Cohen, T. & Murray, M. Modeling epidemics of multidrug-resistant M. tuberculosis of heterogeneous fitness. Nature Med. 10, 1117-1121

Harvard University, Cambridge, Massachusetts, United States
Nature Medicine (Impact Factor: 27.36). 11/2004; 10(10):1117-21. DOI: 10.1038/nm1110
Source: PubMed


Mathematical models have recently been used to predict the future burden of multidrug-resistant tuberculosis (MDRTB). These models suggest the threat of multidrug resistance to TB control will depend on the relative 'fitness' of MDR strains and imply that if the average fitness of MDR strains is considerably less than that of drug-sensitive strains, the emergence of resistance will not jeopardize the success of tuberculosis control efforts. Multidrug resistance in M. tuberculosis is conferred by the sequential acquisition of a number of different single-locus mutations that have been shown to have heterogeneous phenotypic effects. Here we model the impact of initial fitness estimates on the emergence of MDRTB assuming that the relative fitness of MDR strains is heterogeneous. We find that even when the average relative fitness of MDR strains is low and a well-functioning control program is in place, a small subpopulation of a relatively fit MDR strain may eventually outcompete both the drug-sensitive strains and the less fit MDR strains. These results imply that current epidemiological measures and short-term trends in the burden of MDRTB do not provide evidence that MDRTB strains can be contained in the absence of specific efforts to limit transmission from those with MDR disease.

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    • "It is well-known that the condition R 0 < 1 is necessary for disease eradication [26]. Here, the relative reproductive fitness function will be approximated by the basic reproductive number of infection (R 0 ) in the absence of treatment or the effective reproductive number (R) in the presence of treatment [9], [13]. "
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    ABSTRACT: Despite the availability of effective treatment, tuberculosis (TB) remains a major global cause of mortality. Multidrug-resistant tuberculosis (MDR-TB) is a form of TB that is resistant to at least two drugs used for the treatment of TB, and originally is developed when a case of drug-susceptible TB is improperly or incompletely treated. This work is concerned with a mathematical model to evaluate the effect of MDR-TB on TB epidemic and its control. The model assessing the transmission dynamics of both drug-sensitive and drug-resistant TB includes slow TB (cases that result from endogenous reactivation of susceptible and resistant latent infections). We identify the steady states of the model to analyse their stability. We establish threshold conditions for possible scenarios: elimination of sensitive and resistant strains and coexistence of both. We find that the effective reproductive number is composed of two critical values, relative reproductive number for drug-sensitive and drugresistant strains. Our results imply that the potential for the spreading of the drug-resistant strain should be evaluated within the context of several others factors. We have also found that even the considerably less fit drug-resistant strains can lead to a high MDR-TB incidence, because the treatment is less effective against them.
    Mathematical Biosciences and Engineering 08/2014; 11(4):971-993. DOI:10.3934/mbe.2014.11.971 · 0.84 Impact Factor
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    • "Although mutations that confer drug resistance can imply a fitness cost, some MDR Mtb genotypes are able to overcome this disadvantage and are as virulent as fully drug-sensitive genotypes [43]. Unlike other pathogens, Mtb lacks typical virulence factors such as toxins; therefore, epidemiologic fitness of a strain can be influenced by a range of factors, for instance, the genetic background of host and pathogen, host–pathogen interactions, and the environment [44,45]. "
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    ABSTRACT: Background Neutrophils (PMN) are the first cells to infiltrate the lung after infection, and they play a significant protective role in the elimination of pathogen, by releasing preformed oxidants and proteolytic enzymes from granules and generating ROS, thus limiting inflammation by succumbing to apoptosis. In a previous study, we found marked differences in ROS-induced apoptosis between two Mycobacterium tuberculosis (Mtb) strains, M and Ra, representative of widespread Mtb families in South America, i.e. Haarlem and Latin-American Mediterranean (LAM), being strain M able to generate further drug resistance and to disseminate aggressively. Methods In this study we evaluate the nature of bacteria-PMN interaction by assessing ROS production, apoptosis, lipid raft coalescence, and phagocytosis induced by Mtb strains. Results Dectin-1 and TLR2 participate in Mtb-induced ROS generation and apoptosis in PMN involving p38 MAPK and Syk activation with the participation of a TLR2-dependent coalescence of lipid rafts. Further, ROS production occurs during the phagocytosis of non-opsonized bacteria and involves α-glucans on the capsule. In contrast, strain M lacks the ability to induce ROS because of: 1) a reduced phagocytosis and 2) a failure in coalescence of lipid raft. Conclusions The differences in wall composition could explain the success of some strains which stay unnoticed by the host through inhibition of apoptosis and ROS but making possible its replication inside PMN as a potential evasion mechanism. Innate immune responses elicited by Mtb strain-to-strain variations need to be considered in TB vaccine development.
    BMC Infectious Diseases 05/2014; 14(1):262. DOI:10.1186/1471-2334-14-262 · 2.61 Impact Factor
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    • "We were able to rectify this problem either by setting m to a constant or by using an informed prior (we call this form the " ABC method " ). Here, we fix m = 0.52 as the sum of estimates of the rates of self cure, death from causes other than tuberculosis, and death from untreated tuberculosis (Cohen and Murray 2004; Luciani et al. 2009). The Exact method is as follows. "
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    ABSTRACT: Exact computational methods for inference in population genetics are intuitively preferable to approximate analyses. We reconcile two starkly different estimates of the reproductive number of tuberculosis from previous studies that used the same genotyping data and underlying model. This demonstrates the value of approximate analyses in validating exact methods.
    Genetics 02/2014; 196(4). DOI:10.1534/genetics.113.158808 · 5.96 Impact Factor
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