Combination of Mycobacterium indicus pranii and Heat-Induced Promastigotes Cures Drug-Resistant Leishmania Infection: Critical Role of Interleukin-6-Producing Classical Dendritic Cells.

The major issues in available therapeutic modalities against leishmaniasis are cost, toxicity, and the emergence of drug resistance. The aim of this work was to develop a successful therapeutic adjuvant against drug-resistant Leishmania donovani infection by means of combining Mycobacterium indicus pranii with heat-induced promastigotes (HIP). One-month postinfected BALB/c mice were administered subcutaneously with M. indicus pranii (10 ⁸ cells) and HIP (100 μg) for 5 days. Spleens were harvested for flow cytometric and reverse transcriptase PCR analysis. The antileishmanial effect of the combination strategy was associated with induction of a disease-resolving Th1 and Th17 response with simultaneous downregulation of CD4 ⁺ CD25 ⁺ Foxp3 ⁺ (nTreg) cells and CD4 ⁺ CD25 ^- Foxp3 ^- (Tr1) cells in the spleen. The significant expansion of CD4 ⁺ T _CM (CD4 ⁺ CD44 ^hi CD11a ^hi CD62L ^hi ) cells was a further interesting outcome of this therapeutic strategy in the context of long-term protection of hosts against secondary infection. Toll-like receptor 2 (TLR2) was also found instrumental in this antiparasitic therapy. Induced interleukin-6 (IL-6) production from expanded CD11c ⁺ CD8α ⁺ (cDC1) and CD11c ⁺ CD11b ⁺ (cDC2) dendritic cells (DCs) but not from the CD11b ⁺ Ly6c ⁺ inflammatory monocytes (iMOs), was found critical in the protective expansion of Th17 as evidenced by an in vivo IL-6 neutralization assay. It also promoted the hematopoietic conversion toward DC progenitors (pre-DCs) from common dendritic cell progenitors (CDPs), the immediate precursors, in bone marrow. This novel combinational strategy demonstrated that expansion of Th17 by IL-6 released from CD11c ⁺ classical DCs is crucial, together with the conventional Th1 response, to control drug-resistant infection.
(Copyright © 2020 American Society for Microbiology.)