Abstract
Visceral leishmaniasis is a deadly illness caused by Leishmania donovani that provokes liver and spleen inflammation and tissue destruction. In cutaneous leishmaniasis, the protein of L. major, named inhibitor of serine peptidases (ISP) 2, inactivates neutrophil elastase (NE) present at the macrophage surface, resulting in blockade of TLR4 activation, prevention of TNF-α and IFN-β production, and parasite survival. We report poor intracellular growth of L. donovani in macrophages from knockout mice for NE (ela−/−), TLR4, or TLR2. NE and TLR4 colocalized with the parasite in the parasitophorous vacuole. Parasite load in the liver and spleen of ela−/− mice were reduced and accompanied by increased NO and decreased TGF-β production. Expression of ISP2 was not detected in L. donovani, and a transgenic line constitutively expressing ISP2, displayed poor intracellular growth in macrophages and decreased burden in mice. Infected ela−/− macrophages displayed significantly lower IFN-β mRNA than background mice macrophages, and the intracellular growth was fully restored by exogenous IFN-β. We propose that L. donovani utilizes the host NE-TLR machinery to induce IFN-β necessary for parasite survival and growth during early infection. Low or absent expression of parasite ISP2 in L. donovani is necessary to preserve the activation of the NE-TLR pathway.—Dias, B. T., Dias-Teixeira, K. L., Godinho, J. P., Faria, M. S., Calegari-Silva, T., Mukhtar, M. M., Lopes, U. G., Mottram, J. C., Lima, A. P. C. A. Neutrophil elastase promotes Leishmania donovani infection via interferon-β.
Highlights
The leishmaniases comprise a spectrum of diseases that vary from self-healing cutaneous lesions to visceral infections that are caused by more than 20 species of Leishmania
Whereas parasites did not increase in numbers from 3 to 72 h in C57BL6 macrophages, L. donovani:ISP2 displayed a more pronounced phenotype in tlr22/2 macrophages [i.e., the parasite burdens in tlr22/2 at 72 h were decreased by half in relation to the number internalized in 3 h (Fig. 6C)]
Using neutrophil elastase (NE) knockout mice, we showed that NE is required for efficient early liver parasitism and for the successful development of L. donovani MW897 in macrophages in vitro
Summary
The leishmaniases comprise a spectrum of diseases that vary from self-healing cutaneous lesions to visceral infections that are caused by more than 20 species of Leishmania. ABBREVIATIONS: Ag, antigen; BSA, bovine serum albumin; FCS, fetal calf serum; IRF, IFN regulatory transcription factor; IRAK, interleukin-1 receptor-associated kinase 1; ISP, inhibitor of serine peptidases; LdISP2, Leishmania donovani inhibitor of serine peptidase 2; L-NAME, NW-nitroL-arginine methyl ester hydrochlorid; MyD88, myeloid differentiation primary response 88; NE, neutrophil elastase; NEI, irreversible inhibitor of NE; qPCR, quantitative PCR; ROS, reactive oxygen species; poly:IC, polyinosinic-polycytidylic acid sodium salt; RPMI, Roswell Park Memorial Institute; TBS-T, Tris-buffered saline with 0.05% Tween 20; TRAF, TNF receptor-associated factor; TRIF, TIR-domain-containing adapter-inducing interferon b; VL, visceral leishmaniasis; WT, wild type Comparison of the genomes of species that cause cutaneous leishmaniasis with different clinical manifestations [i.e., L. major, L. braziliensis, L. mexicana, and the genome of the L. donovani
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