Leprosy provides a model to investigate mechanisms of immune regulation in humans, given that the disease forms a clinical-immunological spectrum. Here, we identified 13 miRNAs that were differentially expressed in the lesions of subjects with progressive lepromatous (L-lep) vs. the self-limited tuberculoid (T-lep) disease. Bioinformatic analysis revealed a significant enrichment of L-lep-specific miRNAs that preferentially target key immune genes downregulated in L-lep vs. T-lep lesions. The most differentially expressed miRNA in L-lep lesions, hsa-mir-21, was upregulated in M. leprae-infected monocytes. Hsa-mir-21, by downregulating toll-like receptor 2/1 (TLR2/1)-induced CYP27B1 and IL1B as well as upregulating IL-10, inhibited gene expression of the vitamin D-dependent antimicrobial peptides, CAMP and DEFB4A. Conversely, knockdown of hsa-mir-21 in M. leprae-infected monocytes enhanced expression of CAMP and DEFB4A and restored TLR2/1-mediated antimicrobial activity against M. leprae. Therefore, the ability of M. leprae to upregulate hsa-mir-21 targets multiple genes associated with the immunologically localized disease form, providing an effective mechanism to escape from the vitamin D-dependent antimicrobial pathway.

As the role of microRNA in all aspects of biology continues to be unraveled, the interplay between microRNAs and human disease is becoming clearer. It should come of no surprise that microRNAs play a major part in the outcome of infectious diseases, since early work has implicated microRNAs as regulators of the immune response. Here, we provide a review on how microRNAs influence the course of mycobacterial infections, which cause two of humanity’s most ancient infectious diseases: tuberculosis and leprosy. Evidence derived from profiling and functional experiments suggests that regulation of specific microRNAs during infection can either enhance the immune response or facilitate pathogen immune evasion. Now, it remains to be seen if the manipulation of host cell microRNA profiles can be an opportunity for therapeutic intervention for these difficult-to-treat diseases.

Summary Macrophage (MΦ) polarization is triggered during the innate immune response to defend against microbial pathogens, but can also contribute to disease pathogenesis. In a previous study, we found that interleukin‐15 (IL‐15) ‐derived classically activated macrophages (M1 MΦ) have enhanced antimicrobial activity, whereas IL‐10‐derived alternatively activated macrophages (M2 MΦ) were highly phagocytic but lacked antimicrobial activity. Given that the ability to modulate MΦ polarization from M2 MΦ to M1 MΦ may promote a more effective immune response to infection, we investigated the plasticity of these MΦ programs. Addition of IL‐10 to M1 MΦ induced M2‐like MΦ, but IL‐15 had little effect on M2 MΦ. We determined the set of immune receptors that are present on M2 MΦ, elucidating two candidates for inducing plasticity of M2 MΦ, Toll‐like receptor 1 (TLR1) and interferonγ (IFN‐γ) receptor 1. Stimulation of M2 MΦ with TLR2/1 ligand (TLR2/1L) or IFN‐γ alone was not sufficient to alter M2 MΦ phenotype or function. However, co‐addition of TLR2/1L and IFN‐γ re‐educated M2 MΦ towards the M1 MΦ phenotype, with a decrease in the phagocytosis of lipids and mycobacteria, as well as recovery of the vitamin‐D‐dependent antimicrobial pathway compared with M2 MΦ maintained in polarizing conditions. Similarly, treatment of M2 MΦ with both TLR2/1L and anti‐IL‐10 neutralizing antibodies led to polarization to the M1‐like MΦ phenotype and function. Together, our data demonstrate an approach to induce MΦ plasticity that provides the potential for re‐educating MΦ function in human mycobacterial disease to promote host defense and limit pathogenesis.

The initial interaction between a microbial pathogen and the host immune response influences the outcome of the battle between the host and the foreign invader. Leprosy, caused by the obligate intracellular pathogen Mycobacterium leprae , provides a model to study relevant human immune responses. Previous studies have adopted a targeted approach to investigate host response to M . leprae infection, focusing on the induction of specific molecules and pathways. By measuring the host transcriptome triggered by M . leprae infection of human macrophages, we were able to detect a host gene signature 24–48 hours after infection characterized by specific innate immune pathways involving the cell fate mechanisms autophagy and apoptosis. The top upstream regulator in the M . leprae -induced gene signature was NUPR1 , which is found in the M . leprae -induced cell fate pathways. The induction of NUPR1 by M . leprae was dependent on the production of the type I interferon (IFN), IFN-β. Furthermore, NUPR1 mRNA and protein were upregulated in the skin lesions from patients with the multibacillary form of leprosy. Together, these data indicate that M . leprae induces a cell fate program which includes NUPR1 as part of the host response in the progressive form of leprosy.

MicroRNAs have been shown to be crucial in regulation of immune cell development and cancer progression. Recently, it has become increasingly clear that their involvement in regulation of immune responses to infection is also important. Here we use Mycobacterium leprae, the causative agent of leprosy, as a model to determine the potential roles of microRNAs in infectious disease. The immune response to M. leprae has been well-characterized as presenting as a spectrum, ranging from a contained infection characterized by a Th1 response in tuberculoid (T-lep) patients to a disseminated infection reflecting a Th2 response in lepromatous (L-lep) patients. We performed mRNA and microRNA microarray analysis on 6 T-lep and 4 L-lep lesions and subsequently integrated this data using Ingenuity. Preliminary gene network analysis of differentially expressed microRNAs in L-lep versus T-lep yielded multiple networks potentially targeted, including antigen presentation. A supervised analysis of Th1 and Th2 gene targeting indicates that microRNAs more highly expressed in L-lep lesions, such as miR-21 and miR-146a, may preferentially target proinflammatory genes required for a Th1 immune response. Further analysis to determine the functional effects of these microRNAs and their involvement in skewing towards a Th2 immune response to infection could explain the bias in disease outcome.