Cholera infection and vaccination in children
Cholera is an acute dehydrating diarrheal disease caused by Vibrio cholerae, endemic in over 50 countries, and affecting over 3 million people each year. Currently available oral cholera vaccines have a lower efficacy and shorter duration of protection in young children compared to adults. Funded by the NIAID, and in collaboration with colleagues at the International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b), we are investigating the immune responses of children following both wild type cholera infection and cholera vaccination. We have identified a number of major differences between infection and vaccination, specifically pertaining to memory B cells, memory T cells, innate T cells, antibody avidity, and polysaccharide-specific responses. We are interested in how these factors differ between children and adults, and the impact of host factors, such as malnutrition, micronutrient deficiency, and enteropathy, on these responses. We have recently begun a collaboration with investigators at Johns Hopkins, MSF, and the WHO on a project to examine antibody decay kinetics in cholera patients with the goal of estimating the burden of cholera using serological surveys, in locations where infrastructure for microbial and clinical detection may be suboptimal. To facilitate seri-epidemiological investigations, we have embarked on efforts to develop cholera-specific antibody assays that can be deployed in the field, such as the use of dried blood spots.
Mucosal Associated Invariant T (MAIT) cells in mucosal infections
MAIT cells are innate-type T cells that represent 3-8% of circulating T cells in healthy adults, and are found in the intestinal mucosa, mesenteric lymph nodes, and the liver. In acute pulmonary bacterial and mycobacterial infection, MAIT cells home to mucosal sites and are depleted in the periphery. Little is known about the role of MAIT cells in enteric infections. We have recently demonstrated that in both adults and children, circulating MAIT cells are activated during acute V. cholerae infection, and that they are possibly associated with antibody responses to T cell-independent antigens. We are continuing our investigation of MAIT cells by examining their function during mucosal infections, including their capacity for B cell help, their role in longterm immune dysfunction following sepsis, and their antiviral activity in HIV infection. We have recently also begun to examine the epigenetic and micro-RNA factors regulating MAIT cell function.
Immune responses after acute intestinal infection
Suboptimal oral vaccine responses in children of developing countries have been linked to environmental enteropathy, a poorly understood condition that refers to chronic alterations in intestinal permeability, absorption, and inflammation. We are interested in how enteropathy influences antigen-specific antibody and T cell responses in children receiving oral cholera vaccine, and the contribution of innate immune effectors to longterm enteropathy following acute enteric infection. We have an ongoing study examining the fecal host trancriptomics of children as they recover from different types of diarrheal diseases, and in vivo studies using an animal model looking at systemic immunity following acute intestinal infection.
Post-Infectious Irritable Bowel Syndrome (PI-IBS) and enteropathy following longterm travel
Longterm travelers to developing countries, such as missionaries, aid workers, and military personnel, frequently suffer from diarrheal diseases while abroad, and many continue to experience gastrointestinal symptoms even after return. Studies of Peace Corp Volunteers returning from South Asia, performed nearly 50 years ago, characterized persistent episodic diarrhea in a subset of volunteers, some of whom continued to have symptoms several years later. These symptoms were associated with increased gut permeability, malabsorption, and small intestinal inflammation on histology. In collaboration with Dr. Ashok Tuteja in the Division of Gastroenterology, we are investigating the immune correlates of Post-Infectious IBS and enteropathy in longterm travelers returning from Low-Income Countries. We are interested in characterizing the immunological and microbial factors associated with gut healing, in hopes of uncovering potential interventions to treat those with enteropathy.
Laboratory of Daniel Leung, M.D., Division of Infectious Diseases, University of Utah