Chronic COVID infections source of variants of concern, study shows

An electron microscopic image shows an isolate from the first U.S. case of COVID-19, caused by SARS-CoV-2. The virus has since evolved into five variants of concern.  "If we want to stay a step ahead of this virus, we need to be more actively identifying and surveilling people with chronic infections," says Emory graduate Mahan Ghafari, first author of a new study on how the virus evolves. (CDC)

By Carol Clark

The coronavirus variants of concern are emerging from chronic, long-term COVID infections in people who may be immune comprised and unable to clear the virus, a new study strongly suggests. Frontiers in Virology published the findings by scientists at Emory University and the University of Oxford. 

“Rather than evolving from transmission chains of acute COVID infections in hundreds of millions of people, our results show that the variants of concern come from rare cases when someone may have an active infection for months,” says Daniel Weissman, a corresponding author and Emory professor of biology and physics focused on quantitative evolutionary theory. 

“A key take-home message is that it is important to find these individuals who are chronically infected and provide support for them to recover,” adds Mahan Ghafari, first author of the paper and a postdoctoral researcher at the University of Oxford. “In many cases they may be asymptomatic and not even realize that they are infected with COVID although they are actively shedding the virus.” 

Ghafari graduated from Emory in 2018 with a masters in physics. 

Additional authors of the paper include Aris Katzourakis, a professor of evolution and genomics at the University of Oxford; Qihan Liu, an Emory graduate student in physics; and Emory undergraduate Arushi Dhillon. 

Random mutations

Viruses like SARS-CoV-2 continuously evolve due to occasional mutations in the genetic code that may occur when they replicate. “When a virus copies itself, it doesn’t always make perfect copies,” Weissman explains. 

Usually, such random mutations do not benefit the virus or raise the concerns of scientists monitoring these changes. Occasionally, however, the mutations result in a variant of the virus that may make it more transmissible, more difficult to detect and treat, and even more lethal. 

The World Health Organization defines a SARS-CoV-2 variant of concern as one that is more likely to cause infections even in those who are vaccinated or in those who were previously infected. 

“During the first few months of the pandemic, it didn’t look like the coronavirus was going to adapt into a variant of concern,” Weissman says. “But then, boom, boom, boom! Not only did the coronavirus evolve into VOCs, it did it three times in quick succession in late 2020.” 

The WHO dubbed these first three variants of concern alpha, beta and gamma. 

Mysteries surrounding VOCs

Why had all three of these VOCs emerged at roughly the same time and apparently in three far-flung areas of the world? 

Another mystery was why large clusters of mutations occurred in the VOCs. “A key element that distinguished these VOCs from other lineages of virus that were circulating is that each of them has a vastly elevated number of mutations,” Ghafari notes. “That’s a major distinction point in evolutionary terms.” 

At least some of the mutations from the VOC had been detected in chronic cases of COVID, leading to the hypothesis that these long-term cases may be the source of the VOCs. The other main theory was that VOCs were emerging from sustained transmission of acute infections in areas of the world with poor genomic surveillance of the virus. 

Ghafari, Weissman and their collaborators were among the first teams to methodically test these theories surrounding the emergence of the alpha, beta and gamma VOCs. 

The researchers built a mechanistic, theoretical model to study the problem, using existing data and software they developed. 

The resulting model rules out the theory that the VOCs emerged from sustained transmission of acute infections and fully supports the theory that each variant evolved within a single individual with a chronic infection. 

The model shows how multiple mutations were needed, each of which may have been either neutral or slightly advantageous to viral fitness. In this way, a variant eventually acquires a constellation of mutations that allow it to become more transmissible. 

Model explains delta and omicron emergence

Although the current paper drew from data for the alpha, beta and gamma variants, the resulting theoretical model also explains the later independent emergence of the delta and omicron VOCs. Delta emerged in India in late 2020, rapidly sweeping through that country and spreading around the world. Delta subsided after omicron, which is not a descendent of the delta variant, emerged in South Africa in late 2021. Omicron quickly became the dominant global VOC. 

The researchers have made their model and software publicly available for others to study the evolution of SARS-CoV-2 variants. 

“Ideally, we’d like to eventually be able to quantify the timing at which new variants might emerge in the future,” Weissman says. “That has huge implications from a public health perspective.” 

Studies have shown that some immune-compromised people, such as those taking medication for other chronic disorders, have carried active COVID infections for a year or even longer. It’s critical to identify these people, the researchers stress, not only to help them get treated for COVID, but also to conduct genomic surveillance of the SARS-CoV-2 viruses that they carry. 

“Who knows what variant could be boiling up next from a chronically infected individual?” Ghafari says. “Our study shows that from an evolutionary point of view, we can expect something completely different from the previous VOCs. If we want to stay a step ahead of this virus, we need to be more actively identifying and surveilling people with chronic infections.” 

The work was funded by the National Science Foundation, the Simons Foundation, the Sloan Foundation, the Biotechnology and Biological Science Research Council and the European Research Council. 

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Emory physicist Daniel Weissman awarded 2021 Sloan Research Fellowship

Testosterone promotes 'cuddling,' not just aggression, animal study finds

The research used the experimental model of Mongolian gerbils, rodents that form lasting pair bonds and raise their pups together. In addition to demonstrating testosterone's effects on prosocial behavior, the work also revealed how testosterone influences the neural activity of oxytocin cells — the so-called "love hormone" associated with social bonding. (Photo by Aubrey Kelly)

By Carol Clark

Testosterone can foster friendly, prosocial behavior in males, a new animal study finds. The Proceedings of the Royal Society B published the research on Mongolian gerbils conducted by neuroscientists at Emory University. 

“For what we believe is the first time, we’ve demonstrated that testosterone can directly promote nonsexual, prosocial behavior, in addition to aggression, in the same individual,” says Aubrey Kelly, Emory assistant professor of psychology and first author of the study. “It’s surprising because normally we think of testosterone as increasing sexual behaviors and aggression. But we’ve shown that it can have more nuanced effects, depending on the social context.”

The work also revealed how testosterone influences the neural activity of oxytocin cells — the so-called “love hormone” associated with social bonding. 

Richmond Thompson, a neuroscientist at Oxford College of Emory University, is co-author of the study. 

Kelly’s lab has recently focused on the neural effects of oxytocin using rodent experimental models. Thompson’s lab investigates the neural effects of steroids in fish. Both scientists are trying to get at the question of how hormones work in the brain to allow an animal to rapidly change its behavior, depending on the social context. 

In addition to sharing this research interest, Kelly and Thompson share a home as a married couple.

“The idea for this paper was borne out of us talking together over a glass of wine,” Kelly says. “It blends our two research worlds.” 

Testing new questions 

The majority of human studies show that testosterone enhances aggressive behavior. Kelly and Thompson wondered if maybe testosterone might, in lockstep with being able to increase aggression toward intruders, also generally dampen prosocial behaviors. However, they also hypothesized that it might do something more radical — actually enhance positive social responses in contexts in which acting prosocially is appropriate. 

To test this question, the Kelly lab conducted experiments on Mongolian gerbils, rodents that form lasting pair bonds and raise their pups together. While males can become aggressive during mating and in defense of their territory, they also exhibit cuddling behavior after a female becomes pregnant, and they demonstrate protective behavior toward their pups. 

In one experiment, a male gerbil was introduced to a female gerbil. After they formed a pair bond and the female became pregnant, the males displayed the usual cuddling behaviors toward their partners. The researchers then gave the male subjects an injection of testosterone. They expected that the resulting acute rise in a male’s testosterone level would lessen his cuddling behaviors if testosterone generally acts as an antisocial molecule. 

“Instead, we were surprised that a male gerbil became even more cuddly and prosocial with his partner,” Kelly says. “He became like ‘super partner.’” 

Switching contexts 

In a follow-up experiment a week later, the researchers conducted a resident-intruder test. The females were removed from the cages so that each male gerbil that had previously received a testosterone injection was alone in his home cage. An unknown male was then introduced into the cage. 

“Normally, a male would chase another male that came into its cage, or try to avoid it,” Kelly says. “Instead, the resident males that had previously been injected with testosterone were more friendly to the intruder.” 

The friendly behavior abruptly changed, however, when the original male subjects were given another injection of testosterone. They then began exhibiting normal chasing and/or avoidance behaviors with the intruder. “It was like they suddenly woke up and realized they weren’t supposed to be friendly in that context,” Kelly says. 

The researchers theorize that because the male subjects experienced a surge in testosterone while they were with their partners, it not only rapidly increased positive social responses toward them but also primed the males to act more prosocially in the future, even when the context changed and they were in the presence of another male. However, the second testosterone injection then rapidly prompted them to switch their behavior to become more aggressive, as appropriate to the context of a male intruder. 

“It appears that testosterone enhances context-appropriate behavior,” Kelly says. “It seems to play a role in amplifying the tendency to be cuddly and protective or aggressive.” 

The laboratory experiments, in a sense, slowed down what the males might experience almost simultaneously in the wild. In their natural habitat, Kelly explains, mating with a partner elevates testosterone, which primes them to act cuddly in the moment and in the near future while living with their partner, even if the testosterone levels decline. If a rival entered its burrow the gerbil would likely experience another surge of testosterone that would immediately help adjust his behavior so he can fend off the rival and protect his pups. Testosterone, then appears to help animals rapidly pivot between pro- and antisocial responses as the social world changes. 

‘A complicated dashboard’ 

The current study also looked at how testosterone and oxytocin interact biologically. The results showed that the male subjects receiving injections of testosterone exhibited more oxytocin activity in their brains during interactions with a partner compared to males that did not receive the injections. 

“We know that systems of oxytocin and testosterone overlap in the brain but we don’t really understand why,” Kelly says. “Taken together, our results suggest that one of the reasons for this overlap may be so they can work together to promote prosocial behavior.” 

Rather than just flipping an “on” or “off” button to modulate behaviors, hormones seem to play a more nuanced role, Kelly says. “It‘s like a complicated dashboard where one dial may need to move up a bit while another one moves down.” 

Human behaviors are far more complex than those of Mongolian gerbils, but the researchers hope that their findings provide a basis for complementary studies in other species, including humans. 

“Our hormones are the same, and the parts of the brain they act upon are even the same,” Thompson says. “So, learning how hormones like testosterone help other animals adjust to rapidly changing social contexts will not only help us understand the biological nuts and bolts that affect their behavior, but also predict and ultimately understand how the same molecules in human brains help shape our own responses to the social world around us.” 

Jose Gonzalez Abreu, a former research specialist in the Kelly lab, is a co-author of the study. The work was supported by the National Science Foundation. 

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