The influence of host and bacterial genotype on the development of disseminated disease with Mycobacterium tuberculosis

Maxine Caws, Guy Thwaites, Sarah Dunstan, Thomas R Hawn, Nguyen Thi Ngoc Lan, Nguyen Thuy Thuong Thuong, Kasia Stepniewska, Mai Nguyet Thu Huyen, Nguyen Duc Bang, Tran Huu Loc, Sebastien Gagneux, Dick van Soolingen, Kristin Kremer, Marianne van der Sande, Peter Small, Phan Thi Hoang Anh, Nguyen Tran Chinh, Hoang Thi Quy, Nguyen Thi Hong Duyen, Dau Quang ThoNguyen T Hieu, Estee Torok, Tran Tinh Hien, Nguyen Huy Dung, Nguyen Thi Quynh Nhu, Phan Minh Duy, Nguyen van Vinh Chau, Jeremy Farrar

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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.

Original languageEnglish
Article numbere1000034
JournalPLoS Pathogens
Issue number3
Publication statusPublished - 2008


  • Adolescent
  • Adult
  • Aged
  • Female
  • Genes, Bacterial
  • Genetic Predisposition to Disease
  • Genotype
  • Host-Pathogen Interactions/genetics
  • Humans
  • Immunity, Cellular
  • Male
  • Middle Aged
  • Mycobacterium tuberculosis/genetics
  • Polymorphism, Single Nucleotide
  • Toll-Like Receptor 2/genetics
  • Tuberculosis, Meningeal/genetics
  • Tuberculosis, Pulmonary/genetics
  • Vietnam


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