Niklas Arnberg's reserch
Virus binding to host cells: implications for tropism and treatment
Viral infections are a huge burden to the society not only from the health perspective but also from a financial perspective, since most viral infections, unlike most bacterial infections, can rarely be treated. A few vaccines available for protection, and a few drugs are available for treatment of a handful of viral pathogens but we can neither prevent or treat the vast majority of viral infections that cause disease in humans.
The main challenges with antiviral drug development is that viruses are relatively small in relation to for example bacteria, with fewer viral antiviral drug targets, and that all viruses replicate inside host cells. As a consequence, most approved antiviral drugs have to enter cells, sometimes also to the nucleus of the cells where many viruses replicate, in order to limit replication. This is extremely challenging without causing toxicity.
The main interest of our group is to explore the molecules and mechanisms involved in the early stage of the viral life cycle: attachment and entry. This is a critical step in the life cycle that sometimes determine the tropism of the virus (i.e. which cells, tissues and organs that are infected), but is also essential for subsequent replication and transmission to other cells and to other hosts. A main goal of our research is to explore this step in order to identify novel antiviral drug targets acting outside host cells. Thus, the main mission of our group is to identify the interacting molecules on surface of host cells and on virus particles, and to characterize these interactions in detail.
The viruses that we are currenty working on belongs to the families of Adenoviridae, Caliciviridae, Flavirididae, Paramyxoviridae, and Picornaviridae, which cause disease in eyes (adenovirus, picornavirus), airways (adenovirus, paramyxovirus), gut (adenovirus, calicivirus), and brain (flavivirus). Hitherto, we have identified cellular receptors for several members of the Adenoviridae and Picornaviridae families. We have also developed an antiviral drug candidate for treatment of ocular adenoviruses, which is now in phase IIa clinical trials.
We are mainly working with in vitro model systems, using transformed cell lines that correspond to the tropism of each virus, in order to mimic the in vivo environment. We have also developed a 3D airway model using primary, respiratory cells. We consider the importance of surrounding body fluids, which may either mediate indirect binding to target cells, or, to present molecules serving as decoy receptors.
To study virus binding to and infection of host cells we purify wild type virions from infected cell cultures and quantify binding to and infection of host cells by advanced immunofluorescence microscopy. To simplify quantification of attachment and entry, we sometimes employ genetically modified viruses that encode for example green or red fluorescent proteins. Interactions between cells and specific capsid proteins are analyzed by means of flow cytometry. Affinity and kinetics are determined by surface plasmon resonance. We collaborate with world leading experts in other relevant fields, including chemistry, structural biology, and glycobiology.
The current projects are funded by grants from the Swedish Research Council, the Knut and Alice Wallenberg foundation, FP7, and Umeå university.