A bug in the system: how does Salmonella induce novel B cell responses?

We are trying to understand how proteins called antibodies and the cells that make them work to protect against Salmonella infections. This should help improve vaccines against Salmonella and other bacteria since nearly all vaccines work via antibody.
Salmonella infections can have deadly consequences killing hundreds of thousands around the world yearly. In some cases if Salmonella is found in an infant’s blood then that child has a near 25% chance of dying.
Salmonella travels through the blood to infect and grow in many sites such as the liver or spleen. Yet the body is not defenceless against this spread because antibodies can bind Salmonella and lead to its killing. But to be effective the antibody needs to be present before the infection and this can be achieved by vaccination.
Using a mouse model, since these complex events cannot be effectively mimicked in other systems, we have found that antibodies to some Salmonella proteins can prevent infection and may help us design an effective, safe vaccine. Since these Salmonella proteins and the cells that make the antibody have some unusual properties we hope that these studies may help us better understand how we fight bacteria and then use this information to design vaccines to other bacterial diseases.

Salmonella infections have deadly consequences. In sub-Saharan Africa non-typhoidal Salmonella infections (NTS) are a leading killer and the most susceptible groups are children 6 months but 24 months of age and HIV+ adults. Death is associated with bacteraemia in the absence of antibody, implicating antibody may be protective although the role of humoral responses in immunity to Salmonella has been controversial. Recently we published that Salmonella infection induces a novel antibody response characterized by a rapid, extensive T-independent extrafollicular (EF) response concomitant with accelerated T-dependent switching. This response is selective since switched antibody to outer membrane proteins (OMPs), but not LPS or flagellin, is detected early in the infection and occurs in the absence of germinal centres (GC) and associated high-affinity antibody and memory B cell formation. The antibody induced during the response reduces bacteraemia and subsequent colonization. We have extended these findings to show that antibody protects mice with defective cell-mediated immunity and that the proteins, OmpF and C, but not LPS induce a population of self-renewing B220intCD5- B1b B cells. This B1b population, the first identified to a protein antigen, offers strong protection against infection when transferred into B cell-deficient mice. This project aims to improve our understanding of the biology of the B cell response to Salmonella and how we can exploit this to improve vaccine design by using murine models of infection and protection. We will use immunohistology, confocal microscopy, cell sorting and PCR to identify the cell populations involved, the sites of their activities and their individual molecular signatures. We will identify the capacity of individual cell populations to contribute to protection by transferring different populations of cells into recipient mice. In particular we want to determine 1) How important are these B1b cells to the massive EF response induced by Salmonella? 2) How do T cells interact with these cells, are they responsible for the early switched antibody and do they form part of the GC response? 3) How can we improve the protection offered by vaccinating with these proteins? 4) What is the mechanism by which protection is conferred? Together this information will contribute to improving our understanding of basic immunological processes during bacterial infection and to developing vaccines against NTS infections.