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

Abstract

SUMMARY 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.

Mixed Infections and Rifampin Heteroresistance among Mycobacterium tuberculosis Clinical Isolates

“…According to the available literature, there was no link between the detection rate of mixed infections and the discriminatory power of the loci (Table 5). Recently, 12% of mixed M. tuberculosis infections were identified by whole-genome sequencing (28); however, this method is limited by the cost, complexity of data analysis, and the short sequencing reads used to account for repeat regions (5). Mixed Beijing and non-Beijing strains caused the most pathogen-pathogen compatibility (10,14,29,30); however, the mixed non-Beijing strains were also reported to be primary in some regions (12,31).…”

“…Mixed infections can assist M. tuberculosis strains in acquiring additional mutations, facilitate the spread of drug-resistant strains, and boost the rate of treatment failure (3,5). With the popularization of genetic analysis tools, the situation in which a single patient gets infected with more than one M. tuberculosis isolate was found to be more common than we previously expected (6).…”

“…Mixed infections and heteroresistance may be particularly common in regions with a high rate of tuberculosis (TB), especially drug-resistant TB (5,6,11). Sichuan is the province with the second-largest number of TB cases in China, where the prevalence of drug-resistant TB is much higher than the average level observed in eastern China (13).…”

“…With the popularization of genetic analysis tools, the situation in which a single patient gets infected with more than one M. tuberculosis isolate was found to be more common than we previously expected (6). Currently, mycobacterial interspersed repetitive unit-variable-number tandem repeat (MIRU-VNTR)-based methods have been the most widely used to detect mixed infections (5). Mixed infections are defined by the presence of strains with different MIRU-VNTR patterns at two or more loci in the same sputum, lymph, or other sample while having clonal heterogeneity with a different MIRU-VNTR pattern at a single locus (7)(8)(9).…”

HapFlow: Visualising haplotypes in sequencing data

“…Infections frequently contain multiple strains 24 of the same species (Darch, et al, 2015;Taylor, et al, 1995). This has important implications 25 for detecting transmission events (Bachmann, et al, 2015) and determining treatment 26 outcomes (Cohen, et al, 2012). Several methods have been developed to analyse mixed-27 strain populations.…”