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Uncovering how T cells recognise the SARS-CoV-2 virus spike protein

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The immune system is vitally important for resolving COVID-19 when individuals are infected with the SARS-CoV-2 virus. Moreover, the vaccines that are being administered to millions of people across the globe are designed to ‘pre-warn and arm’ the immune system so that if infected with SARS-CoV-2, individuals are significantly less likely to develop severe disease or die.  Here, two crucial arms of the immune system, namely B cells and T cells, play a central role.

While we have a molecular understanding of how antibodies, which are produced by B cells, can bind and neutralise the spike protein from SARS-CoV-2, up until now researchers did not know how T cell receptors (TCRs), which are found on T cells, recognise antigens that arise from the spike protein.

“T cells play an important role in immunity against both SARS-CoV-2 vaccination and severe acute respiratory infection. Although T cells in COVID-19 have been studied previously, the molecular basis underpinning TCR recognition of SARS-CoV-2 remained unknown. It has been a pleasure working with the Monash University team to conduct this extremely important work to understand how T cells recognise an antigen from SARS-CoV-2,” said University of Melbourne Professor Katherine Kedzierska, a laboratory head at the Peter Doherty Institute for Infection and Immunity.

In a world first finding, co-led by Monash University’s Dr Priyanka Chaurasia, Dr Jan Petersen and Professor Jamie Rossjohn, and Professor Kedzierska, the team analysed the TCR recognition of a spike protein fragment when presented by an immune molecule, termed Human Leukocyte Antigen A2 (HLA-A2). This work, which utilised the Australian Synchrotron, was published in the Journal of Biological Chemistry. 

“This is a piece of a larger puzzle. While SARS-CoV-2 continues to evolve, we have to build our understanding of how effective immune responses work,” said Dr Jan Petersen.

The team provided important molecular insight into understanding how T cells of the human immune system respond to SARS-CoV-2. Different individuals mount differing immune responses to SARS-CoV-2, and this work provided fundamental insight into such an immune response.

Read the publication in the Journal of Biological Chemistry titled Structural basis of biased T cell receptor recognition of an immunodominant HLA-A2 epitope of the SARS-CoV-2 spike protein

[Paper: J Biol Chem. 2021 Aug 10;297(3):101065. doi: 10.1016/j.jbc.2021.101065.]

Original article

Also featured in ANSTO article: Understanding how adaptive immune cells recognise and interact with the SARS CoV-2 virus

Mapping the Structure of a Covid-19 Protein, NSP9

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A team of researchers at the ARC Centre of Excellence in Advanced Molecular Imaging at Monash University, using the Australian Synchrotron, have determined the 3D-structure of a SARS-CoV-2 protein at atomic resolution. Determining the shape of a protein is a key step in understanding its function and role in viral replication.

The COVID 19 virus only produces 27 or so proteins, and scientists across the world are currently trying to understand the structure and function of these 27 proteins. Dr Dene Littler, within the laboratory of ARC Laureate Fellow, Professor Jamie Rossjohn from the Biomedicine Discovery Institute, Faculty of Medicine at Monash University, have been examining some of the lesser-understood proteins produced by SARS-CoV-2. One of these, the non-structural protein 9 (Nsp9)  is thought to have a role in RNA replication and the related version of the protein in SARS-CoV is known to be important in viral replication.

This will be part of a broad strategy by the world’s scientists to develop entirely new drugs that are specifically targeted at the coronaviral proteins, blocking its ability to reproduce and infect. Technological developments such as these spurred the first forays into rational drug design, in which scientists study the structure and function of molecules in order to work out what drugs might bind to them—and in the case of viruses, preventing them from replicating.

Professor Rossjohn says that this represents the start of an accelerated program of research within Monash that is aimed at developing new anti-viral treatments as well as understanding how the immune system combats this virus.

Original article: Melbourne Researchers Map the Structure of a Covid-19 Protein—Aiding The Global Research Effort

Image: The crystal structure of Nsp9

Full publication in bioRxiv or iScience