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Though recent clinical reports suggest an association of distinct <jats:italic>Mycobacterium tuberculosis<\/jats:italic> strains with central nervous system disease, the microbial virulence factors required have not been described previously.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>We screened 398 unique <jats:italic>M. tuberculosis<\/jats:italic> mutants in guinea pigs to identify genes required for central nervous system tuberculosis. We found <jats:italic>M. tuberculosis pknD<\/jats:italic> (<jats:italic>Rv0931c<\/jats:italic>) to be required for central nervous system disease. These findings were central nervous system tissue-specific and were not observed in lung tissues. We demonstrated that <jats:italic>pknD<\/jats:italic> is required for invasion of brain endothelia (primary components of the blood-brain barrier protecting the central nervous system), but not macrophages, lung epithelia, or other endothelia. <jats:italic>M. tuberculosis pknD<\/jats:italic> encodes a \"eukaryotic-like\" serine-threonine protein kinase, with a predicted intracellular kinase and an extracellular (sensor) domain. Using confocal microscopy and flow cytometry we demonstrated that the <jats:italic>M. tuberculosis<\/jats:italic> PknD sensor is sufficient to trigger invasion of brain endothelia, a process which was neutralized by specific antiserum.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>Our findings demonstrate a novel <jats:italic>in vivo<\/jats:italic> role for <jats:italic>M. tuberculosis pknD<\/jats:italic> and represent an important mechanism for bacterial invasion and virulence in central nervous system tuberculosis, a devastating and understudied disease primarily affecting young children.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/1471-2180-12-7","type":"journal-article","created":{"date-parts":[[2012,1,13]],"date-time":"2012-01-13T19:26:51Z","timestamp":1326482811000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":70,"title":["Role of Mycobacterium tuberculosis pknD in the Pathogenesis of central nervous system tuberculosis"],"prefix":"10.1186","volume":"12","author":[{"given":"Nicholas A","family":"Be","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William R","family":"Bishai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanjay K","family":"Jain","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2012,1,13]]},"reference":[{"issue":"2","key":"1576_CR1","doi-asserted-by":"publisher","first-page":"243","DOI":"10.1128\/CMR.00042-07","volume":"21","author":"RB Rock","year":"2008","unstructured":"Rock RB, Olin M, Baker CA, Molitor TW, Peterson PK: Central nervous system tuberculosis: pathogenesis and clinical aspects. 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