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Infection with enteroviruses, including poliovirus and coxsackievirus, such as coxsackievirus B3 (CVB3), has been proposed as a possible causal\/risk factor for ALS due to the evidence that enteroviruses can target motor neurons and establish a persistent infection in the central nervous system (CNS), and recent findings that enteroviral infection-induced molecular and pathological phenotypes closely resemble ALS. However, a causal relationship has not yet been affirmed.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>Wild-type C57BL\/6J and G85R mutant superoxide dismutase 1 (SOD1<jats:sup>G85R<\/jats:sup>) ALS mice were intracerebroventricularly infected with a sublethal dose of CVB3 or sham-infected. For a subset of mice, ribavirin (a broad-spectrum anti-RNA viral drug) was given subcutaneously during the acute or chronic stage of infection. Following viral infection, general activity and survival were monitored daily for up to week 60. Starting at week 20 post-infection (PI), motor functions were measured weekly. Mouse brains and\/or spinal cords were harvested at day 10, week 20\u00a0and week 60 PI for histopathological evaluation of neurotoxicity, immunohistochemical staining of viral protein, neuroinflammatory\/immune and ALS pathology markers, and NanoString and RT-qPCR analysis of inflammatory gene expression.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>We found that sublethal infection (mimicking chronic infection) of SOD1<jats:sup>G85R<\/jats:sup> ALS mice with CVB3 resulted in early onset and progressive motor dysfunction, and shortened lifespan, while similar viral infection in C57BL\/6J, the background strain of SOD1<jats:sup>G85R<\/jats:sup> mice, did not significantly affect motor function and mortality as compared to mock infection within the timeframe of the current study (60\u00a0weeks PI). Furthermore, we showed that CVB3 infection led to a significant increase in proinflammatory gene expression and immune cell infiltration and induced ALS-related pathologies (i.e.<jats:italic>,<\/jats:italic> TAR DNA-binding protein 43 (TDP-43) pathology and neuronal damage) in the CNS of both SOD1<jats:sup>G85R<\/jats:sup> and C57BL\/6J mice. Finally, we discovered that early (day 1) but not late (day 15) administration of ribavirin could rescue ALS-like neuropathology and symptoms induced by CVB3 infection.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>Our study identifies a new risk factor that contributes to early onset and accelerated progression of ALS and offers opportunities for the development of novel targeted therapies.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s12974-022-02380-7","type":"journal-article","created":{"date-parts":[[2022,1,12]],"date-time":"2022-01-12T07:08:01Z","timestamp":1641971281000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Sublethal enteroviral infection exacerbates disease progression in an ALS mouse model"],"prefix":"10.1186","volume":"19","author":[{"given":"Yuan Chao","family":"Xue","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huitao","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasir","family":"Mohamud","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amirhossein","family":"Bahreyni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingchun","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neil R.","family":"Cashman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7708-7840","authenticated-orcid":false,"given":"Honglin","family":"Luo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,1,12]]},"reference":[{"key":"2380_CR1","doi-asserted-by":"publisher","first-page":"1108","DOI":"10.1016\/S1474-4422(14)70219-4","volume":"13","author":"A Al-Chalabi","year":"2014","unstructured":"Al-Chalabi A, Calvo A, Chio A, Colville S, Ellis CM, Hardiman O, Heverin M, Howard RS, Huisman MHB, Keren N, et al. 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