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Nov 25: Virus-host interactions resolved through manipulation of viral and host gene expression

Nov 25: Virus-host interactions resolved through manipulation of viral and host gene expression

Human herpesvirus infections often go unnoticed, but they can be responsible for severe disease in susceptible individuals. As these viruses are difficult to clear from the body, Hendrik de Buhr from UMC Utrecht investigated host-virus interactions that are involved in herpesviruses circumventing the immune system for their own benefit. Identifying and characterizing these mechanisms advances the understanding of viral infections and might aid in the development of new antiviral approaches.

Viruses existed long before modern humans evolved and might have been there from the beginning of the evolution of living cells. The corona pandemic shows us the danger of acute infections and how easy viruses can spread and evolve. While SARS-CoV-2 is omnipresent, general awareness of herpesvirus infections, which can cause severe and fatal illnesses, is limited. Both coronaviruses and herpesviruses share the ability to evolve with their hosts to develop sophisticated mechanisms to interfere with their host’s immune system to prevent clearance. While Epstein-Barr virus (EBV), for example, can limit the expression of viral proteins to curtail immune recognition, viral microRNAs (miRNAs) are expressed during all stages of infection and likely play important roles in EBV infection. The PhD research of Hendrik de Buhr (Department of Medical Microbiology, UMC Utrecht) focused on methods to investigate, control and understand host-pathogen interactions involved in viral clearance.

Thermodynamic properties

In his research, Hendrik de Buhr showed that the generation and optimization of potent EBV miRNA inhibitors efficiently depends on their thermodynamic properties. These inhibitors were subsequently employed to pinpoint which EBV miRNAs target specific host genes that were identified in a screen for EBV miRNA targets. He identified many new host genes that are regulated by EBV miRNAs. Moreover, de Buhr and co-workers characterized one specific miRNA that downregulated two genes involved in autophagy, resulting in enhanced autophagic flux, which could subsequently aid in viral survival.

Immune evasion

Herpesviruses are not only adept in evading immune responses, they also establish latency. Since latent infections cannot be cleared yet with traditional treatments, new methods are needed to tackle this problem. Genome engineering with CRISPR/Cas9 shows great promise in clearing cells of latent viral genomes. Therefore, the researchers reviewed how CRISPR/Cas9 is being utilized as an anti-viral tool to target pathogenic human viruses. In addition, de Buhr and colleagues used CRISPR/Cas9 as a genetic tool to screen for host factors involved in human cytomegalovirus (HCMV) infection. The investigators identified and characterized known and novel genes that are involved in the HCMV infection cycle.

Virus detection

Viruses can interfere with their detection by the host to ensure their survival by e.g. limiting the presentation of viral antigens on the surface of infected cells. In this way, they evade recognition by surveying cytotoxic T cells, thus preventing the clearance of virus infected cells. Hendrik de Buhr described a flow cytometry-based method to assess how viral proteins can interfere with the MHC class I antigen pathway. The method can also aid to pinpoint the possible mode of action. Finally, they screened the viral proteins of SARS-CoV-2 for their effect on MHC class I expression and identified a single gene product that interferes with surface expression of HLA-I.

Human herpes viruses as pathogens

Most infections with human herpesviruses go unnoticed and proceed asymptomatically. Nevertheless, they can cause a broad range of diseases, many of which can be severe or even fatal. Most human herpesviruses are known for causing specific common diseases such as cold sores (herpes simplex virus-1 or HSV-1), genital herpes (HSV-1, HSV-2), Chickenpox or shingles (varicella zoster virus) and mononucleosis (EBV). Additionally, EBV is also responsible for 1,5 percent of all cancers in humans, such as nasopharyngeal carcinoma, gastric cancer, non-Hodgkin’s lymphoma, and Burkitt’s lymphoma. HCMV on the other hand is the main cause for malignancies in immunocompromised individuals, such as transplant recipients, and can cause non-hereditary congenital defects in neonates during pregnancy.

PhD defense

Hendrik de Buhr (1987, Twistringen, Germany) defended his PhD thesis on November 17, 2022 at Utrecht University. The title of his thesis was “Virus-host interactions resolved through manipulation of viral and host gene expression.” Supervisor was prof. dr. Emmanuel Wiertz and co-supervisor was dr. ir. Robert Jan Lebbink (both Department of Medical Microbiology, UMC Utrecht). Hendrik de Buhr currently works as a researcher at Wageningen Bioveterinary Research in Lelystad, the Netherlands, where he is involved in virology and prion projects.

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