Virus World

A study found that the floor and walls around the toilet could still get contaminated with viruses from the toilet bowl even when the lid is down during flushing. Will shutting the toilet lid when you flush really keep nasty microbes from leaving the bowl and spraying all over the place? Well, it’s not exactly an open and shut case, according to a new study published in the American Journal of Infection Control. The study found that the floor and walls around the toilet could still go quite viral, so to speak, even when the lid stays down during the flush. Yes, even the walls around the toilet ended up getting contaminated with viruses from the toilet bowl. For the study, a team of researchers from the University of Arizona (Madison P. Goforth, BS Stephanie A. Boone, PhD Justin Clark, MS Priscilla B. Valenzuela, MS, FRSPH, and Charles P. Gerba, PhD) and Reckitt Benckiser, LLC, the makers of Lysol (Julie McKinney, PhD, and M. Khalid Ijaz, DVM, PhD) dumped some bacteriophage MS2 into two different types of toilets...

While studies in mice and people can be slow, researchers are making fast progress testing medications in miniature airways and guts made of human cells. To the naked eye, the blobs in Josef Penninger’s lab dishes don’t look like much. Suspended in nutritious gel, they’re pale in color and a millimeter or so across. But look closer, with a microscope, and you see tiny networks of interconnected blood vessels. “They are seriously beautiful,” says Penninger, a medical geneticist at the University of British Columbia in Vancouver. Starting with human stem cells, he and his team have created miniature replicas of the vascular system. And they’ve used them to test a treatment for Covid-19.

Called organoids, these tissue bits come in diverse varieties: lung mimics with air sacs, gut versions sporting the tendrils that absorb nutrients, and more. They’re handy for viral research, offering a way to study how viruses enter cells and cause disease, as well as how the tissues fight back. They’re not the only option, of course. The Covid-19 crisis has scientists scrambling to study infection and test treatments in as many ways as they can. Trials for drugs and vaccines have already started in people, but many medications aren’t ready for that stage yet, and it’s difficult to study the viral life cycle in human beings. Others are working with mice, but those experiments can be slow, and animal responses to infections often differ from those of people. Results come faster with cells that thrive in flat layers, such as African green monkey kidney cells or those from a human liver cancer — but these tend to be highly abnormal, more akin to tumors than healthy body tissues in all their 3-D complexity.

Organoids, in contrast, host many of the cell types in the real tissue, organized in the right way, says Hans Clevers, a cancer and stem cell biologist at the Hubrecht Institute in Utrecht, Netherlands, a pioneer in organoid research and coauthor of an overview of the field in the 2020 Annual Review of Pathology. They are about as close as scientists can get to working on human tissues outside of actual people, and provide a useful intermediate between abnormal cell lines and whole-animal studies. Scientists have been working on organoids for about a decade, and infecting them with viruses since at least 2012. The Zika virus that caused an outbreak in 2015–16, for example, was linked to small brains in newborns, but since scientists couldn’t study the infection in growing fetuses, they turned to brain organoids. Among other things, that helped them to identify which cells the Zika virus infects (progenitor cells that give rise to other brain cell types were especially susceptible) and what might cause small brains (the infection killed or slowed replication of progenitor cells, leading to smaller organoids). Scientists also recently developed an intestinal organoid model that they could infect with the norovirus that causes stomach flu, which should lead to development of treatments, Clevers says....

A new structural analysis of four norovirus strains reveals that the virus’s shell varies in size and molecular arrangement – a surprise finding that could help scientists developing vaccines.

Norovirus, best known for sweeping through daycares and cruise ships, can form small, medium, and large structures depending on the viral strain. The discovery, reported June 10, 2019, in the journal Proceedings of the National Academy of Sciences, overturns nearly two decades of conventional wisdom about norovirus. Until now, the only structural data about the virus that scientists had came from a single, not particularly prevalent, strain. “Everyone thought that all the strains would look about the same – like the one that was solved 20 years ago,” says Howard Hughes Medical Institute Investigator Leemor Joshua-Tor. “It turns out that they don’t!” Joshua-Tor’s team used a microscopy technique called cryo-electron microscopy (cryo-EM) to visualize the shells of four viral strains, including one responsible for up to roughly 80 percent of norovirus outbreaks. That strain was 71 percent larger (by volume) than the one previously reported. Its shell was also decorated with a different pattern of molecular spikes.

Those structural details will be crucial for scientists working on vaccines or antiviral therapies to treat norovirus infection, says Joshua-Tor, a structural biologist at Cold Spring Harbor Laboratory (CSHL). Though norovirus causes about 21 million cases of foodborne illness in the United States every year, there are currently no approved therapies. At least one vaccine candidate is working its way through clinical trials now. But CSHL study coauthor James Jung says scientists will need to take the virus’s newfound variation into account – so any new vaccine protects against a broad array of strains.

HHMI talked with Jung and Joshua-Tor to find out more about the “stomach flu,” the virus that causes it, and how they finally solved the structure of outbreak strains’ shells......

Published in PNAS on June 25, 2019:

 https://doi.org/10.1073/pnas.1903562116

So far this year the CDC has already reported 11 outbreaks of vomiting and diarrhea on cruise ships visiting U.S. ports, more than the total for 2019. As cruise passengers return to the seas in force following a pandemic lull, an unwelcome side effect is also back: outbreaks of gastrointestinal illness. According to the Centers for Disease Control and Prevention, so far this year there have been 11 outbreaks of vomiting and diarrhea that reach the threshold for public notification on cruise ships visiting U.S. ports. The mid-May tally has already exceeded the total number of outbreaks reported in 2019 and tied the yearly number for both 2017 and 2018. Norovirus has been identified as the culprit in four of the 2023 cases; the others are all classified as unknown. The CDC did not immediately provide responses to questions about the increase in cases this year. In the latest outbreak, aboard Holland America Line’s Nieuw Amsterdam, 160 passengers and 26 crew have reported being ill. That represents a little more than 8 percent of guests and 3 percent of workers. The ship is on a 14-day Alaska cruise that returns to Vancouver on Sunday.

The highly contagious norovirus causes diarrhea and vomiting and is notorious for spreading rapidly through densely populated spaces, such as cruise ships, nursing homes, schools and day care centers. Each year, it is responsible for some 200,000 deaths, mostly in the developing world. There are no treatments for this intestinal virus, often incorrectly referred to as stomach flu. Now, a new study led by scientists at Washington University School of Medicine in St. Louis has shown that gut microbes can tamp down or boost the severity of norovirus infection based on where along the intestine the virus takes hold.  The study, published Nov. 25 in the journal Nature Microbiology, suggests new routes to possible therapies for norovirus infection. Collaborators included researchers at the University of Florida, the University of Michigan and Yale University Medical School.

"There are currently no treatments for norovirus, which is very easily spread through fecal-oral transmission," said co-senior author Megan T. Baldridge, MD, Ph.D., an assistant professor of medicine at Washington University. "Norovirus is especially dangerous in young children, older adults and people with compromised immune systems. We are trying to understand how the gut microbes interact with norovirus in an effort to pursue new therapeutic strategies." In these mouse studies, the researchers found that normal gut bacteria boosted the severity of viral infection in the lower small intestine, which is in line with past work in the field. But simultaneously, normal gut bacteria blocked or inhibited viral infection in the upper small intestine. In other words, gut microbes can have totally opposite effects on norovirus infection depending on the infection's location along the length of the gut. "These results were a huge surprise to us," Baldridge said. "We showed that different parts of the intestine can show dramatically different responses to this type of infection. Our research reveals that we can't view the gut as a homogeneous tube that responds to infection in a uniform way."

Baldridge and her colleagues found that the difference in response was driven by bile acids, which are mainly known for their roles in digestion. "Bile acids are powerfully regulated by bacteria all along the gut," Baldridge said. "But there had not been a realization that these bile acids could prime the gut to mount an immune response against intestinal viruses." In the new study, the researchers showed that bile acids in the upper small intestine—but not the lower—stimulated the immune system to respond to the infection. The researchers determined that bile acids in that region of the gut triggered a molecule called interferon III—one of the body's key antiviral defenses in the intestine—to become activated. Baldridge noted that this complexity of interactions between gut microbes and bile acids could explain some of the variability seen in norovirus infections. Some people become extremely ill with this virus; others develop no symptoms at all. "The different ways people respond to viral infections could be related to their individual gut microbial community," Baldridge said. "The severity of an infection could be tied to where exactly along the gut you get an infection, and that might be controlled by your individual microbiome. Subtle differences along the intestine could end up having dramatic effects on how the gut perceives the virus and responds to it."...

Published in Nature Microbiology (25 November 2019):

https://nature.com/articles/s41564-019-0602-7

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