Teadustöö

Research overview

Alphaviruses

Alphaviruses are emerging human pathogens. They have positive-strand RNA genome and are transmitted by arthropod vectors. In our research group we use Semliki Forest virus (SFV) and Sindbis virus (SINV) as none-pathogenic model viruses and Chikungunya virus (CHIKV) as representative of alphaviruses pathogenic to humans. Alphavirus infection is generally cytotoxic for vertebrate cells and non-cytotoxic (persistent) in invertebrate cells.

Alphavirus replicase and host factors

Alphaviruse replicase precursor represents a non-structural (ns) polyprotein(s), translated directly from incoming genomic RNA. It is subsequently processed by viral protease which generates first processing intermediates and finally fully processed ns-proteins, nsP1-nsP4. All these components and their assemblies are important for the virus infection. nsP-s of alphaviruses are multifunctional enzymes and have also number of essential non-enzymatic activities. In infected cells part of nsPs co-localize with each other in membrane-bound replicase complexes termed spherules.

The research interests of our group include analysis of the functions of ns-proteins of alphaviruses using enzymatic assays and methods based on microscopy, analysis of host proteins and their co-localizing with replicase complexes of alphaviruses; mechanisms of virus adaptations to different mutations and other selection factors; the role of nsP2 in regulation of virus replication; studies of the modular structure of alphavirus replication complex.

Alphavirus induced pathogenesis and host response to virus infection

Ability of SFV to induce lethal encephalitis in mice depends both from virus strain and age of the host; pathogenesis of CHIKV (generally not neuropathogenic, instead the infection results in fever and arthritis) is less understood. Neither of these viruses normally causes pathogenesis in invertebrates. We have developed systems for monitoring virus infection in different hosts and are interested in the analysis of different host mechanisms involved in detection and controlling of the virus infection. The chimerical viruses (different SFV strains, CHIKV mutants) are constructed and used for pathogenesis studies

Alphavirus based biotechnology

Alphaviruses represent considerable interest as vectors due their ability to express foreign genes at high level, activate host immune responses and kill tumor cells. The alphavirus-based vectors are easy to manipulate but difficult to control due their intrinsic genetic instability (high level of mutations and recombinations). We are involved in development of different novel alphavirus-based vectors as well as new strategies to control the gene expression, stability and spread of these vectors; we also work with alphavirus-based vectors constructed for screening of antiviral compounds and for anti-cancer approaches.

Hepatitis C virus (HCV)

HCV is a major human pathogen. Similar to alphaviruses it has positive-strand RNA genome and expresses its proteins in form of polyprotein precursor. However, unlike alphaviruses the replication of HCV is not toxic for the cells, virus has extremely narrow host range and its molecular biology is tightly connected with lipid metabolism of the host.

Our main research interests with HCV include development of novel models for studies of HCV infection and compounds/strategies blocking early stages of HCV infection.