Mixed-Strain Mycobacterium tuberculosis Infections and the Implications for Tuberculosis Treatment and Control

Division of Global Health Equity, Brigham and Women's Hospital, Boston, Massachusetts, USA.
Clinical microbiology reviews (Impact Factor: 17.41). 10/2012; 25(4):708-19. DOI: 10.1128/CMR.00021-12
Source: PubMed


Numerous studies have reported that individuals can simultaneously harbor multiple distinct strains of Mycobacterium tuberculosis. To date, there has been limited discussion of the consequences for the individual or the epidemiological importance of mixed infections. Here, we review studies that documented mixed infections, highlight challenges associated with the detection of mixed infections, and discuss possible implications of mixed infections for the diagnosis and treatment of patients and for the community impact of tuberculosis control strategies. We conclude by highlighting questions that should be resolved in order to improve our understanding of the importance of mixed-strain M. tuberculosis infections.

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    • "Overall, the observations in the present study fortify the awareness regarding the existence of clonally complex TB infections that has been growing in recent years. The realization that polyclonal infections constitute a reality has important implications for patient care considering the potential occurrence of heteroresistance [7]. Further research is needed to better document the frequency of mixed infections and their relevance for disease progression and treatment outcome in affected patients, as well as their implication for vaccine development. "
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    ABSTRACT: Introduction: The advent of molecular typing using MIRU-VNTR mini-satellites has largely facilitated tuberculosis (TB) molecular epidemiological studies. Apart from detecting the chains of transmission and risk factors, these markers have also allowed to study the phenomena of mixed strain infections versus microevolutionary events. Methods: An initial set of Mycobacterium tuberculosis strains (n = 161) genotyped using spoligotyping and MIRU-VNTRs in Guyana and Suriname was evaluated for indications of mixed strain infections (characterized by the detection of double alleles in 2 or more MIRU loci) versus ‘‘in-patient’’ microevolutionary events (characterized by the detection of double alleles in a single locus). Results: The present study hereby reports evidence of microevolution in 3.7% (n = 6/161) of the studied population, vs. 0.6% (n = 1/161) for mixed infection. The strains belonged to three different spoligotyping-based lineages, namely the T (SITs 44, 53, and 1081), Haarlem (SIT47), and EAI (SITs 72 and 349) lineages, while 1 isolate (SIT237) could not be assigned to any lineage. Discussion: By comparing these results on microevolutionary cases (n = 6) to 112,000 strains present in the SITVIT2 database, evidence is presented that in 2/6 cases (each case corresponding to 2 patterns due to MIRU double bands), one of the patterns corresponded to a shared type found exclusively in Suriname or Guyana. Phylogenetic analysis showed that no spoligotyping lineage in particular was more prone to microevolutionary events in this study’s sample. Overall, the observations fortify the awareness regarding the existence of microevolution and polyclonal TB infections which has important implications for patient care.
    International Journal of Mycobacteriology 06/2015; 4(3):222-227. DOI:10.1016/j.ijmyco.2015.05.005
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    • "Although the designs of previous studies for detecting mixed strains have differed in important ways (Cohen et al., 2012), for the purposes of this analysis, we have generalized the study design to include several steps common to nearly all of these investigations: 1. Specimen collection from the patient (samples of 0. "
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    ABSTRACT: High resolution tests for genetic variation reveal that individuals may simultaneously host more than one distinct strain of M. tuberculosis. Previous studies find that this phenomenon, which we will refer to as "mixed infection", may affect the outcomes of treatment for infected individuals and may influence the impact of population-level interventions against tuberculosis. In areas where the incidence of TB is high, mixed infections have been found in nearly 20% of patients; these studies may underestimate the actual prevalence of mixed infection given that tests may not be sufficiently sensitive for detecting minority strains. Specific reasons for failing to detect mixed infections would include low initial numbers of minority strain cells in sputum, stochastic growth in culture and the physical division of initial samples into parts (typically only one of which is genotyped). In this paper, we develop a mathematical framework that models the study designs aimed to detect mixed infections. Using both a deterministic and a stochastic approach, we obtain posterior estimates of the prevalence of mixed infection. We find that the posterior estimate of the prevalence of mixed infection may be substantially higher than the fraction of cases in which it is detected. We characterize this bias in terms of the sensitivity of the genotyping method and the relative growth rates and initial population sizes of the different strains collected in sputum. Copyright © 2014. Published by Elsevier Ltd.
    Journal of Theoretical Biology 12/2014; 368. DOI:10.1016/j.jtbi.2014.12.009 · 2.12 Impact Factor
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    ABSTRACT: Microevolved Mycobacterium tuberculosis clonal variants from a parental strain can emerge within a single patient infection and during transmission events. Genotypic rearrangements may involve functional changes conferring advantages to favor strain adaptation to the host. In the present study, we analyzed in depth some genotypic characteristics of a strain with a high tendency to microevolve, that generated 6 clonal variants during transmission of sequential hosts. In order to identify genetic features potentially associated to microevolution in MTB, we analyzed 56 3R genes and the IS6110 insertion sites from this strain and identified an SNP in alkA and an IS6110 copy located upstream of a transposase (Rv0755A). These markers could be involved in mechanisms leading to genotypic variation. Both features were shared by strains from our collection that were also involved in microevolution events, suggesting their putative association with these events.
    Infection, genetics and evolution: journal of molecular epidemiology and evolutionary genetics in infectious diseases 03/2013; 16. DOI:10.1016/j.meegid.2013.02.016 · 3.02 Impact Factor
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