THE CHILLING KINSHIP OF COVID
Date: 2024-01-16During a span of a few weeks in November 1889, a respiratory malady launched a relentless assault on half the populace of St. Petersburg, Russia. Swiftly, it embarked on a global odyssey, weaving its way through Europe and beyond. The affliction, later christened the "Russian influenza" epidemic, persisted with unabated fury until 1894, leaving an indelible mark on communities worldwide. In a meticulously detailed tome published two years later, British medical officer H. Franklin Parsons chronicled the harrowing narrative of this insidious outbreak.
Eerily reminiscent of more recent pandemics, the Russian influenza exhibited perplexing characteristics. Transmission appeared to occur even before the onset of symptoms, confounding efforts to contain its rapid dissemination. The affliction displayed a capricious predilection for the elderly, sparing the young from its more severe manifestations. A dry cough became a telltale sign of the malady, and some victims experienced a peculiar "perversion of taste and smell." Meanwhile, mortality rates surged, amplifying the pervasive anxiety that a pathogen had made a perilous leap from animals to humans, echoing contemporary concerns surrounding zoonotic origins.
Sound like COVID-19?
In the year 2005, researchers in Belgium postulated that the root cause of the earlier pandemic was not an influenza virus, but rather an instance of a coronavirus. Three years prior to the official publication of their theory, a coronavirus had traversed the species barrier, initiating a highly fatal outbreak termed severe acute respiratory syndrome (SARS). Originating in China, this disease thrust these once-obscure viruses into the spotlight. Contemplating events in Russia over a century ago, the Belgian team pondered if a similar scenario had unfolded. Drawing on molecular evidence, they proposed that the once-lethal virus still persists today, manifesting as a coronavirus named OC43, typically inducing nothing more severe than a common cold in most individuals. While concrete evidence for the group's hypothesis is currently lacking, two other research teams aim to scrutinize tissue samples from the late 19th century, endeavoring to discern the virus's emergence as a human pathogen.
This forthcoming quest for the origins of OC43 is part of a surge in research spurred by the global eruption of COVID-19 four years ago this month. Researchers are delving into the intricacies of this virus and the three other coronaviruses responsible for causing common colds. Once relegated to the periphery of scientific interest, these pathogens, bearing alphanumeric monikers like NL63, 229E, and HKU1, are now receiving overdue attention. Some groups are reassessing the mechanisms by which these viruses jumped from animals to humans, seeking insights into the potential origins of SARS-CoV-2, the culprit behind COVID-19. The exploration of these four coronaviruses may also shed light on whether other coronaviruses identified in wild and domesticated animals pose a threat to humanity. Concurrently, scientists are delving into how immune responses to these four viruses intersect and influence the body's reaction to SARS-CoV-2.
Every autumn and winter, the quartet of viruses makes its seasonal appearance, contributing to as much as 30% of the colds that afflict us. However, indications suggest that these viruses might have once provoked more severe illnesses, prompting certain virologists to envision a potentially optimistic trajectory for the future of COVID-19. In the eyes of Lia van der Hoek, a virologist credited with the discovery of NL63 in 2003 at Amsterdam University Medical Centers, these four viruses serve as a prototype, offering insight into what lies ahead. "Those four are the model system of what's ahead for us," she anticipates. A prophecy takes shape: SARS-CoV-2, the culprit behind COVID-19, is envisioned to transition into a commonplace ailment, eventually assuming the status of a common cold. Such a transformation, at least according to the hopes of the scientific community, appears to be on the horizon.
Six decades in the past, the inaugural encounter with a human coronavirus unfolded in a rather unassuming setting—the runny noses of English schoolboys. In the wintry months of 1960–61, David Tyrrell, a virologist at the helm of the Common Cold Unit in the United Kingdom, embarked on a quest with his colleagues. Their mission: to scrutinize the viral landscape within the gooey contents of the boys' handkerchiefs. Faced with an absence of any known cold virus in their analysis, they took a bold step. In an effort to pinpoint the elusive culprit, adult volunteers were inoculated with extracts derived from the nasal washings. The goal was clear: to ascertain whether something concealed within those samples wielded the power to induce the common cold.
Nevertheless, the samples harvested from these disease-laden sources exhibited a peculiar resistance to flourishing in conventional culture media. Faced with this perplexing challenge, the scientific team redirected their efforts toward an unconventional culture system, a recent innovation tailored for specific influenza and adenoviruses. This system involved utilizing cilia-bearing cells from the trachea, the natural abode for respiratory viruses, which were sourced from aborted fetuses. In this unconventional terrain, one particular sample, christened B814, proved to be a watershed moment, yielding a novel virus.
"In a noteworthy revelation, we now harbor the conviction that the B814 strain is a virus virtually disconnected from any other known virus inhabiting the human respiratory tract," declared Tyrrell and his colleagues in a report published in 1965. Undeterred by initial skepticism, their findings marked a significant leap in understanding the enigmatic virus.
In the subsequent year, Tyrrell dispatched samples of B814 to June Almeida, an adept electron microscopist lacking a university degree, stationed at St. Thomas' Hospital in London. Almeida's microscopic scrutiny unveiled a revelation—similar viral particles existed in samples from chickens afflicted with infectious bronchitis and mice suffering from hepatitis. However, her attempts to publish these observations faced resistance. As Tyrrell recounted in his co-authored book, "Cold Wars: The Fight Against the Common Cold," referees dismissed Almeida's images as mere subpar depictions of influenza virus particles. The struggle to recognize the true nature of the virus persisted.
Her recent depictions of B814 compellingly argued that the diverse viruses formed a related, yet unrecognized, cluster. The quest for a suitable moniker unfolded, and Tyrrell reflected, " 'Influenza-like' appeared somewhat feeble, veering into vagueness and potential misdirection." Perceptive observations by both Tyrrell and Almeida noted a distinctive halo encircling these viral entities, giving birth to the nomenclature "coronavirus."
Simultaneously, infectious disease specialists Dorothy Hamre and John Procknow at the University of Chicago pursued their own investigation into novel cold viruses among medical students. In 1966, their findings unveiled the isolation of a virus named 229E from a participant with a "minor upper respiratory illness." Providing samples to Tyrrell's team, intentional infections affirmed, through meticulous handkerchief counts, that 229E, akin to B814, induced a mild cold. Although the two viruses exhibited identical appearances under the microscope, the inability to adapt B814 to a cell line led to its historical disappearance before any genetic comparisons could occur.
Concurrently, the researchers involved in a protracted cold study at the U.S. National Institutes of Health (NIH) reported a distinct second coronavirus, OC43, in 1967. Ken McIntosh, overseeing the project in Robert Chanock's laboratory, recalled their unique approach: inviting NIH employees with cold symptoms to participate, allowing the collection of nasal fluids for analysis. Electron microscopy revealed a virus resembling the one causing avian infectious bronchitis. Although initially restricted to the organ culture medium used by Tyrrell, OC43 was eventually adapted to a cell line.
Yet, despite these discoveries, enthusiasm for coronavirus research waned. The cumbersome and challenging nature of working with these viruses deterred many researchers. McIntosh lamented, "Working with them was so awkward and difficult that nobody wanted to do it." By January 2003, only a few hundred studies had delved into human coronaviruses, with most researchers focused on those afflicting animals. Interest in human medicine-focused coronavirus research was scarce, recalled Leiden University virologist Eric Snijder, who struggled to attract scientists to a meeting he co-organized on nidoviruses, the broader order encompassing coronaviruses, in January of that year.
Subsequently, in April 2003, revelations surfaced that the insidious and atypical pneumonia rapidly spreading across China, later identified as SARS, was attributable to a coronavirus. As the malady cast its ominous shadow beyond China, inducing international apprehension, the May meeting witnessed a surge in last-minute registrations, escalating from 130 to 170 participants. Swiftly, SARS was incorporated into the agenda. At long last, a human coronavirus had seized the broader scientific community's attention, and the unveiling of two more was imminent.
Van der Hoek pinpointed the one she dubbed NL63 in a nasal specimen extracted from a 7-month-old girl in the Netherlands, recently afflicted by fever, pink eye, and a runny nose. Simultaneously, Ron Fouchier's laboratory at the nearby Erasmus Medical Center stumbled upon what appeared to be the same virus. Both teams swiftly disseminated their findings online within a few weeks of each other in the early spring of 2004. Before the year's end, a team led by clinical microbiologist Patrick Woo at the University of Hong Kong brought another human coronavirus to light—HKU1, identified in a 71-year-old man grappling with unexplained pneumonia.
Both van der Hoek and Woo, currently affiliated with National Chung Hsing University, express skepticism regarding the existence of additional widely circulating human coronaviruses that remain undetected by researchers. "For an extensive period, people have scrutinized respiratory samples, and no other common cold coronavirus has emerged," asserts van der Hoek. "I'm firmly convinced that the tally rests at those four."
Yet, certain seasoned coronavirologists adopt a more cautious stance. Susan Weiss at the University of Pennsylvania, with four decades of coronavirus research under her belt, questions the notion of a limited count. "How can there be only four?" she queries. The University of Iowa's Stanley Perlman, another stalwart in the field of coronaviruses, emphasizes the importance of sustained exploration for novel human coronaviruses. Perlman reflects, "In 2002, we believed we had concluded our investigation with 229E and OC43. We consistently find ourselves misled when we assume we've reached the endpoint."
In the span of a few years following the identification of the coronavirus responsible for SARS, scientists successfully unraveled a compelling narrative surrounding its origins. The virus detected in civets and raccoon dogs, prevalent in markets across southern China, closely matched the one afflicting humans. Concurrently, a virus discovered in bats exhibited striking resemblances to the ancestral form of the virus. This revelation triggered a global initiative to systematically collect samples from bats and various other animals, aiming to identify coronaviruses with the potential to endanger human health. The outcome was the cataloging of thousands of viral sequences. Although the majority of these coronaviruses have only been pinpointed through the sequencing of fragments within their genome—a task rendered challenging due to difficulties in cultivating intact viruses in culture—it is evident that the viral family is prolific across numerous species. Moreover, indications suggest that other mammals serve as the reservoir for all known coronaviruses responsible for causing the common cold.
Family history
Coronaviruses have recurrently crossed the species barrier, transitioning from bats or rodents—their natural reservoir—to other animals like camels, cows, or civets before making the leap to humans. In the case of SARS-CoV-2, the possibility exists that raccoon dogs and various other mammals traded at a market in Wuhan, China, may have served as intermediate hosts, although this remains a topic of debate within the scientific community.
The Belgian researchers investigating the pandemic of the 1890s, for instance, decoded the genome of OC43 and identified "remarkable" genetic resemblances to a coronavirus observed in cows. Employing the estimated mutation rates of the bovine virus and OC43, they constructed a molecular clock, determining that the two viruses shared a common ancestor around 1890, with the timeframe ranging from 1815 to 1918. This temporal alignment prompted speculation among the scientists regarding the possibility that the bovine counterpart might have initially leaped into humans as a more formidable pathogen, subsequently evolving over time into the comparatively mild OC43 observed today.
Philippe Lemey of KU Leuven, a co-author of the study published in the Journal of Virology, noted, "It seemed like an interesting coincidence that when we estimated the divergence time of the bovine virus and human OC43, it was basically spot on the date you would expect with the Russian flu epidemic." Lemey and his colleagues highlighted a critical period between 1870 and 1890 when an epidemic of pneumonia in cows prompted "massive culling" of the animals in industrialized nations. This, they suggested, created an "ample opportunity for the culling personnel to come into contact with bovine respiratory secretions" containing the precursor to OC43.
In 2022, a French team published findings in Microbial Biotechnology presenting "very preliminary" biological evidence supporting the OC43 hypothesis. They discovered antibodies to the virus in the dental pulp of World War I soldiers who were alive during the Russian flu and perished in battle in 1914.
However, these analyses linking OC43 to the Russian flu fail to convince Michael Worobey, an evolutionary biologist at the University of Arizona who has collaborated with Lemey on influential studies regarding the origin of SARS-CoV-2. Worobey dismisses the notion, deeming it "extremely unlikely." As argued in a 2014 paper in the Proceedings of the National Academy of Sciences, he contends that "compelling evidence" associates the global outbreak with a specific influenza viral variant. This includes a study examining stored samples from individuals born as far back as 1876, which revealed antibodies to a novel flu virus from the time of the pandemic.
Worobey aims to settle the ongoing debate by procuring archived tissue from individuals treated at a London hospital around 1890 and searching for lingering genetic sequences of influenza or coronaviruses. A Spanish research group has also identified "suitable samples" from that era at the Basque Museum of the History of Medicine and Science and plans to investigate them soon.
The other coronaviruses responsible for common colds are believed to have similarly made the leap from animals. In 2009, a team led by virologist Christian Drosten, now at Charité University Hospital in Berlin, revealed that Hipposideros bats in Ghana harbor a relative of 229E. Their estimates indicate that the bat virus and 229E share a common ancestor dating back to between 1659 and 1803, suggesting the period when it breached the human barrier.
As with the SARS virus, the transmission may have occurred through an intermediate species. Drosten's team discovered relatives of 229E in healthy dromedary camels in the Arabian Peninsula and Africa, reinforcing this theory. They also outlined a bat-to-camel-to-human transmission pathway for the highly lethal coronavirus causing Middle East respiratory syndrome, first identified in 2012. A parallel scenario appears plausible for SARS-CoV-2, with evidence suggesting transmission from bats to humans via an animal host like raccoon dogs or other susceptible species sold in a Wuhan food market, the site of the earliest cluster of COVID-19 cases.
The origins of the other two cold coronaviruses are less clear. NL63 traces back to an ancestor found in tricolored bats in Maryland, with a genetic comparison suggesting its crossover into humans occurred 563 to 822 years ago. HKU1, with the murkiest evolutionary history, shares a genetic sequence close to the murine hepatitis virus, indicating a potential rodent origin.
In a chapter on human coronaviruses authored by Drosten and colleagues in Advances in Virus Research in 2018, they noted the "peculiar" absence of coronaviruses in great apes other than humans. They hypothesized that contact with domestic animals might be crucial for human acquisition of most or all endemic CoV, an idea supported by ongoing efforts led by Anastasia Vlasova at Ohio State University to discover novel coronaviruses in farmers handling livestock.
J. Glenn Morris, an epidemiologist leading the Emerging Pathogens Institute at the University of Florida, suggests there's likely frequent transfer of zoonotic coronaviruses into the human population. However, many of these infections may not progress further. Over the years, researchers like Morris and Vlasova have identified coronaviruses from cows, dogs, cats, and pigs that seemingly infected people but then faded away.
For Gregory Gray, an epidemiologist at the University of Texas Medical Branch, humanity constantly faces a low-level siege from these viruses. He believes that numerous animal coronaviruses circulate, challenging human immune systems regularly.
As SARS-CoV-2 commenced its global spread, researchers pondered whether our immune recollections of its four milder counterparts could mitigate the impact of the formidable new virus. The shared fundamental repertoire of proteins among all coronaviruses suggested that immune responses cultivated through recurrent exposure to common colds might alleviate the severity of COVID-19. However, the evidence presents a mixed picture.
One notable distinction arises from the surface protein of SARS-CoV-2, known as spike, which significantly differs from those adorning its common cold-causing relatives. Consequently, antibodies targeting the coronaviruses responsible for common colds fail to prevent SARS-CoV-2 infections or mitigate the symptoms it induces. A study published in the September 6, 2023, issue of Science Translational Medicine even posits that prior exposure to OC43 may lead individuals to possess antibodies against its spike protein, potentially impeding the immune system's ability to generate antibodies against the surface protein of SARS-CoV-2. This could elevate the risk of developing persistent and debilitating symptoms known as Long Covid.
Yet, amidst this complexity, a multitude of early pandemic studies suggests that certain immune memories of common cold coronaviruses do confer assistance. Immunologist Alessandro Sette, from the La Jolla Institute for Immunology, notes, "It has been well established that prepandemic, some people had preexisting immune reactivity to SARS-CoV-2, and it was consequential." His research group, along with several others, reported that T cells extracted from individuals with no prior SARS-CoV-2 infection could, in test tube experiments, recognize and eliminate cells infected by the virus. Sette elaborates, "We and others have shown that, at least in some cases, this could be mapped to similarities between common cold [coronavirus] sequences and SARS-CoV-2 sequences."
Amidst the pandemic's early days, individuals possessing preexisting immunity to common cold coronaviruses, as indicated by T cell responses to specific viral proteins other than spike, exhibited a potential defense against SARS-CoV-2 infections among health care workers. Further investigations revealed that household contacts of individuals with SARS-CoV-2 had a reduced risk of infection if their T cells reacted to proteins within the viral capsule of OC43 and HKU1. Notably, immunity to these common cold cousins correlated with milder COVID-19 outcomes, and Sette’s research group demonstrated enhanced responses to COVID-19 vaccines among those with preexisting coronavirus immunity.
This preexisting coronavirus immunity likely played a substantial role in mitigating the toll of SARS-CoV-2 during the early stages of the pandemic. However, its significance has waned over time, according to Sette, given the widespread exposure to and vaccination against SARS-CoV-2 across the majority of the global population.
Taking an unconventional approach, infectious disease specialist Manish Sagar and colleagues from Boston University investigated whether immunity to SARS-CoV-2 could protect against the common cold. Their examination involved nasal swabs from nearly 5000 individuals visiting the Boston Medical Center between November 2020 and October 2021. Those with prior SARS-CoV-2 infections exhibited a 50% lower likelihood of symptomatic disease from one of the four common cold coronaviruses, as reported in a bioRxiv preprint on October 24, 2023. The benefit was likely attributed to T cells targeting internal proteins of OC43, the most prevalent cold coronavirus in their study.
In contrast, van der Hoek's examination of cross-immunity led to a different conclusion. In the fall of 2021, her team commenced testing respiratory samples to assess whether SARS-CoV-2 influenced the presence of common cold coronaviruses. According to her unpublished analysis, after the Netherlands lifted its COVID-19 lockdowns, all four common cold coronaviruses re-emerged. "I don't think that SARS-CoV-2 has any effect on their circulation," she asserts.
Van der Hoek perceives the significance of the "other" coronaviruses differently: she believes they foreshadow the probable future of SARS-CoV-2. She is intrigued by the substantial decline in severe disease and death from SARS-CoV-2 over the past four years, transforming it from a widely feared killer into just another human coronavirus causing little acute harm, especially in individuals under 65 with no comorbidities. Notably, Long Covid has become a more prominent concern than immediate hospitalization.
The initial ferocity of the virus can be attributed to the fact that, apart from potential modest protection from previous colds, the global population in January 2020 was immunologically blindsided by the new infection. However, van der Hoek suggests an evolutionary "trade-off" may have contributed to the defanging of SARS-CoV-2. As the virus proliferated among billions of people, it might have become less virulent to facilitate more efficient spread. She emphasizes that when viruses jump species, they are initially ill-adapted to their hosts and fail to consider the host's survival for their own perpetuation.
According to van der Hoek, each of the four common cold coronaviruses likely entered the human population with high lethality and subsequently mellowed. She contends that this pattern holds true for all four of them, positioning SARS-CoV-2 as the fifth in line. The idea is that as these viruses adapt to their hosts, they transition from being highly virulent to allowing infected individuals to move freely in the community, emphasizing that containing an acute respiratory virus is hindered when people are confined to their beds.
However, evolutionary biologist Jemma Geoghegan at the University of Otago remains doubtful. Geoghegan, a co-author of a December 2018 article in Nature Reviews Genetics, challenges the entrenched notion that emerging viruses evolve to become less virulent for persistence. Disputing the classic perspective, Geoghegan cites examples, including HIV, where viruses did not weaken over time.
Geoghegan underscores that SARS-CoV-2 initiates its spread before individuals show symptoms and often does not cause illness in those who are immunologically naive. This lack of symptomatic manifestation implies little evolutionary pressure for the virus to become less virulent. She argues that there is no imperative selection for a reduced virulence/transmission trade-off.
The skepticism voiced by Geoghegan is further fueled by the procession of SARS-CoV-2 variants. Delta, a variant of the virus, exhibited heightened virulence compared to the original strain from Wuhan. Omicron, the subsequent variant, became predominant due to its increased transmissibility, not diminished severity. Geoghegan contends that there is no indication of the anticipated trade-off.
Thus, it is essential to add a caveat to the notion that SARS-CoV-2 is on a trajectory toward becoming as mild as OC43 and other cold coronaviruses. Geoghegan asserts, "Omicron still hospitalizes and kills lots of people. It's not there yet."