The Broad GCID will focus on four project areas, devoted to viral, bacterial, fungal, and parasitic diseases, and vectors responsible for transmission. We will target high priority pathogens and pathogen-host-vector systems with a major impact on the global burden of disease. Each project combines genomic expertise with deep knowledge of the specific pathogens and diseases, along with carefully selected samples and well developed model systems. Among our program aims, we address the following:
• Molecular basis of evolution and spread of infectious diseases
• Genomic basis for pathogen traits
• Host-pathogen interactions
• Metagenomic approaches to identify new infectious agents
Broad’s GCID is one of three centers funded by NIAID. All data, as well as new analytical tools, are shared publicly to advance research in infectious diseases.
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Defining the Genetic Determinants of Multiple Drug Resistance in Mycobacterium Tuberculosis
The overarching goal of this project is to identify the entire complement of naturally occurring mutations that are responsible for drug resistance (DR) in clinical Mycobacterium tuberculosis (Mtb). We will create a comprehensive catalog of DR-conferring mutations by sequencing large numbers of geographically and phenotypically diverse Mtb strains that have been quantitatively characterized for their resistance to a broad spectrum of first and second line antibiotics. The DR catalog will provide a critical resource for addressing some of the most pressing needs in treating tuberculosis (TB) in the clinic:
- Rapid tests for accurate diagnosis of drug resistance in TB to guide treatment
- New targets for developing improved anti-TB therapeutics
Among bacterial diseases, TB is the leading cause of death worldwide, with an estimated 1.3 million deaths attributed to TB in 2008. Though historically treatable with standard first-line anti-TB therapy (primarily rifampin, isoniazid, pyrazinamide and sometimes ethambutol), new strains are emerging that are resistant to some and, in some reports, ALL first and second line antibiotics (fluoroquinolones and aminoglycosides). The inability of clinicians to quickly and accurately determine the DR profile of strains associated with new clinical cases of TB further confounds TB treatment and control. The weeks-long time period required to profile new strains for DR means that many patients face delays in treatment, treatment with ineffective drugs and, worse yet, treatment with unnecessary first-line drugs that increase the opportunity for new DR forms of the bacterium to arise and spread among the bacterial population and the humans that carry them.
The lack of adequate diagnostic tools to assess DR in TB patients reflects both the difficulty of culturing the organism as well as an incomplete understanding of what to be assaying for. At present our knowledge of DR-mutations is woefully incomplete. The fact that we can only identify 85% of the causative mutations for isoniazid resistance, one of the best-studied drugs for mechanism of action in Mtb, underscores the need for a massive effort to comprehensively identify the mutations associated with DR in TB. These mutations, in turn, will become the basis for new tests for resistance.
A further concern with respect to drug resistant TB is that DR strains, traditionally thought to be less ‘fit’ (i.e., less virulent) than their drug susceptible (DS progenitors, are showing extremely high levels of virulence, both in their ability to rapidly spread from person-to-person as well as causing rapid disease progression. Thus, there is an urgent need to identify those compensatory mutations that allow DR organisms to thrive as rampantly disseminating, highly successful pathogens. These compensatory mutations will appear as part of the DR catalog by virtue of their association with resistance phenotypes. Newly identified DR and virulence genes will not only provide the scientific community with a deeper understanding of the mechanisms by which Mtb resists treatment and evolves greater virulence, but will also point to new cellular targets for the development of novel anti-TB therapeutics.
To create the needed catalog of DR mutations, we will work in partnership with leading TB clinical researchers who hold collections of phenotypically characterized Mtb strains from patients across the globe. Within this network of collaborators we will establish common standards for contributing and describing drug susceptibility testing (DST) data and patient metadata. Geographically disparate collections of strains will allow us to identify DR-causing mutations that are common and distinct among different Mtb genetic backgrounds (lineages).
image courtesy of WHO's Global Tuberculosis Control 2011 Report