{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,29]],"date-time":"2025-10-29T19:43:51Z","timestamp":1761767031958,"version":"build-2065373602"},"reference-count":33,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2022,3,11]],"date-time":"2022-03-11T00:00:00Z","timestamp":1646956800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000030","name":"Centers for Disease Control and Prevention","doi-asserted-by":"publisher","award":["core funding"],"award-info":[{"award-number":["core funding"]}],"id":[{"id":"10.13039\/100000030","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pathogens"],"abstract":"<jats:p>A strong association between rubella virus (RuV) and chronic granulomas, in individuals with inborn errors of immunity, has been recently established. Both the RA27\/3 vaccine and wild-type RuV strains were highly sensitive to a broad-spectrum antiviral drug, nitazoxanide (NTZ), in vitro. However, NTZ treatment, used as a salvage therapy, resulted in little or no improvements of RuV-associated cutaneous granulomas in patients. Here, we report investigations of possible causes of treatment failures in two ataxia-telangiectasia patients. Although a reduction in RuV RNA in skin lesions was detected by real-time RT-PCR, live immunodeficiency-related vaccine-derived rubella viruses (iVDRV) were recovered from granulomas, before and after the treatments. Tizoxanide, an active NTZ metabolite, inhibited replications of all iVDRVs in cultured A549 cells, but the 50% and 90% inhibitory concentrations were 10\u201340 times higher than those for the RA27\/3 strain. There were no substantial differences in iVDRV sensitivities, neither before nor after treatments. Analysis of quasispecies in the E1 gene, a suspected NTZ target, showed no effect of NTZ treatments on quasispecies\u2019 complexity in lesions. Thus, failures of NTZ therapies were likely due to low sensitivities of iVDRVs to the drug, and not related to the emergence of resistance, following long-term NTZ treatments.<\/jats:p>","DOI":"10.3390\/pathogens11030338","type":"journal-article","created":{"date-parts":[[2022,3,13]],"date-time":"2022-03-13T21:44:17Z","timestamp":1647207857000},"page":"338","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Drug Sensitivity of Vaccine-Derived Rubella Viruses and Quasispecies Evolution in Granulomatous Lesions of Two Ataxia-Telangiectasia Patients Treated with Nitazoxanide"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8350-7274","authenticated-orcid":false,"given":"Raeesa","family":"Faisthalab","sequence":"first","affiliation":[{"name":"Division of Viral Diseases, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Suganthi","family":"Suppiah","sequence":"additional","affiliation":[{"name":"Division of Viral Diseases, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9432-3542","authenticated-orcid":false,"given":"Morna","family":"Dorsey","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of California San Francisco, San Francisco, CA 94143, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kathleen E.","family":"Sullivan","sequence":"additional","affiliation":[{"name":"Division of Allergy and Immunology, The Children\u2019s Hospital of Philadelphia, Philadelphia, PA 19104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joseph","family":"Icenogle","sequence":"additional","affiliation":[{"name":"Division of Viral Diseases, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ludmila","family":"Perelygina","sequence":"additional","affiliation":[{"name":"Division of Viral Diseases, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,3,11]]},"reference":[{"key":"ref_1","unstructured":"David, M., and Knipe, P.H. (2013). Rubella virus. Fields Virology 1, Lippincott Williams & Wilkins."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2297","DOI":"10.1016\/S0140-6736(14)60539-0","article-title":"Rubella","volume":"385","author":"Lambert","year":"2015","journal-title":"Lancet"},{"key":"ref_3","unstructured":"Remington, J., Klein, J., Wilson, C., Nizet, V., and Maldonato, Y. (2011). Rubella. Infectious Diseases of the Fetus and Newborn Infant, Elsveier."},{"key":"ref_4","first-page":"1","article-title":"Prevention of measles, rubella, congenital rubella syndrome, and mumps, 2013: Summary recommendations of the Advisory Committee on Immunization Practices (ACIP)","volume":"62","author":"McLean","year":"2013","journal-title":"Morb. Mortal. Wkly. Rep. Recomm. Rep."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1093\/cid\/cit816","article-title":"Executive Summary: 2013 IDSA Clinical Practice Guideline for Vaccination of the Immunocompromised Host","volume":"58","author":"Rubin","year":"2014","journal-title":"Clin. Infect. Dis."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1007\/s10875-018-0534-7","article-title":"Prevalence of Granulomas in Patients With Primary Immunodeficiency Disorders, United States: Data From National Health Care Claims and the US Immunodeficiency Network Registry","volume":"38","author":"Leung","year":"2018","journal-title":"J. Clin. Immunol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1146\/annurev-immunol-032712-100022","article-title":"The Formation and Function of Granulomas","volume":"36","author":"Ramakrishnan","year":"2018","journal-title":"Annu. Rev. Immunol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1412","DOI":"10.1111\/jdv.15568","article-title":"Cutaneous granulomas with primary immunodeficiency in children: A report of 17 new patients and a review of the literature","volume":"33","author":"Moshous","year":"2019","journal-title":"J. Eur. Acad. Dermatol. Venereol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"O656","DOI":"10.1111\/1469-0691.12573","article-title":"Live rubella virus vaccine long-term persistence as an antigenic trigger of cutaneous granulomas in patients with primary immunodeficiency","volume":"20","author":"Bodemer","year":"2014","journal-title":"Clin. Microbiol. Infect."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1436","DOI":"10.1016\/j.jaci.2016.06.030","article-title":"Rubella persistence in epidermal keratinocytes and granuloma M2 macrophages in patients with primary immunodeficiencies","volume":"138","author":"Perelygina","year":"2016","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"574","DOI":"10.1097\/ACI.0000000000000694","article-title":"Rubella virus-associated chronic inflammation in primary immunodeficiency diseases","volume":"20","author":"Perelygina","year":"2020","journal-title":"Curr. Opin. Allergy Clin. Immunol."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Perelygina, L., Chen, M.-H., Suppiah, S., Adebayo, A., Abernathy, E., Dorsey, M., Bercovitch, L., Paris, K., White, K.P., and Krol, A. (2019). Infectious vaccine-derived rubella viruses emerge, persist, and evolve in cutaneous granulomas of children with primary immunodeficiencies. PLoS Pathog., 15.","DOI":"10.1371\/journal.ppat.1008080"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1016\/j.antiviral.2017.09.019","article-title":"Inhibition of rubella virus replication by the broad-spectrum drug nitazoxanide in cell culture and in a patient with a primary immune deficiency","volume":"147","author":"Perelygina","year":"2017","journal-title":"Antivir. Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1016\/j.antiviral.2014.07.014","article-title":"Nitazoxanide: A first-in-class broad-spectrum antiviral agent","volume":"110","author":"Rossignol","year":"2014","journal-title":"Antivir. Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"660710","DOI":"10.3389\/fphar.2021.660710","article-title":"Strategy, Progress, and Challenges of Drug Repurposing for Efficient Antiviral Discovery","volume":"12","author":"Li","year":"2021","journal-title":"Front. Pharmacol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1007\/s10875-019-0589-0","article-title":"Outcomes for Nitazoxanide Treatment in a Case Series of Patients with Primary Immunodeficiencies and Rubella Virus-Associated Granuloma","volume":"39","author":"Perelygina","year":"2019","journal-title":"J. Clin. Immunol."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Domingo, E., and Perales, C. (2019). Viral quasispecies. PLoS Genet., 15.","DOI":"10.1371\/journal.pgen.1008271"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1186\/s43141-020-00055-5","article-title":"Drug repurposing of nitazoxanide: Can it be an effective therapy for COVID-19?","volume":"18","author":"Mahmoud","year":"2020","journal-title":"J. Genet. Eng. Biotechnol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1317","DOI":"10.1021\/acsinfecdis.0c00478","article-title":"Therapeutic Potential of Nitazoxanide: An Appropriate Choice for Repurposing versus SARS-CoV-2?","volume":"7","author":"Stachulski","year":"2021","journal-title":"ACS Infect. Dis."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2003725","DOI":"10.1183\/13993003.03725-2020","article-title":"Early use of nitazoxanide in mild COVID-19 disease: Randomised, placebo-controlled trial","volume":"58","author":"Rocco","year":"2021","journal-title":"Eur. Respir. J."},{"key":"ref_21","first-page":"43","article-title":"Bioavailability of Two Oral-Suspension Formulations of a Single Dose of Nitazoxanide 500 mg: An Open-Label, Randomized-Sequence, Two-Period Crossover, Comparison in Healthy Fasted Mexican Adult Volunteers","volume":"3","author":"Bueno","year":"2011","journal-title":"J. Bioequiv. Bioavailab."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1038\/nrmicro3200","article-title":"The path of anti-tuberculosis drugs: From blood to lesions to mycobacterial cells","volume":"12","author":"Dartois","year":"2014","journal-title":"Nat. Rev. Genet."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1208","DOI":"10.1164\/rccm.201711-2333OC","article-title":"Drug-Penetration Gradients Associated with Acquired Drug Resistance in Patients with Tuberculosis","volume":"198","author":"Dheda","year":"2018","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"27148","DOI":"10.1038\/srep27148","article-title":"Thiazolides Elicit Anti-Viral Innate Immunity and Reduce HIV Replication","volume":"6","author":"Trabattoni","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1279","DOI":"10.1016\/j.isci.2019.07.003","article-title":"The FDA-Approved Oral Drug Nitazoxanide Amplifies Host Antiviral Responses and Inhibits Ebola Virus","volume":"19","author":"Jasenosky","year":"2019","journal-title":"iScience"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"660","DOI":"10.1136\/bmj.317.7159.660","article-title":"Antiviral drug resistance","volume":"317","author":"Pillay","year":"1998","journal-title":"BMJ"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1016\/S1473-3099(14)70717-0","article-title":"Effect of nitazoxanide in adults and adolescents with acute uncomplicated influenza: A double-blind, randomised, placebo-controlled, phase 2b\/3 trial","volume":"14","author":"Haffizulla","year":"2014","journal-title":"Lancet Infect. Dis."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3659","DOI":"10.1007\/s00018-014-1615-2","article-title":"Antiviral strategies against influenza virus: Towards new therapeutic approaches","volume":"71","author":"Loregian","year":"2014","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"104278","DOI":"10.1016\/j.meegid.2020.104278","article-title":"A new implication of quasispecies dynamics: Broad virus diversification in absence of external perturbations","volume":"82","author":"Domingo","year":"2020","journal-title":"Infect. Genet. Evol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1016\/j.virol.2015.03.022","article-title":"Viral quasispecies","volume":"479\u2013480","author":"Andino","year":"2015","journal-title":"Virology"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1007\/s00249-018-1282-6","article-title":"Quasispecies and virus","volume":"47","author":"Domingo","year":"2018","journal-title":"Eur. Biophys. J."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1547","DOI":"10.1093\/molbev\/msy096","article-title":"MEGA X: Molecular Evolutionary Genetics Analysis across Computing Platforms","volume":"35","author":"Kumar","year":"2018","journal-title":"Mol. Biol. Evol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1016\/j.virol.2016.03.017","article-title":"Viral quasispecies complexity measures","volume":"493","author":"Gregori","year":"2016","journal-title":"Virology"}],"container-title":["Pathogens"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-0817\/11\/3\/338\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:34:46Z","timestamp":1760135686000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-0817\/11\/3\/338"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,3,11]]},"references-count":33,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2022,3]]}},"alternative-id":["pathogens11030338"],"URL":"https:\/\/doi.org\/10.3390\/pathogens11030338","relation":{},"ISSN":["2076-0817"],"issn-type":[{"type":"electronic","value":"2076-0817"}],"subject":[],"published":{"date-parts":[[2022,3,11]]}}}