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

Basophils are innate effector cells that contribute to allergic reactions and provide protection against parasites. Using basophil-deficient  mice, we have previously shown that these granulocytes contributed to the immune mediated early control of the gastrointestinal helminth  in mice. In this study, we analyze the impact of basophils on the immune response and defense against the tissue-dwelling filarial helminth parasite  Although basophils and IgE increased at the site of infection, the absence of basophils did not change the outcome of  infection. Worm burden in the thoracic cavity and microfilaremiae in the peripheral blood were alike in -infected  mice compared with  wild type littermates during the entire course of infection. Analysis of the cytokine and Ab response to  revealed no consistent alterations in the absence of basophils. Furthermore, basophil-deficient and -competent mice were protected to the same extent during a secondary infection with  In summary, our findings suggest that basophils are dispensable for the initiation of the appropriate immune response and host defense against   infection in mice.

Basophils Are Dispensable for the Control of a Filarial Infection.

Mast cells are innate effector cells that due to their localization in the tissue form the first line of defense against parasites. We have previously shown that specifically mucosal mast cells were essential for the termination of the intestinal Strongyloides ratti infection. Here, we analyze the impact of mast cells on the immune response and defense against the tissue-dwelling filarial nematode Litomosoides sigmodontis using mast cell-deficient Cpa3cre mice. Despite an increase and an activation of mast cells at the site of infection in wildtype BALB/c mice the outcome of L. sigmodontis infection was not changed in mast cell-deficient BALB/c Cpa3cre mice. In Cpa3cre mice neither vascular permeability induced by blood-sucking mites nor the migration of L3 was altered compared to Cpa3 wildtype littermates. Worm burden in the thoracic cavity was alike in the presence and absence of mast cells during the entire course of infection. Although microfilaremiae in the peripheral blood increased in mast cell-deficient mice at some time points, the infection was cleared with comparable kinetics in the presence and absence of mast cells. Moreover, mast cell deficiency had no impact on the cytokine and antibody response to L. sigmodontis. In summary, our findings suggest that mast cells are not mandatory for the initiation of an appropriate immune response and host defense during L. sigmodontis infection in mice.

Limited role of mast cells during infection with the parasitic nematode Litomosoides sigmodontis.

Parasitic nematodes such as hookworms actively penetrate the skin of their hosts, encountering skin-resident innate immune cells that represent the host´s first line of defense. Here we use  as a model for an intestinal helminth parasite with tissue migrating stages. We show that interception and killing of migrating larvae in mice during a 1 infection occurred predominantly in skin and muscle tissue before larvae migrated  lung and head tissue to the intestine. Inhibition of larval migration was even more efficient in immune mice during a 2 infection where larvae barely left the site of entry i.e. the foot. Using cell-deficient mice we show that interception in the tissue was predominantly mediated by neutrophils and eosinophils while basophils and mast cells were dispensable . Likewise, neutrophils and eosinophils inhibited  L3 motility  in the context of ETosis. Thereby eosinophils were strictly dependent on the presence of anti- antibodies while neutrophils inhibited L3 motility as such. Also, MPO and MMP-9 were released by neutrophils in response to L3 alone, but immune plasma further stimulated MPO release in an antibody-dependent manner. In summary, our findings highlight the central role of the skin as first line of defense against helminth parasites in both, innate and adaptive immunity.

Eosinophils and Neutrophils Eliminate Migrating  Larvae at the Site of Infection in the Context of Extracellular DNA Trap Formation.

[This corrects the article DOI: 10.3389/fimmu.2021.715766.].

Corrigendum: Eosinophils and Neutrophils Eliminate Migrating  Larvae at the Site of Infection in the Context of Extracellular DNA Trap Formation.

Adaptation of immune cells to tissue-specific microenvironments is a crucial process in homeostasis and inflammation. Here, we show that murine effector type 2 innate lymphoid cells (ILC2s) from various organs are equally effective in repopulating ILC2 niches in other anatomical locations where they adapt tissue-specific phenotypes of target organs. Single-cell transcriptomics of ILC2 populations revealed upregulation of retinoic acid (RA) signaling in ILC2s during adaptation to the small intestinal microenvironment, and RA signaling mediated reprogramming of kidney effector ILC2s toward the small intestinal phenotype in vitro and in vivo. Inhibition of intestinal ILC2 adaptation by blocking RA signaling impaired worm expulsion during Strongyloides ratti infection, indicating functional importance of ILC2 tissue imprinting. In conclusion, this study highlights that effector ILC2s retain the ability to adapt to changing tissue-specific microenvironments, enabling them to exert tissue-specific functions, such as promoting control of intestinal helminth infections.

Retinoic acid drives intestine-specific adaptation of effector ILC2s originating from distant sites.

 is a natural parasite of wild rats and most laboratory mouse strains are also fully permissive. The infection can be divided into three distinct phases: the tissue migration of the infective third stage larvae during the first two days, the early intestinal establishment of  parasites molting to adults on days three to six and the later intestinal parasitic phase until the end of infection. Immunocompetent mice terminate the  infection after one month and are semi-resistant to a second infection. Employing the powerful tools of mouse immunology has facilitated a detailed analysis of the initiation, execution and regulation of the immune response to . Here we review the information collected to date on the protective immune response to migrating  larvae in tissues and to adult parasites in the intestine. We show that depending on the phase of infection, a site-specific portfolio of immune effector mechanisms is required for infection control. In addition, we summarize the strategies employed by  to evade the immune system and survive long enough in its host to replicate despite an effective immune response. Selected murine studies using the closely related  will be discussed. This article is part of the Theo Murphy meeting issue ': omics to worm-free populations'.

 infection in mice: immune response and immune modulation.

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.

The effect of sex on the prevalence and severity of parasitic diseases is an emerging area of research. Several factors underlie sex-based differences, including sociocultural influences that affect exposure to parasites, and physiological disparities linked to biological sex. Hence, human studies must be interpreted cautiously; however, studies conducted under controlled laboratory conditions are important to validate findings in humans. Such research can more effectively elucidate the role of sex-determining physiological factors (particularly their impact on immune responses), as well as the role of sex-specific differences in resistance to, or severity of, parasitic diseases. This review focuses on the overarching impact of biological sex variables on immunity. Both human and rodent experimental data are discussed, with a focus on selected protozoan and helminth infections.

Immunological clues to sex differences in parasitic diseases.

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
Basophils Are Dispensable for the Control of a Filarial Infection. ImmunoHorizons\| PubMed ID: 31022700	2018
Limited role of mast cells during infection with the parasitic nematode Litomosoides sigmodontis. PLoS neglected tropical diseases\| PubMed ID: 32735561	2020
Eosinophils and Neutrophils Eliminate Migrating Larvae at the Site of Infection in the Context of Extracellular DNA Trap Formation. Frontiers in immunology\| PubMed ID: 34475874	2021
Corrigendum: Eosinophils and Neutrophils Eliminate Migrating Larvae at the Site of Infection in the Context of Extracellular DNA Trap Formation. Frontiers in immunology\| PubMed ID: 35386718	2022
Retinoic acid drives intestine-specific adaptation of effector ILC2s originating from distant sites. The Journal of experimental medicine\| PubMed ID: 37773047	2023
infection in mice: immune response and immune modulation. Philosophical transactions of the Royal Society of London. Series B, Biological sciences\| PubMed ID: 38008111	2024
Evaluating alternative compounds for strongyloidiasis therapy: Novel insights from larval migration inhibition test. PLoS neglected tropical diseases\| PubMed ID: 39374184	2024
Immunological clues to sex differences in parasitic diseases. Trends in parasitology\| PubMed ID: 39379261	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

Lara Linnemann

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