Diverging biological roles among human monocyte subsets in the context of tuberculosis infection

BALBOA LUCIANA

Seminario; Seminario Institucional en el Institute of Pharmacology and Structural Biology; 2014

Institute of Pharmacology and Structural Biology

Tuberculosis (TB), caused by Mycobacterium tuberculosis, is one of the most devastating human diseases being responsible of ~2 million deaths worldwide each year. In chronic infections such as TB, circulating monocytes arrive to the infected site and play a central role in the host response, as they represent a large pool of precursors of macrophages (MΦ) and dendritic cells (DC). In the past, we demonstrated that human CD16pos monocytes, which preferentially expand in TB patients, correlate with disease severity and are refractory to DC differentiation, suggesting diverging biological roles among human monocyte subsets in the context of TB infection. In this study, we investigated if human monocyte subsets (CD16neg and CD16pos) are differentially recruited to lungs during Mtb infection, and whether this early event could modulate the immune response and affect the outcome of the disease. To accomplish this, we employed a humanized mouse model (SCID/Beige) to transfer each monocyte subset, track their migratory fate during Mtb infection, and determine their overall impact on the host immune response. We found that under steady state conditions the percentages of CD16pos monocytes recovered from lungs were higher in contrast to CD16neg monocytes, but under infectious conditions, the latter subset was more prone to migrate to lungs. These migration patterns were confirmed for each human monocyte subset using a combination of an in vitro transwell system and different chemo-attractant gradients including cell-free pleural effusions from TB patients and conditioned medium from Mtb-stimulated cells. In terms of the host immune response, we observed that CD16pos monocytes induced the recruitment of leukocytes into the lung accompanied by untypical higher levels of IL-1βpos cells under steady-state conditions. However, under M. tuberculosis infection, the adoptive transfer of the CD16neg subset was characterized by an increase in leukocyte infiltration and cells positive for anti-inflammatory cytokines (i.e. IL-10, TGF-β) in the lung as compared to that of CD16pos monocytes. In terms of the impact on the M. tuberculosis load, we show that the adoptive transfer of CD16neg monocytes significantly decrease the bacterial charge in the lungs; reciprocally, CD16pos monocytes augmented significantly the bacillary load detected in the bronchoalveolar lavage. When challenged in vitro with M. tuberculosis, the CD16neg monocytes were indeed more resistant to bacillus intracellular growth than the CD16pos subset. Finally, while the adoptive transfer of either monocyte subset failed to alter the survival curves of the infected mice, CD16pos monocytes had a surprising effect reducing the pneumonia index in the lungs caused by M. tuberculosis. Collectively, our findings indicate that human monocyte subsets display divergent biological roles during the context of TB infection, a scenario in which CD16neg monocytes may contribute to the host immune response against M. tuberculosis while the CD16pos subset may preserve tissue integrity and indirectly promote this pathogen´s resilience.