The Rv1619 protein of Mycobacterium tuberculosis increases resistance to beta-defensins

Tuberculosis is a major health problem that yearly causes the death of 2 million people and disease in 9 million people. Many of the pulmonary tuberculosis cases in adults result from the reactivation of an initially controlled latent Mycobacterium tuberculosis infection and it is estimated that about one third of the world population is latently infected with the bacillus. The immune mechanisms preventing reactivation of Mycobacterium tuberculosis infection are poorly understood, but recent studies indicate that over the different stages of infection the bacterial antigen composition is changing, implying that the extent of recognition of specific antigens could also vary. In this study, we are analyzing the immune response to several mycobacterial antigens in two murine models of latent and reactivation tuberculosis. The selection of the analyzed antigens (Ag85A, Ag85B, ppe44, Rv2626c, HspX, PstS-3 and ESAT-6) is primarily based on published works, in which some of these have been described as differentially expressed during latency and reactivation tuberculosis. In the first murine model, (B6*D2)F1 are infected intravenously with 1x105 colony forming units of Mycobacterium tuberculosis H37Rv, rested for 4 weeks, treated for 8 weeks with isoniazid and pyrazinamide, rested for 10 weeks and finally treated with the nitric oxide synthase regulator aminoguanidine for reactivation of the infection. In the second model, (B6*D2)F1 are infected intratracheally with 4x103 colony forming units of Mycobacterium tuberculosis H37Rv, rested for 10 weeks and treated with aminoguanidine for reactivation. In both models, spontaneous reactivation will be assessed in mice that are not treated with aminoguanidine. At regular intervals, the humoral and cell-mediated immune response to the selected antigens and their immunodominant peptides will be analyzed. In parallel, the antigenic expression in the lungs of the infected mice will be assessed by reverse transcription real-time PCR. This study should clarify whether the extent of the recognition of specific antigens is varying over the different stages of the infection and whether this variation correlates with a variation in antigen expression