GHES U.S. Fellow 2014-2015
Fellowship Site: Fiocruz, Bahia, Brazil
U.S. Institution: Yale University School of Medicine
Project Title: Immunopathogenesis in Human Leptospirosis
Leptospirosis is a disease that has a large economic and health impact on the world’s poorest populations. The disease causes a broad spectrum of illness, including leptospirosis-associated pulmonary hemorrhage syndrome (LPHS) which has high mortality rates. Despite the incidence of this disease, key knowledge gaps pertaining to the human immune response to Leptospira infections exist. The immune responses necessary for clearance of infection and development of long-term immunity have not been characterized nor is the role of the immune system in the pathogenesis of LPHS defined. We aim to identify the specific immune responses associated with development of severe disease outcomes. SPECIFIC AIMS 1) Define the kinetics of the human immune response during symptomatic Leptospira infection. In a cohort of patients hospitalized for leptospirosis, we will immunophenotype cells involved in the innate and acquired immune responses. We will measure the proportion of activated neutrophils and monocytes, quantitate cytokines, and characterize T cell and B cell responses over time using longitudinal samples. 2) Determine whether a specific immune response is associated with severe clinical outcomes. We will characterize innate and adaptive immune responses present at hospital admission in patients with poor disease outcomes (LPHS, death, renal failure, sepsis) and in patients with classic leptospirosis. We will compare the resultant immunoprofiles from the two groups to identify specific factors that are associated with poor disease outcomes. This work will be the first to identify the key components and kinetics of the immune response to Leptospira in patients presenting a range of clinical severity. Additionally, we will elucidate whether there is an immune signature that influences poor disease outcome.