Chemokine receptor 5 and its ligands in the immune response to murine tuberculosis

Setting: The ability of chemokines such as macrophage inflammatory protein (MIP)-1 alpha, MIP-1 beta, and regulated-upon-activation, normal T cell expressed and secreted (RANTES), to attract and activate T cells and monocytes, the building blocks of the granuloma, suggests that these chemokines may have a role in modulating immune responses to Mycobacterium tuberculosis infection. Objective: We hypothesized that the chemokine receptor 5 (CCR5) ligands, MIP-1 alpha, MIP-1 beta and RANTES, are virulence correlates in M. tuberculosis infection and are indispensable to granuloma formation. Design: The ability of virulent (H37Rv) and avirulent (H37Ra) strains of M. tuberculosis to induce chemokine production in vivo and in vitro was determined at protein and mRNA levels. We also compared bacterial. burden, and granuloma numbers and size in H37Rv-infected CCR5-/- or wild-type C57BL/6 mice. Results: In vivo, lung mRNA and protein measurements of MIP-1 alpha, MIP-1 beta and RANTES indicate significantly higher (p < 0.05) values (days 14-28) in the H37Rv-infected than the H37Ra-infected mice. This is consistent with a higher infection burden of the virulent strain. However, in vitro alveolar macrophage stimulation by H37Rv or H37Ra yielded no significant differences in production of the three chemokines at all time points. Histological analysis of granulomas did not show any significant differences in granuloma numbers, size and M. tuberculosis growth in CCR5-/- compared to wild-type mice. Conclusions: The production of the CCR5 ligands, MIP-1 alpha, MIP-1 beta, and RANTES, does not clearly correlate with virulence of M. tuberculosis. These ligands and their receptors may not be indispensable to the development of granulomas in murine tuberculosis. (c) 2004 Elsevier Ltd. All rights reserved.