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Heterogeneous Streptomycin Resistance Level Among Mycobacterium tuberculosis Strains From the Same Transmission Cluster.

ABSTRACT: Widespread and frequent resistance to the second-line tuberculosis (TB) medicine streptomycin, suggests ongoing transmission of low fitness cost streptomycin resistance mutations. To investigate this hypothesis, we studied a cohort of 681 individuals from a TB epidemic in Portugal. Whole-genome sequencing (WGS) analyses were combined with phenotypic growth studies in culture media and in mouse bone marrow derived macrophages. Streptomycin resistance was the most frequent resistance in the cohort accounting for 82.7% (n = 67) of the resistant Mycobacterium tuberculosis isolates. WGS of 149 clinical isolates identified 13 transmission clusters, including three clusters containing only streptomycin resistant isolates. The biggest cluster was formed by eight streptomycin resistant isolates with a maximum of five pairwise single nucleotide polymorphisms of difference. Interestingly, despite their genetic similarity, these isolates displayed different resistance levels to streptomycin, as measured both in culture media and in infected mouse bone marrow derived macrophages. The genetic bases underlying this phenotype are a combination of mutations in gid and other genes. This study suggests that specific streptomycin resistance mutations were transmitted in the cohort, with the resistant isolates evolving at the cluster level to allow low-to-high streptomycin resistance levels without a significative fitness cost. This is relevant not only to better understand transmission of streptomycin resistance in a clinical setting dominated by Lineage 4 M. tuberculosis infections, but mainly because it opens new prospects for the investigation of selection and spread of drug resistance in general.

SUBMITTER: Rocha DMGC

PROVIDER: S-EPMC8226182 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Introduction: Tuberculosis (TB) is a serious human disease caused by the bacterium Mycobacterium tuberculosis (Mtb). One third of the world’s population is estimated to be latently infected with Mtb. Exact mechanisms and properties of latent TB infection (LTBI) are not fully elucidated. In essence, the pathogen can enter a dormant or latent state characterized by limited growth and metabolism, resulting in absence of clinical symptoms in the host, and most importantly by increased phenotypic tolerance to the commonly used medications, thereby allowing indefinite persistence in the human body. This persistence is the main reason why the current treatment of new-onset pulmonary TB is very long, consisting of a six months therapy of four antibiotics (rifampicin, isoniazid, pyrazinamide, and ethambutol for the first two months, and only rifampicin and isoniazid for the last four months). Current state of the art: To fight TB globally and more efficiently, it is essential to shorten the treatment for TB with new drugs that are efficient also against LTBI. To facilitate discovery of such drugs, in vitro models for LTBI can be used for high throughput screening of chemical libraries. Current in vitro models such as nutrient starvation (Betts et al. 2002), nutrient depletion (Hampshire et al. 2004; Rifat, Bishai, and Karakousis 2009), progressive hypoxia (Wayne and Hayes 1996), nitric oxide treatment (Martin I. Voskuil et al. 2003) and multiple stress (Deb et al. 2009) mimic the dormant state of Mtb, but the technical settings and equipment required for these models obstruct high throughput applications. Proposed model: The streptomycin (STR)-starved 18b model (SS18b) is a simple and drug discovery efficient Mtb latency model successfully applicable to both in vitro and in vivo settings (Zhang et al. 2012). It is based on the Mtb strain 18b, which is a STR-dependent mutant that enters a viable but nonreplicating state in the absence of STR (Hashimoto 1955). Despite the successful model, we know very little about 18b. How well does SS18b mimic the bacterial response to the complex host-pathogen interactions underlying LTBI, and how does the SS18b response compare to that of other dormancy models are still open questions. In this work we analyse the complete genome of 18b and describe the transcriptomic response of 18b to STR depletion.

Project description:Transmission of Mycobacterium tuberculosis bacilli from one individual to another is the basis of the disease process. While considerable emphasis has been placed on the role of host mechanisms of resistance in establishing or preventing new infection, far less has been expended on understanding possible factors operative at the bacterial level. In this study we established a panel of clinical isolates of M. tuberculosis strains obtained from the Western Cape region of South Africa, each of which had been carefully tracked in terms of their degree of transmission in the community. Each of the panel were used to infect guinea pigs with 15-20 bacilli by aerosol exposure and the course of the infection then determined. Strains with different degrees of transmission could not be distinguished in terms of their capacity to grow in the main target organs of infected animals. However, rather surprisingly, while strains with no evidence of transmission [NOT] in general caused moderate to severe lung damage, this parameter in animals infected with highly transmitted [HT] strains was mostly mild. In terms of TH1 immunity these signals were strongest in these latter animals, as was IL-17 gene expression, whereas minimal signals for regulatory molecules including IL-10 and FoxP3 were seen across the entire panel. In terms of T cell numbers, responses of both CD4 and CD8 were both far faster and far higher in animals infected with the HT strains. At the gene expression level we observed a major three-fold difference [both up and down] between NOT and HT strains, but in terms of proteins of key interest only a few [including PD-L1 and HIF-3] showed major differences between the two groups. Overall, it was apparent that NOT strains were far more inflammatory that HT strains, and appeared to trigger a much larger number of genes, possibly explaining the observed damage to the lungs and progressive pathology. In contrast, the HT strains, while equally virulent, were more immunogenic and developed much stronger T cell responses, while keeping lung damage to a minimum. Hence, in terms of trying to explain the capacity of these strains to cause transmission, these results are clearly paradoxical.

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Heterogeneous Streptomycin Resistance Level Among Mycobacterium tuberculosis Strains From the Same Transmission Cluster.

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