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Tissue Antigens ; PLoS One ;7:e We will determine if increasing their expression increases the killing capacity of TB-infected macrophages and we will examine how these molecules interact to aid clearance of the TB bacilli. This will further our understanding of the complex immune response to TB organisms and may lead to the development of novel therapies to treat TB infection and prevent reactivation of latent disease.
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Genetics of tuberculosis
Genetic control of resistance and susceptibility to tuberculosis. University Home Research Supervisor Connect. Returning User? Log in. Further progress towards an understanding of the genetics of severe TB came from the study of the syndrome of Mendelian susceptibility to mycobacterial diseases MSMDs , which is defined by a selective vulnerability to weakly virulent mycobacterial species, such as BCG and environmental mycobacteria [ 51 ].
MSMD patients also often suffer from non-typhoidal, extra-intestinal salmonellosis. High levels of locus and allelic heterogeneity have resulted in the definition of 17 different disorders, accounting for about half the known cases [ 56 ]. The first answer to this question came when several siblings of MSMD patients carrying the same genetic defect as the index case were found to display severe TB as their sole infectious phenotype.
Overall, these results provided proof of principle for monogenic predisposition to severe TB, and raised the possibility that a substantial proportion of children with severe TB carry single-gene inborn errors of immunity.
These findings have already paved the way for new treatments based on physiopathology. While until recently it was difficult to envision how point-of-care genotyping could be implemented in TB diagnosis, recent advances in hand-held PCR technology now suggest patient genotyping as a viable tool even in low- and middle-income countries [ 65 , 66 ]. Most people infected with M. Molecular epidemiology studies have shown that active TB due to reactivation of the original strain can occur decades after the initial infection [ 69 ].
However, in subjects without overt immunodeficiency, the pathogenesis of reactivation remains unclear. As mentioned above, there is strong evidence that the development of PTB is influenced by host genetic factors.
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This genetic control is also likely to be different from that involved in primary TB [ 23 , 70 ]. Indeed, the study of genetic susceptibility to adulthood PTB has proved more difficult than that of susceptibility to severe childhood TB.
Current knowledge resulting from attempts to identify the genetic variants associated with PTB points to underlying heterogeneity, possibly due, at least in part, to the long-standing, multistep relationship between M. In particular, it is possible that specific subgroups of individuals with PTB have certain genetic risk factors, whereas other subgroups have other genetic risk factors. Such subgroups could potentially be defined on the basis of individual factors, such as clinical characteristics, or extrinsic factors, such as pathogen variability. The vast majority of studies conducted to date to determine the molecular basis of PTB susceptibility have been association studies investigating the role of specific candidate genes.
However, there has been a lack of consistency between most of the reported results of independent studies [ 73 , 74 ]. Following the initial association reported in a Gambian population [ 75 ], a meta-analysis of a large number of studies showed that several NRAMP1 polymorphisms were significantly associated with PTB in African and Asian populations, but not in populations of European descent [ 76 ].
These observations are consistent with the hypothesis that NRAMP1 polymorphisms affect the speed of progression from infection to TB disease, accounting for the high frequency of some common alleles in patients with pediatric disease and the paucity of patients with the same alleles among TB cases with disease onset during adulthood.
Overall, these studies provide strong support for a role of NRAMP1 in TB, with an effect that is heterogeneous across populations, epidemiological settings and clinical phenotypes. They also highlight the importance of considering age at TB onset in these analyses. Generally, in the field of infectious diseases, stronger genetic effects are more pronounced in early-onset cases than in late-onset cases [ 70 ]. For example, in leprosy the association of genetic variants with disease has been shown repeatedly to be highly age-dependent [ 79 , 80 ].
The concept of stronger genetic effects associated with early-onset disease was further supported by the positional cloning of the first major locus conferring predisposition to PTB, which was found to be linked to chromosome region 8q [ 81 ].
Further imputation of the original Ghanaian data identified a second locus on chromosome 11p13 as protective against TB [ 87 ]. The main protective SNP allele was well replicated in the Gambian sample but displayed only borderline associations in Indonesian patients and in a very large sample more than 10 subjects of subjects from Russia [ 87 ]. Another GWAS recently conducted in a South African population confirmed the protective effect of the chromosome 11p13 factor but identified no new risk loci of GW significance [ 88 ].
Based on the observed age distribution of this latter study, young cases were defined as having an onset of TB before the age of 45 years, although more refined analyses with lower age thresholds showed that higher deviations of p -values from the null hypothesis were observed with younger age cut-offs despite the lower number of cases in each subset [ 89 ].
Overall, a striking feature of these GWASs is the lack of replication of the PTB susceptibility factors previously detected in candidate gene analyses [ 8 , 73 , 74 ]. Overall, the GWAS results suggest that common variants may have a limited impact on predisposition to adult PTB, at least when considered as a single phenotype, and point to underlying heterogeneity, possibly in phenotype definition.
TB was long considered to be purely infectious, but there is increasing evidence to suggest that this disease also reflects host genetic vulnerability. However, the precise nature of the genetic factors involved remains largely unknown. Several non-mutually exclusive explanations can account for the difficulties experienced in identifying the causal variants, especially in GWASs. Genetic heterogeneity may play a role, together with a complex mode of inheritance involving incomplete penetrance and modifier genes [ 90 , 91 ].
Likewise, the contribution of rare variants to TB pathogenesis is attracting attention for two main reasons: i conceptually, rare variants bridge the gap between Mendelian and complex inheritance, and may account for the major loci identified through linkage studies [ 56 , 70 , 92 ]; ii experimentally, these variants abound in the genome and can now be studied by whole-exome and whole-genome sequencing [ 93 , 94 ]. However, the phenotypic heterogeneity of TB-related traits causes more serious problems. For example, three measurements of immune reactivity are currently used to detect infection with M.
However, the results of these tests display limited concordance, and each assay captures a different aspect of the antimycobacterial response [ 27 ]. MSMD probably provides the best example of the critical interplay between phenotype and genetic control. The syndromic phenotype is MSMD, but the identification of the underlying genetic defects was greatly facilitated by establishing endophenotypes e.
Endophenotypes are more closely related to gene function and are likely to be generally useful for the dissection of TB phenotypes. In PTB, the most commonly used phenotype-defining characteristic is the presence of M.