Abstract
Leishmania major is the causative agent of the neglected tropical disease, cutaneous leishmaniasis. In the mouse, protective immunity to Leishmania is associated with inflammatory responses. Here, we assess the dynamics of the inflammatory responses at the lesion site during experimental long-term, low-dose intradermal infection of the ear, employing noninvasive imaging and genetically modified L. major. Significant infiltrates of neutrophils and monocytes occurred at 1–4 d and 2–4 wk, whereas dermal macrophage and dendritic cell (DC) numbers were only slightly elevated in the first days. Quantitative whole-body bioluminescence imaging of myeloperoxidase activity and the quantification of parasite loads indicated that the Leishmania virulence factor, inhibitor of serine peptidase 2 (ISP2), is required to modulate phagocyte activation and is important for parasite survival at the infection site. ISP2 played a role in the control of monocyte, monocyte-derived macrophage, and monocyte-derived DC (moDC) influx, and was required to reduce iNOS expression in monocytes, monocyte-derived cells, and dermal DCs; the expression of CD80 in moDCs; and levels of IFN-γ in situ. Our findings indicate that the increased survival of L. major in the dermis during acute infection is associated with the down-regulation of inflammatory monocytes and monocyte-derived cells via ISP2.—Goundry, A., Romano, A., Lima, A. P. C. A., Mottram, J. C., Myburgh, E. Inhibitor of serine peptidase 2 enhances Leishmania major survival in the skin through control of monocytes and monocyte-derived cells.
Highlights
Leishmania spp. are protozoan parasites that cause a spectrum of pathologies, ranging from skin ulceration to visceral dissemination, depending on the parasite species and the genetic background of the host, in humans and other vertebrates
We have previously shown that L. major metacyclic promastigotes that are deficient in inhibitor of serine peptidase 2 (ISP2) and ISP3 (Disp2/3) are killed more efficiently by murine macrophages after their internalization, and that those remaining display delayed intracellular development [19]
Disp2/3 burdens remained unchanged by 5 wk, whereas wild type (WT) and Disp2/3:ISP2/3 had increased compared with levels at 2 wk, with more Disp2/3:ISP2/3 compared with Disp2/3
Summary
Similar observations using Leishmania mexicana have provided evidence that neutrophils contribute largely to block both the development of a protective immune response and the control of lesion progression [11] These studies have contributed to our knowledge of the dynamics of the initial steps of innate responses and how this affects parasitism; systematic in vivo studies of the dynamics of cellular populations at the lesion site and their responses at later chronic stages (i.e., after 2 wk) are still lacking. We asked how the infiltration and activation of immune cell populations develop over time (i.e., up to 10 wk) during L. major infection in vivo, and whether ISP2 can influence these cellular dynamics, affecting local parasitism. We propose that recruited monocytes are major players in the control of L. major infection of the skin, and that the infiltration and activation of these cells is modulated by ISP2 to facilitate parasite survival at the site of inoculation
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