In:
Infection and Immunity, American Society for Microbiology, Vol. 88, No. 6 ( 2020-05-20)
Abstract:
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.
Type of Medium:
Online Resource
ISSN:
0019-9567
,
1098-5522
DOI:
10.1128/IAI.00222-19
Language:
English
Publisher:
American Society for Microbiology
Publication Date:
2020
detail.hit.zdb_id:
1483247-1
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