Rhesus enteric calicivirus surrogate model for human norovirus gastroenteritis

Abstract

Human noroviruses are one of the major causes of acute gastroenteritis worldwide. Due to the lack of an efficient human norovirus cell culture system coupled with an animal model, human norovirus research mainly relies on human volunteer studies and surrogate models. Current models either utilize human norovirus-infected animals including the gnotobiotic pig or calf and the chimpanzee models, or employ other members of the family Caliciviridae including cell culture propagable surrogate caliciviruses such as the feline calicivirus, murine norovirus and most recently the Tulane virus. One of the major features of human noroviruses is their extreme biological diversity, including genetic, antigenic and histo-blood group antigen binding diversity, and possible differences of virulence and environmental stability. This extreme biological diversity and its effect on intervention/prevention strategies cannot be modelled by uniform groups of surrogates, much less by single isolates. Tulane virus, the prototype recovirus strain, was discovered in 2008. Since then, several other novel recoviruses have been described and cell culture adapted. Recent studies indicate that the epidemiology, the biological features and diversity of recoviruses and the course of infection and clinical disease in recovirus-infected macaques more closely reflect those properties of human noroviruses than any of the current surrogates. This review aims to summarize what is currently known about recoviruses, highlight their biological similarities to human noroviruses and discuss applications of the model in addressing questions relevant for human norovirus research.

Evaluation of 405‐nm monochromatic light for inactivation of Tulane virus on blueberry surfaces

“…In vitro propagation of HuNoV is currently very challenging (Ettayebi et al 2016), making assessment of viability and inactivation of HuNoV problematic. Therefore, research on nonthermal inactivation methods for HuNoV often utilizes genetically related surrogates, such as murine norovirus and Tulane virus (TV; Farkas 2015).…”

Recovirus NS1-2 has viroporin activity that induces aberrant cellular calcium signaling to facilitate virus replication

“…One step growth curves for TV were performed using a modified protocol from previous reports (11, 15). Briefly, LLC-MK2 cells were inoculated with TV at MOI 1 in serum-free DMEM (0% FBS DMEM).…”

Norovirus vaccines: Correlates of protection, challenges and limitations

“…103 While many experimental vaccine designs have used the murine model, a number of concerns remain in place in the results presented above: 1) the different disease biology between mice and humans whereby only immunocompromised mice clinically manifest diarrhea as demonstrated by severe illness following MNV infection among innate-immunity-deficient mice (IFN-a/b and IFN-g receptor-deficient) 114 ; 2) the difficulty in extrapolating the clearance of MNV from the intestines to the possible physiological results in humans; 3) MNV does not use HBGA for attachment and is characterized by little genetic and antigenic variation. 115 Nevertheless, the mouse model is still a convenient and a cost effective platform for potential NoV vaccine studies. 98 Recently, the use of the Tulane virus (TV), a recovirus strain (ReCV), isolated from the stool of rhesus macaques 116 has been advanced as a possible surrogate model for human NoV gastroenteritis.…”

“…11,75 While a number of animal and human studies are being studied for a potential NoV vaccine, the problem of cross-reactivity being skewed by previous exposure to NoV and its variability among individuals remains a major obstacle. In addition, the current state of studies on NoV vaccine in animal and human models is still faced with many imperfections: 1) the immunocompetent mouse model does not produce similar diarrheal disease as human NoV; 114 2) the murine model does not allow for strain heterogeneity as the case among human NoVs; 3) the failed attempts to culture NoV in macrophages, DC and other cells lines of human and animal tissues 131,132 result in the inability to generate live attenuated or killed virus and consequently disrupting the possibility of analyzing a strong and long-term protection; 4) while the ReCV model has demonstrated its feasibility as a surrogate model for human disease and vaccine especially due to the similarities between the clinical disease manipulation in humans and the non-human primate macaques and more importantly the diversity observed in both, 115 this model is yet to be explored further; 5) many of the human studies listed above are performed in young healthy adults, leaving a burning question unanswered as to the extension of the findings to other age groups. This remains an impediment to vaccinologists trying to assess the impact of pre-existing immunity on successful immunization strategies; 6) finally, the duration of the vaccine-induced immunity and its toll on the NoV diversity and antigenic variability.…”

“…Due to all the above, this model is thought to reflect the diversity of human NoVs, the reproducibility of the disease symptoms, the feasibility of testing the susceptibility to infection and attachment to receptors as a result of the availability of susceptible and non-susceptible cell lines. 115,120 The non-human primate model is genetically and immunologically close to humans and consequently could be the next-generation model to characterize and investigate NoV infection and potential vaccines.…”