S100A8/S100A9 deficiency increases neutrophil activation and protective immune responses against invading infective L3 larvae of the filarial nematode Litomosoides sigmodontis

Frohberger, Stefan J.; Fercoq, Frédéric; Neumann, Anna-Lena; Surendar, Jayagopi; Stamminger, Wiebke; Ehrens, Alexandra; Indulekha, Karunakaran; Remion, Estelle; Vogl, Thomas; Hoerauf, Achim; Martin, Coralie; Hübner, Marc P.

doi:10.1371/journal.pntd.0008119

Cited by 17 publications

(22 citation statements)

References 72 publications

(104 reference statements)

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“…For example, the increased parasite load in IL-6 and NOD2-deficient mice, which show a delayed neutrophil recruitment at the site of infection, is overcome by subcutaneous infection [ 47 , 49 ], resulting in a worm burden comparable to that of immunocompetent WT mice. However, mice deficient in S100A9 (which together with S100A8 forms a calprotectin that accounts for 40% of the cytosolic content of neutrophils) showed a similar decrease in parasite burden and an identical cell response in the pleural cavity, whether subcutaneously inoculated or naturally infected [ 50 ]. Also, at 8 days p.i., i.e.…”

Section: Discussionmentioning

confidence: 99%

Microfilaria-dependent thoracic pathology associated with eosinophilic and fibrotic polyps in filaria-infected rodents

et al. 2020

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Background Pulmonary manifestations are regularly reported in both human and animal filariasis. In human filariasis, the main known lung manifestations are the tropical pulmonary eosinophilia syndrome. Its duration and severity are correlated with the presence of microfilariae. Litomosoides sigmodontis is a filarial parasite residing in the pleural cavity of rodents. This model is widely used to understand the immune mechanisms that are established during infection and for the screening of therapeutic molecules. Some pulmonary manifestations during the patent phase of infection with L. sigmodontis have been described in different rodent hosts more or less permissive to infection. Methods Here, the permissive Mongolian gerbil (Meriones unguiculatus) was infected with L. sigmodontis. Prevalence and density of microfilariae and adult parasites were evaluated. Lungs were analyzed for pathological signatures using immunohistochemistry and 3D imaging techniques (two-photon and light sheet microscopy). Results Microfilaremia in gerbils was correlated with parasite load, as amicrofilaremic individuals had fewer parasites in their pleural cavities. Fibrotic polypoid structures were observed on both pleurae of infected gerbils. Polyps were of variable size and developed from the visceral mesothelium over the entire pleura. The larger polyps were vascularized and strongly infiltrated by immune cells such as eosinophils, macrophages or lymphocytes. The formation of these structures was induced by the presence of adult filariae since small and rare polyps were observed before patency, but they were exacerbated by the presence of gravid females and microfilariae. Conclusions Altogether, these data emphasize the role of host-specific factors in the pathogenesis of filarial infections.

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Section: Discussionmentioning

confidence: 99%

Microfilaria-dependent thoracic pathology associated with eosinophilic and fibrotic polyps in filaria-infected rodents

et al. 2020

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“…Key results in immunological research include the discovery of a strong cross-reactivity between Onchocerca volvulus and L. sigmodontis antigen (Marcoullis and Gräsbeck 1976), the development of various vaccine protocols (primarily focused on attenuated L3 larvae with different adjuvants and treatment regiments) with varying degrees of success (reviewed in depth in Morris et al 2013), IgE dependent killing of MF by neutrophils and macrophages (Mehta et al 1980(Mehta et al , 1982, and the significance of IL-4, IL-4R, IL-5, and IL-17 for the containment of the infection (Le Martin et al 2000aMartin et al , 2000bVolkmann et al 2001Volkmann et al , 2003aTaylor et al 2006;Jenkins et al 2011;Ritter et al 2017Ritter et al , 2018aFrohberger et al 2019). Various studies have further shown that the protective immune responses against L. sigmodontis consist of both type 1 (Saeftel et al 2003;Muhsin et al 2018;Babayan et al 2003) and type 2 immune responses.…”

Section: Acanthocheilonema Viteae (Krepkogorskaja 1933)mentioning

confidence: 99%

“…With regard to granulocytes, eosinophils were shown to mediate protection via the major basic protein, eosinophil peroxidase, eotaxin-1 (Specht et al 2006;Gentil et al 2014), and eosinophil extracellular DNA traps (EETosis; Ehrens et al 2021), which contributes to MF and adult worm clearance (Martin et al 2000a). Neutrophils on the other hand are required for protective responses to invading infective L3 larvae and adult worms (Al-Qaoud et al 2000;Ajendra et al 2016;Frohberger et al 2020;Pionnier et al 2016). Studies on basophils during L. sigmodontis infection showed that basophil responses are suppressed during chronic infection, and basophils have no effect on the adult worm burden during primary infection (Larson et al 2012;Torrero et al 2010;Hartmann et al 2018).…”

Section: Acanthocheilonema Viteae (Krepkogorskaja 1933)mentioning

confidence: 99%

“…Recent studies showed that the entry of L3s into the pleural cavity is associated with hemorrhages, granuloma formation, inflammation, and infiltration of neutrophils expressing calprotectin (Karadjian et al 2017 ). The role of calprotectin, one of the most abundant proteins in neutrophils, during filarial infections is still unclear, but a follow-up study with calprotectin-deficient mice suggested an anti-inflammatory role of calprotectin that facilitates the migration of L. sigmodontis L3 larvae (Frohberger et al 2020 ). Similarly, the L. sigmodontis rodent model has been used to investigate lung morbidity during chronic infections and different studies highlighted the role of the Th2 cytokines IL-4 and IL-5 in regulating inflammation at the site of infection (Ritter et al 2017 ; Fercoq et al 2019 ).…”

Section: Human Filarial Speciesmentioning

confidence: 99%

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Human filariasis—contributions of the Litomosoides sigmodontis and Acanthocheilonema viteae animal model

et al. 2021

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Filariae are vector-borne parasitic nematodes that are endemic worldwide, in tropical and subtropical regions. Important human filariae spp. include Onchocerca volvulus, Wuchereria bancrofti and Brugia spp., and Loa loa and Mansonella spp. causing onchocerciasis (river blindness), lymphatic filariasis (lymphedema and hydrocele), loiasis (eye worm), and mansonelliasis, respectively. It is estimated that over 1 billion individuals live in endemic regions where filarial diseases are a public health concern contributing to significant disability adjusted life years (DALYs). Thus, efforts to control and eliminate filarial diseases were already launched by the WHO in the 1970s, especially against lymphatic filariasis and onchocerciasis, and are mainly based on mass drug administration (MDA) of microfilaricidal drugs (ivermectin, diethylcarbamazine, albendazole) to filarial endemic areas accompanied with vector control strategies with the goal to reduce the transmission. With the United Nations Sustainable Development Goals (SDGs), it was decided to eliminate transmission of onchocerciasis and stop lymphatic filariasis as a public health problem by 2030. It was also requested that novel drugs and treatment strategies be developed. Mouse models provide an important platform for anti-filarial drug research in a preclinical setting. This review presents an overview about the Litomosoides sigmodontis and Acanthocheilonema viteae filarial mouse models and their role in immunological research as well as preclinical studies about novel anti-filarial drugs and treatment strategies.

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“…(associated with neutrophil recruitment [66]), and Retlnb (associated with worm death [48]), as well as ccl3 and cxcl5 (inflammatory chemokines) expression. Surprisingly, we found no differences between the trickle and bolus infections in any genes linked to Fc receptor signalling, despite the importance of antibody-mediated worm killing by macrophages and/or eosinophils within granulomas [14].…”

Section: In C56bl/6 Mice Granulomas From Bolus and Trickle-infected mentioning

confidence: 99%

Co-infection withToxoplasma gondiileads to a loss of resistance inHeligmosomoides bakeritrickle-infected mice due to ineffective granulomas

Ariyaratne

Kim

Pollo

et al. 2020

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Intestinal roundworms cause chronic debilitating disease in animals, including humans. A lack of effective vaccines and the emergence of widespread drug resistance only increase the need to better understand parasite clearance mechanisms within the host. Heligmosomoides polygyrus larvae induce a strong intestinal granuloma response within their murine host, which has been associated with resistance. Immune cells, mostly alternatively activated macrophages and eosinophils, accumulate around the tissue encysted parasites to immobilize and damage/kill developing worms. In a one dose (bolus) experimental infection, infected C57Bl/6 mice are unable to clear parasites which results in chronic infection with high worm burdens. However, using a frequent dose trickle model of infection, we, like others, have found that C57Bl/6 mice can clear infection. We found that the clearance is associated with higher granuloma numbers, but no changes in systemic/intestinal Th2 responses. Within the granulomas, we found that myeloid cells had a different transcriptional profile in each of the infected groups, and that high IgG1, but not IgG2c, IgA or IgE, levels were observed around the larvae of only trickle-infected mice. Our results highlight the importance of the granuloma in the host’s ability to clear H. polygyrus and emphasise the need to study this key tissue in more depth, rather than using correlates such as general intestinal or systemic responses.AUTHOR’S SUMMARYDespite decades of research on intestinal parasitic worms, we are still unable to clearly point to why so many people (approximately 1.8 billion) and most livestock/wild animals are infected with these parasites. We have made progress in understanding how the immune system responds to parasitic worms, and how these parasites manipulate our immune system. However, identifying effective clearance mechanisms is complex and context dependent. We have used a model of trickle infection (multiple low doses of parasites) to simulate how people/animals get infected in the real world. Using this model, we have identified the host/parasite interface (the granuloma) within the intestinal tissue to be key in determining the host’s ability to clear worms. Specific gene expression signatures in granuloma immune cells and the presence/absence of antibodies within the granuloma are key factors associated with parasite clearance. Surprisingly, more common identifiers of parasitic worm infections (increased serum antibody levels and/or generalized immune markers) did not associate with protection. These novel findings contribute to a better understanding of the mechanisms underlying effective parasitic worm clearance.

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S100A8/S100A9 deficiency increases neutrophil activation and protective immune responses against invading infective L3 larvae of the filarial nematode Litomosoides sigmodontis

Abstract: PLOS NEGLECTED TROPICAL DISEASESPLOS Neglected Tropical Diseases | https://doi.

Cited by 17 publications

References 72 publications

Microfilaria-dependent thoracic pathology associated with eosinophilic and fibrotic polyps in filaria-infected rodents

Microfilaria-dependent thoracic pathology associated with eosinophilic and fibrotic polyps in filaria-infected rodents

Human filariasis—contributions of the Litomosoides sigmodontis and Acanthocheilonema viteae animal model

Co-infection withToxoplasma gondiileads to a loss of resistance inHeligmosomoides bakeritrickle-infected mice due to ineffective granulomas

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