Abstract
Phlebotomus perniciosus (Diptera: Phlebotominae) is a medically and veterinary important insect vector. It transmits the unicellular parasite Leishmania infantum that multiplies intracellularly in macrophages causing life-threatening visceral diseases. Leishmania establishment in the vertebrate host is substantially influenced by immunomodulatory properties of vector saliva that are obligatorily co-injected into the feeding site. The repertoire of P. perniciosus salivary molecules has already been revealed and, subsequently, several salivary proteins have been expressed. However, their immunogenic properties have never been studied. In our study, we tested three P. perniciosus recombinant salivary proteins—an apyrase rSP01 and yellow-related proteins rSP03 and rSP03B—and showed their anti-inflammatory nature on the murine bone-marrow derived macrophages. Even in the presence of pro-inflammatory stimuli (IFN-γ and bacterial lipopolysaccharide, LPS), all three recombinant proteins inhibited nitric oxide production. Moreover, rSP03 seems to have a very strong anti-inflammatory effect since it enhanced arginase activity, increased the production of IL-10, and inhibited the production of TNF-α even in macrophages stimulated with IFN-γ and LPS. These results suggest that P. perniciosus apyrase and yellow-related proteins may serve as enhancing factors in sand fly saliva, facilitating the development of Leishmania infection along with their anti-haemostatic properties. Additionally, rSP03 and rSP03B did not elicit the delayed-type hypersensitivity response in mice pre-exposed to P. perniciosus bites (measured as visible skin reaction). The results of our study may help to understand the potential function of recombinant's native counterparts and their role in Leishmania transmission and establishment within the host.
Highlights
Phlebotomus perniciosus (Diptera: Phlebotominae) is a sand fly species distributed in western part of Mediterranean basin
Recombinant yellow-related proteins rSP03 and rSP03B, apyrase rSP01, and crude P. perniciosus salivary gland homogenate (SGH) (Per-SGH) were incubated with the bone marrow-derived macrophages to measure the urea production (Figure 1A) as a marker of arginase activity that is typical for tissue-repairing macrophages
The Effect of Salivary Proteins on inducible nitric oxide synthetase (iNOS) Activity rSP03, rSP03B, rSP01, and crude Per-SGH were incubated with BMMF to measure nitrite production (Figure 1B) as a marker of iNOS activity that is typical for pro-inflammatory macrophages
Summary
Phlebotomus perniciosus (Diptera: Phlebotominae) is a sand fly species distributed in western part of Mediterranean basin. This species is medically and veterinary important as a vector of phleboviruses (e.g., Toscana virus) and, most importantly, as a vector of Leishmania infantum (Kinetoplastea: Trypanosomatida), a protozoan intracellular parasite that causes zoonotic human leishmaniasis with canids as the main reservoirs (Maroli et al, 2013). Besides being anti-haemostatic, the sand fly salivary molecules are immunogenic, eliciting both humoral and cellular immune responses in repeatedly bitten host. Such antisaliva immune response can be employed in leishmaniasis control. The anti-saliva antibody response can be utilized as the tool to screen hosts for the sand fly exposure at the individual level (e.g., in vector control programs), while the anti-saliva cellular immune response has been shown to protect the host against severe leishmaniasis (Lestinova et al, 2017)
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