This week researchers at Vanderbilt University Medical Center (VUMC), the University of North Carolina at Chapel Hill and Gilead Sciences reported that remdesivir potently inhibited SARS-CoV-2, the virus which causes COVID-19, in human lung cell cultures and that it improved lung function in mice infected with the virus.

These preclinical findings help explain the clinical effect the drug has had in treating COVID-19 patients. Remdesivir has been given to patients hospitalized with COVID-19 on a compassionate use basis since late January and through clinical trials since February.

In April, a preliminary report from the multicenter Adaptive COVID-19 Treatment Trial (which included VUMC) suggested that patients who received the drug recovered more quickly.

“All of the results with remdesivir have been very encouraging, even more so than we would have hoped, but it is still investigational, so it was important to directly demonstrate its activity against SARS-CoV-2 in the lab and in an animal model of disease,” said VUMC’s Andrea Pruijssers, PhD.

Pruijssers, research assistant professor of Pediatrics at VUMC and lead antiviral scientist in the laboratory of Mark Denison, MD, is the paper’s co-corresponding author with Timothy Sheahan, PhD, assistant professor of Epidemiology at UNC-Chapel Hill.

Denison, the E.C. Stahlman Professor of Pediatrics at VUMC, directs the Division of Pediatric Infectious Diseases. He and Ralph Baric, PhD, the William R. Kenan, Jr. Distinguished Professor of Epidemiology at UNC-Chapel Hill, and colleagues have been studying remdesivir since 2014.

They were the first to perform detailed studies to demonstrate that the drug, which was developed by Gilead Sciences to combat hepatitis C and respiratory syncytial virus, and later the Ebola virus, also showed broad and highly potent activity against coronaviruses in laboratory tests.

The current findings, reported this week in the journal Cell Reports, provide “the first rigorous demonstration of potent inhibition of SARS-CoV-2 in continuous and primary human lung cultures.” The study is also the first to suggest that remdesivir can block the virus in a mouse model.

Ongoing clinical trials will determine precisely how much it benefits patients in different stages of COVID-19 disease.

Meanwhile in the laboratory, Pruijssers said, “We also are focusing on how to use remdesivir and other drugs in combinations to increase their effectiveness during COVID-19 and to be able to treat at different times of infection.”

COVID-19, which to date has infected more then 12 million people and killed nearly 600,000 worldwide, is at least the third instance since 2003 in which a coronavirus originally transmitted from bats has caused serious illness in humans.

Thus there is an urgent need to identify and evaluate broadly efficacious and robust therapies that can limit and prevent coronavirus infections. “Broad-spectrum antiviral drugs, antibodies, and vaccines are needed to combat the current pandemic and those that will emerge in the future,” the researchers said.

In addition to SARS-CoV-2, studies in the Denison and Baric labs have shown that remdesivir is effective against a vast array of coronaviruses, including other bat viruses that could emerge in the future in humans.

“We hope that will never happen, but just as we were working to characterize remdesivir over the past six years to be ready for a virus like SARS-CoV-2, we are working and investing now to prepare for any future coronavirus,” Denison said. “We want remdesivir and other drugs to be useful both now and in the future.”

Others VUMC co-authors were Amelia George, MS, Maria Agostini, PhD, Laura Stevens, MS, James Chappell, MD, PhD, Xiaotao Lu, MS, and Tia Hughes, MS.

The study was supported by National Institutes of Health grants AI142759, AI132178 and AI132178-03S1, AI081197 and AI007151, the Dolly Parton COVID-19 Research Fund and the Elizabeth B. Lamb Center for Pediatric Research at Vanderbilt.

Bruce Edgar, PhD, a stem cell biologist at HCI and professor of oncological sciences at the U of U, together with Aurelio Teleman, PhD, division head at DKFZ and professor at Heidelberg University jointly led the work. They asked whether sex hormones affect intestinal stem cells’ ability to multiply and contribute to gut growth. “My lab and many others around the world have studied the Drosophila gut for some time to better understand how stem cells are regulated,” says Edgar. “We knew that male and female fruit flies exhibited differences in their intestine — for example, the female’s intestine is larger than the male’s, and females develop intestinal tumors much more readily than males — but we didn’t know why.” This study adds significant insights into these differences, and how they arise.

The Edgar and Teleman teams found that ecdysone, a sex-specific hormone, can drastically alter the growth properties of stem cells in an organ that, remarkably, is not directly involved in reproduction. They found that these changes affect the structure and function of the entire organ. They discovered that subjecting male flies to ecdysone caused their otherwise slow dividing stem cells to divide as fast as in females, leading to intestinal growth in males as well. This suggests that the limiting difference between the division of stem cells in male and female flies is the circulating levels of the hormone.

This process confers both advantages and disadvantages to the female fruit fly during the course of its life. Initially, more ecdysone in females helps with the evolutionarily critical processes of reproduction. It promotes gut enlargement, facilitating nutrient absorption, which helps the fly lay more eggs. But later in life, the ecdysone hormone, produced by the ovaries, eventually causes gut disfunction that can shorten the lifespan in female fruit flies by creating an environment that favors tumor growth. While humans don’t produce ecdysone, they do have related steroid hormones such as estrogen, progesterone and testosterone, which have similar mechanisms of action.

The experimental work on this study was performed primarily by Sara Ahmed, a joint PhD student between the Edgar and Teleman labs at the Zentrum für Molekulare Biologie der Universität Heidelberg (ZMBH) and the DKFZ. Ahmed designed experiments utilizing various genetic tools to switch genes on and off in different cell types in the fly’s intestine and in its ovaries, which produce ecdysone. “Our study provides conclusive evidence that sex hormones alter the behavior of non-sex organs like the intestine,” says Ahmed. She further speculates that long-term implications of this research may include exploration of new paths to treating human cancers.

According to the researchers, understanding whether a similar stem cell-hormone relationship operates in human organs will require further studies. They plan to explore this in the future. In addition to the critical role played by sex hormones in intestinal stem cell behavior, the authors believe this study in Drosophila potentially unveils a new mechanism that may play out in human physiology and pathology. Insights from this study add to a growing body of work showing that the incidence cancers of non-reproductive organs, including colon and gastric cancers, are different in males and females.

This study was supported by the National Institutes of Health including the National Cancer Institute P30 CA01420114, the National Institute of General Medical Sciences R01 124434, the European Research Council AdG268515, DKFZ, and Huntsman Cancer Foundation.

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New research by the team from Wits, with collaborators from the University of Cape Town and University of Pretoria, reveals what a shift from night-time to daytime activity means for the well-being of aardvarks in a warming and drying world. The researchers studied aardvarks living at Tswalu, a reserve in the Kalahari that lies at the edge of the aardvark’s distribution and provides support and infrastructure for researchers through the Tswalu Foundation. The results are published in the journal Frontiers in Physiology.

Using biologgers, the researchers recorded body temperature and activity of aardvarks for three years, during which Dr Nora Weyer followed the aardvarks as part of her PhD research.

Assisted by satellite imaging that showed her how droughts affected the vegetation, Weyer was able to connect changes in aardvark behaviour and body temperature to what was happening in the aardvarks’ environment.

Weyer’s research confirmed earlier findings by the team that there are times when the aardvarks switched their feeding to the day, and showed, for the first time, that drought caused that switch. “We suspected that it was drought,” says co-worker Dr Robyn Hetem, “but we needed a long-term, comprehensive data set to confirm that it really was drought causing this unusual behaviour.”

The Kalahari is arid at the best of times, but drought killed the vegetation that fed the ants and termites. Most of the ants and termites disappeared, leaving the aardvarks starving. “It was heart-breaking to watch our aardvarks waste away as they starved,” says Weyer.

By shifting their activity from the cold nights to the warm days during dry winter months, aardvarks can save some of the energy needed to keep their body temperatures up. But those energy savings were not enough to see the aardvarks through a particularly bad drought in which many aardvarks died.

“Aardvarks have coped with the Kalahari’s harsh environment in the past, but it is getting hotter and drier, and the current and future changes to our climate might be too much for the aardvarks to bear,” says Weyer. “Because the Kalahari is such a unique and potentially vulnerable ecosystem, we need to better understand whether its animals can cope with the increasingly dry conditions,” says Professor Andrea Fuller, co-worker and project leader of the Kalahari Endangered Ecosystem Project (KEEP).

Disappearance of aardvarks from the Kalahari would be devastating for many other animals in this ecosystem. The large burrows which aardvarks build provide important shelters for many other species that cannot dig their own burrows, earning the aardvark the title of ?ecosystem engineer’.

“Unfortunately, the future looks grim for Kalahari aardvarks and the animals that use their burrows. Tackling climate change is key, but there is no quick fix,” says Weyer. What conservationists do know is that any solution will require a much better understanding of what capacities animals have to cope with drought. And that means many more long-term comprehensive studies of physiology and behaviour, like the study that Dr Weyer and her colleagues carried out at Tswalu.

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The tomcat — which was examined by a team led by Dr Ashleigh Haruda from the Central Natural Science Collections at MLU — did not have an easy life. “The cat suffered several broken bones during its lifetime,” says Haruda. And yet, based on a very conservative estimate, the animal had most likely made it past its first year of life. For Haruda and her colleagues, this is a clear indication that people had taken care of this cat.

During a research stay in Kazakhstan, the scientist examined the findings of an excavation in Dzhankent, an early medieval settlement in the south of the country which had been mainly populated by the Oghuz, a pastoralist Turkic tribe. There she discovered a very well-preserved skeleton of a cat. According to Haruda, this is quite rare because normally only individual bones of an animal are found during an excavation, which prevents any systematic conclusions from being drawn about the animal’s life. The situation is different when it comes to humans since usually whole skeletons are found. “A human skeleton is like a biography of that person. The bones provide a great deal of information about how the person lived and what they experienced,” says Haruda. In this case, however, the researchers got lucky: after its death, the tomcat was apparently buried and therefore the entire skull including its lower jaw, parts of its upper body, legs and four vertebrae had been preserved.

Haruda worked together with an international team of archaeologists and ancient DNA specialists. An examination of the tomcat’s skeleton revealed astonishing details about its life. First, the team took 3D images and X-rays of its bones. “This cat suffered a number of fractures, but survived,” says Haruda. Isotope analyses of bone samples also provided the team with information about the cat’s diet. Compared to the dogs found during the excavation and to other cats from that time period, this tomcat’s diet was very high in protein. “It must have been fed by humans since the animal had lost almost all its teeth towards the end of its life.”

DNA analyses also proved that the animal was indeed likely to be a domestic cat of the Felis catus L. species and not a closely related wild steppe cat. According to Haruda, it is remarkable that cats were already being kept as pets in this region around the 8th century AD: “The Oghuz were people who only kept animals when they were essential to their lives. Dogs, for example, can watch over the herd. They had no obvious use for cats back then,” explains the researcher. The fact that people at the time kept and cared for such “exotic” animals indicates a cultural change, which was thought to have occurred at a much later point in time in Central Asia. The region was thought to have been slow in making changes with respect to agriculture and animal husbandry.

The Dhzankent settlement, where the remains of the cat were found, was located along the Silk Road, an ancient network of important caravan routes that connected Central and East Asia with the Mediterranean region by land. According to Haruda, the find is also an indication of cultural exchange between the regions located along the Silk Road.

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