experimental-infection-mice-with-parasitic-nematode-strongyloides

Experimental Infection of Mice with the Parasitic Nematode  <i>Strongyloides ratti </i>

Strongyloides ratti is a parasitic nematode that naturally infects wild rats. However, most laboratory rat and mouse strains are fully susceptible to ...

Bernhard Nocht Institute for Tropical Medicine

Strongyloidiasis is a neglected tropical disease estimated to affect more than 600 million people worldwide. Recently, the World Health Organization road map on neglected tropical diseases 2021-2030 has put the focus on strongyloidiasis, including this disease within its mass drug administration campaigns. With the use of ivermectin in extensive treatment of all populations at-risk, identifying effective therapeutic alternatives is crucial in case ivermectin resistance arises. The objective of the present study was the development of a larval migration inhibition assay to evaluate the anthelmintic efficacy of commercial drugs and diamine and aminoalcohol derivatives against infective Strongyloides ratti third stage larvae. Through this technique, we successfully screened and estimated the in vitro anthelmintic efficacy of six commercial drugs, seven diamine derivatives and eight aminoalcohol derivatives. Unexpectedly, the half-maximal effective concentration of ivermectin and moxidectin (2.21 and 2.34 μM, respectively) were observed as the highest value obtained among all commercial drugs tested by this in vitro technique. Moreover, some diamine and aminoalcohol derivatives showed superior efficacy inhibiting S. ratti motility compared to ivermectin, with five compounds (AA23, AA34, AO2 AO7 and AO14b) also displaying selectivity indexes on HepG2 and Caco2 higher than 1. These findings underscore the potential of these derivatives as promising alternatives for strongyloidiasis treatment, warranting further investigation and in vivo efficacy assessment.

Evaluating alternative compounds for strongyloidiasis therapy: Novel insights from larval migration inhibition test.

Strongyloides ratti is a helminth parasite that displays tissue-migrating and intestinal life stages. Myeloid C-type lectin receptors (CLRs) are pattern recognition receptors that recognize pathogen-derived ligands and initiate immune responses. To date, the role of CLRs in S. ratti infection has not been investigated. Here, we show that S. ratti-derived ligands are recognized by the CLR Macrophage inducible Ca-dependent lectin receptor (MINCLE). While MINCLE-deficiency did not affect initiation of a protective anti-S. ratti type 2 immunity, MINCLE-deficient mice had a transient advantage in intestinal immunity. Unravelling the underlying mechanism, we show that next to macrophages, dendritic cells and neutrophils, a fraction of eosinophils express MINCLE and expand during S. ratti infection. MINCLE-deficient eosinophils exhibited a more active phenotype and prolonged expansion in vivo and displayed increased capacity to reduce S. ratti motility and produce reactive oxygen species in vitro, compared to wild-type (WT) eosinophils. Depletion of eosinophils in S. ratti-infected mice after the tissue-migration phase elevated intestinal worm burden in MINCLE-deficient mice to the WT level. Thus, our findings establish a central contribution of eosinophils to parasite ejection from the intestine and suggest that S. ratti-triggered signalling via MINCLE interferes with eosinophil mediated ejection of S. ratti from the intestine.

Article	Year
Evaluating alternative compounds for strongyloidiasis therapy: Novel insights from larval migration inhibition test. PLoS neglected tropical diseases\| PubMed ID: 39374184	2024
The C-type lectin receptor MINCLE interferes with eosinophil function and protective intestinal immunity in Strongyloides ratti-infected mice. Mucosal immunology\| PubMed ID: 39581231	2024

Jennifer Antwi-Ekwuruke

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