The route towards T cell activation: how TB and I crossed paths
The story behind the paper: "Mycobacterium tuberculosis EsxH inhibits ESCRT-dependent CD4 T cell activation"
Is life a series of random events or, as in a Greek tragedy, are our destinies pre-determined? The path to the publication of this article has a little of both visions of life. I grew up in Mexico City and initiated my clinical training there, which exposed me to multiple patients with tuberculosis (TB), a disease that still imposes a high burden of morbidity and mortality in developing countries like mine. This experience nurtured my desire to become a physician scientist and to study host-pathogen interactions.
Half way through my training in Internal Medicine at Universidad Nacional Autónoma de Mexico in Mexico City, life circumstances brought my family to New York City. As luck would have it, I found a position in a laboratory in New York University, which led me to start a PhD in Microbiology. Upon completion of my PhD, I went back to practicing medicine, but as a foreign medical graduate the road was complicated, challenging, and time-consuming. However, it took me to Bellevue Hospital, where once again I was exposed to multiple patients with TB. Again I was struck by the medical importance of TB and the imperative to develop new diagnostics, therapeutics, and an effective vaccine. Now I had the scientific training to contribute to these endeavors.
In particular, I wanted to understand why our immune response does not provide sterilizing immunity, as this would be key to developing an effective vaccine. As a second year infectious diseases fellow, I joined the laboratory of Dr. Jennifer Philips, which studies host-pathogen interactions between Mycobacterium tuberculosis (Mtb) and innate immune cells. Previous work in the laboratory had established that a substrate of the bacterial type VII secretion systems (T7SS), EsxH, interacts with the host protein, hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs), a component of the endosomal sorting complex required for transport (ESCRT). I hypothesized that this interaction was important in allowing Mtb to evade immune-mediated clearance.
In the current issue of Nature Microbiology, we report that EsxH inhibits MHC-II antigen presentation by targeting ESCRT, which would otherwise promote T cell activation by facilitating antigen processing. Our findings provide a molecular explanation for the delay in the initiation of the adaptive immune response during Mtb infection and the failure of CD4+ T cells to promote sterilizing immunity.
The tribulations of completing a PhD and the complications of going back to medical training as a foreigner could not have been a better preparation for working with Mtb. The complex nature of the pathogen, such as extremely slow growth rate, difficulty in performing genetic experiments, and the need to work under stringent biosafety conditions, presents unique challenges for the researcher. Mtb has proven to be a good mirror for life: it is uncertain, resistant, takes patience, and, whether stochastic or pre-determined, there is beauty in it. Our findings reveal one important mechanism employed by Mtb to evade the immune response and may lead to the development of novel therapeutics or vaccines with the potential to achieve bacterial clearance.
To read the full article, please go to Nature Microbiology website: http://www.nature.com/articles/nmicrobiol2016232