We identified data for this Review from MEDLINE and PubMed with the search terms “host genomics AND tuberculosis”, “susceptibility to tuberculosis”, and “innate resistance to tuberculosis”. Because the Review traces the history of tuberculosis through the 20th century including the colonial period, we have included articles published in English from the database search between Jan 1, 1940, and January 31, 2017. We also identified data from our earlier work and from the references cited in these
ReviewGenetics of human susceptibility to active and latent tuberculosis: present knowledge and future perspectives
Section snippets
Background
Infectious diseases have ravaged mankind throughout the ages; therefore, they represent a major force in human evolution.1, 2 Response to pathogen exposure is highly variable between people, and a better understanding of the biological basis of interindividual differences in infection outcomes could result in new preventive and therapeutic strategies. Exploration of the genetic underpinning of human susceptibility to infections started decades ago, but only increased in size and scope in the
Early observations on the genetic basis for tuberculosis susceptibility
In Lübeck, Germany, from Dec 10, 1929, to April 30, 1930, 251 neonates were accidentally given preparations of the BCG vaccine that had been contaminated with virulent M tuberculosis.13 Of the vaccinated children, 72 died of tuberculosis and the surviving 174 children (five children died of non-tuberculosis causes) presented with a wide range of clinical presentations. A careful follow-up investigation of the accident identified variable concentrations of contamination (ie, the infectious dose)
Insight from inbred animal models of tuberculosis susceptibility
Mice and rabbits have often been used in studies to investigate genetic susceptibility to tuberculosis. Cross-breeding between resistant and susceptible inbred mice strains has shown that resistance to tuberculosis follows a complex, non-Mendelian inheritance.24 In 1981, Gros and colleagues25 found that susceptibility to infection with avirulent BCG derived from Mycobacterium bovis was determined by a host genetic locus Bcg on mouse chromosome 1. Subsequently, the gene encoding the natural
Genetic control of tuberculosis infection
There is no direct test for infection with M tuberculosis, and the latent tuberculosis infection phenotype is inferred indirectly from quantitative measurements of antimycobacterial immunity.11, 39 TST is the most widely used method to test for latent infection.40 Additionally, two in-vitro blood assays measuring either the secretion of interferon γ by lymphocytes or the frequency of interferon-γ-producing blood cells in response to M tuberculosis antigens (interferon-γ release assays [IGRAs])
Future direction and perspectives
The identification of the genetic factors involved in tuberculosis susceptibility has proven difficult. As in several other human diseases, the role of common variants in pulmonary tuberculosis seems to be scarce, leading to the concept of missing heritability.131 Among the several non-mutually exclusive hypotheses that might account for this concept, an important one in tuberculosis is the oversimplification of the studied phenotypes.12 For example, tests used to assess tuberculosis infection
Conclusion
Historical observations, heritability estimates, linkage analyses, and genome-wide scans indicate that human resistance to tuberculosis infection has a strong genetic basis, which is likely to be a consequence of evolutionary counter-response to microbial virulence. Mendelian studies have also provided the first evidence that severe tuberculosis in children could be due to single gene inborn errors of immunity. However, much is yet to be learned regarding susceptibility to disease, in
Search strategy and selection criteria
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