Ressner, R. | Search bioRxiv

bioRxiv2025

Lutzomyia longipalpis salivary proteins elicit human innate and adaptive immune responses detrimental to Leishmania parasites

In Leishmania-endemic areas, humans are constantly exposed to sand fly bites. To explore the immune consequences of this chronic vector exposure, we performed a human challenge study with the sand fly Lutzomyia longipalpis. Peripheral blood mononuclear cells were collected from fifteen healthy volunteers who underwent multiple controlled exposures to sand fly bites. We identified two Lu. longipalpis salivary proteins, LJM19 and LJL143, which elicited type 1 cytokine responses in cells from exposed individuals and which correlated with enhanced killing of Leishmania parasites in co-cultured macrophages. Interestingly, LJM19 also exerted this parasite-killing effect in cells from unexposed individuals, consistent with innate immune activation. In support of this, both LJM19 and LJL143 stimulated the production of the innate cytokines IL-1{beta} and IFN-. Our results demonstrate that repeated exposure to sand fly bites induces innate and adaptive cytokine responses to vector salivary proteins that can be co-opted to protect humans against Leishmania infection.

immunology↗

bioRxiv2024

Identification of potential sepsis therapeutic drugs using a zebrafish rapid screening approach

In the military, combat wound infections can progress rapidly to life-threatening sepsis. Discovery of effective small molecule drugs to prevent and/or treat sepsis is a priority. To identify potential sepsis drug candidates, we used an optimized larval zebrafish model of endotoxicity/sepsis (Philip et al., 2017) to screen commercial libraries of U.S. Food and Drug Administration (FDA)- approved drugs and other active pharmaceutical ingredients (API) known to affect pathways implicated in the initiation and progression of sepsis in humans (i.e., inflammation, mitochondrial dysfunction, coagulation, and apoptosis). We induced endotoxicity in 3- and 5-day post fertilization larval zebrafish (characterized by mortality and tail fin edema (vascular leakage)) by immersion exposure to Pseudomonas aeruginosa 60 g/mL lipopolysaccharide (LPS) for 24 hours, then screened for the rescue potential of 644 selected drugs simultaneously with LPS at 10 M. After LPS exposure, we used a neurobehavioral assay (light-dark test) to further evaluate rescue from endotoxicity and to determine possible off-target drug side effects. We identified 29 drugs with > 60% rescue of tail edema and mortality. Three drugs (Ketanserin, Tegaserod, and Brexpiprazole) produced 100% rescue and did not differ from the controls in the light-dark test, suggesting a lack of off-target neurobehavioral effects. Further testing of these three drugs at a nearly 100% lethal concentration of Klebsiella pneumoniae LPS (45 g/mL) showed 100% rescue from mortality and 88%-100% mitigation against tail edema. The success of the three identified drugs in a zebrafish endotoxicity/sepsis model warrants further evaluation in mammalian sepsis models.

pharmacology and toxicology↗