{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T10:06:21Z","timestamp":1790762781982,"version":"4.1.0"},"reference-count":53,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,6,27]],"date-time":"2023-06-27T00:00:00Z","timestamp":1687824000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Microbiol."],"abstract":"<jats:p>Filarial nematodes can cause debilitating diseases such as lymphatic filariasis and onchocerciasis. Oxfendazole (OXF) is one promising macrofilaricidal candidate with improved oral availability compared to flubendazole (FBZ), and OXF is currently under preparation for phase 2 clinical trials in filariasis patients. This study aimed to investigate the immune system\u2019s role during treatment with OXF and FBZ and explore the potential to boost the treatment efficacy via stimulation of the immune system. Wild type (WT) BALB\/c, eosinophil-deficient <jats:italic>\u0394dblGata1<\/jats:italic>, <jats:italic>IL-4r\/IL-5<jats:sup>\u2212\/\u2212<\/jats:sup><\/jats:italic>, antibody-deficient \u03bcMT and B-, T-, NK-cell and ILC-deficient <jats:italic>Rag2\/IL-2r\u03b3<jats:sup>\u2212\/\u2212<\/jats:sup><\/jats:italic> mice were infected with the rodent filaria <jats:italic>Litomosoides sigmodontis<\/jats:italic> and treated with an optimal and suboptimal regimen of OXF and FBZ for up to 5 days. In the second part, WT mice were treated for 2\u20133 days with a combination of OXF and IL-4, IL-5, or IL-33. Treatment of WT mice reduced the adult worm burden by up to 94% (OXF) and 100% (FBZ) compared to vehicle controls. In contrast, treatment efficacy was lower in all immunodeficient strains with a reduction of up to 90% (OXF) and 75% (FBZ) for <jats:italic>\u0394dblGata1<\/jats:italic>, 50 and 92% for <jats:italic>IL-4r\/IL-5<jats:sup>\u2212\/\u2212<\/jats:sup><\/jats:italic>, 64 and 78% for \u03bcMT or 0% for <jats:italic>Rag2\/IL-2r\u03b3<jats:sup>\u2212\/\u2212<\/jats:sup><\/jats:italic> mice. The effect of OXF on microfilariae and embryogenesis displayed a similar pattern, while FBZ\u2019s ability to prevent microfilaremia was independent of the host\u2019s immune status. Furthermore, flow cytometric analysis revealed strain-and treatment-specific immunological changes. The efficacy of a shortened 3-day treatment of OXF (\u221233% adult worms vs. vehicle) could be boosted to a 91% worm burden reduction via combination with IL-5, but not IL-4 or IL-33. Our results suggest that various components of the immune system support the filaricidal effect of benzimidazoles <jats:italic>in vivo<\/jats:italic> and present an opportunity to boost treatment efficacy.<\/jats:p>","DOI":"10.3389\/fmicb.2023.1213143","type":"journal-article","created":{"date-parts":[[2023,6,27]],"date-time":"2023-06-27T15:52:09Z","timestamp":1687881129000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":11,"title":["The efficacy of the benzimidazoles oxfendazole and flubendazole against Litomosoides sigmodontis is dependent on the adaptive and innate immune system"],"prefix":"10.3389","volume":"14","author":[{"given":"Frederic","family":"Risch","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johanna F.","family":"Scheunemann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia J.","family":"Reichwald","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin","family":"Lenz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra","family":"Ehrens","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9phine","family":"Gal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fr\u00e9d\u00e9ric","family":"Fercoq","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marianne","family":"Koschel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martina","family":"Fendler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Achim","family":"Hoerauf","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Coralie","family":"Martin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc P.","family":"H\u00fcbner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,6,27]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1093\/intimm\/10.1.17","article-title":"The Xid defect imparts susceptibility to experimental murine filariosis--association with a lack of antibody and IL-10 production by B cells in response to phosphorylcholine","volume":"10","author":"Al-Qaoud","year":"1998","journal-title":"Int. Immunol."},{"key":"ref2","doi-asserted-by":"publisher","first-page":"2457","DOI":"10.1128\/iai.65.6.2457-2461.1997","article-title":"Infection of BALB\/c mice with the filarial nematode Litomosoides sigmodontis: role of CD4+ T cells in controlling larval development","volume":"65","author":"Al-Qaoud","year":"1997","journal-title":"Infect. Immun."},{"key":"ref3","doi-asserted-by":"publisher","first-page":"e01018-20","DOI":"10.1128\/AAC.01018-20","article-title":"Pharmacokinetics, safety, and tolerability of Oxfendazole in healthy adults in an open-label phase 1 multiple ascending dose and food effect study","volume":"64","author":"Bach","year":"2020","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref4","doi-asserted-by":"publisher","first-page":"16878","DOI":"10.1038\/s41598-017-17204-5","article-title":"QuPath: open source software for digital pathology image analysis","volume":"7","author":"Bankhead","year":"2017","journal-title":"Sci. Rep."},{"key":"ref5","doi-asserted-by":"publisher","first-page":"550","DOI":"10.4049\/jimmunol.1901116","article-title":"Single and synergistic effects of type 2 cytokines on eosinophils and asthma hallmarks","volume":"204","author":"Beckert","year":"2020","journal-title":"J. Immunol."},{"key":"ref6","doi-asserted-by":"publisher","first-page":"S4","DOI":"10.1186\/1475-2883-2-S1-S4","article-title":"Clinical picture, epidemiology and outcome of Loa-associated serious adverse events related to mass ivermectin treatment of onchocerciasis in Cameroon","author":"Boussinesq","year":"2003","journal-title":"Filaria J."},{"key":"ref7","doi-asserted-by":"publisher","first-page":"S27","DOI":"10.3978\/j.issn.2072-1439.2015.01.48","article-title":"Pleura space anatomy","volume":"7","author":"Charalampidis","year":"2015","journal-title":"J. Thorac. Dis."},{"key":"ref8","doi-asserted-by":"publisher","first-page":"673","DOI":"10.1016\/0035-9203(79)90018-x","article-title":"The anthelmintic effects of flubendazole on Brugia pahangi","volume":"73","author":"Denham","year":"1979","journal-title":"Trans. R. Soc. Trop. Med. Hyg."},{"key":"ref9","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1016\/s0140-6736(83)92753-8","article-title":"Comparison of flubendazole and diethylcarbamazine in treatment of onchocerciasis","volume":"1","author":"Dominguez-Vazquez","year":"1983","journal-title":"Lancet"},{"key":"ref10","doi-asserted-by":"publisher","first-page":"3947","DOI":"10.1128\/IAI.71.7.3947-3953.2003","article-title":"Combined treatment with interleukin-12 and mebendazole lessens the severity of experimental eosinophilic meningitis caused by Angiostrongylus cantonensis in ICR mice","volume":"71","author":"Du","year":"2003","journal-title":"Infect. Immun."},{"key":"ref11","doi-asserted-by":"publisher","first-page":"1067","DOI":"10.1007\/s00436-009-1520-z","article-title":"Immune response of mice with alveolar echinococcosis to therapy with transfer factor, alone and in combination with albendazole","volume":"105","author":"Dvoroznakova","year":"2009","journal-title":"Parasitol. Res."},{"key":"ref12","doi-asserted-by":"publisher","first-page":"Doc02","DOI":"10.3205\/id000079","article-title":"Current perspective of new anti-Wolbachial and direct-acting macrofilaricidal drugs as treatment strategies for human filariasis","volume":"10","author":"Ehrens","year":"","journal-title":"GMS Infect. Dis."},{"key":"ref13","doi-asserted-by":"publisher","first-page":"983812","DOI":"10.3389\/fimmu.2022.983812","article-title":"Eosinophils in filarial infections: inducers of protection or pathology?","volume":"13","author":"Ehrens","year":"","journal-title":"Front. Immunol."},{"key":"ref14","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1016\/0001-706x(94)90093-0","article-title":"Chemotherapy of experimental filariasis: enhancement of activity profile of ivermectin with immunomodulators","volume":"57","author":"Fatma","year":"1994","journal-title":"Acta Trop."},{"key":"ref15","doi-asserted-by":"publisher","first-page":"e0007691","DOI":"10.1371\/journal.pntd.0007691","article-title":"IL-4 receptor dependent expansion of lung CD169+ macrophages in microfilaria-driven inflammation","volume":"13","author":"Fercoq","year":"2019","journal-title":"PLoS Negl. Trop. Dis."},{"key":"ref16","doi-asserted-by":"publisher","first-page":"e12708","DOI":"10.1111\/pim.12708","article-title":"The immune response of inbred laboratory mice to Litomosoides sigmodontis: a route to discovery in myeloid cell biology","volume":"42","author":"Finlay","year":"2020","journal-title":"Parasite Immunol."},{"key":"ref17","doi-asserted-by":"publisher","first-page":"e0006787","DOI":"10.1371\/journal.pntd.0006787","article-title":"Efficacy of subcutaneous doses and a new oral amorphous solid dispersion formulation of flubendazole on male jirds (Meriones unguiculatus) infected with the filarial nematode Brugia pahangi","volume":"13","author":"Fischer","year":"2019","journal-title":"PLoS Negl. Trop. Dis."},{"key":"ref18","doi-asserted-by":"publisher","first-page":"529","DOI":"10.4269\/ajtmh.1985.34.529","article-title":"The Mazzotti reaction following treatment of onchocerciasis with diethylcarbamazine: clinical severity as a function of infection intensity","volume":"34","author":"Francis","year":"1985","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"ref19","doi-asserted-by":"publisher","first-page":"248","DOI":"10.1186\/s13071-019-3502-z","article-title":"Susceptibility to L. sigmodontis infection is highest in animals lacking IL-4R\/IL-5 compared to single knockouts of IL-4R, IL-5 or eosinophils","volume":"12","author":"Frohberger","year":"2019","journal-title":"Parasit. Vectors"},{"key":"ref20","doi-asserted-by":"publisher","first-page":"e0011146","DOI":"10.1371\/journal.pntd.0011146","article-title":"Contextual determinants of mass drug administration performance: modelling fourteen years of lymphatic filariasis treatments in West Africa","volume":"17","author":"Fuller","year":"2023","journal-title":"PLoS Negl. Trop. Dis."},{"key":"ref21","doi-asserted-by":"publisher","first-page":"e0006436","DOI":"10.1371\/journal.pntd.0006436","article-title":"Flubendazole as a macrofilaricide: history and background","volume":"13","author":"Geary","year":"2019","journal-title":"PLoS Negl. Trop. Dis."},{"key":"ref22","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1080\/14787210.2018.1555241","article-title":"Oxfendazole: a promising agent for the treatment and control of helminth infections in humans","volume":"17","author":"Gonzalez","year":"2019","journal-title":"Expert Rev. Anti Infect. Ther."},{"key":"ref23","doi-asserted-by":"publisher","first-page":"662","DOI":"10.1021\/acsinfecdis.9b00469","article-title":"Macrofilaricides: an unmet medical need for filarial diseases","volume":"6","author":"Hawryluk","year":"2020","journal-title":"ACS Infect. Dis."},{"key":"ref24","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1079\/JOH2001081","article-title":"Treatment of Toxocara canis infections in mice with liposome-incorporated benzimidazole carbamates and immunomodulator glucan","volume":"75","author":"Hrckova","year":"2001","journal-title":"J. Helminthol."},{"key":"ref25","doi-asserted-by":"publisher","first-page":"e0006320","DOI":"10.1371\/journal.pntd.0006320","article-title":"Macrofilaricidal efficacy of single and repeated oral and subcutaneous doses of flubendazole in Litomosoides sigmodontis infected jirds","volume":"13","author":"H\u00fcbner","year":"2019","journal-title":"PLoS Negl. Trop. Dis."},{"key":"ref26","doi-asserted-by":"publisher","first-page":"e0008427","DOI":"10.1371\/journal.pntd.0008427","article-title":"Oxfendazole mediates macrofilaricidal efficacy against the filarial nematode Litomosoides sigmodontis in vivo and inhibits Onchocerca spec. Motility in vitro","volume":"14","author":"H\u00fcbner","year":"2020","journal-title":"PLoS Negl. Trop. Dis."},{"key":"ref27","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1016\/j.exppara.2009.05.009","article-title":"Litomosoides sigmodontis: a simple method to infect mice with L3 larvae obtained from the pleural space of recently infected jirds (Meriones unguiculatus)","volume":"123","author":"H\u00fcbner","year":"2009","journal-title":"Exp. Parasitol."},{"key":"ref28","doi-asserted-by":"publisher","first-page":"451","DOI":"10.1016\/S1473-3099(16)30467-4","article-title":"Effectiveness of a triple-drug regimen for global elimination of lymphatic filariasis: a modelling study","volume":"17","author":"Irvine","year":"2017","journal-title":"Lancet Infect. Dis."},{"key":"ref29","doi-asserted-by":"publisher","first-page":"2311","DOI":"10.1002\/eji.201646442","article-title":"IL-33 delivery induces serous cavity macrophage proliferation independent of interleukin-4 receptor alpha","volume":"46","author":"Jackson-Jones","year":"2016","journal-title":"Eur. J. Immunol."},{"key":"ref30","doi-asserted-by":"publisher","first-page":"1789","DOI":"10.1016\/S0140-6736(18)32279-7","article-title":"Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990\u20132017: a systematic analysis for the global burden of disease study 2017","volume":"392","author":"James","year":"2018","journal-title":"Lancet"},{"key":"ref31","doi-asserted-by":"publisher","first-page":"268","DOI":"10.1111\/imm.12842","article-title":"Bone marrow type 2 innate lymphoid cells: a local source of interleukin-5 in interleukin-33-driven eosinophilia","volume":"153","author":"Johansson","year":"2018","journal-title":"Immunology"},{"key":"ref32","doi-asserted-by":"publisher","first-page":"1801","DOI":"10.1056\/NEJMoa1706854","article-title":"A trial of a triple-drug treatment for lymphatic filariasis","volume":"379","author":"King","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref33","doi-asserted-by":"publisher","first-page":"112","DOI":"10.1016\/0169-4758(90)90227-u","article-title":"Mode of action of benzimidazoles","volume":"6","author":"Lacey","year":"1990","journal-title":"Parasitol. Today"},{"key":"ref34","doi-asserted-by":"publisher","first-page":"e0007026","DOI":"10.1371\/journal.pntd.0007026","article-title":"Preclinical toxicity and pharmacokinetics of a new orally bioavailable flubendazole formulation and the impact for clinical trials and risk\/benefit to patients","volume":"13","author":"Lachau-Durand","year":"2019","journal-title":"PLoS Negl. Trop. Dis."},{"key":"ref35","doi-asserted-by":"publisher","first-page":"422","DOI":"10.4103\/lungindia.lungindia_39_19","article-title":"Pidotimod: in-depth review of current evidence","volume":"36","author":"Mahashur","year":"2019","journal-title":"Lung India"},{"key":"ref36","doi-asserted-by":"publisher","first-page":"7067","DOI":"10.1128\/IAI.69.11.7067-7073.2001","article-title":"B-cell deficiency suppresses vaccine-induced protection against murine filariasis but does not increase the recovery rate for primary infection","volume":"69","author":"Martin","year":"2001","journal-title":"Infect. Immun."},{"key":"ref37","doi-asserted-by":"publisher","first-page":"100591","DOI":"10.1016\/j.epidem.2022.100591","article-title":"Modelling lymphatic filariasis elimination in American Samoa: GEOFIL predicts need for new targets and six rounds of mass drug administration","volume":"40","author":"Mclure","year":"2022","journal-title":"Epidemics"},{"key":"ref38","doi-asserted-by":"publisher","first-page":"219","DOI":"10.1183\/09031936.97.10010219","article-title":"Physiology and pathophysiology of pleural fluid turnover","volume":"10","author":"Miserocchi","year":"1997","journal-title":"Eur. Respir. J."},{"key":"ref39","first-page":"51","article-title":"Brugia malayi in Mastomys natalensis: efficacy of mebendazole in combination with Freund's complete adjuvant","volume":"39","author":"Murthy","year":"1992","journal-title":"Folia Parasitol."},{"key":"ref40","doi-asserted-by":"publisher","first-page":"247","DOI":"10.1080\/10611860310001620707","article-title":"Immunomodulator tuftsin augments antifilarial activity of diethylcarbamazine against experimental brugian filariasis","volume":"11","author":"Owais","year":"2003","journal-title":"J. Drug Target."},{"key":"ref41","doi-asserted-by":"publisher","first-page":"144","DOI":"10.1051\/parasite\/1992675144","article-title":"Maturation of the filaria Litomosoides sigmodontis in BALB\/c mice; comparative susceptibility of nine other inbred strains","volume":"67","author":"Petit","year":"1992","journal-title":"Ann. Parasitol. Hum. Comp."},{"key":"ref42","doi-asserted-by":"publisher","first-page":"105206","DOI":"10.1016\/j.actatropica.2019.105206","article-title":"The combination of cytokines and albendazole therapy for prophylaxis and treatment of experimental\/hydatid cyst","volume":"201","author":"Rahdar","year":"2020","journal-title":"Acta Trop."},{"key":"ref43","doi-asserted-by":"publisher","first-page":"863663","DOI":"10.3389\/fimmu.2022.863663","article-title":"ILC2s control Microfilaremia during Litomosoides sigmodontis infection in Rag2(\u2212\/\u2212) mice","volume":"13","author":"Reichwald","year":"2022","journal-title":"Front. Immunol."},{"key":"ref44","doi-asserted-by":"publisher","first-page":"4125","DOI":"10.1007\/s00436-020-07026-2","article-title":"Human filariasis-contributions of the Litomosoides sigmodontis and Acanthocheilonema viteae animal model","volume":"120","author":"Risch","year":"2021","journal-title":"Parasitol. Res."},{"key":"ref45","doi-asserted-by":"publisher","first-page":"105359","DOI":"10.1016\/j.actatropica.2020.105359","article-title":"Praziquantel versus praziquantel associated with immunomodulators in mice infected with schistosoma mansoni: a systematic review and meta-analysis","volume":"204","author":"Silva","year":"2020","journal-title":"Acta Trop."},{"key":"ref46","doi-asserted-by":"publisher","first-page":"e0006356","DOI":"10.1371\/journal.pntd.0006356","article-title":"Short-course, oral flubendazole does not mediate significant efficacy against Onchocerca adult male worms or Brugia microfilariae in murine infection models","volume":"13","author":"Sjoberg","year":"2019","journal-title":"PLoS Negl. Trop. Dis."},{"key":"ref47","doi-asserted-by":"publisher","first-page":"411","DOI":"10.1016\/j.ijpara.2022.10.006","article-title":"Helminth infections: enabling the World Health Organization road map","volume":"53","author":"Specht","year":"2022","journal-title":"Int. J. Parasitol."},{"key":"ref48","doi-asserted-by":"publisher","first-page":"232","DOI":"10.1017\/s0022149x00012219","article-title":"Comparative susceptibility to anthelmintics of Brugia pahangi in jirds infected by different methods","volume":"64","author":"Surin","year":"1990","journal-title":"J. Helminthol."},{"key":"ref49","doi-asserted-by":"publisher","first-page":"1175","DOI":"10.1016\/S0140-6736(10)60586-7","article-title":"Lymphatic filariasis and onchocerciasis","volume":"376","author":"Taylor","year":"2010","journal-title":"Lancet"},{"key":"ref50","doi-asserted-by":"publisher","first-page":"e0006750","DOI":"10.1371\/journal.pntd.0006750","article-title":"Impact of repeated annual community directed treatment with ivermectin on loiasis parasitological indicators in Cameroon: implications for onchocerciasis and lymphatic filariasis elimination in areas co-endemic with Loa loa in Africa","volume":"12","author":"Wanji","year":"2018","journal-title":"PLoS Negl. Trop. Dis."},{"key":"ref51","volume-title":"Ending the neglect to attain the sustainable development goals: A road map for neglected tropical diseases 2021\u20132030","year":"2020"},{"key":"ref52","doi-asserted-by":"publisher","first-page":"735","DOI":"10.1007\/s00436-016-5339-0","article-title":"In vivo evaluation of the efficacy of combined albedazole-IFN-alpha treatment for cystic echinococcosis in mice","volume":"116","author":"Zhang","year":"2017","journal-title":"Parasitol. Res."},{"key":"ref53","doi-asserted-by":"publisher","first-page":"e1558","DOI":"10.1371\/journal.pntd.0001558","article-title":"Immunization with L. sigmodontis microfilariae reduces peripheral microfilaraemia after challenge infection by inhibition of filarial embryogenesis","volume":"6","author":"Ziewer","year":"2012","journal-title":"PLoS Negl. Trop. Dis."}],"container-title":["Frontiers in Microbiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmicb.2023.1213143\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,6,27]],"date-time":"2023-06-27T15:52:17Z","timestamp":1687881137000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmicb.2023.1213143\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,6,27]]},"references-count":53,"alternative-id":["10.3389\/fmicb.2023.1213143"],"URL":"https:\/\/doi.org\/10.3389\/fmicb.2023.1213143","relation":{},"ISSN":["1664-302X"],"issn-type":[{"value":"1664-302X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,6,27]]},"article-number":"1213143"}}