The immunological basis of susceptibility to nontyphoidal Salmonella bacteraemia among HIV-infected adults in Uganda Nontyphoidal strains of Salmonella are a major cause of fatal bloodstream infection in Africa, particularly among young children and people living with HIV/AIDS. These Salmonella infections are difficult to diagnose and antibiotic resistance is an increasing problem, so an effective vaccine against nontyphoidal Salmonella (NTS) has the potential to save many lives. Vaccines currently in development against NTS aim to work by stimulating the production of antibodies to a sugar known as O-antigen which is part of the lipopolysaccharide (LPS) molecule and found on the Salmonella surface. My previous research has shown that some HIV-infected adults in Africa have very high levels of these antibodies which then block killing of the Salmonella bacteria. Hence there is a risk that these vaccines may cause harm to people with HIV.  This project aims to understand the basis for susceptibility to NTS bloodstream infections in HIV-infected Africans, and in particular to understand the phenomenon of blocking antibodies, with a view to designing improved vaccines that will protect HIV-infected groups against NTS. I hypothesise that NTS is present at increased levels in the gut in HIV infection and that because the gut wall does not function properly in these patients, the Salmonella bacteria are able to invade the bloodstream. Here they can go on to cause severe disease and death due to the inability of the immune system to kill these bacteria, because of the presence of blocking levels of antibodies. I hypothesise that the continual movement of Salmonella and Salmonella LPS into the circulation drives the production of these high levels of blocking antibodies, because antibody production is no longer appropriately regulated in HIV infection.  I will test this hypothesis in a group of adults newly-diagnosed with HIV infection in Uganda, studying them for two years after they commence antiretroviral therapy (ART) and comparing them with HIV-uninfected subjects. Incidence of NTS bloodstream infections initially rises when starting ART and then falls, but remains much higher than in HIV-uninfected subjects. Therefore, looking at specific immune parameters with time on ART will help understand which are most relevant to susceptibility to NTS infection. Since compromise of the barrier state of the gut is key to my hypothesis, I will study samples of gut tissue taken at endoscopy, as well as peripheral blood.  First, I will test to see whether NTS is present in the gut of HIV-infected participants and whether it occurs more frequently and at higher levels than in HIV-uninfected controls. Then I will investigate the transfer of Salmonella from the gut to the bloodstream and compare this with the immune status of the gut wall, seeing whether this transfer is associated with loss of particular groups of immune cells known as Th17 and mucosal-associated invariant T (MAIT) cells. Finally, I will study the levels and function of antibodies targeting LPS O-antigen, to determine whether they block or kill Salmonella, comparing them with antibodies to a protein known as flagellin which is also present on the Salmonella surface. I will test whether levels and function of these antibodies associate with changes in the numbers and function of two further groups of immune cells, Tfh and Treg cells, which are infected by HIV and which regulate antibody production.  I will follow changes in these immune parameters in the group of HIV-infected participants over time on ART, and look for associations at time points with known differences in susceptibility to NTS. This will enable me to better understand which factors are most relevant for susceptibility to NTS, the mechanism of susceptibility and production of blocking antibodies, and what vaccine or other therapeutic strategies might best protect HIV-infected populations against NTS. The Global Challenges Research Fund (GCRF) supports cutting-edge research to address challenges faced by developing countries. The fund addresses the UN sustainable development goals. It aims to maximise the impact of research and innovation to improve lives and opportunity in the developing world.