TY - JOUR
T1 - Mycobacterium tuberculosis invasion and traversal across an in vitro human blood-brain barrier as a pathogenic mechanism for central nervous system tuberculosis
AU - Jain, Sanjay K.
AU - Paul-Satyaseela, Maneesh
AU - Lamichhane, Gyanu
AU - Kim, Kwang S.
AU - Bishai, William R.
N1 - Funding Information:
Financial support: Eudowood Foundation (Baurenschmidt Postdoctoral Research Fellowship to S.K.J.); National Institutes of Health (grants/contracts AI47225 and NS26310 to K.S.K. and AI36973, AI37856, AI43846, AI51668, and AI30036 to W.R.B.).
PY - 2006/5/1
Y1 - 2006/5/1
N2 - Background. Central nervous system (CNS) tuberculosis is a serious, often fatal disease that disproportionately affects young children. It is thought to develop when Mycobacterium tuberculosis breaches the blood-brain barrier (BBB), which is composed of tightly apposed brain microvascular endothelial cells. However, the mechanism(s) involved in this process are poorly understood. Methods To better understand these processes, we developed an in vitro model of M. tuberculosis BBB infection using primary human brain microvascular endothelial cells. Results. M. tuberculosis was found to both invade and traverse the model BBB significantly more than did M. smegmatis (a nonpathogenic mycobacterium). Invasion by M. tuberculosis across the BBB required host-cell actin cytoskeletal rearrangements. By microarray expression profiling, we found 33 M. tuberculosis genes to be highly up-regulated during the early stages of invasion of the BBB by M. tuberculosis; 18 of them belong to a previously described in vivo-expressed genomic island (Rv0960-Rv1001). Defined M. tuberculosis isogenic transposon mutants for the up-regulated genes Rv0980c, Rv0987, Rv0989c, and Rv1801 were found to be deficient in their ability to invade the BBB model. Conclusions. We developed an in vitro model of M. tuberculosis BBB infection and identified M. tuberculosis genes that may be involved in CNS invasion.
AB - Background. Central nervous system (CNS) tuberculosis is a serious, often fatal disease that disproportionately affects young children. It is thought to develop when Mycobacterium tuberculosis breaches the blood-brain barrier (BBB), which is composed of tightly apposed brain microvascular endothelial cells. However, the mechanism(s) involved in this process are poorly understood. Methods To better understand these processes, we developed an in vitro model of M. tuberculosis BBB infection using primary human brain microvascular endothelial cells. Results. M. tuberculosis was found to both invade and traverse the model BBB significantly more than did M. smegmatis (a nonpathogenic mycobacterium). Invasion by M. tuberculosis across the BBB required host-cell actin cytoskeletal rearrangements. By microarray expression profiling, we found 33 M. tuberculosis genes to be highly up-regulated during the early stages of invasion of the BBB by M. tuberculosis; 18 of them belong to a previously described in vivo-expressed genomic island (Rv0960-Rv1001). Defined M. tuberculosis isogenic transposon mutants for the up-regulated genes Rv0980c, Rv0987, Rv0989c, and Rv1801 were found to be deficient in their ability to invade the BBB model. Conclusions. We developed an in vitro model of M. tuberculosis BBB infection and identified M. tuberculosis genes that may be involved in CNS invasion.
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U2 - 10.1086/502631
DO - 10.1086/502631
M3 - Article
C2 - 16586367
AN - SCOPUS:33646041335
SN - 0022-1899
VL - 193
SP - 1287
EP - 1295
JO - Journal of Infectious Diseases
JF - Journal of Infectious Diseases
IS - 9
ER -