Project 454699

A feature of many human infections is that only a proportion of exposed individuals develop clinical disease. To date, the primary research focus has been on the communicable nature of infections, and little is known about genetic factors that modulate host susceptibility or resistance to any given pathogen. Tuberculosis (TB) is of particular interest as it infects an estimated ten million people a year with Mycobacterium tuberculosis, but only 10% of those infected go on to develop the disease. Most new cases of active TB arise from latently infected individuals, and urgent measures to control reactivation are required. Genetic variation within the human population can contribute to TB infection/progression, as well as to resistance to treatment. However, what causes these person-to-person differences in disease susceptibility remains poorly understood. While various biological factors will certainly play a role, variation in the activity of hormones such as corticosteroids may be a key determinant. The main corticosteroid in our body is cortisol, which can activate two types of receptor proteins that mediate both pro-inflammatory and anti-inflammatory properties. We will examine how cortisol regulates the activity of the immune system and how changes to the circulating levels of this hormone will impact disease progression, resistance, and susceptibility in a zebrafish model for TB. This project will provide essential information on key endocrine factors which may determine to why some people are more susceptible to this infectious disease compared to others