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Intestine ‘organoid’ grown in lab to see why bats live with viruses but don’t get sick

Experiments attempting to explain why bats can be infected with many viruses at a time without succumbing to diseases such as COVID-19—knowledge that could help us to reduce the threat to humans of infectious disease—have struggled until now with…

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Experiments attempting to explain why bats can be infected with many viruses at a time without succumbing to diseases such as COVID-19—knowledge that could help us to reduce the threat to humans of infectious disease—have struggled until now with the fact that live wild bats make poor research subjects. To overcome this obstacle, for the first time researchers have grown rousette bat “organoids,” which reproduce intestines in vitro.

Credit: Tsutomu Omatsu, TUAT

Experiments attempting to explain why bats can be infected with many viruses at a time without succumbing to diseases such as COVID-19—knowledge that could help us to reduce the threat to humans of infectious disease—have struggled until now with the fact that live wild bats make poor research subjects. To overcome this obstacle, for the first time researchers have grown rousette bat “organoids,” which reproduce intestines in vitro.

A paper describing the bat organoid growth technique appeared in the International Journal of Molecular Sciences on October 5.

Bats are the natural source of a raft of human pathogens (or, in epidemiological jargon, the ‘reservoir’—the host in which a pathogen survives without causing disease). These include the viruses that cause a great many illnesses such as Ebola, Marburg, Nipah, Hendra, SARS, MERS, and COVID-19. In fact, a single bat can host      these viruses without getting sick. Why bats can live with so many viruses without themselves falling ill remains one of the great mysteries of virology and its neighbouring disciplines. And solving this mystery has been made all the more urgent by the ongoing COVID-19 pandemic.

Yet bats are wild animals, not domesticated experimental animal subjects. It is much more difficult to conduct reproducible investigations on bats than on more common experimental animals such as mice or pigs. And so most experiments have had to take place on cell lines taken from bats rather than bats themselves or bat organs.

“If this experimental blockage could be overcome, virus-bat relationships could be understood and lead to reduce human illness and death.,” said Tsutomu Omatsu, one of the authors of the paper and an associate professor with the Center for Infectious Diseases of Epidemiology and Prevention Research at Tokyo University of Agriculture and Technology.

So the researchers developed a bat organoid that could be used for such experimentation. An organoid is a three-dimensional tissue construct grown ‘in vitro’ (in a petri dish or with other laboratory equipment) from stem cells and that mimics the organ in the living animal. In this case, they grew organoids from cells from the intestine of a flying fox, the species Rousettus leschenaultia within the wider genus of Rousettus, also known as Rousette bats.

They chose Rousette bats, a type of megabat or fruit bat, because they are thought to be a natural reservoir of the filovirus family of viruses, including the Ebola and Marburg viruses. This particular species of rousette bat was also selected because in previous research, another species of rousette bat, Rousettus leschenaultii,  had shown a transient but not robust infection from an experimental inoculation of SARS-CoV-2, the virus that causes COVID-19, while a cell line from the intestine of Rousettus leschenaultia had not been infected at all. Several species of flying foxes in Southeast Asia and Australia have also been found to be hosts of Pteropine orthoreovirus (PRV), which has caused respiratory disease in humans.

The researchers first had to find an optimum medium for the growth of bat intestine cells. They did this by attempting to culture organoids with nine different growth supplements (nutrients and other molecules that encourage cell proliferation). Three out of the nine achieved significantly higher cell growth and proliferation rates after seven days.

In addition, the rousette bat intestinal organoids grown with these three supplements were long-lived, being able to maintain active proliferation for up to ten passages (up to 10 times of reconstructions of organoids from separated cells that were composed of the previous organoids). Organoids that were long-term cryopreserved (in essence frozen) could also grow normally once thawed.

To confirm that the organoid was mimicking the epithelial (outer) tissue of the bat’s intestine—the part of the bat organ that first encounters virus particles and thus of particular scientific interest—the researchers deployed two techniques. First, they used transmission electron microscopy to investigate the cellular anatomy (histology) of the organoids. Second, they used immunofluorescence staining—a common method used to detect and visualize molecules in biological samples—to look for molecular markers that indicate that the tissue under investigation comes from bat intestines. Together, these two techniques told the researchers that the organoids were indeed recreating the typical cellular components of rousette bat intestine tissues.

An initial test of the use of the organoids to investigate viral relationships was also performed. They were shown to be susceptible to PRV but not to SARS-CoV-2 in experimental inoculation.

Having successfully produced bat organoids for the first time, the researchers now want to repeat their trick with other flying fox organs such as lungs, liver, and kidneys. The researchers will then infect this mass of bat ‘insides’ with highly pathogenic viruses to analyse their gene expression (turning genes on and off) in detail to be able to clarify the mechanism of why bats can host such pathogens without getting sick.

 

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For more information about the Omatsu laboratory, please visit https://sites.google.com/view/teamomatsu?fbclid=IwAR3QTDlRh8n7kBKcBKj8fKs1deqrmWNdwLQtYYTIPof1xnwNk7yBYdCOu0Y

 

Original publication:

Mohamed Elbadawy, Yuki Kato, Nagisa Saito, Kimika Hayashi, Amira Abugomaa, Mio Kobayashi, Toshinori Yoshida, Makoto Shibutani, Masahiro Kaneda, Hideyuki Yamawaki, Tetsuya Mizutani, Chang-Kweng Lim, Masayuki Saijo, Kazuaki Sasaki, Tatsuya Usui, and Tsutomu Omatsu.

“Establishment of Intestinal Organoid from Rousettus leschenaultii and the Susceptibility to Bat-Associated Viruses, SARS-CoV-2 and Pteropine Orthoreovirus” International Journal of Molecular Sciences 22, no. 19: 10763,2021.

https://doi.org/10.3390/ijms221910763

 

About Tokyo University of Agriculture and Technology (TUAT):

TUAT is a distinguished university in Japan dedicated to science and technology. TUAT focuses on agriculture and engineering that form the foundation of industry, and promotes education and research fields that incorporate them. Boasting a history of over 140 years since our founding in 1874, TUAT continues to boldly take on new challenges and steadily promote fields. With high ethics, TUAT fulfills social responsibility in the capacity of transmitting science and technology information towards the construction of a sustainable society where both human beings and nature can thrive in a symbiotic relationship. For more information, please visit http://www.tuat.ac.jp/en/.

 

Contact:

Tsutomu Omatsu, DVM, PhD

Associate Professor

Center for Infectious Diseases Epidemiology and Prevention Research

Tokyo University of Agriculture and Technology, Japan

tomatsu@cc.tuat.ac.jp

 


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There will soon be one million seats on this popular Amtrak route

“More people are taking the train than ever before,” says Amtrak’s Executive Vice President.

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While the size of the United States makes it hard for it to compete with the inter-city train access available in places like Japan and many European countries, Amtrak trains are a very popular transportation option in certain pockets of the country — so much so that the country’s national railway company is expanding its Northeast Corridor by more than one million seats.

Related: This is what it's like to take a 19-hour train from New York to Chicago

Running from Boston all the way south to Washington, D.C., the route is one of the most popular as it passes through the most densely populated part of the country and serves as a commuter train for those who need to go between East Coast cities such as New York and Philadelphia for business.

Veronika Bondarenko captured this photo of New York’s Moynihan Train Hall. 

Veronika Bondarenko

Amtrak launches new routes, promises travelers ‘additional travel options’

Earlier this month, Amtrak announced that it was adding four additional Northeastern routes to its schedule — two more routes between New York’s Penn Station and Union Station in Washington, D.C. on the weekend, a new early-morning weekday route between New York and Philadelphia’s William H. Gray III 30th Street Station and a weekend route between Philadelphia and Boston’s South Station.

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According to Amtrak, these additions will increase Northeast Corridor’s service by 20% on the weekdays and 10% on the weekends for a total of one million additional seats when counted by how many will ride the corridor over the year.

“More people are taking the train than ever before and we’re proud to offer our customers additional travel options when they ride with us on the Northeast Regional,” Amtrak Executive Vice President and Chief Commercial Officer Eliot Hamlisch said in a statement on the new routes. “The Northeast Regional gets you where you want to go comfortably, conveniently and sustainably as you breeze past traffic on I-95 for a more enjoyable travel experience.”

Here are some of the other Amtrak changes you can expect to see

Amtrak also said that, in the 2023 financial year, the Northeast Corridor had nearly 9.2 million riders — 8% more than it had pre-pandemic and a 29% increase from 2022. The higher demand, particularly during both off-peak hours and the time when many business travelers use to get to work, is pushing Amtrak to invest into this corridor in particular.

To reach more customers, Amtrak has also made several changes to both its routes and pricing system. In the fall of 2023, it introduced a type of new “Night Owl Fare” — if traveling during very late or very early hours, one can go between cities like New York and Philadelphia or Philadelphia and Washington. D.C. for $5 to $15.

As travel on the same routes during peak hours can reach as much as $300, this was a deliberate move to reach those who have the flexibility of time and might have otherwise preferred more affordable methods of transportation such as the bus. After seeing strong uptake, Amtrak added this type of fare to more Boston routes.

The largest distances, such as the ones between Boston and New York or New York and Washington, are available at the lowest rate for $20.

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The next pandemic? It’s already here for Earth’s wildlife

Bird flu is decimating species already threatened by climate change and habitat loss.

I am a conservation biologist who studies emerging infectious diseases. When people ask me what I think the next pandemic will be I often say that we are in the midst of one – it’s just afflicting a great many species more than ours.

I am referring to the highly pathogenic strain of avian influenza H5N1 (HPAI H5N1), otherwise known as bird flu, which has killed millions of birds and unknown numbers of mammals, particularly during the past three years.

This is the strain that emerged in domestic geese in China in 1997 and quickly jumped to humans in south-east Asia with a mortality rate of around 40-50%. My research group encountered the virus when it killed a mammal, an endangered Owston’s palm civet, in a captive breeding programme in Cuc Phuong National Park Vietnam in 2005.

How these animals caught bird flu was never confirmed. Their diet is mainly earthworms, so they had not been infected by eating diseased poultry like many captive tigers in the region.

This discovery prompted us to collate all confirmed reports of fatal infection with bird flu to assess just how broad a threat to wildlife this virus might pose.

This is how a newly discovered virus in Chinese poultry came to threaten so much of the world’s biodiversity.

H5N1 originated on a Chinese poultry farm in 1997. ChameleonsEye/Shutterstock

The first signs

Until December 2005, most confirmed infections had been found in a few zoos and rescue centres in Thailand and Cambodia. Our analysis in 2006 showed that nearly half (48%) of all the different groups of birds (known to taxonomists as “orders”) contained a species in which a fatal infection of bird flu had been reported. These 13 orders comprised 84% of all bird species.

We reasoned 20 years ago that the strains of H5N1 circulating were probably highly pathogenic to all bird orders. We also showed that the list of confirmed infected species included those that were globally threatened and that important habitats, such as Vietnam’s Mekong delta, lay close to reported poultry outbreaks.

Mammals known to be susceptible to bird flu during the early 2000s included primates, rodents, pigs and rabbits. Large carnivores such as Bengal tigers and clouded leopards were reported to have been killed, as well as domestic cats.

Our 2006 paper showed the ease with which this virus crossed species barriers and suggested it might one day produce a pandemic-scale threat to global biodiversity.

Unfortunately, our warnings were correct.

A roving sickness

Two decades on, bird flu is killing species from the high Arctic to mainland Antarctica.

In the past couple of years, bird flu has spread rapidly across Europe and infiltrated North and South America, killing millions of poultry and a variety of bird and mammal species. A recent paper found that 26 countries have reported at least 48 mammal species that have died from the virus since 2020, when the latest increase in reported infections started.

Not even the ocean is safe. Since 2020, 13 species of aquatic mammal have succumbed, including American sea lions, porpoises and dolphins, often dying in their thousands in South America. A wide range of scavenging and predatory mammals that live on land are now also confirmed to be susceptible, including mountain lions, lynx, brown, black and polar bears.

The UK alone has lost over 75% of its great skuas and seen a 25% decline in northern gannets. Recent declines in sandwich terns (35%) and common terns (42%) were also largely driven by the virus.

Scientists haven’t managed to completely sequence the virus in all affected species. Research and continuous surveillance could tell us how adaptable it ultimately becomes, and whether it can jump to even more species. We know it can already infect humans – one or more genetic mutations may make it more infectious.

At the crossroads

Between January 1 2003 and December 21 2023, 882 cases of human infection with the H5N1 virus were reported from 23 countries, of which 461 (52%) were fatal.

Of these fatal cases, more than half were in Vietnam, China, Cambodia and Laos. Poultry-to-human infections were first recorded in Cambodia in December 2003. Intermittent cases were reported until 2014, followed by a gap until 2023, yielding 41 deaths from 64 cases. The subtype of H5N1 virus responsible has been detected in poultry in Cambodia since 2014. In the early 2000s, the H5N1 virus circulating had a high human mortality rate, so it is worrying that we are now starting to see people dying after contact with poultry again.

It’s not just H5 subtypes of bird flu that concern humans. The H10N1 virus was originally isolated from wild birds in South Korea, but has also been reported in samples from China and Mongolia.

Recent research found that these particular virus subtypes may be able to jump to humans after they were found to be pathogenic in laboratory mice and ferrets. The first person who was confirmed to be infected with H10N5 died in China on January 27 2024, but this patient was also suffering from seasonal flu (H3N2). They had been exposed to live poultry which also tested positive for H10N5.

Species already threatened with extinction are among those which have died due to bird flu in the past three years. The first deaths from the virus in mainland Antarctica have just been confirmed in skuas, highlighting a looming threat to penguin colonies whose eggs and chicks skuas prey on. Humboldt penguins have already been killed by the virus in Chile.

A colony of king penguins.
Remote penguin colonies are already threatened by climate change. AndreAnita/Shutterstock

How can we stem this tsunami of H5N1 and other avian influenzas? Completely overhaul poultry production on a global scale. Make farms self-sufficient in rearing eggs and chicks instead of exporting them internationally. The trend towards megafarms containing over a million birds must be stopped in its tracks.

To prevent the worst outcomes for this virus, we must revisit its primary source: the incubator of intensive poultry farms.

Diana Bell does not work for, consult, own shares in or receive funding from any company or organisation that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.

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This is the biggest money mistake you’re making during travel

A retail expert talks of some common money mistakes travelers make on their trips.

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Travel is expensive. Despite the explosion of travel demand in the two years since the world opened up from the pandemic, survey after survey shows that financial reasons are the biggest factor keeping some from taking their desired trips.

Airfare, accommodation as well as food and entertainment during the trip have all outpaced inflation over the last four years.

Related: This is why we're still spending an insane amount of money on travel

But while there are multiple tricks and “travel hacks” for finding cheaper plane tickets and accommodation, the biggest financial mistake that leads to blown travel budgets is much smaller and more insidious.

A traveler watches a plane takeoff at an airport gate.

Jeshoots on Unsplash

This is what you should (and shouldn’t) spend your money on while abroad

“When it comes to traveling, it's hard to resist buying items so you can have a piece of that memory at home,” Kristen Gall, a retail expert who heads the financial planning section at points-back platform Rakuten, told Travel + Leisure in an interview. “However, it's important to remember that you don't need every souvenir that catches your eye.”

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According to Gall, souvenirs not only have a tendency to add up in price but also weight which can in turn require one to pay for extra weight or even another suitcase at the airport — over the last two months, airlines like Delta  (DAL) , American Airlines  (AAL)  and JetBlue Airways  (JBLU)  have all followed each other in increasing baggage prices to in some cases as much as $60 for a first bag and $100 for a second one.

While such extras may not seem like a lot compared to the thousands one might have spent on the hotel and ticket, they all have what is sometimes known as a “coffee” or “takeout effect” in which small expenses can lead one to overspend by a large amount.

‘Save up for one special thing rather than a bunch of trinkets…’

“When traveling abroad, I recommend only purchasing items that you can't get back at home, or that are small enough to not impact your luggage weight,” Gall said. “If you’re set on bringing home a souvenir, save up for one special thing, rather than wasting your money on a bunch of trinkets you may not think twice about once you return home.”

Along with the immediate costs, there is also the risk of purchasing things that go to waste when returning home from an international vacation. Alcohol is subject to airlines’ liquid rules while certain types of foods, particularly meat and other animal products, can be confiscated by customs. 

While one incident of losing an expensive bottle of liquor or cheese brought back from a country like France will often make travelers forever careful, those who travel internationally less frequently will often be unaware of specific rules and be forced to part with something they spent money on at the airport.

“It's important to keep in mind that you're going to have to travel back with everything you purchased,” Gall continued. “[…] Be careful when buying food or wine, as it may not make it through customs. Foods like chocolate are typically fine, but items like meat and produce are likely prohibited to come back into the country.

Related: Veteran fund manager picks favorite stocks for 2024

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