Virus World

It’s not just the lungs — the pathogen may enter brain cells, causing symptoms like delirium and confusion, scientists reported. The coronavirus targets the lungs foremost, but also the kidneys, liver and blood vessels. Still, about half of patients report neurological symptoms, including headaches, confusion and delirium, suggesting the virus may also attack the brain. A new study offers the first clear evidence that, in some people, the coronavirus invades brain cells, hijacking them to make copies of itself. The virus also seems to suck up all of the oxygen nearby, starving neighboring cells to death. It’s unclear how the virus gets to the brain or how often it sets off this trail of destruction. Infection of the brain is likely to be rare, but some people may be susceptible because of their genetic backgrounds, a high viral load or other reasons. “If the brain does become infected, it could have a lethal consequence,” said Akiko Iwasaki, an immunologist at Yale University who led the work. The study was posted online on Wednesday and has not yet been vetted by experts for publication. But several researchers said it was careful and elegant, showing in multiple ways that the virus can infect brain cells.

Scientists have had to rely on brain imaging and patient symptoms to infer effects on the brain, but “we hadn’t really seen much evidence that the virus can infect the brain, even though we knew it was a potential possibility,” said Dr. Michael Zandi, consultant neurologist at the National Hospital for Neurology and Neurosurgery in Britain. “This data just provides a little bit more evidence that it certainly can.” Dr. Zandi and his colleagues published research in July showing that some patients with Covid-19, the illness caused by the coronavirus, develop serious neurological complications, including nerve damage. In the new study, Dr. Iwasaki and her colleagues documented brain infection in three ways: in brain tissue from a person who died of Covid-19, in a mouse model and in organoids — clusters of brain cells in a lab dish meant to mimic the brain’s three-dimensional structure. 

Other pathogens — including the Zika virus — are known to infect brain cells. Immune cells then flood the damaged sites, trying to cleanse the brain by destroying infected cells. The coronavirus is much stealthier: It exploits the brain cells’ machinery to multiply, but doesn’t destroy them. Instead, it chokes off oxygen to adjacent cells, causing them to wither and die. The researchers didn’t find any evidence of an immune response to remedy this problem. “It’s kind of a silent infection,” Dr. Iwasaki said. “This virus has a lot of evasion mechanisms.” These findings are consistent with other observations in organoids infected with the coronavirus, said Alysson Muotri, a neuroscientist at the University of California, San Diego, who has also studied the Zika virus. The coronavirus seems to rapidly decrease the number of synapses, the connections between neurons. “Days after infection, and we already see a dramatic reduction in the amount of synapses,” Dr. Muotri said. “We don’t know yet if that is reversible or not.” The virus infects a cell via a protein on its surface called ACE2. That protein appears throughout the body and especially in the lungs, explaining why they are favored targets of the virus. Previous studies have suggested, based on a proxy for protein levels, that the brain has very little ACE2 and is likely to be spared. But Dr. Iwasaki and her colleagues looked more closely and found that the virus could indeed enter brain cells using this doorway.  “It’s pretty clear that it is expressed in the neurons and it’s required for entry,” Dr. Iwasaki said.  Her team then looked at two sets of mice — one with the ACE2 receptor expressed only in the brain, and the other with the receptor only in the lungs. When researchers introduced the virus into these mice, the brain-infected mice rapidly lost weight and died within six days. The lung-infected mice did neither...

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....

The virus can damage lung, liver and kidney tissue grown in the lab, which might explain some severe COVID-19 complications in people. Researchers are growing miniature organs in the laboratory to study how the new coronavirus ravages the body. Studies in these organoids are revealing the virus’s versatility at invading organs, from the lungs to the liver, kidneys and gut. Researchers are also experimenting with drugs in these mini tissues to see whether such therapies might be candidates to treat people.

Physicians know from hospitalised patients and autopsies that SARS-CoV-2 can have a devastating effect on organs. But it’s unclear whether some of this damage is directly caused by the virus or by secondary complications of the infection. Multiple groups are using organoid studies to show where in the body the virus travels, which cells it infects and what damage it does. “The beauty of organoids is that they resemble the true morphology of tissues,” says Thomas Efferth, a cell biologist at Johannes Gutenberg University of Mainz, Germany. Virologists typically study viruses using cell lines or animal cells cultured in a dish1. But these don’t model SARS-CoV-2 infection well because they don’t mimic what happens in the body, say researchers. 

Organoids better demonstrate what SARS-CoV-2 does to human tissue, says Núria Montserrat, a stem-cell biologist at the Institute for Bioengineering of Catalonia in Barcelona, Spain. They can be grown to include multiple cell types, and take the shape of the original organ in weeks, says Montserrat. They’re also less expensive than animal models, and avoid the ethical concerns they pose. But studies of SARS-CoV-2 in organoids have limitations because they do not reflect the crosstalk between organs that happens in the body, which means that findings will still need to be validated in animal models and clinical studies, says Bart Haagmans, a virologist at Erasmus MC in Rotterdam, the Netherlands...