Mycobacterium tuberculosis (Mtb) is among the most notorious and deadly pathogens of man.  This bacterium, the causative agent of tuberculosis (TB) currently infects a third of the world’s population, approximately 2 billion people, and these infections are extremely difficult to treat.  Indeed, Mtb cells become inherently tolerant to antibiotics upon infection and can persist for years in tissues despite robust immune responses that would quickly eliminate most other invaders.  Furthermore, there is a sharp increase in the global burden of drug resistant TB, exacerbating this problem.  Eradication of this stubborn infection is among the most challenging problems in global infectious diseases, yet we know very little about the biological basis for what makes Mtb such an extraordinary pathogen.

Mtb has co-evolved with the human species since the expansion of modern human populations, nearly 40,000 years ago. Over this time, this pathogen has enmeshed its physiology deeply with that of its human host, making it extremely difficult to eradicate.  This pathogen has sevolved sophisticated mechanisms that enable the bacterium to evade host defenses and persist in host tissues.  In the Cox lab, we seek to use novel experimental tools to identify and understand these strategies at the molecular level.  In particular, we are interested in defining the host-pathogen interface essential for establishment and maintenance of this long-term relationship between prokaryote and eukaryote.  Our long term goal is to find critical points where drug interventions may lead to greater efficacy, and to uncover the immune evasion strategies that would allow us to engineer new vaccines.

The TB field has entered a new era with the convergence of genetic tools, genome sequencing, bioinformatics, advanced imaging techniques, animal models of infection, and high-throughput assays that allow us to study this multi-faceted interaction between Mtb and its host. We use all of these tools to probe the molecular and cellular events that enable M. tuberculosis to evade host defense mechanisms. We are interested in the following questions

1.  How does Mtb evade macrophage killing mechanisms?

2.  What are the physical interactions mediated by the bacterium that are responsible for virulence?

3.  How does the host discriminate between pathogen and non-pathogen?

4.  What are the innate immune defense mechanisms specifically activated by virulent mycobacteria?

5.  How does Mtb persist during robust, specific immune responses?
         - Immune evasion strategies
         - Host-activated, phenotypic tolerance

 

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