Near-universal T cell immunity towards a broad range of bacteria

Typically, T cells of the immune system respond to a specific feature (antigen) of a microbe, thereby generating protective immunity. As reported in the journal Immunity, an international team of scientists have discovered an exception to this rule. Namely, a group of divergent bacterial pathogens, including pneumococci, all share a small highly conserved protein sequence, which is both presented and recognized by human T cells in a conserved population-wide manner.

The study set out to understand immune mechanisms that protect against pneumococcus, a bacterial pathobiont that can reside harmlessly in the upper respiratory mucosae but can also cause infectious disease, especially in infants and older adults, which can range from middle ear and sinus infections to pneumococcal pneumonia and invasive bloodstream infections.

Most currently used pneumococcal polysaccharide-based conjugate vaccines (PCVs) are effective against 10–13 serotypes, but growing serotype replacement becomes a problem.

WHO estimates that 1.6 million people die of pneumococcal disease every year, including 0.7–1 million children aged under 5, most of whom live in developing countries.

The Monash Biomedicine Discovery Institute-co-led study, in collaboration with the National Institute for Public Health and the Environment (RIVM) and Utrecht University in the Netherlands and Cardiff University in the UK, identified a crucial fragment of the pneumococcal toxin pneumolysin that was commonly presented by a particular class of human antigen presenting molecules and recognized by T cells from most people who naturally develop specific immunity to pneumococcal proteins.

The study further found that the uniformly presented and broadly recognized bacterial protein fragment was not unique for the pneumococcal pneumolysin but was shared by a large family of bacterial so-called cholesterol dependent cytolysins (CDCs). These are produced by divergent bacterial pathogens mostly affecting humans and cause a range of respiratory, gastro-intestinal, or vaginal infectious diseases.

Neutralizing the bacterially derived cytotoxic bomb: the pneumococci lie in the background, an array of macrophages and dendritic cells are arranged around the central image of a T cell. Rows of TCRs interacting with the identified pneumolysin epitope bound to HLA (white) cross the length and breadth of the artwork, emphasising their centrality in the immune response. Artwork by Dr. Erica Tandori.

First author Dr Lisa Ciacchi said “The use of the National synchrotron was key to provide molecular insight into how the T cell receptors see these conserved antigens when presented by common Human Leukocyte Antigen (HLA) molecules”.

Shared first author Dr Martijn van de Garde said “We have not yet identified the exact function of the near-ubiquitous T cell populations to this commonly presented conserved protein fragment during ongoing colonizations or infections with CDC producing bacteria. Whether the T cells have a cross-protective mode of action or have an anti-inflammatory tolerizing function, remains to be investigated”.

Shared first author Dr Kristin Ladell said “The identification of T cells that recognize a ubiquitous bacterial motif using T cell receptors that are shared between individuals with prevalent HLAs is very exciting. Reagents generated for this study can now be used to study patient groups to examine how prevalent these shared TCRs are and how they are related to immune protection”.

Continuing investigations could instruct the development of interventions for people to more efficiently resist or clear CDC-related bacterial diseases.

Read the full Immunity paper: CD4+ T cell-mediated recognition of a conserved cholesterol-dependent cytolysin epitope generates broad antibacterial immunity

DOI: 10.1016/j.immuni.2023.03.020

Artwork: Surveying the bacterial horizon and Fighting against the bacteria we breathe, by Dr Erica Tandori.

Surveying the bacterial horizon: a scientist surveys a landscape of pneumococci, under a blue sky with a T cell sun and macrophage clouds. The flying machine is buoyed by dendritic cell balloons and fans of private and public TCRs bound to pneumolysin epitope-HLA complex, which recognise the bacterial threat. Artwork by Dr. Erica Tandori.

Fighting against the bacteria we breathe: our immune machinery; T cells, macrophages, and dendritic cells combat a pneumococcal infection and other bacteria (top left and bottom right), within the lungs. The artwork also features an overlay of public and private TCRs binding pneumolysin epitope-HLA complex, emphasising their importance in detecting this harmful cytotoxin. Artwork by Dr. Erica Tandori.

Original article

Congrats Praveena on the award of the ARC DECRA

Monash BDI early career researchers awarded more than $2m ARC DECRA funding

Five Monash Biomedicine Discovery Institute (BDI) researchers have been awarded $2.23 million under the 2023 ARC Discovery Early Career Researcher Award (DECRA) scheme.

Minister for Education, Hon Jason Clare MP, announced $85 million for 200 projects nationwide to support early career researchers under the DECRA scheme.

Researchers at the Monash BDI received five awards to support a diverse range of discovery research into nanobiotechnology, bacterial membrane remodelling, microbial life in the atmosphere, lipid-mediated T cell immunity, and understanding how T cells recognise and respond to foreign antigens.

“This success is a testament to the depth of excellence in our early career researcher cohort, and I congratulate this outstanding group of recipients,” said Professor John Carroll, Director of the Monash BDI.

The grants awarded to the Monash BDI are:

Project: ‘Molecular insights into lipid-mediated T cell immunity.’ Dr Praveena ThirunavukkarasuRossjohn Lab, awarded $421,485

This project involves the discovery of novel lipids produced by the microbiome that play a significant role in T cell-mediated immunity. Using a combination of cutting-edge technologies such as mass spectrometry, protein crystallography, immunology and biophysics, this project will elucidate the molecular factors that govern the interaction between the identified lipids and T cells. This innovative research will provide fundamental insights into the recognition mechanism of lipids by T cells at a molecular level, thus broadening our knowledge in the field of biological sciences. The expected research outcomes will increase Australia’s international research standing in this burgeoning area of lipid-mediated T cell immunity.

Project: ‘A novel bacterial secretion system for applications in nanobiotechnology.’ Dr Christopher StubenrauchLithgow Lab, awarded $429,449

This project aims to characterise a new molecular machine, called the S-Pump. Molecular machines drive the complex biology in all cells and are an exciting area of translational research, with broad potential for industrial applications. This project expects to provide fundamental insights into how bacterial S-Pumps contribute to antimicrobial resistance and enhancing food production. Expected outcomes include new tools for molecular machine discovery and identification of ways to adapt molecular machines for biotechnological applications. This work should enhance Australia-UK ties through collaboration, provide benefits toward nanobiotechnology and economic benefits through more efficient food production.

Project: ‘Bacterial membrane remodelling and the interaction with peptides.’ Dr Meiling HanJian Li Lab, awarded $450,241

This project aims to elucidate the fundamental mechanism of lipid remodelling in the Gram-negative outer membrane, which is critical both in preventing noxious compounds and evading host immune defence. For the first time, the complex interplay between bacterial cellular metabolism and membrane remodelling will be defined through systems pharmacology, and the precise membrane-peptide interaction will be examined by computational and biophysical approaches. Novel knowledge will be generated to improve our understanding of how bacteria remodel their outer membrane in response to environmental stress. This will benefit the future design of much-needed antimicrobial strategies including products and technologies to target bacterial membranes.

Project: ‘Microbial life in the atmosphere.’ Dr Rachael LappanGreening Lab, awarded $454,741

This project aims to resolve the nature and basis of microbial life in the atmosphere, the largest but most unexplored potential ecosystem on Earth. The atmosphere plays a role in transporting microbes, but our understanding of resident atmospheric microbial communities and their role in global atmospheric processes is minimal. Using cutting-edge molecular and biogeochemical approaches, this project aims to identify true microbial residents of the atmosphere, understand their mechanisms for survival in this environment and explore their role in seeding newly formed environments. The anticipated outcomes include fundamental knowledge on atmospheric microbial ecosystems, and their influence on global atmospheric processes.

Project: ‘Redefining how T cell recognition drives T cell activation.’ Dr Pirooz ZareieLa Gruta Lab, awarded $470,789

This proposal aims to define the key mechanisms that determine how T cells recognise and respond to foreign antigens; a critical feature that defines effective immunity. To achieve this goal, this proposal will leverage multidisciplinary collaborations and innovative methods to understand how structural and biochemical features of T cell receptor recognition influence T cell mediated immunity and development. In turn, this project will facilitate further research and development in the burgeoning field of T cell biology and advance life science research in Australia. Furthermore, as T cell biology is relevant to all vertebrates, this research will greatly benefit the conservation of threatened animal species and agriculture.

The DECRA scheme is designed to expand the knowledge base and research capacity in Australia and to provide economic, commercial, environmental, social and/or cultural benefits for Australia.

A full list of the 2023 ARC DECRA recipients and their projects is available on the ARC website.

Read the ARC Media Release announcing the DECRA scheme recipients on 16 September.

About the Monash Biomedicine Discovery Institute

Committed to making the discoveries that will relieve the future burden of disease, the Monash Biomedicine Discovery Institute (BDI) at Monash University brings together more than 120 internationally-renowned research teams. Spanning seven discovery programs across Cancer, Cardiovascular Disease, Development and Stem Cells, Infection, Immunity, Metabolism, Diabetes and Obesity, and Neuroscience, Monash BDI is one of the largest biomedical research institutes in Australia. Our researchers are supported by world-class technology and infrastructure, and partner with industry, clinicians and researchers internationally to enhance lives through discovery.

Original article

Also here

Congrats Wael on your ARC DECRA

Congratulations to Monash Biomedicine Discovery Institute researcher Dr Wael Awad who is one of 15 Monash researchers recognised with Discovery Early Career Researcher Awards (DECRA) from the Australian Research Council (ARC).

Dr Awad’s (Le Nours Lab) project aims to undertake discovery research to investigate the roles of metabolites in T cell immunity. This project expects to generate new knowledge in the areas of cellular biology and immunology by using cutting-edge molecular and immunological approaches. This will provide fundamental insights into the mechanisms that govern microbial metabolite-based T cell immunity, which may advise future research into vaccines or therapeutics.

In addition to knowledge gains, Dr Awad’s expected project outcomes include developing innovative methodology and building international collaborations to enhance national research capabilities. This will place Australia at the forefront of conceptually innovative discovery in the life sciences.

More than $6.25 million has been awarded to the 15 Monash researchers under the DECRA scheme, which provides focused research support for early career researchers in both teaching and research, and research-only positions.

Deputy Vice-Chancellor (Research) and Senior Vice-President Professor Rebekah Brown said: “This is great recognition of the excellent research these researchers are doing so early in their careers.”

“This investment allows them to build their career pathway and grow the impact of their research. The diverse range of projects across disciplines and faculties – and the real-world impact of these projects – shows that the future is bright for research at Monash.”

Read about each of the 15 Monash researchers who have been recognised with DECRAs from ARC.

A total of $83 million was distributed in the 2021 round. Read the full details on the ARC website.

Original article