Norovirus Genetic Diversity – from within patient viral evolution to global distribution

textabstractNoroviruses belong to the family of Caliciviridae and cause acute gastroenteritis. The genetic diversity within the genus Norovirus is extremely large and novel genotypes, recombinants within and between genotypes, and antigenic drift variants are regularly discovered. The distribution and incidence of norovirus genotypes changes over time and by geographic region, with GII.4 as the predominant genotype responsible for approximately 70% of the outbreaks detected worldwide. This thesis contributes to a better understanding of the global norovirus diversity, and the role of chronic norovirus infection among immunocompromised individuals on virus diversity, antigenic variation and evolution. We describe the emergence of a novel GII.4 drift variant and novel GII.17 in chapter 2.1 and 2.2, respectively. Chapter 3 provides an overview of the global norovirus molecular epidemiology using data obtained by the NoroNet surveillance network in the last ten years. Chapter 4 shows that GII.4 was not predominant before the wide spread use of norovirus molecular typing methods in the mid-1990s. Chapter 5 shows that chronic norovirus infection is common among solid organ transplant patients and more than doubled the number of described patients in literature. Finally, chapter 6 shows that virus populations in the immunocompromised host are genetically distinct from viruses circulating in the general population. These hosts therefore may contain a reservoir of newly emerging strains and future studies need to address whether these new strains can be transmitted to other immunocompromised patients or individuals in the general population. Norovirus vaccines are currently tested in clinical trials. The observed global changes in the norovirus molecular epidemiology require a norovirus vaccine with broad immune protection and an antigenic component that can be easily updated within a limited time span. Immunocompromised patients with chronic norovirus infection may suffer of persistent symptoms of diarrhoea with a consequent severe loss of quality of life and future studies need to address how these patients can be treated to eliminate infection