Leprosy as a Model of Immunity

Yang Degang; Kazuaki Nakamura; Takeshi Akama; Yuko Ishido; Yuqian Luo; Norihisa Ishii; Koichi Suzuki


Future Microbiol. 2014;9(1):43-54. 

In This Article

Host Cell Parasitism & Bacterial Survival: Evasion of M. leprae From the Host Immune Defense

Macrophages and Schwann cells are the principal host cells for M. leprae.[1–4] The bacteria may have adopted a variety of mechanisms to avoid or circumvent host immune responses and survive within these cells.[60–62] Phagosome maturation and subsequent fusing with lysosomes are essential for pathogen destruction, antigen processing and presentation for effective recognition by the adaptive immune system. It is well known that mycobacteria have evolved the ability to block this fusion, reportedly via cell wall components such as the C-type lectin receptor CD209/DC-SIGN and the mannose receptor bind the mannose-capped lipoarabinomannan.[63–66]Mycobacterium tuberculosis secretes glycosylated LAM to inhibit the phosphorylation of PI3P, which arrests phagosome maturation and effectively prevents fusion with the lysosome.[67,68] The complement receptor 1[69,70] or the mannose receptor[71] prevents the fusion of lysosomes with phagosomes, favoring the survival of mycobacteria in host cells. Inhibition of phagosome–lysosome fusion by M. leprae surface components was confirmed by a study in which the coating of M. leprae by its antiserum partly reversed the inhibition of phagosome–lysosome fusion.[72] TACO, which inhibits phagosome–lysosome fusion[73] is highly expressed in the foamy histiocytes in BL/LL skin lesions.[74] TLR2 activation can decrease TACO expression, which may contribute to the phagosome-lysosomal fusion; however, live M. leprae infection was found to inhibit TLR-mediated TACO suppression.[75]

Lipids also play key roles in the phagocytosis of bacteria.[76] Survival of M. leprae (and also M. tuberculosis) bacilli in the hostile intracellular environment of the macrophage or Schwann cell is critically dependent on lipid metabolism and the recruitment and utilization of host lipids. Indeed, in 1863, Virchow first described the hallmark of LL leprosy found in the lipid bodies that accumulate within the cells and are primarily responsible for the appearance of 'foamy macrophages' in lesion sites of the skin. M. leprae appears to actively upregulate the biogenesis of lipid droplets by increasing the expression of ADRP and perilipin, and to suppress its catabolism by activating hormone-sensitive lipase both in macrophage and Schwann cells.[57,77–81] We now know that lipid plays an essential role in the intracellular parasitization of M. leprae; however, whether and how the lipid status would affect the host immune responses against M. leprae, thus contributing to its intracellular parasitization, remains an open question.

Two other mechanisms notable of mycobacterial escape include: progressive translocation of M. tuberculosis from the fused phagosome–lysosome into the cytoplasm thus avoiding digestion, a process that is dependent on the secretion of the mycobacterial antigens CFP-10 and ESAT-6;[62] and vesicular proton ATPase inhibition of the fusion of Mycobacterium-containing vacuoles to prevent phagosome acidification and, hence, mycobacterial killing.[82] Although evasion of the phagosome–lysosome fusion takes place in cases of M. leprae infection, it is unlikely to be permanent and stable, but instead dynamic and balanced as evidenced by the high incidence of type I reactions. Decreased bacilli viability in addition to a damaged cell wall structure may also contribute to triggering such dynamic changes in M. leprae evasion.