Fever, cough, sore throat — symptoms in the spotlight in the era of COVID-19 — are just some of the tell-tale signs of our body’s immune system kicking into action against an unwanted intruder. Whether triggered by an infection, an allergen, or a vaccine, immune responses are driven by a complex array of cellular processes that can play out over several days or even weeks.

A lot is known about the overarching processes at play in immune responses. But because of the sheer numbers of variables involved, pinpointing what to focus on to develop treatments or vaccines proves very much like looking for a needle in a haystack. This may now change thanks to a new study by researchers from McGill University and the US National Cancer Institute (NCI), published recently in Science.

It focused on a fundamental process in the immune system: the role of proteins called cytokines in signalling and kickstarting a body’s responses.

The crucial role of the messengers

Our immune system is often characterized as a battle. Certain critical white blood cells (called T cells) travel through the bloodstream and lymphatic systems and into tissues, searching for traces of microorganisms and other invaders known as antigens. To avoid attacking healthy cells indiscriminately, T cells circulate until they recognize a specific antigen; only then do they send out messengers in the form of cytokines to activate an alert system and signal that all is not well.

“You might think that there are many, very different parameters in the immune response that are crucial — for instance, the number of T cells produced to fight the invaders might vary, or the number of invaders (antigens) themselves,” explains Paul François, the McGill biophysicist who led the data analysis team, which included McGill physics PhD students François Bourassa and Thomas Rademaker. “But the big surprise is that, actually, what really matters is antigen strength.”

Crunching numbers helps pinpoint essentials

Until now, it has been difficult to measure antigen strength — seen in how effectively an antigen triggers T cells to respond — independently of the quantity of an antigen present in any given experiment.

But by using a data-driven approach, and thanks to the crucial collaboration with the NCI, François and his colleagues have been able to decode the highly variable phenomenon of cytokine production to give a reliable readout of antigen strength. This is potentially very useful for predicting how well a vaccine candidate or immunotherapy drug might work.

To study this phenomenon in detail, the NCI researchers, led by Grégoire Altan-Bonnet, developed a robotic platform to perform dozens of experiments at once, exposing T cells to various antigens and conditions. Sooraj Achar, a graduate student in the Altan-Bonnet lab, optimized the automated system in order to gather vast amounts of data in a fraction of the time it would have taken to do the same experiments by hand.

“Assembling a comprehensive map of the dynamics of cytokines generated by T cells in very diverse settings present a challenge and an opportunity to better understand how T cells “see” the antigenic world, and orchestrate immune responses,” pointed out Altan-Bonnet.

The McGill members of the team then used machine learning to process the data generated by those experiments, and mathematical models to capture meaningful patterns in the data. This data-driven modelling revealed surprisingly simple rules at the heart of what otherwise might appear to be a highly complex process subject to multiple variables.

A spectrum of immune reactions?

The analysis also showed that patterns of cytokine release carried information about the type of antigen encountered and distinguished six distinct cellular responses rather than the three types usually recognized.

“This supports the idea that immune responses exist along a spectrum rather than as a binary on-off switch,” adds François. “There may be different levels of immune response that can be tuned to the right level of alert depending on the complexity of the situation.”

This new understanding is likely to enhance strategies for immunotherapies that rely on T cells engineered to target the tumors of a patient.

The team, led by Dr James R. Allan from the University of Amsterdam, used advanced geospatial algorithms to map the optimal areas for conserving terrestrial species and ecosystems across the world. They further used spatially explicit land-use scenarios to quantify how much of this land is at risk from human activities by 2030.

“Our study is the current best estimate of how much land we must conserve to stop the biodiversity crisis — it is essentially a conservation plan for the planet,” said lead author James Allan. “We must act fast, our models show that over 1.3 million km² of this important land — an area larger than South Africa — is likely to have its habitat cleared for human uses by 2030, which would be devastating for wildlife.”

The work has important policy implications since governments are currently negotiating a post-2020 global biodiversity framework under the Convention on Biological Diversity, with new goals and targets for biodiversity which will hopefully come into effect later this year. This will set the conservation agenda for at least the next decade, and governments will have to report progress against these targets on a regular basis.

“More than a decade ago, governments set a global target to conserve at least 17 per cent of terrestrial areas through protected areas and other site-based approaches for improving the status of biodiversity and ecosystems,” explains co-author Dr Kendall Jones, Conservation Planning Specialist at the Wildlife Conservation Society. “However, by 2020 it was clear that this was not enough for halting biodiversity declines and averting the biodiversity crisis.”

A high-profile target being now discussed for 2030 is that nations should conserve 30% of their land through protected areas and other site-based approaches.

Added Jones: “While this is a great step in the right direction, our study suggests that more ambitious goals and policies to maintain ecological integrity beyond this 30% target are crucial. If nations are serious about safeguarding biodiversity and ecosystem services that underpin life on Earth, then they need immediately to scale-up their conservation efforts, not only in extent and intensity but also in effectiveness.”

The authors said the study provides essential information for conservation and development planning, and can help guide future national and global conservation agendas. They also emphasized that all the identified land should not necessarily be designated as protected areas, but rather managed through a wide range of strategies for species and ecosystem conservation, including including other effective area-based conservation measures, and effective sustainable land-use policies when appropriate.

“Conservation actions that promote the autonomy and self-determination of people living on this land, whilst also maintaining ecological integrity are crucial,” said Dr Allan. “We have many effective conservation tools available, from empowering Indigenous Peoples to manage their natural environment, through to policies that limit deforestation or provide sustainable livelihood options, and of course protected areas.”

Story Source:

Materials provided by Wildlife Conservation Society. Note: Content may be edited for style and length.

Melting glaciers have become a symbol of climate change in the Alps. Now, the reduction in snow cover is already visible from space but this is by no means the biggest change. This is the conclusion of a research team led by Professor Sabine Rumpf from the University of Basel and Professor Grégoire Mariéthoz and Professor Antoine Guisan from the University of Lausanne.

Working with colleagues in the Netherlands and Finland, the researchers investigated the change in snow cover and vegetation using high-resolution satellite data from 1984 to 2021. Over this period, plant biomass above the tree line increased in more than 77% of the observed area. This phenomenon of “greening” due to climate change is already well documented in the Arctic and starts also to be detected in mountains.

Greater plant biomass in three-quarters of the Alps

“The scale of the change has turned out to be absolutely massive in the Alps,” says Sabine Rumpf, lead author of the study and, since February, assistant professor at the University of Basel. The Alps are becoming greener because plants are colonizing new areas and the vegetation is generally becoming denser and taller.

Previous studies have primarily focused on the influence of global warming on Alpine biodiversity and changes in the distribution of plant species. Until now, however, no one had conducted such a comprehensive analysis of the changes in vegetation productivity in the Alps. The authors show that the increase of plant biomass is primarily due to changes in precipitation and longer vegetation periods as a result of rising temperatures.

“Alpine plants are adapted to harsh conditions, but they’re not very competitive,” says Rumpf. As environmental conditions change, she says, these specialized species lose their advantage and are outcompeted: “The unique biodiversity of the Alps is therefore under considerable pressure.”

Already a slight reduction in snow cover

In contrast to vegetation, the extent of snow cover above the tree line has only changed slightly since 1984. For their analysis, the researchers excluded regions below 1.700 meters, glaciers and forests. In the remaining regions, they found that snow cover had decreased significantly in almost 10% of the area. This may not sound like a lot, but the researchers are keen to highlight that it is nevertheless a worrying trend.

“Previous analyses of satellite data hadn’t identified any such trend,” explains Antoine Guisan, one of the two senior authors of the study. “This may be because the resolution of the satellite images was insufficient or because the periods considered were too short.”

“For years, local ground-based measurements have shown a decrease in snow depth at low elevations,” adds Grégoire Mariéthoz. “This decrease has already caused some areas to become largely snow-free.” Based on the satellite data, it’s possible to distinguish whether a specific area is covered with snow or not, but doesn’t allow to draw conclusions about snow depth.

As global warming continues, the Alps will turn more and more from white to green, creating a vicious circle: “Greener mountains reflect less sunlight and therefore lead to further warming — and, in turn, to further shrinkage of reflective snow cover,” says Rumpf. Warming also causes further melting of glaciers and the thawing of permafrost, which may lead to more landslides, rockfalls and mudflows. Furthermore, Rumpf emphasizes the important role of snow and ice from the Alps in the supply of drinking water and, not least, for recreation and tourism.

Story Source:

Materials provided by University of Basel. Note: Content may be edited for style and length.

Bronze Age city resurfaced due to drought

Iraq is one of the countries in the world most affected by climate change. The south of the country in particular has been suffering from extreme drought for months. To prevent crops from drying out, large amounts of water have been drawn down from the Mosul reservoir — Iraq’s most important water storage — since December. This led to the reappearance of a Bronze Age city that had been submerged decades ago without any prior archaeological investigations. It is located at Kemune in the Kurdistan Region of Iraq.

This unforeseen event put archaeologists under sudden pressure to excavate and document at least parts of this large, important city as quickly as possible before it was resubmerged. The Kurdish archaeologist Dr. Hasan Ahmed Qasim, chairman of the Kurdistan Archaeology Organization, and the German archaeologists Jun.-Prof. Dr. Ivana Puljiz, University of Freiburg, and Prof. Dr. Peter Pfälzner, University of Tübingen, spontaneously decided to undertake joint rescue excavations at Kemune. These took place in January and February 2022 in collaboration with the Directorate of Antiquities and Heritage in Duhok (Kurdistan Region of Iraq).

Fritz Thyssen Foundation supported excavations

A team for the rescue excavations was put together within days. Funding for the work was obtained at short notice from the Fritz Thyssen Foundation through the University of Freiburg. The German-Kurdish archaeological team was under immense time pressure because it was not clear when the water in the reservoir would rise again.

Massive fortification, multi-storey storage building, industrial complex

Within a short time, the researchers succeeded in largely mapping the city. In addition to a palace, which had already been documented during a short campaign in 2018, several other large buildings were uncovered — a massive fortification with wall and towers, a monumental, multi-storey storage building and an industrial complex. The extensive urban complex dates to the time of the Empire of Mittani (approx. 1550-1350 BC), which controlled large parts of northern Mesopotamia and Syria.

“The huge magazine building is of particular importance because enormous quantities of goods must have been stored in it, probably brought from all over the region,” says Puljiz. Qasim concludes, “The excavation results show that the site was an important center in the Mittani Empire.”

The research team was stunned by the well-preserved state of the walls — sometimes to a height of several meters — despite the fact that the walls are made of sun-dried mud bricks and were under water for more than 40 years. This good preservation is due to the fact that the city was destroyed in an earthquake around 1350 BC, during which the collapsing upper parts of the walls buried the buildings.

Ceramic vessels with over 100 cuneiform tablets

Of particular interest is the discovery of five ceramic vessels that contained an archive of over 100 cuneiform tablets. They date to the Middle Assyrian period, shortly after the earthquake disaster struck the city. Some clay tablets, which may be letters, are even still in their clay envelopes. The researchers hope this discovery will provide important information about the end of the Mittani-period city and the beginning of Assyrian rule in the region. “It is close to a miracle that cuneiform tablets made of unfired clay survived so many decades under water,” Pfälzner says.

Conservation project to prevent damage by rising water

To avert further damage to the important site by the rising water, the excavated buildings were completely covered with tight-fitting plastic sheeting and covered with gravel fill as part of an extensive conservation project funded by the Gerda Henkel Foundation. This is intended to protect the walls of unbaked clay and any other finds still hidden in the ruins during times of flooding. The site is now once more completely submerged.

Story Source:

Materials provided by University of Freiburg. Note: Content may be edited for style and length.

It’s not surprising these days to see new inventions that either incorporate or have benefitted from artificial intelligence (AI) in some way, but what about inventions dreamt up by AI — do we award a patent to a machine?

This is the quandary facing lawmakers around the world with a live test case in the works that its supporters say is the first true example of an AI system named as the sole inventor.

In commentary published in the journal Nature, two leading academics from UNSW Sydney examine the implications of patents being awarded to an AI entity.

Intellectual Property (IP) law specialist Associate Professor Alexandra George and AI expert, Laureate Fellow and Scientia Professor Toby Walsh argue that patent law as it stands is inadequate to deal with such cases and requires legislators to amend laws around IP and patents — laws that have been operating under the same assumptions for hundreds of years.

The case in question revolves around a machine called DABUS (Device for the Autonomous Bootstrapping of Unified Sentience) created by Dr Stephen Thaler, who is president and chief executive of US-based AI firm Imagination Engines. Dr Thaler has named DABUS as the inventor of two products — a food container with a fractal surface that helps with insulation and stacking, and a flashing light for attracting attention in emergencies.

For a short time in Australia, DABUS looked like it might be recognised as the inventor because, in late July 2021, a trial judge accepted Dr Thaler’s appeal against IP Australia’s rejection of the patent application five months earlier. But after the Commissioner of Patents appealed the decision to the Full Court of the Federal Court of Australia, the five-judge panel upheld the appeal, agreeing with the Commissioner that an AI system couldn’t be named the inventor.

A/Prof. George says the attempt to have DABUS awarded a patent for the two inventions instantly creates challenges for existing laws which has only ever considered humans or entities comprised of humans as inventors and patent-holders.

“Even if we do accept that an AI system is the true inventor, the first big problem is ownership. How do you work out who the owner is? An owner needs to be a legal person, and an AI is not recognised as a legal person,” she says.

Ownership is crucial to IP law. Without it there would be little incentive for others to invest in the new inventions to make them a reality.

“Another problem with ownership when it comes to AI-conceived inventions, is even if you could transfer ownership from the AI inventor to a person: is it the original software writer of the AI? Is it a person who has bought the AI and trained it for their own purposes? Or is it the people whose copyrighted material has been fed into the AI to give it all that information?” asks A/Prof. George.

For obvious reasons

Prof. Walsh says what makes AI systems so different to humans is their capacity to learn and store so much more information than an expert ever could. One of the requirements of inventions and patents is that the product or idea is novel, not obvious and is useful.

“There are certain assumptions built into the law that an invention should not be obvious to a knowledgeable person in the field,” Prof. Walsh says.

“Well, what might be obvious to an AI won’t be obvious to a human because AI might have ingested all the human knowledge on this topic, way more than a human could, so the nature of what is obvious changes.”

Prof. Walsh says this isn’t the first time that AI has been instrumental in coming up with new inventions. In the area of drug development, a new antibiotic was created in 2019 — Halicin — that used deep learning to find a chemical compound that was effective against drug-resistant strains of bacteria.

“Halicin was originally meant to treat diabetes, but its effectiveness as an antibiotic was only discovered by AI that was directed to examine a vast catalogue of drugs that could be repurposed as antibiotics. So there’s a mixture of human and machine coming into this discovery.”

Prof. Walsh says in the case of DABUS, it’s not entirely clear whether the system is truly responsible for the inventions.

“There’s lots of involvement of Dr Thaler in these inventions, first in setting up the problem, then guiding the search for the solution to the problem, and then interpreting the result,” Prof. Walsh says.

“But it’s certainly the case that without the system, you wouldn’t have come up with the inventions.”

Change the laws

Either way, both authors argue that governing bodies around the world will need to modernise the legal structures that determine whether or not AI systems can be awarded IP protection. They recommend the introduction of a new ‘sui generis’ form of IP law — which they’ve dubbed ‘AI-IP’ — that would be specifically tailored to the circumstances of AI-generated inventiveness. This, they argue, would be more effective than trying to retrofit and shoehorn AI-inventiveness into existing patent laws.

Looking forward, after examining the legal questions around AI and patent law, the authors are currently working on answering the technical question of how AI is going to be inventing in the future.

Dr Thaler has sought ‘special leave to appeal’ the case concerning DABUS to the High Court of Australia. It remains to be seen whether the High Court will agree to hear it. Meanwhile, the case continues to be fought in multiple other jurisdictions around the world.

Neutrinos are subatomic particles that are both famously elusive and tremendously abundant. They endlessly bombard every inch of Earth’s surface at nearly the speed of light, but rarely interact with matter. They can travel through a lightyear’s worth of lead without ever disturbing a single atom.

One of the defining characteristics of these ghost-like particles is their ability to oscillate between three distinct “flavors”: muon neutrino, tau neutrino, and electron neutrino. The Daya Bay Reactor Neutrino Experiment was designed to investigate the properties that dictate the probability of those oscillations, or what are known as mixing angles and mass splittings.

Only one of the three mixing angles remained unknown at the time Daya Bay was designed in 2007: theta13. So, Daya Bay was built to measure theta13* with higher sensitivity than any other experiment.

Operating in Guangdong, China, the Daya Bay Reactor Neutrino Experiment consists of large, cylindrical particle detectors immersed in pools of water in three underground caverns. The eight detectors pick up light signals generated by antineutrinos streaming from nearby nuclear power plants. Antineutrinos are the antiparticles of neutrinos, and they are produced in abundance by nuclear reactors. Daya Bay was built through an international effort and a first-of-its-kind partnership for a major physics project between China and the United States. The Beijing-based Institute of High Energy Physics (IHEP) of the Chinese Academy of Sciences leads China’s role in the collaboration, while the U.S. Department of Energy’s (DOE) Lawrence Berkeley National Laboratory and Brookhaven National Laboratory co-lead U.S. participation.

To determine the value of theta13, Daya Bay scientists detected neutrinos of a specific flavor — in this case, electron antineutrinos — in each of the underground caverns. Two caverns are near the nuclear reactors and the third cavern is farther away, providing ample distance for the antineutrinos to oscillate. By comparing the number of electron antineutrinos picked up by the near and far detectors, physicists calculated how many changed flavors and, consequently, the value of theta13.

Daya Bay physicists made the world’s first conclusive measurement of theta13 in 2012 and subsequently improved upon the measurement’s precision as the experiment continued taking data. Now, after nine years of operation and the end of data collection in December 2020, excellent detector performance, and dedicated data analysis, Daya Bay has far exceeded expectations. Working with the complete dataset, physicists have now measured the value of theta13 with a precision two and a half times greater than the experiment’s design goal. No other existing or planned experiment is expected to reach such an exquisite level of precision.

“We had multiple analysis teams that painstakingly scrutinized the entire dataset, carefully taking into account the evolution of detector performance over the nine years of operation,” said Daya Bay co-spokesperson Jun Cao of IHEP. “The teams took advantage of the large dataset not only to refine the selection of antineutrino events but also to improve the determination of backgrounds. This dedicated effort allowed us to reach an unrivaled level of precision.”

The precision measurement of theta13 will enable physicists to more easily measure other parameters in neutrino physics, as well as develop more accurate models of subatomic particles and how they interact.

By investigating the properties and interactions of antineutrinos, physicists may gain insight into the imbalance of matter and antimatter in the universe. Physicists believe that matter and antimatter were created in equal amounts at the time of the Big Bang. But if that were the case, these two opposites should have annihilated, leaving behind only light. Some difference between the two must have tipped the balance to explain the preponderance of matter (and lack of antimatter) in the universe today.

“We expect there might be some difference between neutrinos and antineutrinos,” said Berkeley physicist and Daya Bay co-spokesperson Kam-Biu Luk. “We’ve never detected differences between particles and antiparticles for leptons, the type of particles that includes neutrinos. We’ve only detected differences between particles and antiparticles for quarks. But the differences we see with the quarks aren’t enough to explain why there’s more matter than antimatter in the universe. It’s possible that neutrinos might be the smoking gun.”

The latest analysis of Daya Bay’s final dataset also provided physicists with a precise measurement of the mass splitting. This property dictates the frequency of neutrino oscillations.

“The measurement of mass splitting was not one of Daya Bay’s original design goals, but it became accessible thanks to the relatively large value of theta13,” Luk said. “We measured the mass splitting to 2.3% with the final Daya Bay dataset, an improvement over the 2.8% precision of the previous Daya Bay measurement.”

Moving forward, the international Daya Bay collaboration expects to report additional findings from the final dataset, including updates to previous measurements.

Next-generation neutrino experiments, such as the Deep Underground Neutrino Experiment (DUNE), will leverage the Daya Bay results to precisely measure and compare properties of neutrinos and antineutrinos. Currently under construction, DUNE will provide physicists with the world’s most intense neutrino beam, underground detectors separated by 800 miles, and the opportunity to study the behavior of neutrinos like never before.

“As one of many physics goals, DUNE expects to eventually measure theta13 almost as precisely as Daya Bay,” said Brookhaven experimental physicist and Daya Bay collaborator Elizabeth Worcester. “This is exciting because we will then have precise theta13 measurements from different oscillation channels, which will rigorously test the three-neutrino model. Until DUNE reaches that high precision, we can use Daya Bay’s precise theta13 measurement as a constraint to enable the search for differences between neutrino and antineutrino properties.”

Scientists will also leverage the large theta13 value and reactor neutrinos to determine which of the three neutrinos is the lightest. “The precise theta13 measurement of Daya Bay improves the mass-ordering sensitivity of the Jiangmen Underground Neutrino Observatory (JUNO), which will complete construction in China next year,” said Yifang Wang, JUNO spokesperson and IHEP director. “Furthermore, JUNO will achieve sub-percent level precision on the mass splitting measured by Daya Bay in several years.”

The Daya Bay Reactor Neutrino experiment is supported by the Ministry of Science and Technology of China, the DOE Office of Science High Energy Physics program, the Chinese Academy of Sciences, the National Natural Science Foundation of China, and other funding agencies. The Daya Bay collaboration has 237 participants at 42 institutions in Asia, Europe, and North America.

*Physicists measure theta13 in terms of its oscillation amplitude, or what is mathematically written as sin²2θ₁₃.

In a new study, corresponding authors Cheryl Nickerson, Jennifer Barrila and their colleagues demonstrate that under low fluid shear force conditions that simulate those found in microgravity culture during spaceflight, the foodborne pathogen Salmonella infects 3-D models of human intestinal tissue at much higher levels, and induces unique alterations in gene expression.

This study advances previous work by the same team showing that physical forces of fluid shear acting on both the pathogen and host can transform the landscape of infection.

Understanding this subtle interplay of host and pathogen during infection is critical to ensuring astronaut health, particularly on extended space missions. Such research also sheds new light on the still largely mysterious processes of infection on earth, as low fluid shear forces are also found in certain tissues in our bodies that pathogens infect, including the intestinal tract.

While the team has extensively characterized the interaction between conventionally grown shake flask cultures of Salmonella Typhimurium and 3-D intestinal models, this study marks the first time that S. Typhimurium has been grown under the low fluid shear conditions of simulated microgravity and then used to infect a 3-D model of human intestinal epithelium co-cultured with macrophage immune cells, key cell types targeted by Salmonella during infection.

The 3-D co-culture intestinal model used in this study more faithfully replicates the structure and behavior of the same tissue within the human body and is more predictive of responses to infection, as compared with conventional laboratory cell cultures.

Results showed dramatic changes in gene expression of 3-D intestinal cells following infection with both wild-type and mutant S. Typhimurium strains grown under simulated microgravity conditions. Many of these changes occurred in genes known to be intimately involved with S. Typhimurium’s prodigious ability to invade and colonize host cells and escape surveillance and destruction by the host’s immune system.

“A major challenge limiting human exploration of space is the lack of a comprehensive understanding of the impact of space travel on crew health,” Nickerson says. “This challenge will negatively impact both deep space exploration by professional astronauts, as well as civilians participating in the rapidly expanding commercial space market in low Earth orbit. Since microbes accompany humans wherever they travel and are essential for controlling the balance between health and disease, understanding the relationship between spaceflight, immune cell function, and microorganisms will be essential to understand infectious disease risk for humans.”

Nickerson, who co-directed the new study with Jennifer Barrila, is a researcher in the Biodesign Center for Fundamental and Applied Microbiomics and is also a professor with ASU’s School of Life Sciences. The research appears in the current issue of the journal Frontiers in Cellular and Infection Microbiology

Life-altering force

Life on earth has diversified into an almost incomprehensibly vast array of forms, evolving under wildly dissimilar environmental conditions. Yet one parameter has remained constant. Throughout the 3.7-billion-year history of life on earth, all living organisms evolved under, and respond to, the pull of Earth’s gravity.

For more than 20 years, Nickerson has been a pioneer in exploring the effects of the reduced microgravity environment of spaceflight on a range of pathogenic microbes and the impact on interactions with human cells and animals they infect. She and her colleagues have doggedly pursued this research in both land-based and spaceflight settings, the results of which helped lay the foundation for the rapidly growing research field, mechanobiology of infectious disease, the study of how physical forces impact infection and disease outcomes.

Among their important findings is that the low fluid shear conditions associated with the reduced gravity environment of spaceflight and spaceflight analog culture are similar to those encountered by pathogens inside the infected host, and that these conditions can induce unique changes in the ability of pathogenic microbes like Salmonella to aggressively infect host cells and exacerbate disease, a property known as virulence.

The infectious agent explored in the new study, Salmonella Typhimurium, is a bacterial pathogen responsible for gastrointestinal disease in humans and animals. Salmonella is the leading cause of death from food-borne illness in the United States. According to the CDC, Salmonella bacteria cause about 1.35 million infections, 26,500 hospitalizations, and 420 deaths in the United States each year. Foods contaminated by the bacteria are the primary source for most of these illnesses.

Salmonella infection typically causes diarrhea, fever, and stomach cramps, beginning 6 hours to 6 days after infection. Illness from the disease usually lasts 4 to 7 days. In severe cases, hospitalization may be required.

‘Shear’ probability?

Cells in mammalian organisms, including humans, as well as the bacterial cells that infect them, are exposed to extracellular fluid flowing over their outer surfaces. Just as a gentle downstream current will affect the pebbles in the underlying streambed differently than a raging torrent, so the force of fluid gliding over cell surfaces can cause changes to affected cells. This liquid abrasion of cell surfaces is known as fluid shear.

Since spaceflight experiments are rare and access to the space research platform is currently limited, researchers often simulate the low fluid shear conditions that microbes encounter during culture in spaceflight by growing cells in liquid growth media within a device known as a rotating wall vessel bioreactor or RWV. As the cylindrical reactor rotates, cells are maintained in suspension, gently and continuously tumbling in their surrounding culture medium. This process mimics the low fluid shear conditions of microgravity that cells experience during culture in spaceflight.

The team has also shown that this fluid shear level is relevant to conditions that microbial cells encounter in the human intestine and other tissues during infection, triggering changes in gene expression that can help some pathogens better colonize host cells and evade the immune system’s efforts to destroy them.

Portrait of an intruder

The study found significant changes in both gene expression and ability to infect 3-D intestinal models by Salmonella bacteria cultured in the RWV bioreactor. These experiments involved two S. Typhimurium strains, one unaltered or wild type strain and one mutant strain.

The mutant strain was otherwise identical to the wild type but lacked an important protein known as Hfq, a major stress response regulator in Salmonella. In earlier research, Nickerson and her team discovered that Hfq acts as a master regulator of Salmonella’s infection process in both spaceflight and spaceflight analog culture. They later discovered additional pathogens that also use Hfq to regulate their responses to these same conditions.

Unexpectedly, in the current study, the hfq mutant strain was still able to attach, invade into, and survive within 3-D tissue models at levels comparable to the wild type strain. In agreement with this finding, many genes responsible for Salmonella’s ability to colonize human cells, including those associated with cell adherence, motility, and invasion were still activated in the mutant strain under simulated microgravity conditions, despite the removal of Hfq.

From the host perspective, the 3-D intestinal co-culture model responded to Salmonella infection by upregulating genes involved in inflammation, tissue remodeling, and wound healing at higher levels when the bacteria were grown under simulated microgravity conditions prior to use in infection studies. This was observed for both wild type and hfq mutant strains of the pathogen.

Data from this new spaceflight analog study reinforces previous findings from the team’s 2006, 2008 and 2010 Space Shuttle experiments. In particular, the 2010 flight experiment conducted aboard Space Shuttle Discovery, called STL-IMMUNE, used the same wild type strain of S. Typhimurium to infect a 3-D model of human intestinal tissue made from the same epithelial cells used in the new study.

Several commonalities were observed between host cell responses to infection in the new spaceflight analog study and those previously reported when infections took place in true spaceflight during the STL-IMMUNE experiment. These results further reinforce the RWV as a predictive ground-based spaceflight analogue culture system that mimics key aspects of microbial responses to true spaceflight culture.

“During STL-IMMUNE, we discovered that infection of a human 3-D intestinal epithelial model by Salmonella during spaceflight induced key transcriptional and proteomic biosignatures that were consistent with enhanced infection by the pathogen,” Barrila says. “However, due to the technical challenges of performing in-flight infections, we could not quantify whether the bacteria were actually attaching and invading into the tissue at higher levels. The use of the RWV bioreactor as a spaceflight analog culture system in our current study has been a powerful tool which allowed us to explore this experimental question at a deeper level.”

New horizons

Astronauts face a double risk from infectious disease during their missions far from earth. The combined rigors of spaceflight act to weaken their immune systems. At the same time, some pathogens like Salmonella may be triggered by low fluid shear conditions induced by microgravity to become more effective infectious agents.

With longer spaceflight missions in the advanced planning stages and the advent of civilian space travel rapidly emerging, safeguarding space travelers from infectious disease is vital.

Studies like the current one are also helping to pull back the curtain on the infection process, revealing foundational details with broad relevance for the battle against diseases, on Earth and beyond.