Digging for melioidosis: New insights into the epidemiology and pathophysiology

Melioidosis, caused by the Gram-negative soil dwelling bacterium Burkholderia pseudomallei, is an important cause of community-acquired pneumonia and sepsis in Southeast Asia and Northern Australia. Globally, melioidosis accounts for an estimated 169,000 cases and 89,000 deaths per year, yet the true burden remains poorly understood. There is a clear discrepancy between melioidosis estimates and the number of reported cases, explainable mostly by the lack of awareness and under-developed or non-existent microbiological facilities. The aims of this thesis are to provide new insights into the burden of melioidosis, the distribution of B. pseudomallei in sub-Saharan Africa, the pathophysiology of melioidosis, and new treatment strategies and vaccines. First, we quantify the global burden of melioidosis in terms of disability-adjusted life years (DALYs). We show that the DALY of melioidosis is higher than other recognized neglected tropical diseases, such as schistosomiasis and dengue. Second, we provide a literature overview of B. pseudomallei in Africa and demonstrate the presence of B. pseudomallei in humans and soil in Gabon. We characterize the inflammatory response induced by the Gabonese isolate. In Sierra Leone, we detected no B. pseudomallei in the environment, but multiple new B. thailandensis sequence types. Third, we focus on host-pathogen interactions during melioidosis. We show that thrombocytopenia impairs the host defense and that the gut microbiota is a potential modulator of the host response. Lastly, we investigate a potential novel vaccine against B. pseudomallei. In conclusion, this thesis adds to the growing understanding that melioidosis needs to be recognized as a deadly neglected tropical disease.