Contribution of Intra- and Interhost Dynamics to Norovirus Evolution

Abstract

c Norovirus (NoV) is an emerging RNA virus that has been associated with global epidemics of gastroenteritis. Each global epidemic arises with the emergence of novel antigenic variants. While the majority of NoV infections are mild and self-limiting, in the young, elderly, and immunocompromised, severe and prolonged illness can result. As yet, there is no vaccine or therapeutic treatment to prevent or control infection. In order to design effective control strategies, it is important to understand the mechanisms and source of the new antigenic variants. In this study, we used next-generation sequencing (NGS) technology to investigate genetic diversification in three contexts: the impact of a NoV transmission event on viral diversity and the contribution to diversity of intrahost evolution over both a short period of time (10 days), in accordance with a typical acute NoV infection, and a prolonged period of time (288 days), as observed for NoV chronic infections of immunocompromised individuals. Investigations of the transmission event revealed that minor variants at frequencies as low as 0.01% were successfully transmitted, indicating that transmission is an important source of diversity at the interhost level of NoV evolution. Our results also suggest that chronically infected immunocompromised subjects represent a potential reservoir for the emergence of new viral variants. In contrast, in a typical acute NoV infection, the viral population was highly homogenous and relatively stable. These results indicate that the evolution of NoV occurs through multiple mechanisms.

Within-Host Evolution Results in Antigenically Distinct GII.4 Noroviruses

“…From these limited studies, it is difficult to discern whether there are characteristics of chronic norovirus infection that are broadly applicable to all populations and characteristics that are true to specific populations, or whether characteristics vary by each individual case. Previous work has shown that during the course of chronic infection, virus genetic diversity can expand quickly (22,23,25,35); however, it was previously unknown whether this genetic variation translated into antigenic variation or the emergence of antigenically unique isolates that differ significantly from contemporary epidemic strains. For the first time, our work clearly demonstrates the potential for significant antigenic variation over the course of chronic infection within an individual, which is important in terms of therapeutic treatment considerations and for studying the potential role of chronic shedders as reservoirs for evolving new outbreak strains.…”

“…However, some immu-nocompromised individuals, such as transplant patients on immunosuppressive drugs, those with primary immunodeficiencies, cancer patients undergoing chemotherapy, and those with HIV infections, may develop chronic norovirus infection. Symptomatic infection and virus shedding in these patients can persist for weeks to years (20)(21)(22)(23)(24)(25) and can result in medical issues, such as dehydration and nutrient deficiencies (26), making development of treatment options for these patients an important priority. Unfortunately, there are no approved therapeutics or vaccines for controlling norovirus infections.…”

“…Although unconfirmed, one recent hypothesis is that chronically infected norovirus patients may be important sources of infection, both in health care settings (33) and as potential reservoirs for new, emergent GII.4 norovirus strains (20,23,25). Although the fitness and the infectivity of chronically shed virus are currently unknown, potential accounts of chronic norovirus shedders involved in hospital outbreaks and transmission of virus to both immunocompromised and immunocompetent individuals have been documented (21,33,34).…”

“…Siebenga et al found that the capsid mutation rate was linked to immune impairment, suggesting that immune-driven selection drives evolution in the capsid during chronic infection (35) and explains differences in evolution, depending on the level of immunosuppression. Additional studies have corroborated a role for intrahost immune-driven selection by demonstrating that virus isolated from chronically infected patients undergoes positive selection and exhibits higher genetic diversity in the capsid protein than virus from acutely infected individuals (23,25). In some chronically infected patients with GII.4 strain infections, many of the changes occur in blockade epitopes, areas of known or predicted antigenic importance, but antigenic comparisons have not been performed (13-15, 22, 35).…”

Métagénomique virale et pathologie

“…Des travaux sur les cardiovirus humains ont ainsi mis en évidence la trace d'une recombinaison avec un theilovirus de rat, suggérant que l'ancêtre commun de ces virus proviendrait du rat [35]. La puissance de ces méthodes permet par ailleurs de caractériser la dynamique évolutive des virus chez un hôte ou entre différents hôtes [36]. La génération de la diversité peut également être explorée dans différents sites chez un même hôte et ce en fonction du développement de l'infection [37].…”