The influence of host and bacterial genotype on the development of disseminated disease with Mycobacterium tuberculosis.
The influence of host and bacterial genotype on the development of disseminated disease with Mycobacterium tuberculosis.
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DOI：
10.1371/journal.ppat.1000034
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发表时间：
2008-03-28
期刊：
影响因子：
6.7
通讯作者：
Farrar J
中科院分区：
文献类型：
--
作者：
Caws M;Thwaites G;Dunstan S;Hawn TR;Lan NT;Thuong NT;Stepniewska K;Huyen MN;Bang ND;Loc TH;Gagneux S;van Soolingen D;Kremer K;van der Sande M;Small P;Anh PT;Chinh NT;Quy HT;Duyen NT;Tho DQ;Hieu NT;Torok E;Hien TT;Dung NH;Nhu NT;Duy PM;van Vinh Chau N;Farrar J
控制结核病发展的因素还不完全清楚。我们推测，结核分枝杆菌的某些菌株比其他菌株更有能力引起播散性疾病，可能与宿主基因的多态性有关，宿主基因负责对感染的先天免疫反应。我们比较了187名患有结核性脑膜炎(TBM)的越南成年人和237名无并发症的越南成年人的宿主和细菌基因型。同时将结核病人的宿主基因与同一人群的392例脐带血对照进行了比较。对结核分枝杆菌分离株进行大序列多态性基因分型。宿主由编码Toll-IL-1受体结构域的适配器蛋白(TIRAP)和Toll样受体-2(TLR-2)基因的多态决定。我们发现欧美结核分枝杆菌血统与肺结核病而不是脑膜结核之间存在显著的保护性关联(导致脑膜结核的优势比(OR)为0.395，95%可信区间(C.I.)0.193-0.806，P = 0.009)，这表明这些菌株比研究人群中的其他菌株更不能在肺外传播。我们还发现，携带TLR2T597C等位基因C的个体比其他个体更容易患由东亚/北京基因型(OR = 1.57[95%C.I.1.15-2.15])引起的结核病。这项研究提供了结核分枝杆菌基因型影响临床疾病表型的证据，并首次证明了宿主和细菌基因型与结核病的发展之间存在显著的相互作用。结核病是由结核分枝杆菌引起的，每年导致200多万人死亡。据估计，世界上大约三分之一的人口感染了结核分枝杆菌，尽管大多数人永远不会患上活动性疾病。当细菌扩散到大脑导致脑膜炎时，最严重的结核病就会发生。我们检查了个人和细菌的基因变异是否影响了一个人患上的疾病类型。我们之前已经证明，人类免疫系统的某些基因突变会使越南的成年人容易患上结核性脑膜炎。在这项研究中，我们发现一些常见于欧洲和美国的结核分枝杆菌菌株与主要在亚洲发现的菌株相比，不太可能在越南成年人中引起结核性脑膜炎。然后，我们观察了结核分枝杆菌菌株与人类免疫基因突变之间的相互作用，发现一种特殊的突变TLR2 T597C在感染东亚/北京结核分枝杆菌菌株的患者中更常见。这是第一次同时观察结核感染的宿主和病原体基因类型的研究，研究结果表明，接触结核分枝杆菌的结果可能取决于人类的基因和细菌的基因。
The factors that govern the development of tuberculosis disease are incompletely understood. We hypothesized that some strains of Mycobacterium tuberculosis (M. tuberculosis) are more capable of causing disseminated disease than others and may be associated with polymorphisms in host genes responsible for the innate immune response to infection. We compared the host and bacterial genotype in 187 Vietnamese adults with tuberculous meningitis (TBM) and 237 Vietnamese adults with uncomplicated pulmonary tuberculosis. The host genotype of tuberculosis cases was also compared with the genotype of 392 cord blood controls from the same population. Isolates of M. tuberculosis were genotyped by large sequence polymorphisms. The hosts were defined by polymorphisms in genes encoding Toll-interleukin 1 receptor domain containing adaptor protein (TIRAP) and Toll-like receptor-2 (TLR-2). We found a significant protective association between the Euro-American lineage of M. tuberculosis and pulmonary rather than meningeal tuberculosis (Odds ratio (OR) for causing TBM 0.395, 95% confidence intervals (C.I.) 0.193–0.806, P = 0.009), suggesting these strains are less capable of extra-pulmonary dissemination than others in the study population. We also found that individuals with the C allele of TLR-2 T597C allele were more likely to have tuberculosis caused by the East-Asian/Beijing genotype (OR = 1.57 [95% C.I. 1.15–2.15]) than other individuals. The study provides evidence that M. tuberculosis genotype influences clinical disease phenotype and demonstrates, for the first time, a significant interaction between host and bacterial genotypes and the development of tuberculosis. Tuberculosis, caused by the bacterium Mycobacterium tuberculosis, kills over 2 million people each year. It is estimated that approximately one-third of the world population is infected with M. tuberculosis, though the majority will never develop active disease. The most severe form of tuberculosis occurs when the bacterium spreads to the brain to cause meningitis. We examined whether the genetic variation of the person and the bacteria influenced the type of disease a person develops. We have previously shown that certain mutations in genes of the human immune system can predispose adults in Vietnam to developing tuberculous meningitis. In this study we show that some strains of M. tuberculosis commonly found in Europe and America are less likely to cause tuberculous meningitis in Vietnamese adults than strains predominantly found in Asia. We then looked at the interaction between M. tuberculosis strains and mutations in human immune genes and show that a particular mutation, TLR2 T597C, is more commonly found in patients infected with the East-Asian/Beijing strains of M. tuberculosis. This is the first study to look at both the host and pathogen genotypes together in tuberculosis infection, and the findings suggest that the outcome of exposure to M. tuberculosis can depend on both the human genotype and the bacterial genotype.
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DOI：
10.1084/jem.20050126
发表时间：
2005-12-19
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Flores-Villanueva PO;Ruiz-Morales JA;Song CH;Flores LM;Jo EK;Montaño M;Barnes PF;Selman M;Granados J
通讯作者：
Granados J
DOI：
10.1046/j.1365-2370.2002.00327.x
发表时间：
2002-10-01
期刊：
EUROPEAN JOURNAL OF IMMUNOGENETICS
影响因子：
--
作者：
Lio, D;Marino, V;Caruso, C
通讯作者：
Caruso, C
影响因子：
9.4
作者：
HUNTER, PR;GASTON, MA
通讯作者：
GASTON, MA
影响因子：
9.4
作者：
Kong, Y.;Cave, M. D.;Yang, Z. H.
通讯作者：
Yang, Z. H.
影响因子：
3.1
作者：
Chackerian, AA;Alt, JM;Behar, SM
通讯作者：
Behar, SM