response during acute Pulmonary Tuberculosis in Ghanaian study population. Their differential expression was repressed prior to antituberculous chemotherapy but increased significantly during therapy. The miRNAs are miR-25, miR-26a, miR-29a, miR-99b, miR-101, miR-146a and miR-223. Candidate miRNAs‟ differential expressions were not significantly different from LTBIs. Lastly miR-29a had a tendency to correlate positively with IFN-γ response in tuberculosis patients and LTBIs but this was not statistically significant except for tuberculosis specific ESAT-6 induced IFN-γ response in LTBIs that showed a significant positive correlation. IFN-γ mediated Th1 response is critical for control of Mycobacterium tuberculosis infection. However there exists the possibility of a Th1- (CD4+ T cell) dependent IFN-γ independent mechanism of M. tuberculosis control. IFN-γ repression may be a likely immune evasive mechanism employed by M. tuberculosis to overwhelm the host immunity. Consistent pattern of significantly altered differential expression of miR-25, miR-26a, miR-29a, miR-99b, miR-101, miR-146a and miR-223 suggests a role of these candidates in CD4+ T cell immunity during tuberculosis disease and recovery. These candidates may represent future candidates for immunotherapies and vaccines against M. tuberculosis infections. Although miR-29a may be involved with CD4+ T cell response to M. tuberculosis infection it appears not to be a none redundant repressor of IFN-γ production in tuberculosis patients and LTBIs. Thus, IFN-γ and miRNAs may be important determinants of disease outcome during M. tuberculosis vii infection. Future studies would consider possible targets for successful candidates with significantly altered differential expression and varying expression in CD4+ T cell sub population. The current study is considered as an initial step to characterize the role of IFN-γ and microRNAs in tuberculosis.

Source: KNUST