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Covid19 biomarker discovery for diagnostic and therapeutic purpose

Primary Supervisor: Dr Lijiang Song, Department of Chemistry

Secondary supervisor: Professor Liz Wellington, SLS

PhD project title: Covid19 biomarker discovery for diagnostic and therapeutic purpose

University of Registration: University of Warwick

Project outline:

A novo coronavirus strain, belongs to the beta coronavirus genera, is responsible for the 2019-2020 coronavirus pandemic. The new coronavirus has since been named as Severe Acute Respiratory Syndrome coronavirus 2 (SARS-Cov-2) by the international virus classification commission, and the disease is called coronavirus disease 2019 (Covid19). On the 30th January 2020, the WHO declared the 2019 novo coronavirus outbreak as a Public Health of International Concern, which was re-characterised as a pandemic on the 11th March 2020. Since then, unprecedented fast spreading of virus has been observed in almost every country and region in the world. Up to the 7th of April 2020, there are more than 1.4 million confirmed cases and more than 82,000 fatalities across the world. Covid19 is a serious respiratory disease, which can affect almost everyone in society, particularly the elderly and people with underlying health issues. Severe disease onset can result in death even in health young population.

Lack of detailed understanding of covid19, including its epidemiology, virus pathogenesis and human immunity response, severely hamper the current global effort to contain and control the spread of the disease. To build a true picture of the on-going pandemic, quick, sensitive and reliable diagnostic method is urgently required to determine the number of people who are infected. There are many limitations with the currently employed nucleic acid test methods which are based on RT-qPCR (Reverse Transcribe quantitative Polymerase Chain Reaction). The current methods are relatively expensive to run, and it is very time consuming, it often take days for result to be returned. The requirement for special safety equipment and laboratory (BSL3 is recommended) are also preventing these to be more widely used in resource-poor countries. Another main issue with many of the nucleic acid test kits is the high false negative rate, this is obviously a major concern while we try to control the spread of the disease. People who tested negative but actually carry the virus can spread it even further unintentionally.

Genetic analysis of the SARS-Cov-2 has revealed that its genome is a single strand RNA of 29811 base, it is more closely related with two known bat derived coronaviruses. The SARS-Cov-2 genome is annotated into 14 open reading frames (orfs) and coding at least 27 proteins. Bioinformatic analysis has revealed there are clear differences between SARS-CoV-2 and SARS-CoV despite the 90% similarity at amino acid level. It has been reported that like SARS-Cov, SARS-Cov-2 has the same cellular receptor as angiotensin converting enzyme 2 (hACE2), found on the surface of vascular endothelial cells in the lungs, arteries, heart, kidney and intestines. Virus utilises its S protein (spike glycoprotein) to interact with ACE2 and facilitate the membrane infusion between viral particle and target cell. Spike protein is critical for virus invasion of host cell, therefore it would be an ideal target for neutralising antibody development.

Morden mass spectrometry when coupled with liquid chromatography is widely accepted as one of the most sensitive analytical method, particularly for compounds that can be ionised efficiently in the ionisation source, such as peptides. With triple quadruple mass spectrometer LC-MS/MS operated in MRM mode, offers the highest possible sensitivity, it can potentially reach attomoles (10-18) level. In this project, we proposed to develop a MRM based LC-MS/MS method to target unique peptides generated from the spike protein of the SARS-CoV-2 virus for the reliable diagnosis of covid19 infection, this can also serves a biomarker for therapeutic application.

References:

  1. Wrapp D. et al., Science, 367, Issue 6483, pp. 1260-1263
  2. Li X., et al., of Pharm Analysis, Doi.org/10.1016/j.jpha.2020.03.001

BBSRC Strategic Research Priority: Integrated Understanding of Health Ageing

Techniques that will be undertaken during the project:

  • Advanced analytical chemistry
  • High performance liquid chromatography
  • Mass spectrometry
  • NMR
  • Microbiology
  • Molecular biology

Typical pattern of working hours needed to complete this project:

  • 35 hrs per week with flexible working arrangements

Contact: Dr Lijiang Song, University of Warwick