Defining the functional basis of the enhanced survival and replication of African Salmonella in human phagocytic cells

Invasive non-typhoidal Salmonella disease (iNTS) has emerged as a major killer in sub-Saharan Africa, responsible for ~500,000 deaths since 20091. The disease primarily affects people who are immunocompromised by HIV, malaria, anaemia or malnourishment2, and has a high case-fatality-rate (14.5%1). In Africa, iNTS is caused by one clade of S.Typhimurium and two clades of S.Enteritidis3-5. Despite many decades of research on gene function and infection biology of Salmonella, the pathoadaptive mutations that have driven the emergence of African clades are unknown. Such knowledge is vital to decipher iNTS pathogenesis and develop control strategies in the future. To address this knowledge gap, I will decipher the mechanisms that African and gastroenteritis-associated Salmonella employ to survive and replicate within a core niche, human phagocytic cells. I will achieve this using our powerful combination of comparative genomics and transcriptomics, plus new innovations in experimental evolution and genome-wide, high-throughput fitness assays. By understanding the molecular basis of the intra-macrophage lifestyle, I will determine whether these neglected African-Salmonella pathovariants have used common or divergent approaches to combat the antibacterial properties of human cells. My Research Question is: How do African Salmonella pathovariants survive and replicate so effectively in human macrophages?