Molecular & cellular virology of coronaviruses
Coronaviruses are large positive-strand RNA viruses belonging to the Coronaviridae family. They encompass more than 25 species infecting humans and a broad range of animal species. Human coronaviruses are responsible for many cases of seasonal common cold, whose economic and social impact is probably underestimated. Moreover, the human coronaviruses that are usually associated with mild diseases can cause severe respiratory tract infections in fragile populations (newborn babies, elderly and immunocompromised people). Animal coronaviruses are often highly infectious and responsible mostly for enteric and respiratory diseases in livestock and domestic animals. Their high mortality rates result in a significant global economic burden. But altogether, until 2003, coronaviruses were not considered as a major human health threat. The situation changed since then, with the emergence of two highly pathogenic coronaviruses, namely SARS-CoV (severe acute respiratory syndrome coronavirus) and MERS-CoV (Middle-East respiratory syndrome coronavirus). These two highly pathogenic coronaviruses have emerged from zoonotic reservoirs, and they often cause lethal respiratory infections in humans. The recent identification of other coronaviruses in bats suggests that other viruses from this family could also emerge as novel human pathogens. In the absence of specific treatment, it is essential to better understand how such viruses exploit the cellular machinery for their propagation. Our current objectives are (i) to investigate the mechanisms of entry and assembly of coronaviruses with a special focus of MERS-CoV and (ii) to identify novel host factors involved in the infectious cycle of coronaviruses. Besides a better understanding of coronavirus life cycles, this research program could also lead to the identification of novel antiviral targets.
Molecular & cellular virology of hepatitis E virus
Hepatitis E virus (HEV) infection is a major public health problem that affects more than 20 million people each year and is responsible for 56,000 deaths annually. Infection with HEV causes acute hepatitis but can become chronic in immunosuppressed patients. HEV infection also causes death in fragile patients. For a long time, it was thought that this virus affected only developing countries. However, over the last 10 years, with the development of diagnostic tools, it appeared that the industrialized countries are also affected by this viral infection, but the epidemiology and clinical features of hepatitis E differ between developing and developed countries. HEV is a quasi-enveloped virus that has an icosahedral symmetry capsid. Its genome consists of a single-stranded RNA molecule of positive polarity of approximately 7200 nucleotides encoding three open reading frames (ORFs) called ORF1, ORF2 and ORF3. The ORF1 protein encodes a nonstructural polyprotein involved in viral replication. ORF2 protein is the viral capsid protein, while the ORF3 protein is a small protein involved in secretion and lipidation of particles. Indeed, unlike particles from feces, serum or particles produced in cell culture are associated with lipids. Due to poor replication in cell culture, few data are currently available on the infectious cycle of HEV. In 2018, we adapted a cell culture system for HEV which allows for studying the molecular and cellular mechanisms of the HEV life cycle. In our group, we are mainly studying the replication and assembly mechanisms of HEV, and the biogenesis of ORF2 capsid protein. We are also developing tools to probe viral proteins. Besides a better understanding of the HEV life cycle, our research program aims to identify novel antiviral targets and to develop new diagnostic tools..
Molecular & cellular virology of hepatitis C virus and related viruses
Hepatitis C virus (HCV) infection is one of the major causes of advanced liver disease worldwide. Approximately 180 million individuals are seropositive for HCV and the large majority of them suffer from chronic hepatitis C. After two to three decades, chronic HCV infection can lead to extended liver fibrosis, cirrhosis and hepatocellular carcinoma. Chronic HCV infection is also responsible for metabolic disorders such as hepatic steatosis and insulin resistance which is often associated with type 2 diabetes. Recently, introduction in the clinics of direct-acting antivirals against HCV has shown to effectively cure HCV infection. However, due to the high cost of these treatments and the fact that the majority of infected persons are not aware of their seropositivity, this viral infection will not disappear soon. HCV is a small enveloped virus with a positive stranded RNA genome belonging to Hepacivirus genus in the Flaviviridae family. This viral family also includes major human pathogens such as dengue virus, yellow fever virus and Zika virus which have been classified in the Flavivirus genus. The Flaviviridae family also contains important pathogens for domestic animals in the Pestivirus genus. The HCV genome encodes a single polyprotein that is processed by cellular and viral proteases to produce 10 polypeptides. Although HCV genome was identified in 1989, it is not until 2005 that a cell culture system was developed for this virus. This major breakthrough opened the door to develop functional studies on virus-host interactions. Molecular and cellular characterization of HCV infection rapidly highlighted the close interplay between HCV and the lipid metabolism. Our current objectives are (i) to characterize novel host factors involved in the infectious cycle of HCV and (ii) to better understand the functional role of HCV envelope glycoproteins in virus entry and assembly. In parallel, we also work on the BVDV pestivirus as a model virus to study viral entry.
Identification of antivirals targeting different steps of viral life cycle could serve as basis for the discovery of novel therapies and might help to better understand viral infectious cycle. Plants have been used for centuries in traditional medicine to cure different kind of illnesses and natural products from plant species maintain a strong position in the drug discovery. Even if natural products are not always used directly as medicines, they often remain a source of inspiration for medicinal chemistry like natural products with semisynthetic modifications, or pharmacophore with natural origin. Recently, our team has characterized different antiviral agents from plant origin with antiviral activity against hepatitis C virus (HCV). EGCG extracted from green tea and delphinidin from red berries, were both identified as strong inhibitors of HCV entry, and dehydrojuncusol, extracted from the plant Juncus maritimus was identified as a new inhibitor of HCV replication. We also showed that a compound extracted from the red algae Griffithsia is active against Middle-East respiratory syndrome coronavirus (MERS-CoV). To date, there is no vaccine and no specific therapy against human coronavirus. The emergence of SARS-CoV-2 causing COVID-19 has highlighted the urge to identify new therapy against these viruses. Our current objective is to concentrate on human coronavirus, characterized compounds of natural origin with antiviral activity and understand their mechanisms of action. An effort was made on high content screening of compounds from natural origin inhibiting HCoV-229E, a human coronavirus causing mild upper respiratory tract symptoms. Some compounds identified using this strategy are being tested on SARS-CoV-2. We expect to identify molecules with pan-coronavirus antiviral activity.