Beyond macrophages: the diversity of mononuclear cells in tuberculosis

Mycobacterium tuberculosis, the bacterium that causes tuberculosis (TB), is an intracellular pathogen of mononuclear phagocytes. Although M.tuberculosis has traditionally been thought to survive and replicate in macrophages, recent work in our laboratory and others has revealed that M.tuberculosis infects multiple subsets of mononuclear phagocytes in vivo and in vitro. In experimental animals, M.tuberculosis infects no fewer than five distinct cell subsets in the lungs, including resident alveolar macrophages and 4 types of cells that recruited to the lungs in response to inflammatory signals: neutrophils, monocytes, interstitial macrophages, and dendritic cells. A characteristic of the adaptive immune response in TB is that it is delayed for several weeks following infection, and we have determined that this delay is due to prolonged residence of the bacteria in lung phagocytes prior to acquisition of the bacteria by dendritic cells. Among the mechanisms used by M.tuberculosis to delay acquisition by dendritic cells is to inhibit apoptosis of alveolar macrophages and neutrophils, which sequester the bacteria and prevent their acquisition by dendritic cells in the early stages of infection. We hypothesize that each infected cell subset makes a distinct contribution to the overall biology of M.tuberculosis and allows the bacteria to evade elimination by T-cell responses and to avoid rapid killing by antimycobacterial drugs.