Lutzomyia longipalpissaliva drives apoptosis and enhances parasite burden in neutrophils

Abstract

Neutrophils are considered the host's first line of defense against infections and have been implicated in the immunopathogenesis of Leishmaniasis. Leishmania parasites are inoculated alongside vectors' saliva, which is a rich source of pharmacologically active substances that interfere with host immune response. In the present study, we tested the hypothesis that salivary components from Lutzomyia longipalpis, an important vector of visceral Leishmaniasis, enhance neutrophil apoptosis. Murine inflammatory peritoneal neutrophils cultured in the presence of SGS presented increased surface expression of FasL and underwent caspase-dependent and FasL-mediated apoptosis. This proapoptosis effect of SGS on neutrophils was abrogated by pretreatment with protease as well as preincubation with antisaliva antibodies. Furthermore, in the presence of Leishmania chagasi, SGS also increased apoptosis on neutrophils and increased PGE(2) release and decreased ROS production by neutrophils, while enhancing parasite viability inside these cells. The increased parasite burden was abrogated by treatment with z-VAD, a pan caspase inhibitor, and NS-398, a COX-2 inhibitor. In the presence of SGS, Leishmania-infected neutrophils produced higher levels of MCP-1 and attracted a high number of macrophages by chemotaxis in vitro assays. Both of these events were abrogated by pretreatment of neutrophils with bindarit, an inhibitor of CCL2/MCP-1 expression. Taken together, our data support the hypothesis that vector salivary proteins trigger caspase-dependent and FasL-mediated apoptosis, thereby favoring Leishmania survival inside neutrophils, which may represent an important mechanism for the establishment of Leishmania infection.

Leishmaniasis in rheumatology, haematology and oncology: epidemiological, immunological and clinical aspects and caveats: Figure 1

“…The components of sand fly saliva impede the antileishmanial activity of macrophages and drive neutrophil apoptosis 31. When taken up by macrophages, apoptotic-infected neutrophils deliver an inhibitory signal to these macrophages and thereby support the survival of the parasites and their transformation into amastigotes 32–34.…”

The Role of Inflammatory, Anti-Inflammatory, and Regulatory Cytokines in Patients Infected with Cutaneous Leishmaniasis in Amazonas State, Brazil

“…The pathogenesis of ACL is strongly influenced by factors inherent to the host (such as genetic and immune response), the parasite (such as virulence of Leishmania species infecting), and vector (as its vectorial capacity). As a result of this interaction between different species of the parasite, the vector, and the mechanisms of the immune response of the vertebrate host, a spectrum of clinical, histopathological, and immunopathological manifestations is observed in humans [2, 9, 10]. Cutaneous leishmaniasis may develop into spontaneous healing or progress to the formation of papules, nodules, plaques, and especially ulcers.…”

Smuggling across the Border: How Arthropod-Borne Pathogens Evade and Exploit the Host Defense System of the Skin

“…It also downregulates nitric oxide expression by MOs and the expression of co-stimulatory molecules by DC and T-cell activation (Wheat et al, 2008). The saliva also induces neutrophil apoptosis associated with increased parasite burden (Prates et al, 2011). Other molecules, LJM11, LJM19, PpSP15, and Linb-11 in sand fly saliva, have been correlated with host protection after vaccination trials in mice (Gomes and Oliveira, 2012;de Moura et al, 2013).…”