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Black Death Selected for Immune-Related Genes, Affecting Disease Susceptibility Today

Researchers analyzed DNA from victims and survivors of the bubonic plague pandemic nearly 700 years ago. They identified key genetic differences that impacted…

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The Black Death was the single greatest mortality event in recorded history. Caused by the bacterium Yersinia pestis, the bubonic plague pandemic swept through North Africa, Europe, and Asia nearly 700 years ago, wiping out up to 30-60% of the population. Newly reported research now suggests that the pandemic placed a a significant selective pressure on the human population, changing the frequency of certain immune-related genetic variants and affecting our susceptibility to disease today.

Scientists headed by teams at the University of Chicago (UChicago), McMaster University, and the Institut Pasteur, analyzed centuries-old DNA from victims and survivors of the bubonic plague, and identified key genetic differences that determined who lived and who died, and how those aspects of our immune systems have continued to evolve since that time. The results indicated that the same genes that once conferred protection against the infection are today associated with an increased susceptibility to autoimmune diseases such as Crohn’s and rheumatoid arthritis.

“This is, to my knowledge, the first demonstration that indeed, the Black Death was an important selective pressure to the evolution of the human immune system,” said Luis Barreiro, PhD, Professor of Genetic Medicine at UChicago and co-senior author of the team’s published paper in Nature. “There is a lot of talk about how pathogens have shaped human evolution, so being able to formally demonstrate which pathways and genes have been targeted really helps us understand what allowed humans to adapt and exist today. This tells us about the mechanisms that allowed us to survive throughout history and why we’re still here today.”

The findings are the result of seven years of work by first authors, graduate student Jennifer Klunk, formerly of McMaster’s Ancient DNA Centre, and postdoctoral fellow Tauras Vigylas, PhD, and are reported in a paper titled, “Evolution of immune genes is associated with the Black Death.”  In their paper the authors say the studies provide “empirical evidence for the role played by past pandemics in shaping present-day susceptibility to disease.”

Researchers extracted DNA from the remains of people buried in the East Smithfield plague pits, which were used for mass burials in 1348 and 1349. [Image courtesy of Museum of London Archaeology (MOLA)]
Infectious diseases have presented one of the strongest selective pressures in the evolution of humans and other animals, the authors wrote. “Not surprisingly, many candidates for population-specific positive selection in humans involve immune response genes, consistent with the hypothesis that exposure to new and/or re-emerging pathogens has driven adaptation. Clarifying the dynamics that have shaped the human immune system is key to understanding how historical diseases contributed to disease susceptibility today.”

The Black Death killed up to 50% of the Europeans, who likely represented “immunologically naïve populations with little or no prior adaptation to Y. pestis,” the authors continued. “The high mortality rate suggests that genetic variants that conferred protection against Y. pestis infection might have been under strong selection during this time.”

For their research Barreiro and colleagues aimed to identify genetic signatures of natural selection imposed by the plague. To do this they searched for signs of genetic adaptation related to the plague, and focused on a 100-year window before, during and after the Black Death, which reached London in the mid-1300s. “This was a very direct way to evaluate the impact that a single pathogen had on human evolution,” said  Barreiro. “People have speculated for a long time that the Black Death might be a strong cause of selection, but it’s hard to demonstrate that when looking at modern populations, because humans had to face many other selective pressures between then and now. The only way to address the question is to narrow the time window we’re looking at.”

Using DNA extracted from teeth of people who died before and during the Black Death pandemic, researchers were able to identify genetic differences that dictated who survived and who died from the virus. [Matt Clarke/McMaster University]
For their study the scientists extracted and screened more than 500 DNA samples from the remains of individuals who had died before the plague, died from it or survived the Black Death in London, including individuals buried in the East Smithfield plague pits used for mass burials in 1348-9.  Additional samples were taken from remains buried in five other locations across Denmark. “To identify loci that may have been under selection during the Black Death, we characterized genetic variation around immune-related genes from 206 ancient DNA extracts, stemming from two different European populations before, during and after the Black Death,” the investigators noted.

 

Using targeted sequencing for a set of 300 immune-related genes, the investigators identified four genes that, depending on the variant, either protected against or increased susceptibility to Y. pestis. They homed in one gene in particular, ERAP2, which demonstrated a particularly strong association to susceptibility. Individuals who possessed two copies of one specific genetic variant, dubbed rs2549794, were able to produce full length copies of the ERAP2 transcript, producing more of the functional protein, when compared with another variant that led to a truncated and non-functional version of the transcript.

A member of the Barreiro Lab works in the tissue culture hood [The University of Chicago Medicine]
Functional ERAP2 plays a role in helping the immune system to recognize the presence of an infection. Individuals who carried two copies of the beneficial ERAP2 variant survived the pandemic at a much higher rates than those with the opposing set of copies, because the rs2549749 variant allowed for more efficient neutralization of Y. pestis by immune cells.

The team even went so far as to test how the rs2549794 variant affected the ability of living human cells to help fight the plague, determining that macrophages expressing two copies of the variant were more efficient at neutralizing Y. pestis compared to those without it. “We suggest that this protein increases the presentation of Yersinia-derived antigens to CD8+ T cells, stimulating a protective immune response against Y. pestis,” they wrote in their paper. “Furthermore, we show that macrophages from individuals possessing the selected ERAP2 allele engage in a unique cytokine response to Y. pestis infection and are better able to limit Y. pestis replication in vitro.”

Researchers extracted DNA from the remains of people buried in the East Smithfield plague pits, which were used for mass burials in 1348 and 1349. [Image courtesy of Museum of London Archaeology (MOLA)]
“When a macrophage encounters a bacterium, it chops it into pieces for them to be presented to other immune cells signaling that there’s an infection,” said Barreiro. “Having the functional version of the gene, appears to create an advantage, likely by enhancing the ability of our immune system to sense the invading pathogen. By our estimate, possessing two copies of the rs2549794 variant would have make a person about 40% more likely to survive the Black Death than those who had two copies of the non-functional variant.” And while Europeans living at the time of the Black Death were initially very vulnerable because they had had no recent exposure to Yersinia pestis, as waves of the pandemic occurred again and again over the following centuries, mortality rates decreased.

 

“Examining the effects of the ERAP2 variants in vitro allows us to functionally test how the different variants affect the behavior of immune cells from modern humans when challenged with living Yersinia pestis,” said Javier Pizarro-Cerda, PhD, head of the Yersinia Research Unit and director of the World Health Organization Collaborating Centre for Plague at Institut Pasteur. “The results support the ancient DNA evidence that rs2549794 is protective against the plague … “This highly original work has been possible only through a successful collaboration between very complementary teams working on ancient DNA, on human population genetics and the interaction between live virulent Yersinia pestis and immune cells, Pizarro-Cerda stated.

Barreiro continued, “The selective advantage associated with the selected loci are among the strongest ever reported in humans showing how a single pathogen can have such a strong impact to the evolution of the immune system.”

A member of the Barreiro Lab counts cells under the microscope [The University of Chicago Medicine]
The team further suggested that the selection for rs2549794 represented part of the balancing act that evolution places upon our genome. While this ERAP2 variant identified is protective against the Black Death, in modern populations, the same variant is associated with an increased susceptibility to autoimmune diseases, including acting as a known risk factor for Crohn’s disease.

 

“More broadly, our results highlight the contribution of natural selection to present-day susceptibility towards chronic inflammatory and autoimmune disease,” they wrote. “… the selectively advantageous ERAP2 variant is also a known risk factor for Crohn’s disease, and ERAP2 variation has also been associated with other infectious diseases … Likewise, another of our top candidate loci (rs11571319 near CTLA4) is associated with an increased risk of rheumatoid arthritis and systemic lupus erythematosus, such that retaining the putatively advantageous allele during the Black Death confers increased risk for autoimmune disease in present-day populations.”

 

Understanding the dynamics that have shaped the human immune system is key to understanding how past pandemics, like the plague, contribute to our susceptibility to disease in modern times, noted Hendrik Poinar, PhD, Professor of Anthropology at McMaster University and co-senior author on the study. “Diseases and epidemics like the Black Death leave impacts on our genomes, like archeology projects to detect. This is a first look at how pandemics can modify our genomes but go undetected in modern populations. … Even a slight advantage means the difference between surviving or passing. Of course, those survivors who are of breeding age will pass on their genes.”

Such genes are thus under balancing selection, and what provided tremendous protection during hundreds of years of plague epidemics has turned out to be autoimmune related now, continued Poinar, who is director of McMaster’s Ancient DNA Centre, and a principal investigator with the Michael G. DeGroote Institute for Infectious Disease Research and McMaster’s Global Nexus for Pandemics & Biological Threats. “A hyperactive immune system may have been great in the past but in the environment today it might not be as helpful.”

Members of the Barreiro lab conduct cell culture experiments [The University of Chicago Medicine]
The authors further concluded, “To date, most of the evidence for an association between autoimmune risk alleles and adaptation to past infectious diseases remains indirect, primarily because the aetiological agents driving selection remain hidden. Our ancient genomic and functional analyses suggest that Y. pestis has been one such agent, representing empirical evidence connecting the selective force of past pandemics to present-day susceptibility to disease.”

Future research will scale the project to examine the entire genome, not just a selected set of immune related genes; and the team hopes to explore genetic variants that affect susceptibility to bacteria in modern humans and compare them to these ancient DNA samples to determine if those variants were also a result of natural selection.

Commenting on the newly released research in an accompanying News & Views, David Enard, PhD, at the University of Arizona, said, “it is worth noting that such rapid and strong selection is highly unlikely to occur for human traits other than immune defense. No other set of traits is under such strong evolutionary pressure … Going forward, more studies of ancient DNA could also enable a better understanding of the evolutionary origins of autoimmune diseases.”

The post Black Death Selected for Immune-Related Genes, Affecting Disease Susceptibility Today appeared first on GEN - Genetic Engineering and Biotechnology News.

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FDA advisory committee votes unanimously in favor of a one-shot COVID-19 vaccine approach – 5 questions answered

Many questions remain about next steps for US vaccine policy. But the FDA advisory panel’s hearty endorsement of a single-composition COVID-19 vaccine…

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The FDA advisory committee discussed vaccine safety, effectiveness of the current shots, potential seasonality of COVID-19 and more. wildpixel/iStock via Getty Images Plus

The U.S. Food and Drug Administration’s key science advisory panel, the Vaccines and Related Biological Products Advisory Committee, met on Jan. 26, 2023, to chart a path forward for COVID-19 vaccine policy. During the all-day meeting, the 21-member committee discussed an array of weighty issues including the efficacy of existing vaccines, the composition of future vaccine strains and the need to match them to the circulating variants of SARS-CoV-2, the possibility of moving to an annual-shot model, the potential seasonality of the virus and much more.

But the key question at hand, and the only formal question that was voted on, following a proposal from the FDA earlier in the week, had to do with how to simplify the path to getting people vaccinated.

The Conversation asked immunologist Matthew Woodruff, who has been on the front lines of studying immune responses to COVID-19 since the early days of the pandemic, to walk us through the big questions of the day and what they mean for future COVID-19 vaccine strategies.

What exactly did the advisory committee vote on?

The question put before the committee for a vote was whether to move to one COVID-19 vaccine consisting of a single composition for all people – whether currently vaccinated or not – and away from the current model that includes one formulation given as a primary series and a separate formulation administered as a booster. Importantly, approved formulations could come from any number of vaccine manufacturers, not just those that have currently authorized vaccines.

The U.S. Centers for Disease Control and Prevention currently requires that the primary series of shots, or the first two doses of the vaccine that a patient receives, consist of the first generation of vaccine against the original strain of SARS-CoV-2, known as the “Wuhan” strain of the virus. These shots are given weeks apart, followed months later by a booster shot that was updated in August 2022 to contain a bivalent formulation of vaccine that targets both the original viral strain and newer subvariants of omicron.

The committee’s endorsement simplifies those recommendations. In a 21-to-0 vote, the advisory board recommended fully replacing, or “harmonizing,” the original formulation of the vaccine with a single shot that would consist of – at least for now – the current bivalent vaccine.

In doing so, it has signaled its belief that these new second-generation vaccines are an upgrade over their predecessors in protecting from infection and severe illness at this point in the pandemic.

If the FDA panel’s recommendation is endorsed by the CDC, only a single composition of vaccine – in this case, the updated bivalent shot – will be used for both vaccinated and unvaccinated people.

Will the single shot remain a mixed-strain, or bivalent, vaccine?

For now, the single shot will be bivalent. But this may not always be the case.

There was a general agreement that the current bivalent shot is preferable to the original vaccine targeted at the Wuhan strain of the virus by itself. But committee members debated whether that original Wuhan vaccine strain should continue to be a part of updated vaccine formulations.

There is no current data comparing a monovalent, or single-strain, vaccine that targets omicron and its subvariants against the current bivalent shot. As a result, it’s unclear how a monovalent shot against recent omicron subvariants would perform in comparison to the bivalent version.

What is immune imprinting, and how does it apply here?

A main reason for the debate over monovalent versus bivalent – or, for that matter, trivalent or tetravalent – vaccines is a lack of understanding around how best to sharpen an immune response to a slightly altered threat. This has long been a debate surrounding annual influenza vaccination strategies, where studies have shown that the immune “memory” that forms in response to a prior vaccine can actively repress a robust immune response to the next.

This phenomenon of immune imprinting, originally coined in 1960 as “original antigenic sin,” has been a topic of debate both within the advisory committee and within the broader immunological community.

Although innovative strategies are being developed to overcome potential problems with routinely updated vaccines, they are not yet ready to be tested in humans. In the meantime, it is unclear how bivalent versus monovalent vaccine choices might alter this phenomenon, and it is very clear that more study is needed.

Is the committee considering only mRNA vaccines?

While a significant portion of the discussion focused on the mRNA vaccine platform used by both Pfizer and Moderna, several committee members emphasized the need for new technologies that could provide broader immunological protection. Dr. Pamela McInnes, a now-retired longtime deputy director of the National Center for Advancing Translational Sciences, highlighted this point, saying, “I would make a plea for ongoing research on broader protection, maybe different platforms, maybe a different approach.”

A good deal of attention was also directed toward Novavax, a protein-based formulation that relies on a more traditional approach to vaccination than the mRNA-based vaccines. Although the Novavax vaccine has been authorized by the FDA for use since July 2022, it has received much less national attention – largely because of its latecomer status. Nonetheless, Novavax has boasted efficacy rates on par with its mRNA cousins, with good safety profiles and less demanding long-term storage requirements than the mRNA shots.

By simplifying the vaccine schedule to include only a single vaccine formulation, the committee reasoned, it might be easier for competing vaccination platforms to break into the market. In other words, newer vaccine contenders would not have to rely on patients’ having already received their primary series before using their products. Companies seemed ready to take advantage of that future flexibility, with researchers from Pfizer, Moderna and Novavax all revealing their companies’ exploration of a hybrid COVID-19 and flu shot at various stages of clinical trials and testing.

Would the single shot resemble flu vaccine development?

Not necessarily. Currently, the influenza vaccine is decided by committee through the World Health Organization. Because of its seasonal nature, the strains to be included in each season’s flu vaccine strain for the Southern and Northern hemispheres, with their opposing winters, are selected independently. The Northern Hemisphere’s selection is made in February for the following winter based on a vast network of flu monitoring stations around the globe.

Although there was broad consensus among panelists that the shots against SARS-CoV-2 should be updated regularly to more closely match the most current circulating viral strain, there was less agreement on how frequent that would be.

For instance, rapidly mutating strains of the virus in both summer and winter surges might necessitate two updated shots a year instead of just one. As Dr. Eric Rubin, an infectious disease expert from the Harvard T.H. Chan School of Public Health, noted, “It’s hard to say that it’s going to be annual at this point.”

Matthew Woodruff receives funding from the National Institute of Health and the US Department of Defense to support his academic research.

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Measles virus ‘cooperates’ with itself to cause fatal encephalitis

Fukuoka, Japan—Researchers in Japan have uncovered the mechanism for how the measles virus can cause subacute sclerosing panencephalitis, or SSPE, a…

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Fukuoka, Japan—Researchers in Japan have uncovered the mechanism for how the measles virus can cause subacute sclerosing panencephalitis, or SSPE, a rare but fatal neurological disorder that can occur several years after a measles infection.

Credit: Kyushu University/Hidetaka Harada/Yuta Shirogane

Fukuoka, Japan—Researchers in Japan have uncovered the mechanism for how the measles virus can cause subacute sclerosing panencephalitis, or SSPE, a rare but fatal neurological disorder that can occur several years after a measles infection.

Although the normal form of the measles virus cannot infect the nervous system, the team found that viruses that persist in the body can develop mutations in a key protein that controls how they infect cells. The mutated proteins can interact with its normal form, making it capable of infecting the brain. Their findings were reported in the journal Science Advances.

If you are of a certain age, you may have gotten the measles as a child. Many born after the 1970s have never gotten it thanks to vaccines. The condition is caused by the virus of the same name, which is one of the most contagious pathogens to this day. The World Health Organization estimates that nearly nine million people worldwide were infected with measles in 2021, with the number of deaths reaching 128,000.

“Despite its availability, the recent COVID-19 pandemic has set back vaccinations, especially in the Global South,” explains Yuta Shirogane, Assistant Professor at Kyushu University’s Faculty of Medical Sciences. “SSPE is a rare but fatal condition caused by the measles virus. However, the normal measles virus does not have the ability to propagate in the brain, and thus it is unclear how it causes encephalitis.”

A virus infects cells through a series of proteins that protrude from its surface. Usually, one protein will first facilitate the virus to attach to a cell’s surface, then another surface protein will cause a reaction that lets the virus into the cell, leading to an infection. Therefore, what a virus can or cannot infect can depend heavily on the type of cell.

“Usually, the measles virus only infects your immune and epithelial cells, causing the fever and rash,” continues Shirogane. “Therefore, in patients with SSPE, the measles virus must have remained in their body and mutated, then gained the ability to infect nerve cells. RNA viruses like measles mutate and evolve at very high rates, but the mechanism of how it evolved to infect neurons has been a mystery.”

The key player in allowing the measles virus to infect a cell is a protein called fusion protein, or F protein. In the team’s previous studies, they showed that certain mutations in the F protein puts it in a ‘hyperfusongenic’ state, allowing it to fuse onto neural synapses and infect the brain.

In their latest study, the team analyzed the genome of the measles virus from SSPE patients and found that various mutations had accumulated in their F protein. Interestingly, certain mutations would increase infection activity while others actually decreased it.

“This was surprising to see, but we found an explanation. When the virus infects a neuron, it infects it through ‘en bloc transmission,’ where multiple copies of the viral genome enter the cell,” continues Shirogane. “In this case, the genome encoding the mutant F protein is transmitted simultaneously with the genome of the normal F protein, and both proteins are likely to coexist in the infected cell.”

Based on this hypothesis, the team analyzed the fusion activity of mutant F proteins when normal F proteins were present. Their results showed that fusion activity of a mutant F protein is suppressed due to interference from the normal F proteins, but that interference is overcome by the accumulation of mutations in the F protein.

In another case, the team found that a different set of mutations in the F protein results in a completely opposite result: a reduction in fusion activity. However, to their surprise, this mutation can actually cooperate with normal F proteins to increase fusion activity. Thus, even mutant F proteins that appear to be unable to infect neurons can still infect the brain.

“It is almost counter to the ‘survival of the fittest’ model for viral propagation. In fact, this phenomenon where mutations interfere and/or cooperate with each other is called ‘Sociovirology.’ It’s still a new concept, but viruses have been observed to interact with each other like a group. It’s an exciting prospect” explains Shirogane.

The team hopes that their results will help develop therapeutics for SSPE, as well as elucidate the evolutionary mechanisms common to viruses that have similar infection mechanisms to measles such as novel coronaviruses and herpesviruses.

“There are many mysteries in the mechanisms by which viruses cause diseases. Since I was a medical student, I was interested in how the measles virus caused SSPE. I am happy that we were able to elucidate the mechanism of this disease,” concludes Shirogane.

###

For more information about this research, see “Collective fusion activity determines neurotropism of an en bloc transmitted enveloped virus” Yuta Shirogane, Hidetaka Harada, Yuichi Hirai, Ryuichi Takemoto, Tateki Suzuki, Takao Hashiguchi, Yusuke Yanagi, https://doi.org/10.1126/sciadv.adf3731

About Kyushu University
Kyushu University is one of Japan’s leading research-oriented institutes of higher education since its founding in 1911. Home to around 19,000 students and 8,000 faculty and staff, Kyushu U’s world-class research centers cover a wide range of study areas and research fields, from the humanities and arts to engineering and medical sciences. Its multiple campuses—including the largest in Japan—are located around Fukuoka City, a coastal metropolis on the southwestern Japanese island of Kyushu that is frequently ranked among the world’s most livable cities and historically known as a gateway to Asia.


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Beloved Royal Caribbean Adult Event Still Missing; Another Returns

The cruise line has almost fully returned to normal after the covid pandemic, but one very popular activity hasn’t been brought back.

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The cruise line has almost fully returned to normal after the covid pandemic, but one very popular activity hasn't been brought back.

In the early days of Royal Caribbean Group's (RCL) - Get Free Report return from its 15-month covid pandemic shutdown, cruising looked a lot different. Ships sailed with limited capacities, masks were required in most indoor areas, and social distancing was a thing.

Keeping people six feet apart made certain aspects of taking a cruise impossible. Some were made easier by the lower passenger counts. For example, all Royal Caribbean Windjammer buffets required reservations to keep the crowds down, but in practice that system was generally not needed because capacities were never reached.

Dance parties and nightclub-style events had to be held on the pool decks or in larger spaces, and shows in the big theaters left open seats between parties traveling together. In most cases, accommodations were made and events more or less happened in a sort of normal fashion.

A few very popular events were not possible, however, in an environment where keeping six feet between passengers was a goal. Two of those events -- the first night balloon drop and the adult "Crazy Quest" game show -- simply did not work with social-distancing requirements.

One of those popular events has now made its comeback while the second appears to still be missing (aside from a few one-off appearances).

TheStreet

Crazy Quest Is Still Mostly Missing

In late November, Royal Caribbean's adult scavenger hunt, "The Quest," (sometimes known as "Crazy Quest") began appearing on select sailings. And at the time it appeared like it was coming back across the fleet: A number of people posted about the return of the interactive adult game show in an unofficial Royal Caribbean Facebook group.

It first appeared during a Wonder of the Seas transatlantic sailing.

Since, then it's appearances continue to be spotty and it has not returned on a fleetwide basis. This might not be due to any covid-related issues directly, but covid may play a role.

On some ships, Studio B, which hosts "The Quest," has been used for show rehearsals. That has been more of an issue with the trouble Royal Caribbean has had in getting new crew members onboard. And while that staffing issue has been improving, some shows may not have had full complements of performers, so using the space for rehearsal has been a continuing need.

In addition, while covid rules have gone away, covid has not, and ill cast members may force the need for more rehearsals.

Royal Caribbean has not publicly commented on when (or whether) "The Quest" will make a full comeback

Royal Caribbean Balloon Drops Are Back   

Before the pandemic, Royal Caribbean kicked off many of its cruises with a balloon drop on the Royal Promenade. That went away because it forced people to cluster as music was performed and, at midnight, balloons fell from the ceiling.

Now, the cruise line has brought back the balloon drop, albeit with a twist. The drop itself is appearing on activity schedules for upcoming Royal Caribbean cruises. Immediately after it, however, the cruise line has added something new: "The Big Recycle Balloon Pickup."

Most of the dropped balloons get popped during the drop. Previously, crewmembers picked up the used balloons. Now, the cruise line has made it a "fun" passenger activity.

"Get environmentally friendly as you help us gather our 100% biodegradable balloons in recycle baskets," the cruise line shared in its app. 

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