South Africa amended its research guidelines to allow for heritable human genome editing

The Conversation
November 20, 2024 

New genome editing technologies mean that the genetic modification of embryos is a scientific possibility, and laws governing its practice require extensive public consultation. (Shutterstock)

A little-noticed change to South Africa’s national health research guidelines, published in May of this year, has put the country on an ethical precipice. The newly added language appears to position the country as the first to explicitly permit the use of genome editing to create genetically modified children.

Heritable human genome editing has long been hotly contested, in large part because of its societal and eugenic implications. As experts on the global policy landscape who have observed the high stakes and ongoing controversies over this technology — one from an academic standpoint (Françoise Baylis) and one from public interest advocacy (Katie Hasson) — we find it surprising that South Africa plans to facilitate this type of research.

In November 2018, the media reported on a Chinese scientist who had created the world’s first gene-edited babies using CRISPR technology. He said his goal was to provide children with resistance to HIV, the virus that causes AIDS. When his experiment became public knowledge, twin girls had already been born and a third child was born the following year.


The fate of these three children, and whether they have experienced any negative long-term consequences from the embryonic genome editing, remains a closely guarded secret.

Controversial research

Considerable criticism followed the original birth announcement. Some argued that genetically modifying embryos to alter the traits of future children and generations should never be done.




Genetically modifying embryos to alter the traits of future children and generations has immense societal impacts. (Shutterstock)

Many pointed out that the rationale in this case was medically unconvincing – and indeed that safe reproductive procedures to avoid transmitting genetic diseases are already in widespread use, belying the justification typically given for heritable human genome editing. Others condemned his secretive approach, as well as the absence of any robust public consultation, considered a prerequisite for embarking on such a socially consequential path.


In the immediate aftermath of the 2018 revelation, the organizing committee of the Second International Summit on Human Genome Editing joined the global uproar with a statement condemning this research.

At the same time, however, the committee called for a “responsible translational pathway” toward clinical research. Safety thresholds and “additional criteria” would have to be met, including: “independent oversight, a compelling medical need, an absence of reasonable alternatives, a plan for long-term follow-up, and attention to societal effects.”

Notably, the additional criteria no longer included the earlier standard of “broad societal consensus.”


Nobel laureate David Baltimore, chair of the organizing committee for the Second International Summit on Human Genome Editing, talks about the importance of public global dialogue on gene editing.
New criteria


Now, it appears that South Africa has amended its Ethics in Health Research Guidelines to explicitly envisage research that would result in the birth of gene-edited babies.

Section 4.3.2 of the guidelines on “Heritable Human Genome Editing” includes a few brief and rather vague paragraphs enumerating the following criteria: (a) scientific and medical justification; (b) transparency and informed consent; (c) stringent ethical oversight; (d) ongoing ethical evaluation and adaptation; (e) safety and efficacy; (f) long-term monitoring; and (g) legal compliance.

While these criteria seem to be in line with those laid out in the 2018 summit statement, they are far less stringent than the frameworks put forth in subsequent reports. This includes, for example, the World Health Organization’s report Human Genome Editing: Framework for Governance (co-authored by Françoise Baylis).

Alignment with the law

Further, there is a significant problem with the seemingly permissive stance on heritable human genome editing entrenched in these research guidelines. The guidelines clearly require the research to comply with all laws governing heritable human genome research. Yet, the law and the research guidelines in South Africa are not aligned, which entails a significant inhibition on any possible research.

This is because of a stipulation in section 57(1) of the South African National Health Act 2004 on the “Prohibition of reproductive cloning of human beings.” This stipulates that a “person may not manipulate any genetic material, including genetic material of human gametes, zygotes, or embryos… for the purpose of the reproductive cloning of a human being.”


When this act came into force in 2004, it was not yet possible to genetically modify human embryos and so it’s not surprising there’s no specific reference to this technology. Yet the statutory language is clearly wide enough to encompass it. The objection to the manipulation of human genetic material is therefore clear, and imports a prohibition on heritable human genome editing.
Ethical concerns

The question that concerns us is: why are South Africa’s ethical guidelines on research apparently pushing the envelope with heritable human genome editing?

In 2020, we published alongside our colleagues a global review of policies on research involving heritable human genome editing. At the time, we identified policy documents — legislation, regulations, guidelines, codes and international treaties — prohibiting heritable genome editing in more than 70 countries. We found no policy documents that explicitly permitted heritable human genome editing.


It’s easy to understand why some of South Africa’s ethicists might be disposed to clear the way for somatic human genome editing research. Recently, an effective treatment for sickle cell disease has been developed using genome editing technology. Many children die of this disease before the age of five and somatic genome editing — which does not involve the genetic modification of embryos — promises a cure.



Somatic genome editing may provide a cure for sickle cell disease. (Shutterstock)

Implications on future research

But that’s not what this is about. So, what is the interest in forging a path for research on heritable human genome editing, which involves the genetic modification of embryos and has implications for subsequent generations? And why the seemingly quiet modification of the guidelines?

How many people in South Africa are aware that they’ve just become the only country in the world with research guidelines that envisage accommodating a highly contested technology? Has careful attention been given to the myriad potential harms associated with this use of CRISPR technology, including harms to women, prospective parents, children, society and the gene pool?

Is it plausible that scientists from other countries, who are interested in this area of research, are patiently waiting in the wings to see whether the law in South Africa prohibiting the manipulation of human genetic material will be an insufficient impediment to creating genetically modified children? Should the research guidelines be amended to accord with the 2004 statutory prohibition?

Or if, instead, the law is brought into line with the guidelines, would the result be a wave of scientific tourism with labs moving to South Africa to take advantage of permissive research guidelines and laws?

We hope the questions we ask are alarmist, as now is the time to ask and answer these questions.

Katie Hasson, Associate Director at the Center for Genetics and Society, co-authored this article.

Françoise Baylis, Distinguished Research Professor, Emerita, Dalhousie University

This article is republished from The Conversation under a Creative Commons license. Read the original article.

 

Deaf male mosquitoes don’t mate

Knocking out a single gene rendered the insects deaf and males uninterested in mating

University of California - Santa Barbara

 

image: 

 

If a male mosquito can’t hear a female. It’s as though she doesn’t exist.

view more 

Credit: Matt Perko

Mosquitoes are much more blunt. Mating occurs for a few seconds in midair. And all it takes to woo a male is the sound of a female’s wingbeats. Imagine researchers’ surprise when a single change completely killed the mosquitoes’ libidos.

 

Now a study out of UC Santa Barbara reveals that this is really all there is to it. Researchers in Professor Craig Montell’s lab created deaf mosquitoes and found that the males had absolutely no interest in mating. “You could leave them together with the females for days, and they will not mate,” Montell said.

 

The dramatic change was simple to produce. “The absence of a single gene, trpVa, produced this profound effect on mosquito mating behavior,” explained co-lead author Dhananjay Thakur, a postdoctoral scholar in the Department of Molecular, Cellular, and Developmental Biology.

 

The results, published in the Proceedings of the National Academy of Sciences could have major implications for how we manage disease transmission by better controlling the populations of mosquito vectors, such as Aedes aegypti, that infect hundreds of millions of people every year with viruses that cause diseases.

 

Frisky skeeters

 

“On summer evenings, we often see swarms of mosquitoes gathered by the water or under streetlights. These gatherings are essentially mass mating events,” said co-lead author Yijin Wang, a former postdoc at UCSB. Although mosquitoes possess an extraordinary ability to reproduce, scientists still have a limited understanding of the molecular and neurological mechanisms at work.

 

Courtship for Aedes aegypti usually progresses like this: Females flap their wings at around 500 Hz. When males hear this, they take off, buzzing at about 800 Hz. The males also rapidly modulate this frequency when the ladies are around. Then there’s a quick midair rendezvous, and the paramours go their separate ways. Males are always scouting out new potential partners, but a female that’s successfully mated generally won’t do so again.

 

Montell and co-lead authors Yijin Wang, Thakur and Emma Duge suspected that hearing played a role in this behavior, so they investigated the insect’s auditory neurons. These lie at the base of the antennae in a structure called the Johnston’s organ. The antennae are magnificent multi-sensory apparatuses, chock-full of olfactory, mechanosensory and even thermal infrared sensilla, as Montell’s lab recently discovered. In the current study, the team focused on a particular sensory channel called TRPVa — and the corresponding gene, trpVa — which is the mosquito analogue of a channel required for hearing in fruit flies.

 

The team used CRISPR-Cas9 to knock out the gene that codes for TRPVa in Aedes aegypti mosquitoes. The resulting animals showed no reaction to sound. In fact, they found that sound elicited no electrical activity from neurons in the Johnston’s organ. The insects were truly deaf.

 

And when the authors placed deaf males in chambers with females … nothing happened. “If they can’t hear the female wingbeat, they’re not interested,” Montell said. Their hearing counterparts, on the other hand, wasted no time in getting busy: mating many times in the course of a few minutes.

 

A romantic soundtrack

 

Hearing is not only necessary for males to mate, it seems to be sufficient to rouse their desires. When the authors played the sound of female wingbeats to normal males, the males typically responded with abdominal thrusts. They were primed and ready for action. Deaf males barely twitched.

 

Females, however, were a different story. Deaf females still had some lust left in them. “The impact on the female is minimal, but the impact on the male is absolute,” Montell said. The team plans to study these differences in future work.

 

“I think the reason why our major finding is so shocking is because, in most organisms, mating behavior is dependent on a combination of several sensory cues,” said Duge, one of Montell’s doctoral students. “The fact that taking away a single sense can completely abolish mating is fascinating.”

 

And the authors believe that their results — the role of sound in mating and the function TRPVa plays in hearing — generalize to other species of mosquito.

 

Looking inside

 

A mosquito’s physiology reveals just how important hearing is to these insects. Male mosquitoes have the most auditory neurons of any known insect, Montell explained. Females have half as many. That’s still a lot, but hearing is much more crucial for males.

 

To identify which neurons express the trpVa gene, the authors added a gene coding for green fluorescent protein into the mosquito genome. They did this in a way such that the fluorescent protein was expressed indirectly under the control of the trpVa promoter. A promoter is a DNA sequence usually located at the start of a gene where enzymes bind to initiate transcription, in this case triggering the production of those green fluorescent proteins. Now the mutant mosquitoes would produce green fluorescent protein in all the places that normally would produce TRPVa. So the same mosquitoes provided test subjects for the experiment and a bright green map of TRPVa expression for the analysis.

 

Unsurprisingly, the team found that trpVa is expressed in the Johnston’s organ. And they could clearly follow the paths of auditory neurons from there into the brain, as well as see differences in these paths between male and female mosquitoes.

 

Hijacking mosquito courtship

 

Pathogens spread by the mosquito Aedes aegypti infect some 400 million people a year, of which about 100 million develop diseases like dengue, zika and yellow fever. This means that understanding its behavior and lifecycle can provide us tools and insights in disease prevention.

 

One potential method to control insect vectors is the sterile insect technique (SIT), which works by releasing a large number of sterile males to mate with females. In certain insects, like mosquitoes, successful mating prevents females from seeking other partners. And, if the female mates with a sterile male, she doesn’t actually produce offspring. In theory, this can suppress the population.

 

The technique works marvelously for certain agricultural pests like the California medfly. “The fact that you haven’t heard of this pest is a testament to how successful SIT is, because 30 years ago it was all over the news,” Montell said.

 

But the success of SIT in Aedes aegypti is limited by the competitiveness of the sterile males; they have to get to the females first for the ploy to work. Currently, the technique doesn’t cause enough suppression in mosquito populations for them to drop below the critical threshold and send the population plummeting. Given the central role of hearing in mosquito courtship, trpVa might provide a target for increasing the effectiveness of SIT. Montell’s lab is working on several ways to make sterile males that can outcompete their natural counterparts. Hopefully, the trick will be as straightforward as these unfussy lovers.

 

###

 

Note to editors: Craig Montell is available at cmontell@ucsb.edu. Dhananjay Thakur is available at dhananjay.p.thakur@gmail.com. Emma Duge is available at emmaduge@ucsb.edu. Downloadable images can be found at https://news.ucsb.edu/2024/021664/deaf-male-mosquitoes-dont-mate.

 

(3426)

 

---

Journal

Proceedings of the National Academy of Sciences

 

Breakthrough study shows coral reefs will transform but can persist, if carbon is curbed

University of Hawaii at Manoa

 

image: 

Hawaiian coral reefs are teeming with life. 

view more 

Credit: Andre Seale.

In a breakthrough study published this week in Proceedings of the National Academy of Sciences, researchers in the Hawaiʻi Institute of Marine Biology (HIMB) at the University of Hawai‘i (UH) at Mānoa have shown that, contrary to most projections, coral reefs are not inevitably doomed, but have the potential to persist and adapt over time, if carbon emissions are curbed and local stressors are addressed. This work was conducted by the Toonen-Bowen “ToBo” Lab, with partners across UH Mānoa and The Ohio State University.

In an island-based laboratory adjacent to the coral reefs they study, HIMB researchers created 40 experimental systems known as “mesocosms,” which mimic the diversity and environment of a coral reef in the wild. The mesocosms included eight of the most common Hawaiian coral species, reef sand, rubble, and a menagerie of creatures which helped represent one of the most diverse ecosystems on the planet. For two years, the team exposed the mesocosms to different scenarios of higher temperature, higher acidity, or a combination of both ocean stressors to see how the reef communities would react to future climate scenarios.

“We included the eight most common coral species in Hawai‘i, which constitute about 95% of the coral cover on Hawaiian reefs, and many of the most common coral types across the Pacific and Indian Oceans,” explains HIMB post-doctoral researcher and lead author of the study, Christopher Jury. “By understanding how these species respond to climate change, we should have a better understanding of how Hawaiian reefs and other Indo-Pacific reefs will change over time, and how to better allocate resources as well as plan for the future.”

Reef structures form over time through a process known as “calcification” where individual coral organisms—or polyps—build their own skeletons by secreting a salt known as calcium carbonate, which becomes limestone. Coral reefs are naturally eroded by a variety of species, and if the balance between reef producers and reef eroders shifts, coral reefs could disappear, and the huge diversity of species which live on coral reefs would have nowhere to live.

As the ToBo lab research team controlled levels of temperature and acidity in the mesocosms, they measured the calcification responses of the eight species of coral, the reef communities, and the biodiversity of these systems. Their findings were entirely unexpected.

“These experimental reef communities persisted as new reef communities rather than collapsing,” shares Jury. “This was a very surprising result, since almost all projections of reef futures suggest that the corals should have almost entirely died, the reef communities should have experienced net carbonate dissolution, and reef biodiversity should have collapsed. None of those things happened in this study.”

Their results are unique, and so is the ToBo lab’s approach to how they study their subject.

“Rather than focusing on just one or two species in isolation, we included the entire complement of reef species from microbes, to algae, invertebrates, and fish, under realistic conditions they would experience in nature,” notes Rob Toonen, co-director of the UH Marine Biology Graduate Program, HIMB Professor and Ruth Gates Endowed Chair, and co-senior author of the study. “These more realistic mesocosm experiments help us to understand how coral reefs will change over time.”

These findings suggest that coral conservation in a changing world is possible, but urgent action is essential for these unique ecosystems to persist.

“Reefs are not inevitably doomed,” emphasizes Jury. “The recognition that coral reefs are not doomed if we take appropriate action on climate change and local stressors reinforces the need to accomplish these goals. Under potential future ocean warming and acidification, coral reef communities will change substantially, but are unlikely to collapse if global change is limited to Paris Climate Agreement targets and local stressors are adequately addressed.”

Coral reefs are among the most diverse ecosystems on the planet, and they support hundreds of millions of people around the world. As our planet rapidly changes in unprecedented ways, coral reefs are under severe threat due to ocean warming and acidification. This study shows that with effective and timely climate change mitigation measures in place, coral reefs will continue to change, but global reef collapse may still be avoidable.

Hawai‘i Institute of Marine Biology (HIMB) is located on Moku o Lo‘e, a storied islet in Kāne‘ohe Bay on the Hawaiian island of O‘ahu. HIMB’s unique location provides researchers with unparalleled, immediate access to their research subject. In this image, a research diver encounters Porites evermanni

  

Caption

A mesocosm system at the Hawai‘i Institute of Marine Biology enables researchers to carefully control and study the impact of ocean warming and acidification while preserving realistic conditions, like those on nearby reefs. 

Credit

Mariana Rocha De Souza

Journal

Proceedings of the National Academy of Sciences

DOI

10.1073/pnas.2407112121 

Method of Research

Experimental study

Subject of Research

Animals

Article Title

Experimental coral reef communities transform yet persist under mitigated future ocean warming and acidification

Deep-sea corals are home to previously unknown bacteria with extremely small genomes

Microbes lack ability to break down carbohydrates – species belong to new family of marine bacteria.

Peer-Reviewed Publication

University of Oldenburg

 

image: 

The deep-sea coral Callogorgia delta is often found in the Gulf of Mexico near cold seeps. The pink-coloured brittle stars are probably useful for the corals. The photo was taken at a depth of 439 metres.

view more 

Credit: ECOGIG consortium

A German-American research team led by Professor Iliana Baums from the Helmholtz Institute for Functional Marine Biodiversity at the University of Oldenburg (HIFMB) and Dr Samuel Vohsen from Lehigh University in the US has discovered two highly unusual bacterial species in the tissue of two deep-sea corals from the Gulf of Mexico. These previously unknown coral symbionts have an extremely reduced genome and lack the ability to obtain energy from carbohydrates, the team reports in an article published in the scientific journal Nature Communications. “These species are impressive examples of how few genes are needed for a functional organism,” says Baums, who co-authored the paper.

The research team studied several colonies of two soft coral species, Callogorgia delta and Callogorgia Americana, which are found in the Gulf of Mexico at depths ranging from 300 to 900 metres, where it is completely dark. The researchers discovered two previously unknown, closely related species from the mollicutes class of bacteria. Mollicutes often live as parasites either on or in the cells of plants, animals and humans, and in some cases cause diseases. On the basis of their genetic analyses, the researchers propose a new family called Oceanoplasmataceae, to which the two bacteria are to be assigned.

Further investigations revealed that the bacteria are the dominant symbionts of these corals and live in a gelatinous layer of tissue that forms part of their immune defence system and transports nutrients. One of the species (Oceanoplasma callogorgiae) contains only 359 genes which encode proteins for various metabolic functions. The other (Thalassoplasma callogorgiae) has 385 protein-coding genes. By comparison, the intestinal bacterium Escherichia coli contains more than 4,000 such genes, while humans have around 21,000 of them.

Amino acid is their only source of energy

The question of how the metabolism of the two newly discovered microbes can function with such a reduced genome remains a mystery to the researchers: “These bacteria don’t even carry genes for normal carbohydrate metabolism, in other words, for obtaining energy from carbohydrates – something that basically every living organism has,” Baums explains. According to the research to date, their only source of energy is the amino acid arginine, which is provided by the host coral. “But the breakdown of this amino acid provides only tiny amounts of energy. It is astonishing that the bacteria can survive on so little,” says Vohsen. The bacteria also obtain other essential nutrients from their host.

It remains unclear whether the microbes are purely parasites, or whether the corals benefit in some way from their symbionts. According to the scientists’ genetic analysis, the two bacterial species use various defence mechanisms called CRISPR/Cas systems to remove foreign DNA. These systems are also used in biotechnology to edit genes. The researchers hypothesise that these mechanisms may also be useful to the host corals, helping them to fend off pathogens. Another possibility is that the bacteria provide nitrogen to their host when they break down arginine.

For Baums, whose research focuses on both the ecology and evolution of corals, the symbionts offer an opportunity to gain further insights into the history of this diverse group of animals. “I always find it amazing that corals can colonise so many different habitats despite being very simple animals in terms of their genetic blueprint,” says the researcher. Symbionts are crucial for the ability of corals to adapt to different environmental conditions, she explains: “They provide metabolic functions that the corals themselves lack.” For example, tropical corals, which live in shallow, light-flooded waters, rely on photosynthetic algae to provide them with food and energy. Cold-water corals, many of which live in the dark and nutrient-poor deep sea, are thought to rely on bacteria to convert nutrients or obtain energy from chemical compounds.

Baums, an evolutionary ecologist and coral expert, conducts research at the Helmholtz Institute for Functional Marine Biodiversity at the University of Oldenburg (HIFMB) and holds a joint professorship at the University of Oldenburg and the Alfred Wegener Institute, Helmholtz Centre for Polar and Marine Research in Bremerhaven. In addition to Professor Baums and Dr Vohsen, scientists from the Max Planck Institute for Marine Microbiology in Bremen, Kiel University and Pennsylvania State University in the US were also involved in the current study.

This deep-sea community was discovered in 2016 at a depth of 624 metres in the Mississippi Canyon, Gulf of Mexico. The coral Callogorgia delta is accompanied by tubeworms and a clam.

Credit

ECOGIG Consortium

Journal

Nature Communications

DOI

10.1038/s41467-024-53855-5 

Method of Research

Observational study

Subject of Research

Animals

Article Title

Discovery of deep-sea coral symbionts from a novel family of marine bacteria, Oceanoplasmataceae, with severely reduced genomes

Article Publication Date

4-Nov-2024

 

Bee gene specifies collective behavior

Bee research: publication in Science Advances

Heinrich-Heine University Duesseldorf

 

image: 

Each honeybee is labelled with a QR code so that their individual behaviour can be tracked. (Photo: HHU / Christoph Kawan)

view more 

Credit: HHU / Christoph Kawan

Embargoed: Not for Release Until 2:00 pm U.S. Eastern Time Friday, 01 November 2024.

Researchers at Heinrich Heine University Düsseldorf (HHU) are collaborating with colleagues from Frankfurt/Main, Oxford and Würzburg to investigate how the complex, cooperative behaviour of honey bees (Apis mellifera) is genetically programmed so that it can be passed on to subsequent generations. As they explain in the scientific journal Science Advances, they found an answer in what is known as the doublesex gene (dsx).

Behavioural interactions between organisms are fundamental and often inherited. Every human being and every animal interacts with other individuals in its social group in one way or another through its behaviour. In the animal kingdom, this has considerable advantages in collective foraging for food, defence against predators and the rearing of offspring.

In some animals, such as honeybees, the social behaviour bonds are so strong that the individual members form a tight-knit society that function collectively as a single “superorganism”. Through their individual behaviour, thousands of worker bees protect the entire colony, feed it and care for the brood.

Professor Dr Martin Beye, who heads the Institute of Evolutionary Genetics at HHU and is the corresponding author of the study that has now been published in Science Advances, emphasises: “The behavioural repertoire of the individual bees and their function in the colony are not learned, but rather inherited. Until now, it was not known how such complex behaviours were genetically encoded.”

Together with colleagues from the universities in Frankfurt/Main, Oxford and Würzburg, the team of researchers at HHU led by Beye and first author Dr Vivien Sommer has now discovered that a special gene known as dsx specifies worker bee-specific behaviour.

Sommer: “The gene programmes whether a worker bee takes up a task in the colony and for how long. This includes collective tasks such as caring for the larvae or foraging for food and social exchanges on food sources, for example.”

The biologists used the CRISPR/Cas9 genetic scissors in their investigations to modify or switch off the dsx gene in selected bees. They attached a QR code to the manipulated bees, then monitored their behaviour in the hive with cameras. The resulting video sequences were analysed with the support of artificial intelligence to determine the bees’ individual behavioural patterns.

Sommer: “Our central question was whether and how the inherited behavioural patterns changed as a result of the gene modification. Such changes must be reflected in the nervous system of the worker bees where the specific behaviour is controlled.”

The researchers introduced green fluorescent protein (GFP) into the dsx sequence so that GFP was produced together with the dsx protein. The neuronal circuits could then be viewed using fluorescence microscopy, in both the unmodified bees and in those with genetic modifications. “We were able to use these tools to see exactly which neural pathways the dsx gene creates in the brain and how this gene in turn specifies the inherited behavioural patterns of honeybees,” explains doctoral researcher Jana Seiler, who is also a co-author of the study.

“Our findings indicate a fundamental genetic programme that determines the neuronal circuitry and behaviour of worker bees,” says Professor Dr Wolfgang Rössler from the Department of Behavioural Physiology and Sociobiology, who led the study at the University of Würzburg.

In the next step, the researchers now want to move from the level of the individual honeybee to the bee colony superorganism. Alina Sturm, who is also a doctoral researcher at HHU and study co-author, adds: “We hope to find the link between individual programming and the coordinated behaviour of many individuals.”

The neuronal network in the bee’s brain appears in green. (Image: HHU / Institute for Evolutionary Genetics)

Credit

HHU / Institute for Evolutionary Genetics

Original publication:

Vivien Sommer, Jana Seiler, Alina Sturm, Sven Köhnen, Anna Wagner, Christina Blut, Wolfgang Rössler, Stephen F. Goodwin, Bernd Grünewald, Martin Beye. Dedicated developmental programing for group-supporting behaviors in eusocial honeybees. Science Advances (2024).

DOI: 10.1126/sciadv.adp3953

---

Journal

Science Advances

DOI

10.1126/sciadv.adp3953 

Article Title

Dedicated developmental programing for group-supporting behaviors in eusocial honeybees

Article Publication Date

1-Nov-2024

 

New findings on animal viruses with potential to infect humans

Study shows how virus family gains entry to mammal cells

Ohio State University

COLUMBUS, Ohio – Scientists investigating animal viruses with potential to infect humans have identified a critical protein that could enable spillover of a family of organisms called arteriviruses.

In a new study, researchers identified a protein in mammals that welcomes arteriviruses into host cells to start an infection. The team also found that an existing monoclonal antibody that binds to this protein protects cells from viral infection.

Arteriviruses circulate broadly in many types of mammals around the world that serve as natural hosts – such as nonhuman primates, pigs and horses – but so far have not been detected in humans.

The researchers’ aim is to better understand mechanisms of arterivirus infection to get a handle on how high the infection risk is for humans and what preparation may be needed should a spillover occur in the future.

“It’s important to consider that since we have no known arteriviruses infecting people that we’re essentially immunologically naïve, so we can’t rely on preexisting immunity to help us,” said co-lead author Cody Warren, assistant professor of veterinary biosciences at The Ohio State University.

Warren co-led the work with Adam Bailey, assistant professor of pathology and laboratory medicine at the University of Wisconsin-Madison. The study was published recently in Nature Communications.

Many natural hosts of arteriviruses have no signs of disease, but the virus that infects swine can cause pneumonia, as well as abortions in pregnant pigs, and other strains can cause hemorrhagic fever or encephalitis when they switch animal hosts.

These viruses also have the unusual ability to maintain long-term infections and become more virulent when they find new hosts – which gives them time to evolve and improve their chances of transmission.

The research team set out to find proteins in mammals that arteriviruses use as receptors to gain entry to host cells and make copies of themselves. Bailey used genome-wide CRISPR-knockout screening technology to identify specific genes that, when disrupted, rendered cells resistant to viral infection. Such genes would then be considered essential to the viral infection process. The unbiased screen identified two genes, FCGRT and B2M, whose protein products come together to form the FcRn receptor (neonatal Fc receptor) that is expressed on the surface of cells.

The FcRn receptor molecule has a specific role in shuttling antibodies across the placenta to a fetus, but is also present in immune cells and cells that line blood vessel walls – both of which are targeted by arteriviruses.

Results from this study demonstrated that FcRn is used for host cell entry by at least five arteriviruses that infect monkeys, pigs and horses, respectively: three diverse strains of simian arteriviruses, porcine reproductive and respiratory syndrome virus 2 (PRRSV-2), and equine arteritis virus (EAV).

Knocking out the major component of the FcRn complex – the FCGRT gene – from host cells blocked viral infection, and pre-treating cells with a monoclonal antibody against FcRn protected against infection.

There was also a genetic twist to this story: Some mammal hosts were less susceptible to arterivirus infection based on differences in their species-specific FcRn’s sequence, meaning that in some cases, this protein will function as a barrier to cross-species infections.

“Chimpanzees and humans have pretty much all the same genes, but the sequence of those genes is slightly different,” Bailey said. “All mammals have the FcRn receptor, but their ability to support infection with a given arterivirus may vary.”

The CRISPR screen also identified a gene encoding another surface protein, CD163, which Warren and colleagues previously found to be a gatekeeper for an arterivirus called simian hemorrhagic fever virus (SHFV) to infect a cell.

A series of experiments in different cell types and using multiple viral strains in the new study showed that CD163 does have a role in infection by most arteriviruses, but it cannot act alone – interaction with FcRn is also key to facilitating arteriviral infection of host cells.

Spelling out these arterivirus infection steps is an important milestone, the researchers said.

“If we’re looking at virus biology, one of the most important things we can understand is entry mechanisms. Because if you can stop the ability of a virus to infect a cell through disrupting that initial virus-receptor contact, now you have a potential therapeutic strategy,” Warren said.

One of those “disruptors” could be blocking the receptor – so showing that an existing monoclonal antibody can stop viral infection in cells is also a plus for scientists examining viruses through a lens of pre-pandemic preparedness.

“If one of these viruses emerged in humans, I believe we’d be in big trouble,” Bailey said. “So that is the motivator for me.”

This work was supported by National Institutes of Health grants, University of Wisconsin-Madison startup funds, the G. Harold and Leila Y. Mathers Foundation, and the Burroughs Wellcome Fund Pathogenesis of Infectious Disease Program.

Co-authors included Teressa Shaw, Kylie Nennig, Xueer Qiu, Devon Klipsic and Igor Slukvin of UW-Madison; Devra Huey, Makky Mousa-Makky, Jared Compaleo, Fei Jiang and Haichang Li of Ohio State; Aadit Shah of Stanford University; Raymond Rowland of the University of Illinois Urbana-Champaign; and Meagan Sullender and Megan Baldridge of Washington University in St. Louis.

#

Contacts:

Cody Warren, Warren.802@osu.edu
Adam Bailey, ALBailey@wisc.edu

Written by Emily Caldwell, Caldwell.151@osu.edu

 

---

Journal

Nature Communications

DOI

10.1038/s41467-024-51142-x 

Article Title

The neonatal Fc receptor (FcRn) is a pan-arterivirus receptor