Infection and Immunity Research Network

A self-funded MSc study

Keywords: Bristol, Virology, SARS-CoV-2, Antivirals 

Variants of concern remain a public health threat associated with SARS-CoV-2 infection.

Drug combinations are validated tools to potently inhibit replication of RNA viruses and decrease the likelihood of resistance mutations. However, few antiviral drugs have so far proved effective to treat SARS-CoV-2 and they are commonly given in monotherapy, with only scattered information available on their efficacy and toxicity in combination. 

Recently, we have shown that the pharmacoenhancer cobicistat, typically used in combination with antiretroviral drugs to boost their efficacy against HIV-1, can inhibit the replication of the Wuhan SARS-CoV-2 strain in vitro and in vivo, in Syrian hamsters. 

The present project will expand on these results by using scalable fusion assays and replicon models to screen effective drug combinations that can suppress viral replication across all major variants of concern. The student will be trained to use of multiple cellular models of infection and to combine virologic, biochemical, and imaging techniques for antiviral drug development. 

The student will join a novel, international research group situated in the School of Cellular and Molecular Medicine at the University of Bristol. The work will be conducted in a multidisciplinary environment with great opportunities for building and expanding collaborations, including in topics relevant to the project such as immunology and biochemistry. The city is lively, multicultural, and regularly named among the best places to live in the UK. 

References: 

1. Shytaj IL, Fares M, Gallucci L, Lucic B, Tolba MM, Zimmermann L, Adler JM, Xing N, Bushe J, Gruber AD, Ambiel I, Taha Ayoub A, Cortese M, Neufeldt CJ, Stolp B, Sobhy MH, Fathy M, Zhao M, Laketa V, Diaz RS, Sutton RE, Chlanda P, Boulant S, Bartenschlager R, Stanifer ML, Fackler OT, Trimpert J, Savarino A, Lusic M. The FDA-Approved Drug Cobicistat Synergizes with Remdesivir To Inhibit SARS-CoV-2 Replication In Vitro and Decreases Viral Titers and Disease Progression in Syrian Hamsters. mBio. 2022 Apr 26;13(2):e0370521. doi: 10.1128/mbio.03705-21.
2. Taibe NS, Kord MA, Badawy MA, Shytaj IL, Elhefnawi MM. Progress, pitfalls, and path forward of drug repurposing for COVID-19 treatment. Ther Adv Respir Dis. 2022 Jan-Dec;16:17534666221132736

Contact Luca Shytaj for more information. 

A self-funded PhD project

Human retroviruses are a group of pathogens infecting an estimated 50 million people worldwide. The most widespread human retrovirus is HIV-1, which remains a major cause of morbidity and mortality, particularly in developing countries. Despite the introduction of combinations of effective antiretroviral drugs, a scalable cure is not available for either HIV-1 or other pathogenic human retroviruses. At a cellular level, retroviral infection and persistence is mainly concentrated in memory T-cell lymphocytes, which are a long-lived subset of white blood cells. The in-depth characterisation of the infected cells subsets is therefore a key requirement to eliminate retroviral sanctuaries. 

My laboratory investigates the interplay between cellular metabolism and viral infection, with special focus on latent HIV-1 infection. Cellular metabolism encompasses the fundamental biochemical reactions that are required by cells to convert or utilise energy, and we, and others, have shown that latent HIV-1 infection is associated with profound metabolic rearrangements, including increased reliance on systems to detoxify derivatives of oxygen consumption. 

This project will initially attempt a parallel multi-omics characterisation of primary memory T-lymphocytes infected with HIV-1 or other pathogenic human retroviruses. The analysis will integrate transcriptomic, proteomic and metabolomic profiles that will be further corroborated by epigenomic analysis. Key markers that identify, or correlate with, human retroviral infection and persistence in memory T-lymphocytes will be further explored for their potential to serve as selective therapeutic targets to eliminate infected cells. The studentship will include training in multi-omics sample preparation and data analysis together with virologic, biochemical and imaging techniques. Overall, the project is expected to shed new light on how human retroviruses select and alter the cellular milieu to ensure their own survival, and how this process can be exploited to attempt eradication of retroviral sanctuaries. 

References: 

1. Shytaj IL, Procopio FA, Tarek M et al. Glycolysis downregulation is a hallmark of HIV-1 latency and sensitizes infected cells to oxidative stress. EMBO Mol Med. 2021 Aug 9;13(8):e13901. 
2. Shytaj IL, Lucic B, Forcato M et al. Alterations of redox and iron metabolism accompany the development of HIV latency. EMBO J. 2020 May 4;39(9):e102209. 
3. Benhar M, Shytaj IL, Stamler JS, Savarino A. Dual targeting of the thioredoxin and glutathione systems in cancer and HIV. J Clin Invest. 2016 May 2;126(5):1630-9. 
4. Shytaj IL, Nickel G, Arts E et al. Two-Year Follow-Up of Macaques Developing Intermittent Control of the Human Immunodeficiency Virus Homolog Simian Immunodeficiency Virus SIVmac251 in the Chronic Phase of Infection. J Virol. 2015 Aug;89(15):7521-35.

Contact Luca Shytaj for more information. 

A self-funded PhD project

Summary:

Streptococcus bacteria are exquisitely adapted to the colonisation of humans and other animals and are associated with significant disease. Group A Streptococcus (GAS) causes >600 million human infections each year, including necrotising fasciitis (flesh-eating disease). Group B Streptococcus (GBS) is a leading cause of invasive disease in infants. Oral Streptococcus bacteria cause a severe form of heart disease known as infective endocarditis. This project aims to decipher the molecular basis of Streptococcus colonisation and pathogenesis. Molecular biology-, biochemical- and cell culture-based techniques will be exploited to identify the molecular mechanisms by which Streptococcus bacteria are able to associate with host tissues, modulate the immune response, and interact with other microbes to form polymicrobial communities. This knowledge will inform the development of novel strategies to combat streptococcal disease.

Theme:

Disease mechanisms / Molecular microbiology

For further information contact Angela Nobbs in Bristol Dental School. 

A self-funded PhD project

Summary:

A significant proportion of human infections are caused by microbial pathogens. These organisms interact socially to build highly organised, well-coordinated, hierarchical structures known as biofilms. Biofilms are often polymicrobial, ubiquitous and range from those found within industrial water pipes to dental plaque in humans. Biofilm-embedded microbes are highly resistant to antimicrobial compounds and host defences. Clinically, polymicrobial biofilm infections account for over 80% of all human infections, constituting an overwhelming healthcare burden. This project will utilise a multidisciplinary approach to investigate the molecular interplay and chemical cross-talk between microbial biofilm residents and how this impacts disease pathogenesis and antimicrobial resistance. The findings are expected to aid the design of targeted strategies and tools for preventing life-threatening biofilm infections worldwide. 

Theme:

Disease mechanisms / AMR

For further information contact Angela Nobbs in Bristol Dental School.