Models to understand the population-level impact of mixed strain M. tuberculosis infections

Abstract

Over the past decade, numerous studies have identified tuberculosis patients in whom more than one distinct strain of M. tuberculosis is present. While it has been shown that these mixed strain infections can reduce the probability of treatment success for individuals simultaneously harboring both drug-sensitive and drug-resistant strains, it is not yet known if and how this phenomenon impacts the long-term dynamics for tuberculosis within communities. Strain-specific differences in immunogenicity and associations with drug resistance suggest that a better understanding of how strains compete within hosts will be necessary to project the effects of mixed strain infections on the future burden of drug-sensitive and drug-resistant tuberculosis. In this paper, we develop a modeling framework that allows us to investigate mechanisms of strain competition within hosts and to assess the long-term effects of such competition on the ecology of strains in a population. These models permit us to systematically evaluate the importance of unknown parameters and to suggest priority areas for future experimental research. Despite the current scarcity of data to inform the values of several model parameters, we are able to draw important qualitative conclusions from this work. We find that mixed strain infections may promote the coexistence of drug-sensitive and drug-resistant strains in two ways. First, mixed strain infections allow a strain with a lower basic reproductive number to persist in a population where it would otherwise be outcompeted if has competitive advantages within a co-infected host. Second, some individuals progressing to phenotypically drug-sensitive tuberculosis from a state of mixed drug-sensitive and drug-resistant infection may retain small subpopulations of drug-resistant bacteria that can flourish once the host is treated with antibiotics. We propose that these types of mixed infections, by increasing the ability of low fitness drug-resistant strains to persist, may provide opportunities for compensatory mutations to accumulate and for relatively fit, highly drug-resistant strains of M. tuberculosis to emerge.

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

“…Laboratory, animal model, and epidemiological studies that focus on the within-host complexity of M. tuberculosis infection and disease can contribute complementary information that improves our ability to effectively combat this pathogen. For example, an understanding of the strengths and mechanisms of within-host strain interactions will allow us to better project the trajectories of tuberculosis epidemics and the expected diversity of pathogen populations (8,23,85), understand the effects of the scaling up of existing interventions (e.g., IPT) (21), and evaluate the potential effectiveness of novel vaccines (20,64).…”

“…This can permit the stable coexistence of species (99). A recent mathematical model that allowed for differences in the abilities of M. tuberculosis strains to compete within and between hosts determined that models that allow for mixed infections can permit the long-term persistence of relatively less transmissible drug-resistant strains if these strains benefitted from some competitive advantage within coinfected hosts (85).…”

Magnitude and sources of bias in the detection of mixed strain M. tuberculosis infection

“…Furthermore, the advent of high resolution tests for genetic variation has revealed that individuals may simultaneously harbor infections with more than one distinct strain of M. tuberculosis (Warren et al, 1999;Sola et al, 2003;Kremer et al, 1999;van Embden et al, 1993;Imaeda, 1985). This phenomenon, which we will refer to as "mixed infection", has been linked with poor treatment outcome when the co-infecting strains differ with respect to drug susceptibility (van Rie et al, 2005;Hingley-Wilson et al, 2013) and is predicted to influence the impact of population-level interventions against tuberculosis (Cohen et al, 2008;Rodrigues et al, 2007;Colijn et al, 2009;Sergeev et al, 2011;Mills et al, 2013).…”

Undetected Multidrug-Resistant Tuberculosis Amplified by First-line Therapy in Mixed Infection

“…Possible co-infection of patients with drug-sensitive and drug-resistant M. tuberculosis strains has been described ( 1 , 2 ), and modeling of the effect of such co-infection on the long-term dynamics of tuberculous infection has led to the hypothesis that persons with this type of infection may retain small populations of drug-resistant bacteria that can flourish after the host receives treatment ( 11 ). van Rie et al showed the amplification of a drug-resistant strain after treatment and postulated selection of drug-resistant strains from an initial mixed infection through antimicrobial drug pressure ( 2 ).…”