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

Lead Research Organisation: University of Birmingham
Department Name: Health Service Management Centre

Abstract

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.

Technical Summary

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.

Publications

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Bobat S (2014) Bacterial infections and vaccines. in Advances in experimental medicine and biology

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Flores-Langarica A (2011) T-zone localized monocyte-derived dendritic cells promote Th1 priming to Salmonella. in European journal of immunology

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Gil-Cruz C (2009) The porin OmpD from nontyphoidal Salmonella is a key target for a protective B1b cell antibody response. in Proceedings of the National Academy of Sciences of the United States of America

 
Description Science paper - non-typhoidal Salmonella in those with HIV
Geographic Reach Africa 
Policy Influence Type Citation in clinical reviews
 
Description European Industrial Doctorate
Amount € 1,075,000 (EUR)
Organisation European Commission 
Department Seventh Framework Programme (FP7)
Sector Public
Country European Union (EU)
Start 10/2012 
End 03/2016
 
Description wellcome trust CRF
Amount £250,000 (GBP)
Organisation Wellcome Trust 
Department Wellcome Trust Research Training Fellowship
Sector Charity/Non Profit
Country United Kingdom
Start 10/2013 
End 09/2016
 
Description Australian National University 
Organisation Australian National University (ANU)
Department College of Medicine, Biology & Environment (CMBE)
Country Australia 
Sector Academic/University 
PI Contribution We worked together on different aspects of TfH development
Collaborator Contribution Publication in JEM
Impact PMID: 21708925
Start Year 2009
 
Description MRC Centre for Immune Regulation 
Organisation University of Birmingham
Department MRC Centre for Immune Regulation
Country United Kingdom 
Sector Public 
PI Contribution Contribution to a theme in the Centre: Induction and regulation of immunity in secondary lymphoid tissues. My work examining how immune responses develop to pathogens and their components offers broad cross-theme collaborations.
Collaborator Contribution Access to material and equipment as well as MRC students
Impact From this collaboration nearly all of my publications and patent are due, in part, to this collaboration.
 
Description Mexico 
Organisation Immunochemistry Research Unit
Country Mexico 
Sector Public 
PI Contribution The proteins provided were important for identifying the nature of the antibody response to Salmonella
Collaborator Contribution Unique materials
Impact PNAS paper - 19487686 Science paper - 20413503 We are also collaborating on how best to take the OmpD vaccine forward. We hold the patent on OmpD and they hold the patent on the purification.
Start Year 2006
 
Description NVGH 
Organisation Novartis Institutes for BioMedical Research (NIBR)
Department Novartis Vaccines Institute for Global Health (NVGH)
Country United States 
Sector Private 
PI Contribution We identified the vaccine target and I have been involved in helping develop aspects of the immunological side of the collaboration
Collaborator Contribution Publications and the use of industrial skills to develop our vaccine against non-typhoidal Salmonella
Impact The development of OmpD as a vaccine. NVGH have taken licec of the patent protecting this work. The project is multi-disciplinary as it covers biology and chemistry.
Start Year 2010
 
Description Sanger 
Organisation The Wellcome Trust Sanger Institute
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution We used the bacteria to confirm our hypotheses regarding the protective nature of antigens We have expanded the use of these bacteria to assess the major determinants of protection during Salmonella infection
Collaborator Contribution Gene-deficient bacteria
Impact PNAS paper - 19487686 Science paper - 20413503
Start Year 2007
 
Description Southampton 
Organisation University of Southampton
Department Faculty of Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution We are working on ways that Salmonella interferes
Collaborator Contribution Intellectual input
Impact CD11c paper Immunology - 20465572
Start Year 2009
 
Description UCT 
Organisation University of Cape Town
Country South Africa 
Sector Academic/University 
PI Contribution We have published a number of papers together examining how antibody responses and vaccines work. We have conducted research visits to UCT to perform the work there and also collaborated by providing advice and reagents
Collaborator Contribution They have provided unique reagents and resources enabling us to conduct experiments and studies not possible in their absence.
Impact doi: 10.1007/978-1-4939-1489-0_4 doi: 10.1371/journal.ppat.1003662 doi: 10.1371/journal.pntd.0003341
Start Year 2009
 
Description Vaccine development with GSK Vaccines for Global Health 
Organisation GlaxoSmithKline (GSK)
Country Global 
Sector Private 
PI Contribution We are developing a novel generation of vaccines. We have the expertise to assess how they function
Collaborator Contribution Our partners generate the vaccine candidates
Impact This has just started
Start Year 2017
 
Title NTS OmpD vaccine 
Description That the protein OmpD can be used as the whole or part of a vaccine againstnon-typhoidal Salmonella infection 
IP Reference WO2010029293 
Protection Patent granted
Year Protection Granted 2010
Licensed Yes
Impact This has now been licenced to Novartis Vaccines for Global Health
 
Title NTS OmpD vaccine 
Description A vaccine against non-typhoidal Salmonella infection 
Type Therapeutic Intervention - Vaccines
Current Stage Of Development Refinement. Non-clinical
Year Development Stage Completed 2009
Development Status Under active development/distribution
Impact This is being developed by Novartis Vaccines for Global Health 
 
Description Media agency telephone interview 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Media (as a channel to the public)
Results and Impact Interviewed by telephone regarding the impact of the research for vaccine development

I was invited to interview to Radio 4. The interview was also hosted on a number of websites and newspapers locally, nationally and internationally
Year(s) Of Engagement Activity 2009
 
Description Radio interview 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Interview on Radio 4, discussing the implications of our work for a vaccine against Salmonella infection

Increased profile, liaisons with members of the public emailing me.
Year(s) Of Engagement Activity 2009
 
Description Secondary school student work experience 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? Yes
Type Of Presentation Workshop Facilitator
Geographic Reach Local
Primary Audience Schools
Results and Impact 1 student for work experience.

This has developed into a longer-term relationship. For instance, I will host another student next year and have arranged to talk at the school next year.
Year(s) Of Engagement Activity 2012
 
Description TV interview 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Regional
Primary Audience Media (as a channel to the public)
Results and Impact Interview with BBC Midlands Today, the Midlands BBC news programme

We highlighted the vaccine work undertaken in Birmingham
Year(s) Of Engagement Activity 2012
 
Description University media centre and alumni 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact Interviewed by telephone and generated a press release outlining the work and its importance as well as the clinical problem

Led to other interviews and contacts
Year(s) Of Engagement Activity 2009
 
Description school visit 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Talks at local schools about animal experimentation and immunology, vaccinology and infectious disease. During this it became clear it is important alos to offer career advice. This is something also pursued by members of my group

Increased awareness and involvement with other schools
Year(s) Of Engagement Activity 2010,2011,2012,2013,2014