Human Genomics of Mycobacterium tuberculosis Infection and Disease

Orlova, Marianna; Schurr, Erwin

doi:10.1007/s40142-017-0124-7

Cited by 20 publications

(23 citation statements)

References 59 publications

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“…The underlying causes of the variability in mammalian responses to M. tuberculosis have been topics of intense study. Among these is host genetics, and human genetic loci have been linked to host susceptibility to M. tuberculosis infection and disease (2)(3)(4).…”

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confidence: 99%

The Diversity Outbred Mouse Population Is an Improved Animal Model of Vaccination against Tuberculosis That Reflects Heterogeneity of Protection

Kurtz

Rossi

Beamer

et al. 2020

mSphere

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Many studies of Mycobacterium tuberculosis infection and immunity have used mouse models. However, outcomes of vaccination and challenge with M. tuberculosis in inbred mouse strains do not reflect the full range of outcomes seen in people. Previous studies indicated that the novel Diversity Outbred (DO) mouse population exhibited a spectrum of outcomes after primary aerosol infection with M. tuberculosis. Here, we demonstrate the value of this novel mouse population for studies of vaccination against M. tuberculosis aerosol challenge. Using the only currently licensed tuberculosis vaccine, we found that the DO population readily controlled systemic Mycobacterium bovis BCG bacterial burdens and that BCG vaccination significantly improved survival across the DO population upon challenge with M. tuberculosis. Many individual DO mice that were vaccinated with BCG and then challenged with M. tuberculosis exhibited low bacterial burdens, low or even no systemic dissemination, little weight loss, and only minor lung pathology. In contrast, some BCG-vaccinated DO mice progressed quickly to fulminant disease upon M. tuberculosis challenge. Across the population, most of these disease parameters were at most modestly correlated with each other and were often discordant. This result suggests the need for a multiparameter metric to better characterize “disease” and “protection,” with closer similarity to the complex case definitions used in people. Taken together, these results demonstrate that DO mice provide a novel small-animal model of vaccination against tuberculosis that better reflects the wide spectrum of outcomes seen in people. IMPORTANCE We vaccinated the Diversity Outbred (DO) population of mice with BCG, the only vaccine currently used to protect against tuberculosis, and then challenged them with M. tuberculosis by aerosol. We found that the BCG-vaccinated DO mouse population exhibited a wide range of outcomes, in which outcomes in individual mice ranged from minimal respiratory or systemic disease to fulminant disease and death. The breadth of these outcomes appears similar to the range seen in people, indicating that DO mice may serve as an improved small-animal model to study tuberculosis infection and immunity. Moreover, sophisticated tools are available for the use of these mice to map genes contributing to control of vaccination. Thus, the present studies provided an important new tool in the fight against tuberculosis.

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confidence: 99%

The Diversity Outbred Mouse Population Is an Improved Animal Model of Vaccination against Tuberculosis That Reflects Heterogeneity of Protection

Kurtz

Rossi

Beamer

et al. 2020

mSphere

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“…The identification of a major human genetic component linked to lack of TST reactivity in subjects exposed to M. tuberculosis expands the role of genetic factors to infection resistance (Cobat et al 2009 , 2015 ). Genetic findings of infection resistance to M. tuberculosis were recently reviewed elsewhere (Abel et al 2017 ; Orlova and Schurr 2017 ; Simmons et al 2018 ). Among individuals infected with M. tuberculosis , a person can remain in an asymptomatic state known as latent TB infection (LTBI) and never develop clinical disease or can evolve to clinical TB (active TB), whether it is primary TB or PTB (Abel et al 2014 ; Pai et al 2016 ).…”

Section: Tuberculosismentioning

confidence: 99%

Human genetics of mycobacterial disease

2018

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Mycobacterial diseases are caused by members of the genus Mycobacterium, acid-fast bacteria characterized by the presence of mycolic acids within their cell walls. Claiming almost 2 million lives every year, tuberculosis (TB) is the most common mycobacterial disease and is caused by infection with M. tuberculosis and, in rare cases, by M. bovis or M. africanum. The second and third most common mycobacterial diseases are leprosy and buruli ulcer (BU), respectively. Both diseases affect the skin and can lead to permanent sequelae and deformities. Leprosy is caused by the uncultivable M. leprae while the etiological agent of BU is the environmental bacterium M. ulcerans. After exposure to these mycobacterial species, a majority of individuals will not progress to clinical disease and, among those who do, inter-individual variability in disease manifestation and outcome can be observed. Susceptibility to mycobacterial diseases carries a human genetic component and intense efforts have been applied over the past decades to decipher the exact nature of the genetic factors controlling disease susceptibility. While for BU this search was mostly conducted on the basis of candidate genes association studies, genome-wide approaches have been widely applied for TB and leprosy. In this review, we summarize some of the findings achieved by genome-wide linkage, association and transcriptome analyses in TB disease and leprosy and the recent genetic findings for BU susceptibility.

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“…Although several environmental and clinical conditions, such as diabetes mellitus, malnutrition, alcohol abuse, smoking, age, AIDS and immunosuppressive therapies, are known to promote the development of the disease, many TB patients have no above mentioned or other obvious risk factors. Evidence from animal and human studies indicates the importance of host genetic factors in the development of TB [2].…”

Section: Introductionmentioning

confidence: 99%

Synergistic effect of genetic polymorphisms in TLR6 and TLR10 genes on the risk of pulmonary tuberculosis in Moldavian population

Varzari

Deyneko

Tudor

et al. 2020

Preprint

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BACKGROUND Host immunity is essential for efficient recognition and clearance of M. tuberculosis infection. Polymorphisms in genes that regulate immune response have been reported to influence the susceptibility/resistance to pulmonary tuberculosis (TB). Here we evaluated associations between 14 polymorphisms in 12 core genes involved in immune responses and pulmonary TB in Moldavian population, and investigated whether interactions between these and previously analyzed polymorphisms could exist and modulate the risk of pulmonary TB. METHODS Polymorphisms VDR rs7975232, VDR rs1544410, VDR rs2228570, MR1 rs1052632, TLR1 rs5743618, TLR2 rs111200466, TLR10 rs11096957, SLC11A1 rs2276631, IL1B rs1143643, IL10 rs1800896, IFNG rs2430561, TNF rs1800629, IRAK1 rs1059703, and FOXP3 rs2232365 were genotyped in 271 Moldavian pulmonary TB cases and 251 community-matched healthy controls. Associations were tested using Fisher test and logistic regression. Complemented with the data from our previous study (PMID: 30529560), investigation of gene-gene interactions was performed for a total of 43 loci. Significance level was adjusted by the Bonferroni correction. RESULTS Single polymorphism analysis revealed a nominal association between TNF rs1800629 and pulmonary TB (Fisher exact test p-value = 0.01843). Marginal differences between cases and controls were observed for haplotypes in the gene cluster TLR1-TLR6-TLR10 and gene TLR2. In the pairwise interaction analysis, the combination of genotypes TLR6 rs5743810 GA and TLR10 rs11096957 GT was significantly associated with an increased genetic risk of pulmonary TB (OR = 2.48, 95% CI = 1.62–3.85; Fisher exact test p-value = 1.5 × 10− 5, significant after Bonferroni correction). CONCLUSION The TLR6 rs5743810 and TLR10 rs11096957 two-locus interaction confers a significantly higher risk for pulmonary TB and has potential as a novel biomarker for predicting TB susceptibility.

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Human Genomics of Mycobacterium tuberculosis Infection and Disease

Cited by 20 publications

References 59 publications

The Diversity Outbred Mouse Population Is an Improved Animal Model of Vaccination against Tuberculosis That Reflects Heterogeneity of Protection

The Diversity Outbred Mouse Population Is an Improved Animal Model of Vaccination against Tuberculosis That Reflects Heterogeneity of Protection

Human genetics of mycobacterial disease

Synergistic effect of genetic polymorphisms in TLR6 and TLR10 genes on the risk of pulmonary tuberculosis in Moldavian population

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