Within Host Evolution Selects for a Dominant Genotype of Mycobacterium tuberculosis while T Cells Increase Pathogen Genetic Diversity

Copin, Richard; Louie, Eddie; Escuyer, Vincent; Coscollá, Mireia; Gagneux, Sébastien; Palmer, Guy H.; Ernst, Joel D.

doi:10.1371/journal.ppat.1006111

Cited by 35 publications

(39 citation statements)

References 42 publications

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“…Thus, we next considered these results in light of published patient data. Recent publications have suggested that NGS technologies could facilitate personalized treatment in TB patients, allowing for improved outcomes (Copin et al . 2016; Cancino-Muñoz et al .…”

Section: Resultsmentioning

confidence: 99%

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Within-host Mycobacterium tuberculosis evolution: a population genetics perspective

Morales‐Arce

Harris

Stone

et al. 2019

Preprint

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12The within-host evolutionary dynamics of TB remain unclear, and underlying biological 13 characteristics render standard population genetic approaches based upon the Wright-Fisher 14 model largely inappropriate. In addition, the compact genome combined with an absence of 15 recombination is expected to result in strong purifying selection effects. Thus, it is imperative to 16 establish a biologically-relevant evolutionary framework incorporating these factors in order to 17 enable an accurate study of this important human pathogen. Further, such a model is critical for 18 inferring fundamental evolutionary parameters related to patient treatment, including mutation 19 rates and the severity of infection bottlenecks. We here implement such a model and infer the 20 underlying evolutionary parameters governing within-patient evolutionary dynamics. Results 21 demonstrate that the progeny skew associated with the clonal nature of TB severely reduces 22 polymorphic sites per patient genome-wide. In addition, the observed site frequency spectrum 56 (SFS) is generally characterized by an abundance of rare variants (i.e., it is strongly left-skewed). 57These patterns have partly led to the suggestion that purifying selection effects may be wide-58 spread in the M.TB genome (Brown et al. 2016; Phelan et al. 2016; Mortimer et al. 2018). 59 60 Additional evolutionary factors likely contribute to these genomic patterns as well. For 61 example, population bottlenecks may reduce genetic variation and alter the shape of the SFS 62 (see review Thornton et al. 2007). Previous M.TB studies have investigated these effects 63 3 separately in both the deep-time view of the population bottleneck and subsequent growth 64 experienced by the host human population (Hershberg et al. 2008, Liu et al. 2018, as well as the 65 shallow-time view of the population bottleneck and subsequent growth characterizing each novel 66 transmission event and treatment (e.g., Trauner et al. 2017). Additionally, in fitting the left-67 skewed SFS, Pepperell et al. (2013) found that such a demographic history combined with a mix 68 of both deleterious and neutrally-evolving sites produced the nearest fit to the observed SFS. 69Finally, given the lack of recombination in M.TB, related linkage effects (i.e., background 70 selection (Charlesworth et al. 1993)) have similarly been discussed within these contexts 71 (Pepperell et al. 2010; Copin et al. 2016). 72 73 While these studies have provided many important insights, there remains a relatively 74 unexplored, though potentially highly significant, effect: clonality. Indeed, clonality and the 75 related progeny distribution represents an important violation of commonly used evolutionary 76 inference approaches based upon the Wright-Fisher (WF) model and the related Kingman 77 coalescent (Eldon et al. 2006; Dos Vultos et al. 2008; Huillet et al. 2011; Lapierre et al. 2016). 78 Specifically, progeny distributions under the WF model are Poisson distributed with a mean and 79 variance of 1. Therefore, when an ind...

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Section: Resultsmentioning

confidence: 99%

“…1993)) have similarly been discussed within these contexts (Pepperell et al . 2010; Copin et al . 2016).…”

Section: Introductionmentioning

confidence: 99%

Within-host Mycobacterium tuberculosis evolution: a population genetics perspective

Morales‐Arce

Harris

Stone

et al. 2019

Preprint

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“…The majority (82%) of these absent epitopes are contained in 6 antigenic proteins encoded in RD1 and RD2 deleted in BCG strains. These and related studies further suggested that epitope sequence variation in BCG potentially affects human T cell recognition that could result in ineffective priming of the host immune system [16,17,[50][51][52].…”

Section: The Current Clinical Tb Vaccine Pipelinementioning

confidence: 89%

MTBVAC from discovery to clinical trials in tuberculosis-endemic countries

Marinova

Gonzalo-Asensio

Aguilo

et al. 2017

Expert Review of Vaccines

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Introduction: BCG remains the only vaccine against tuberculosis (TB) in use today and despite its impressive global coverage, the nature of BCG protection against the pulmonary forms of TB remains subject to ongoing debate. Because of the limitations of BCG, novel TB vaccine candidates have been developed and several have reached the clinical pipeline. One of these candidates is MTBVAC, the first and only TB vaccine in the clinical pipeline to date based on live-attenuated Mycobacterium tuberculosis that has successfully entered clinical evaluation, a historic milestone in human vaccinology. Areas covered: This review describes development of MTBVAC from discovery to clinical development in high burden TB-endemic countries. The preclinical experiments where MTBVAC has shown to confer improved safety and efficacy over BCG are presented and the clinical development plans for MTBVAC are revealed. The search of all supportive literature in this manuscript was carried out via Pubmed. Expert commentary: Small experimental medicine trials in humans and preclinical efficacy studies with a strong immunological component mimicking clinical trial design are considered essential by the scientific community to help identify reliable vaccine-specific correlates of protection in order to support and accelerate community-wide efficacy trials of new TB vaccines. ARTICLE HISTORY

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“…The stocks of M. tuberculosis H37Rv, H37Rv:Δ fbpB (Ag85B-null), 4334, and M. africanum 1182 used in our laboratory and for these studies have been previously described (19, 42-44). The M. tuberculosis HN878 strain was obtained from BEI Resources.…”

Section: Methodsmentioning

confidence: 99%

Dynamics ofMycobacterium tuberculosisAg85B revealed by sensitive ELISA

Cornelius

Bolz

2019

Preprint

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31Secretion of specific proteins contributes to pathogenesis and immune responses in tuberculosis and 32 other bacterial infections, yet the kinetics of protein secretion and fate of secreted proteins in vivo are 33 poorly understood. We generated new monoclonal antibodies that recognize the M. tuberculosis 34 secreted protein, Ag85B, and used them to establish and characterize a sensitive ELISA to quantitate 35 Ag85B in samples generated in vitro and in vivo. We found that nutritional or culture conditions had 36 little impact on secretion of Ag85B, and that there is considerable variation in Ag85B secretion by 37 distinct strains in the M. tuberculosis complex: compared with the commonly-used H37Rv strain 38 (Lineage 4), M. africanum (Lineage 6) secretes less, and two strains from Lineage 2 secrete more 39Ag85B. We also used the ELISA to determine that the rate of secretion of Ag85B is 10-to 100-fold 40 lower than that of proteins secreted by gram-negative and gram-positive bacteria, respectively. ELISA 41 quantitation of Ag85B in lung homogenates of M. tuberculosis H37Rv-infected mice revealed that 42 although Ag85B accumulates in the lungs as the bacterial population expands, the amount of Ag85B 43 per bacterium decreases nearly 10,000-fold at later stages of infection, coincident with development of 44 T cell responses and arrest of bacterial population growth. These results indicate that bacterial protein 45 secretion in vivo is dynamic and regulated, and quantitation of secreted bacterial proteins can 46 contribute to understanding pathogenesis and immunity in tuberculosis and other infections. 47Bacterial protein secretion contributes to host-pathogen interactions, yet the process and 49 consequences of bacterial protein secretion during infection are poorly understood. We developed a 50 sensitive ELISA to quantitate a protein (termed Ag85B) secreted by M. tuberculosis and used it to find 51 that Ag85B secretion occurs with slower kinetics than for proteins secreted by gram positive and gram 52 negative bacteria, and that accumulation of Ag85B in the lungs is markedly regulated as a function of 53 the bacterial population density. Our results demonstrate that quantitation of bacterial proteins during 54 infection can reveal novel insights into host-pathogen interactions. 55 56

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Within Host Evolution Selects for a Dominant Genotype of Mycobacterium tuberculosis while T Cells Increase Pathogen Genetic Diversity

Cited by 35 publications

References 42 publications

Within-host Mycobacterium tuberculosis evolution: a population genetics perspective

Within-host Mycobacterium tuberculosis evolution: a population genetics perspective

MTBVAC from discovery to clinical trials in tuberculosis-endemic countries

Dynamics ofMycobacterium tuberculosisAg85B revealed by sensitive ELISA

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