Vector-borne pathogen transmission

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications, trials & patents

Abstract

The accomplishments of this project for this year are: We demonstrated that the prolonged bleeding caused by hematophagous vectors to acquire a blood meal results in in leakage of red blood cells (RBCs) and inflammation. This induces heme oxygenase-1 (HO-1), a pleiotropic cytoprotective isoenzyme that mitigates heme-mediated tissue damage. We also show that HO-1 is induced after bites of sand flies, mosquitoes, and ticks. This study also established that erythrophagocytosis is carried by macrophages, resulting in the identification of a novel subset of skin residing CD163+CD91+ professional iron-recycling subpopulation of macrophages. Through deletion or transient inhibition of HO-1 in mice, we also demonstrated increased inflammation and pathology following Leishmania-infected sand fly bites without affecting parasite number, indicating that HO-1 induction by blood feeding sand flies promotes tolerance to Leishmania infection. We investigated the humoral and cellular human immune response to saliva of Phlebotomus alexandri, a poorly studied vector of visceral leishmaniasis in Iraq. We demonstrated that 64% of 200 soldiers deployed to Iraq developed an antibody response. The levels of IFN- , IL-6, IL-10, IL-13 and IL-17 measured showed that the deployers mounted a cellular response to SGH where the anti-SGH+ asymptomatic subjects developed the highest cytokine levels. Further, stimulation with SGH produced a mixture of pro-inflammatory and anti-inflammatory cytokines. Contrary to our hypothesis, we observed no correlation between the cellular immune response to Ph. alexandri SGH and prevention from asymptomatic infection with L. infantum. We have shown that individuals and dogs exposed to sand fly bites in Tbilisi, Georgia, an endemic area for visceral leishmaniasis (VL), where sand flies are abundant fonly or a short period of 3 months have little immunological memory to saliva of P. kandelakii, the principal vector of VL. Only 30% of humans and 50% of dogs displayed a weak antibody response to saliva after the end of the sand fly season. Likewise, their peripheral blood mononuclear cells mounted a negligible cellular immune response after stimulation with saliva. RNA seq analysis of wild-caught P. kandelakii salivary glands established the presence of a typical salivary repertoire that included proteins commonly found in other sand fly species indicating that the absence of immunity to P. kandelakii saliva in humans and dogs from Tbilisi is probably caused by insufficient exposure to sand fly bites. This absence of immunity to vector saliva will influence the dynamics of VL transmission in Tbilisi and other endemic areas with brief sand fly seasons. We have demonstrated that the sand fly Fever Sicilian Virus (SFSV) is prevalent in the digestive tract of Lutzomyia longipalis. Furthermore, in SFSV-Leishmania major co-infections, the virus modulates innate inflammatory response favoring myeloid cell infections and skin hyperinflammation. SFSV modulates MAP kinase signaling and the IRF3 pathway resulting in a pro-inflammatory phenotype. We also show that SFSVs hyperinflammatory effect is TLR3- and MAVS-dependent. Additionally, SFSV and L. major co-infection resulted in exacerbation of leishmaniasis in vivo with L. major and SFSV co-infected C57BL/6 mice exhibiting significantly higher parasite burden than mice solely infected with L. major. Furthermore, viral presence increased leukocyte influx in vivo that was accompanied by elevated total extracellular vesicle numbers. Relevatnly, L. major displayed higher infectiveness in the presence of SFSV compared to L. major infection alone. We have characterized a biosignature of susceptibility to VL in dogs, the principal reservoir of VL in Latin America and Europe, and a source of human infection. We showed that dogs in a VL endemic area in Salvador, Brazil, exhibited a discriminatory biosignature that distinguished between resistant and susceptible dogs. Splenic parasite load, interaction of several biological mediators, PGE2 serum levels and intensity of exposure to sand fly bites were all elevated in susceptible dogs compared to resistant animals. Building upon our thriving and productive collaboration with the Medical School and Dentistry at the USTTB in Mali, we are continuing our active investigation of new emerging CL foci in the Northern Districts of Mali. The work is primarily focused on isolation and Leishmania strain characterization and post-outbreak assessment of the incidence of the disease in different foci. We also investigated the effect of continued exposure to sand fly bites on immunity to filariasis, another prevalent neglected tropical disease in Mali. In collaboration with Care India and UCSF, we set up two longitudinal study sites in VL endemic villages in Bihar: Chotka Baneya and Rahar Diyara. These studies have clinical and entomological components. To date, we have finalized a complete census of village inhabitants and GPS mapping of their houses in preparation for clinical investigations. I am responsible for the entomological aspects of this investigation. Specifically, we trained an entomology team of speciation and dissection of the vector of VL, Phlebotomus argentipes. We also went on several field visits to choose 5 ecotypes for trapping to elucidate the behavior of the vector in our study sites and to initiate entomological trapping and specimen processing. We also optimized and trained the laboratory team in an ELISA test to monitor fluctuations in antibodies to vector saliva and to a candidate makers of vector exposure specific to P. argentipes in India.