Professor Adam Cunningham

Supervisor Details

Contact Details

Institute of Immunology and Immunotherapy, University of Birmingham

Scientific Background

Research Interests

Themes

B cells, T cells, generation and maintenance of adaptive responses, infection, vaccination, immune homeostasis, immune modulation

Lay summary

Their work aims to understand how infection changes who we are as individuals. Their work has a particular focus on how infection can educate the immune system and the specific elements and cells of the immune system that respond to pathogens. An exciting consequence of this work is that by comparing how they react to the whole pathogen or to individual components of the pathogen they can generate new vaccines to infections and new treatments to infectious and non-infectious diseases.

Overview

Their research uses in vivo models of infection to study how infection and vaccination modifies immune homeostasis, with a particular emphasis on adaptive immunity. Relating these changes to bacterial clearance helps identify how infections are controlled and how vaccines function. Furthermore, understanding the relationship between host and pathogen helps identify novel approaches to exploit bacteria and their components as prophylactics and therapeutics in infectious and non-infectious diseases.

Examples of current themes ongoing in the laboratory include:

The development of vaccines against non-typhoidal Salmonella and the potential of B1b cells as targets for vaccination
How T and B cell responses are regulated after infection and vaccination
How lymphopoiesis is regulated in the thymus and bone marrow during infection
How bacteria and their components immunomodulate the host during infectious and non-infectious disease
How multiple and co-infections impact upon host homeostasis and immune function
How dormant tuberculosis infections in humans are maintained

Such investigations require studies of immune homeostasis in multiple anatomical locations concurrently, the different cellular subsets involved and the kinetics of these events.

Though this work is performed primarily in the context of infection and vaccination, with a particular focus on adaptive immunity and its direction by the innate immune system, the principles allow us to investigate how non-infectious disease impacts on the host.

Their work has shown that the immune system responds differently to the same antigen when presented in different immunological contexts and in different anatomical compartments. This is important since it means they can modify the response to an antigen or promote a particular host function simply by altering how they deliver antigen to the immune system. This capacity to modulate the host response to a pathogen or a component of a pathogen or a vaccine underlies our translational work (see publications). Lastly, using this knowledge they can exploit their findings to maintain and improve health as we age through directing and stimulating beneficial, long-term immune responses. Collectively, their work therefore helps understand how they can improve immunity to infectious and non-infectious disease.

MIBTP Project Details

Current Projects (2025-26)

Primary supervisor for:

How do anti-lipopolysaccharide antibodies inhibit or enhance protection against infection?

See the PhD Opportunities section to see if this project is currently open for applications via MIBTP.

Please Note: The main page lists projects via BBSRC Research Theme(s) quoted and then relevant Topic(s).

How do anti-lipopolysaccharide antibodies inhibit or enhance protection against infection?

Secondary Supervisor(s): Dr Amanda Rossiter

University of Registration: University of Birmingham

BBSRC Research Themes: Integrated Understanding of Health (Ageing)

Project Outline

The typhoid conjugate vaccine has transformed the outlook for controlling Salmonella Typhi infections and has spurred vaccine efforts against non-typhoidal Salmonella (NTS) serovars. The most devastating form of NTS is invasive (i) NTS, caused mostly by S. Typhimurium (STm) and S. Enteritidis (SEn). These serovars lack Vi and so the vaccine focus has been on the lipopolysaccharide (LPS) O-antigen (O-Ag). Understanding how antibodies (Ab) to LPS protect, aided or otherwise by Ab to other bacterial antigens is essential to identify how to exploit O-Ag as a vaccine target, both for Salmonella and other Gram-negative pathogens. However, there is a paradoxical role for Ab to LPS O-Ag, since our work shows having too many Ab to O-Ag actually impedes bacterial killing (to this and other Gram-negatives). It is important to understand the binding of Ab to O-Ag at the “sweet spot” level of killing and when the same Ab are present at inhibitory levels, particularly since a key aim of vaccination is to induce the maximum level of antibodies possible. This timely project will identify how Ab to LPS O-Ag function and combine with Ab to non-O-Ag to kill bacteria and bridges microbiology, immunology and vaccinology.

Objectives

To achieve this we will address 3 objectives:

i) How do Ab to LPS and non-O-antigen combine to bind to single bacteria? We will examine how IgM, IgG and IgA compete to bind to single bacteria (using flow cytometry and imaging) and how this affects complement binding and phagocytosis. If necessary, we can extend to super resolution microscopy (discussions with Profs Dylan Owen / Dirk-Peter Herten), From this, we will: i) identify the frequency of bacteria that bind different antibody classes; ii) how antibody binding to one antigen influences access to a second antigen and iii) how this modulates effector functions of Ab.

ii) How do anti-LPS antibodies inhibit bacterial killing? We will use the data from Objective 1 to examine how Ab to LPS O-Ag inhibit cell-dependent and independent bactericidal killing of Salmonella, using our cell-independent and dependent systems. We will use purified anti-LPS Ab to establish the levels of Ab needed to inhibit killing and i) label bacteria with inhibitory levels of Ab and measure access to bacterial antigens by Ab to non-O-Ag; ii) levels of complement (C3, C4, C5) binding to the bacterial surface and iii) measure C3a, C4a and C5a anaphylatoxin release and downstream pro-inflammatory effects on neutrophils and macrophages. From these experiments we will determine the nature of inhibitory antibodies and how they inhibit killing.

iii) Do anti-LPS antibodies cross-link LPS to enhance access to the bacterial cell surface? We will use the results and techniques generated to determine how combinations of Ab enhance +/- limit bacterial killing through host cell-dependent and independent mechanisms. We will use different concentrations of anti-O-Ag Ab from sub-bactericidal levels to those with lower and higher levels of killing to investigate i) how the addition of Ab targeting non-O-Ag targets influence bactericidal killing and ii) how the presence of anti-LPS Ab influences the level of surface access and binding by non-O-Ag-targeting Ab. These studies will include murine and human Ab and models. We will assess whether non-O-Ag targets enhance the level of killing by anti-O-Ag targets, particularly at lower levels of anti-LPS Ab. The concept tested here is that only a low proportion of anti-O-Ag Ab provide bactericidal killing activity, but that beyond this, these antibodies act to “bundle” O-Ag together to expose the cell membrane enabling access by other non-OAg Ab that synergise to enhance bacterial killing through increasing exposure to the bacterial membrane.

Key References

MacLennan CA, Science, 2010; Schager AE, MBio, 2018; Domínguez-Medina CC, Nat Comms, 2020.