Skip to main content
Open Access Publications from the University of California

Molecular mechanisms by which Mycobacterium leprae survives in human macrophages

  • Author(s): Mehta, Manali D.
  • Advisor(s): Modlin, Robert L
  • et al.

Leprosy, a chronic infectious disease caused by Mycobacterium leprae, is a powerful model to study the human immune response because the clinical manifestations of disease present as a spectrum correlating with the level of immune response to the pathogen. Research investigating mechanisms of host defense and M. leprae-induced suppression of antimicrobial pathways continues to provide insight into which immune pathways are essential for containment of mycobacterial infections. Here, we utilized three bioinformatics approaches to identify mechanisms of modulation of host immune responses by mycobacterium and gain a clearer understanding of disease pathogenesis and potential targets of mitigation, including: i) integration of microRNA and mRNA gene expression profiling of disseminated lepromatous leprosy (L-lep) versus self-containing tuberculoid leprosy (T-lep) lesions to identify microRNAs capable of downregulating antimicrobial peptide production, ii) overlap of highly expressed receptors on IL-15-derived M1 and IL-10-derived M2 macrophages (MΦ) with known drivers of MΦ polarization to identify ligands capable of reeducating MΦ phenotype and function, and iii) comparison of transcriptome profiles of M. leprae-infected monocyte-derived MΦ and leprosy skin lesions to identify genes contributing to suppression of host immune responses and bacterial survival.

Here, we provide evidence illustrating the ability of M. leprae to induce specific microRNAs and host genes to alter host immune responses. M. leprae, but not M. tuberculosis, can induce upregulation of microRNA-21, which then targets and downregulates antimicrobial peptide production and mycobacterial killing. Differential cytokine expression coupled with the presence of mycobacterial ligands can alter MΦ polarization correlating to a change in phagocytic function and expression of antimicrobial genes. Lastly, M. leprae can induce expression of the autophagy regulator NUPR1, which is more highly expressed in L-lep lesions. As more insight is gathered on (i) the functional consequences of host genes regulated during mycobacterial infections on the immune response and ii) how these genes are regulated by the pathogens, an opportunity for directed therapeutic intervention may present itself.

Main Content
Current View