Interplay of strain and race/ethnicity in the innate immune response to M. tuberculosis

Nahid, Payam; Jarlsberg, Leah G.; Kato‐Maeda, Midori; Segal, Mark R.; Osmond, Dennis; Gagneux, Sébastien; Dobos, Karen M.; Gold, Marielle C.; Hopewell, P C; Lewinsohn, David

doi:10.1371/journal.pone.0195392

Cited by 34 publications

(31 citation statements)

References 60 publications

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“…What is clear is the evidence for the higher dissemination ability of "modern" lineages compared with "ancient" ones 21 . The fact that the latter are restricted to specific geographical regions also points to some sort of genetic susceptibility linked to race/ethnic groups, as proposed by several authors 7,17,66 . Our model has not considered this aspect.…”

Section: Discussionmentioning

confidence: 84%

Origin of tuberculosis in the Paleolithic predicts unprecedented population growth and female resistance

Cardona

Català

Prats

2020

Sci Rep

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Current data estimate the origin of Mycobacterium tuberculosis complex (MtbC) infection around 73,000 years before the common era (BCE), and its evolution to “modern” lineages around 46,000 BCE. Being MtbC a major killer of humanity, the question is how both species could persist. To answer this question, we have developed two new epidemiological models (SEIR type), adapted to sex dimorphism and comparing coinfection and superinfection for different MtbC lineages. We have attributed a higher resistance/tolerance to females to explain the lower incidence noted in this sex, a better health status in the Paleolithic compared to the Neolithic, and a higher dissemination of “modern” lineages compared to “ancient” ones. Our findings show the extraordinary impact caused by “modern” lineages, provoking the extinction of the groups infected. This could only be overcomed by an unprecedented population increase (x20 times in 100 years) and helped with the protection generated by previous infection with “ancient” lineages. Our findings also suggest a key role of female resistance against MtbC. This data obliges us to rethink the growth population parameters in the Paleolithic, which is crucial to understanding the survival of both MtbC and humans, and to decipher the nature of human female resistance against TB.

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Section: Discussionmentioning

confidence: 84%

Origin of tuberculosis in the Paleolithic predicts unprecedented population growth and female resistance

Cardona

Català

Prats

2020

Sci Rep

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“…In contrast, if rare resistance variants were in fact rare, 300 years would not have been sufficient for selection to increase the frequency of these variants to epidemiologically significant frequencies. Despite this, evidence for the role of natural selection in TB resistance is bolstered by findings from population genetic studies of the immune system which provide a context for the genetic interface between humans and mycobacteria ( 57 , 58 , 59 , 60 , 61 ).…”

Section: Epidemiological Evidence Of Genetic Susceptibility To mentioning

confidence: 99%

“…The co-evolution of M. tuberculosis and humans has shaped host-pathogen interactions for thousands of years and has likely contributed to the diverse range of responses after infection including the phenotype of the TB resister ( 50 , 61 , 151 ). Host-pathogen interaction investigations are however complicated by the genetic heterogeneity of the bacterium ( 50 ).…”

Section: Controversies Current Research Gaps and Future Developmentmentioning

confidence: 99%

Genetic Resistance to Mycobacterium tuberculosis Infection and Disease

et al. 2018

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Natural history studies of tuberculosis (TB) have revealed a spectrum of clinical outcomes after exposure to Mycobacterium tuberculosis, the cause of TB. Not all individuals exposed to the bacterium will become diseased and depending on the infection pressure, many will remain infection-free. Intriguingly, complete resistance to infection is observed in some individuals (termed resisters) after intense, continuing M. tuberculosis exposure. After successful infection, the majority of individuals will develop latent TB infection (LTBI). This infection state is currently (and perhaps imperfectly) defined by the presence of a positive tuberculin skin test (TST) and/or interferon gamma release assay (IGRA), but no detectable clinical disease symptoms. The majority of healthy individuals with LTBI are resistant to clinical TB, indicating that infection is remarkably well-contained in these non-progressors. The remaining 5–15% of LTBI positive individuals will progress to active TB. Epidemiological investigations have indicated that the host genetic component contributes to these infection and disease phenotypes, influencing both susceptibility and resistance. Elucidating these genetic correlates is therefore a priority as it may translate to new interventions to prevent, diagnose or treat TB. The most successful approaches in resistance/susceptibility investigation have focused on specific infection and disease phenotypes and the resister phenotype may hold the key to the discovery of actionable genetic variants in TB infection and disease. This review will not only discuss lessons from epidemiological studies, but will also focus on the contribution of epidemiology and functional genetics to human genetic resistance to M. tuberculosis infection and disease.

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“…Under the coevolution model, a newly divergent MTB lineage (that has not historically co-existed with the population in question) is expected to cause more severe disease[24]. The potential for human-MTB coevolution has been explored in human and model systems, but studies have not yet identified a definitive effect at the population level[3, 4, 10, 13, 25-27]. Although coevolution may affect the likelihood of developing active disease, to study coevolution in practice, it is necessary to study cases only, as we cannot deduce the MTB lineage(s) to which unaffected individuals have been exposed with certainty.…”

Section: Introductionmentioning

confidence: 99%

“…Because unaffected individuals cannot be examined, all previous studies of host-MTB genome interaction have been case-only studies that at best examine association between lineage and host genotypes, but not explicit interactions [25, 26, 29, 30]. Host-pathogen coevolution has been demonstrated in other organisms, by removing an apparent independent effect of host genetic factors on disease severity, thereby adjusting for host-pathogen interactions[19, 31].…”

Section: Introductionmentioning

confidence: 99%

Interaction between host genes and M. tuberculosis lineage can affect tuberculosis severity: evidence for coevolution

McHenry

Bartlett

Igo

et al. 2019

Preprint

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Genetic studies of both the human host and Mycobacterium tuberculosis (MTB) demonstrate independent association with tuberculosis (TB) risk. However, neither explains a large portion of disease risk or severity. Based on studies in other infectious diseases and animal models of TB, we hypothesized that the genomes of the two interact to modulate risk of developing active TB or increasing the severity of disease, when present. We examined this hypothesis in our TB household contact study in Kampala, Uganda, in which there were 3 MTB lineages of which L4-Ugandan (L4.6) is the most recent. TB severity, measured using the Bandim TBscore, was modeled as a function of host SNP genotype, MTB lineage, and their interaction, within two independent cohorts of TB cases, N=113 and 122. No association was found between lineage and severity, but association between multiple polymorphisms in IL12B and TBscore was replicated in two independent cohorts (most significant rs3212227, combined p=0.0006), supporting previous associations of IL12B with TB susceptibility. We also observed significant interaction between a single nucleotide polymorphism (SNP) in SLC11A1 and the L4-Ugandan lineage in both cohorts (rs17235409, meta p=0.0002). Interestingly, the presence of the L4-Uganda lineage in the presence of the ancestral human allele associated with more severe disease. These findings demonstrate that IL12B is associated with severity of TB in addition to susceptibility, and that the association between TB severity and human genetics can be due to an interaction between genes in the two species, providing evidence of host-pathogen coevolution in TB. AUTHOR SUMMARYSusceptibility to tuberculosis (TB) is affected by genetic variation in both the human host and the causative bacterium, Mycobacterium tuberculosis. However, prior studies of the genetics of each species have not explained a large part of TB risk. The possibility exists that risk can be better estimated from patterns of variation in two species as a unit, such that some combinations provide increased risk, or in the presence of TB, increased disease severity. We hypothesized that alleles in the two species that have co-existed for long periods are more likely to reduce disease severity so as to promote prolonged co-occurrence. We tested this by studying TB severity in two patient cohorts from Uganda for which paired MTB-human DNA were available.We examined severity, as measured by the Bandim TBscore, and assessed whether there was an interaction between MTB lineage and SNPs in the host with this metric. Our results indicate that the most recent TB lineage (L4.6/Uganda) when found together with an ancestral allele in SLC11A1 resulted in more severe disease. This finding is consistent with the conclusion that MTB and human have coevolved to modulate TB severity.

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Interplay of strain and race/ethnicity in the innate immune response to M. tuberculosis

Cited by 34 publications

References 60 publications

Origin of tuberculosis in the Paleolithic predicts unprecedented population growth and female resistance

Origin of tuberculosis in the Paleolithic predicts unprecedented population growth and female resistance

Genetic Resistance to Mycobacterium tuberculosis Infection and Disease

Interaction between host genes and M. tuberculosis lineage can affect tuberculosis severity: evidence for coevolution

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