Virus World

The COVID-19 pandemic has prompted the search for animal models that recapitulate the pathophysiology observed in humans infected with SARS-CoV-2 and allow rapid and high throughput testing of drugs and vaccines. Exposure of larvae to SARS-CoV-2 Spike (S) receptor binding domain (RBD) recombinant protein was sufficient to elevate larval heart rate and treatment with captopril, an ACE inhibitor, reverted this effect. Intranasal administration of SARS-CoV-2 S RBD in adult zebrafish recombinant protein caused severe olfactory and mild renal histopathology.

Zebrafish intranasally treated with SARS-CoV-2 S RBD became hyposmic within minutes and completely anosmic by 1 day to a broad-spectrum of odorants including bile acids and food. Single cell RNA-Seq of the adult zebrafish olfactory organ indicated widespread loss of expression of olfactory receptors as well as inflammatory responses in sustentacular, endothelial, and myeloid cell clusters. Exposure of wildtype zebrafish larvae to SARS-CoV-2 in water did not support active viral replication but caused a sustained inhibition of ace2 expression, triggered type 1 cytokine responses and inhibited type 2 cytokine responses. Combined, our results establish adult and larval zebrafish as useful models to investigate pathophysiological effects of SARS-CoV-2 and perform pre-clinical drug testing and validation in an inexpensive, high throughput vertebrate model.

Preprint available in bioRxiv (Nov. 8 , 2020):

https://doi.org/10.1101/2020.11.06.368191

Researchers at Texas State University, collaborating with a team from the University of New Mexico, have discovered that fish can smell viruses, prompting fast antiviral immune responses. Irene Salinas, associate professor in the Department of Biology at UNM, is the principal investigator of the study. Mar Huertas, assistant professor in the Department of Biology at Texas State, is co-PI in the National Science Foundation project sponsoring the research.The study, "Olfactory sensory neurons mediate ultrarapid antiviral immune responses in a TrkA-dependent manner," was published in the Proceedings of the National Academy of Sciences(PNAS).

"It is a very exciting discovery because we described a new olfactory function in vertebrates – fish can smell viruses," Huertas said. "Also, we are unravelling the connection between the olfactory and immune system, which can be translated from fish to higher vertebrates. This research can have exciting outcomes for fish vaccination in aquaculture. Half of the fish we find in the market comes from aquaculture, and trout is one of the main aquaculture species in the U.S. In addition, since all vertebrates share common traits in their sense of smell and immune system, this study opens a new area of research in mammal immunology.

For the study, Huertas exposed the nose of a trout to a live attenuated infectious hematopoietic necrosis virus (IHNV). She recorded the neural responses, capturing the instant electric responses of the fish nose after the detection of the pathogen – direct evidence that fish can detect pathogens with their sense of smell. Huertas also demonstrated that a drug for a specific receptor in the nose (the TrkA-like receptor), inhibited the fish virus responses. These findings shed new light on immunological responses in vertebrates and could influence the design and delivery of future nasal vaccines. 

Published on June 3, 2019 in P.N.A.S.:

 https://doi.org/10.1073/pnas.1900083116

Small and easy to keep, zebrafish larvae provide a useful system for studying norovirus. The first reliable small-animal model for human norovirus infection, a notorious cause of the illness known as stomach flu, should help researchers to better understand the biology of these pathogens — and might lead to treatments.

Noroviruses are the leading cause of food-borne illness, and the vomiting, nausea, diarrhoea and stomach cramps that go with it. Every year, the viruses cause around 700 million infections and kill more than 200,000 people — at the expense of US$60 billion in lost productivity and healthcare costs. Until now, the only animal models, including large animals such as chimpanzees and pigs, have been unsuitable.

Now Joana Rocha-Pereira, at KU Leuven in Belgium, and her colleagues report successfully cultivating human noroviruses in the larvae of zebrafish (Danio rerio), a freshwater minnow that shares many genes with humans and is a well-established animal model of human disease. 

The model should help to identify the key determinants for human norovirus infection, and — to the relief of many parents — expedite the development of antiviral drugs.

Published in PLOS Pathogens on September 19, 2019:

https://doi.org/10.1371/journal.ppat.1008009