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Here, we demonstrate that prophylaxis with immunomodulatory cytosine-phosphate-guanidine (CpG) oligodeoxynucleotide (ODN), a toll-like receptor 9 (TLR9) agonist, confers protection against<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Yersinia pestis<\/jats:named-content>, the etiologic agent of plague. The data establish that intranasal administration of CpG ODN 1 day prior to lethal pulmonary exposure to<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Y. pestis<\/jats:named-content>strain KIM D27 significantly improves survival of C57BL\/6 mice and reduces bacterial growth in hepatic tissue, despite paradoxically increasing bacterial growth in the lung. All of these CpG ODN-mediated impacts, including the increased pulmonary burden, are TLR9 dependent, as they are not observed in TLR9-deficient mice. The capacity of prophylactic intranasal CpG ODN to enhance survival does not require adaptive immunity, as it is evident in mice lacking B and\/or T cells; however, the presence of T cells improves long-term survival. The prophylactic regimen also improves survival and reduces hepatic bacterial burden in mice challenged intraperitoneally with KIM D27, indicating that intranasal delivery of CpG ODN has systemic impacts. Indeed, intranasal prophylaxis with CpG ODN provides significant protection against subcutaneous challenge with<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Y. pestis<\/jats:named-content>strain CO92 even though it fails to protect mice from intranasal challenge with that fully virulent strain.<\/jats:p>","DOI":"10.1128\/iai.00316-13","type":"journal-article","created":{"date-parts":[[2013,4,2]],"date-time":"2013-04-02T01:20:58Z","timestamp":1364865658000},"page":"2123-2132","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":12,"title":["Intranasal Prophylaxis with CpG Oligodeoxynucleotide Can Protect against Yersinia pestis Infection"],"prefix":"10.1128","volume":"81","author":[{"given":"Anthony J.","family":"Hickey","sequence":"first","affiliation":[{"name":"Trudeau Institute, Saranac Lake, New York, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jr-Shiuan","family":"Lin","sequence":"additional","affiliation":[{"name":"Trudeau Institute, Saranac Lake, New York, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lawrence W.","family":"Kummer","sequence":"additional","affiliation":[{"name":"Trudeau Institute, Saranac Lake, New York, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Frank M.","family":"Szaba","sequence":"additional","affiliation":[{"name":"Trudeau Institute, Saranac Lake, New York, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Debra K.","family":"Duso","sequence":"additional","affiliation":[{"name":"Trudeau Institute, Saranac Lake, New York, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Tighe","sequence":"additional","affiliation":[{"name":"Trudeau Institute, Saranac Lake, New York, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michelle A.","family":"Parent","sequence":"additional","affiliation":[{"name":"Trudeau Institute, Saranac Lake, New York, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephen T.","family":"Smiley","sequence":"additional","affiliation":[{"name":"Trudeau Institute, Saranac Lake, New York, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1128\/CMR.10.1.35"},{"key":"e_1_3_2_3_2","first-page":"1","article-title":"Plague","volume":"22","author":"Pollitzer R","year":"1954","unstructured":"PollitzerR. 1954. 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