Scientists have observed viral interference in different studies and speculated that the key mechanism lies in the body's non-specific immune response to the first virus, allowing individuals to enter an antiviral state to resist potential subsequent invaders.
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Winter has always been the peak season for respiratory infections, and the coronavirus has dominated the global spotlight for the past two years, and various prevention and control measures to contain the spread of the virus, such as wearing masks and social distancing, have also had the unintended effect: the scale of infection with other respiratory viruses has been greatly reduced. As the northern hemisphere enters winter, the former "old rivals" have made a comeback, and it is easy to let people get a few tricks.
This winter's "three epidemics" are coming?
At the World Influenza Congress in November 2022, public health experts from around the world spoke out on alert to this winter's "tripledemic". Specifically, the three plagues are mainly derived from the following three types of viruses:
The first is respiratory syncytial virus (RSV). It causes lung and respiratory infections, and is commonly characterized by cough, wheezing, respiratory distress, and hypoxia, and in most cases mild and self-limited, but poses a greater threat to high-risk groups such as young children, older adults, and pregnant women with weakened immune systems. [1]
This is followed by the influenza virus. It belongs to RNA virus, easy to mutate, many subtypes, many hosts, wide spread, strong infectious ability. The flu virus causes symptoms such as headaches, muscle aches, and high fever. According to the latest statistics of the World Health Organization on December 23 last year [2], the number of influenza virus positive and influenza-like diseases continues to rise rapidly worldwide, especially in North America and Europe, of which influenza A virus subtype H3N2 is the most important influenza virus strain. The US Centers for Disease Control and Prevention (CDC) assessed that as of December 17, this winter's influenza season has seen at least 18 million influenza cases, about 190,000 hospitalizations, and the death toll is as high as 12,000 [3] In the mainland, although the number of infected cases dominated by influenza A virus is not high, the number of infections in the southern region has shown an upward trend [2].
Finally, there is the familiar new coronavirus (SARS-CoV-2). After two years of transmission and mutation, the newly circulating XBB variant and its offspring are the king of immune escape, and although their pathogenicity and lethality have been greatly reduced compared to previous strains, the speed of transmission is unstoppable, bringing great physical and mental suffering to the unfortunate people infected.
In addition, there are coronaviruses, adenoviruses, human metapneumoviruses, rhinoviruses, etc., all of which tend to reach the peak of infection in winter.
Common viruses that cause respiratory infections丨Author: Li Qingchao
Experts are concerned because strict anti-epidemic policies over the past three years have weakened the immunity of the entire population to other respiratory viruses, such as influenza. In addition, vaccination rates such as influenza vaccines are also low, which is easy to cause the recirculation of other viruses. [4] Therefore, no matter what country you are in, you still need to be vigilant about the co-infection of the new coronavirus and other respiratory viruses.
So, what happens during the winter months when various viruses compete to spread, if someone is unfortunate enough to be infected with more than one of the above viruses at the same time?
Viruses compete and interfere with each other
At present, most of our understanding of viral infections, pathogenesis and epidemiology is based on the study of single viral infection, but in the actual life environment, it is likely that multiple viruses will circulate at the same time, resulting in concurrent infection. Until now, scientists have not fully grasped the mechanisms of viral interactions and the mechanisms of individual immune responses.
To get definitive answers, researchers must gather evidence at the population, individual, and cellular levels. In some cases, several viruses are co-infected, resulting in more severe symptoms than if only one virus was infected. But usually, viruses antagonize each other, a phenomenon known in virology as "viral interference."
Research on viral interference dates back to 1957, when Alick Isaacs and Jean Lindemann, two virologists at the National Institute for Medical Research, used egg embryos to experiment and found that after membrane cells were infected with inactivated influenza viruses, the live virus could not cause secondary infection of egg embryos. In this process, the egg embryo secretes interferon, which stimulates a rapid non-specific immune response, which is one of the important "weapons" of the innate immune system to deal with the invasion of foreign viruses. [5]
Since then, scientists have gradually paid attention to this phenomenon. Not only are more evidence of viral interference seen in laboratories, but some epidemiological transmission patterns in response to respiratory disease outbreaks also indicate the presence of viral interference. Data from Norway from 1974 to 1981 proved that respiratory syncytial virus and influenza virus infections did not peak at the same time; Epidemiological analyses in India and Nepal in the 70s found that in a single village, monoadenovirus infection tended to predominate, leaving other viruses without a foothold. [6]
The development and application of virus detection technology has opened a new way for scientists to analyze and track viruses more accurately, especially PCR (polymerase chain reaction) technology - that is, the technology we know as nucleic acid detection - has the advantages of high sensitivity, high specificity, reproducibility, fast and simple, reliable results, etc., which greatly helps more scientists to carry out the study of virus interactions. For example, between the spring of 2009 and August 2010, the world experienced a new influenza virus, pH1N1, dominated by swine flu, and the lack of immunity to the new virus led to early outbreaks of influenza in various places from the spring. However, teams of scientists in Sweden and France used PCR to sequence the virus's genes and found that in both countries, a late-summer rhinovirus infection delayed the peak of the flu outbreak until late autumn, the normal month when the flu season begins. This incident also supports the effect of virus interference. [7, 8]
In 2019, the Proceedings of the National Academy of Sciences (PNAS) published the largest, longest-lasting, and most comprehensive comprehensive study of human respiratory viral infections ever [9]. The study, led by virologist Pablo Murcia at the MRC-University of Glasgow Centre for Virus Research, analysed 44,230 cases of respiratory infections in Scotland from 2005 to 2013, with subjects tested for 11 viruses, including rhinovirus, influenza A and B viruses, respiratory syncytial virus and seasonal coronavirus. All positive patients are infected with at least one of these viruses; A total of 11% of people developed concurrent infections, most commonly with both viruses, but some patients were confirmed to be infected with five viruses in a single sample collection. The data clearly indicate staggered outbreaks of rhinovirus and influenza A virus (see figure below), demonstrating antagonism (or negative interaction) between the two viruses.
Figure 2. From 2005 to 2013, patient testing records for respiratory diseases from Scotland, as well as medical records, revealed off-peak epidemic cycles for influenza A virus and rhinovirus, respectively, suggesting that the two viruses may have interfered with each other. Source: 10.1073/PNAS.1911083116
This finding shows the frequency of concurrent infections from a host perspective and provides new evidence of positive and negative (antagonistic) interactions between viruses. Specifically, the analysis of the prevalence of each pair of viruses in the human population shows that there is a positive interaction between various human parainfluenza viruses that cause respiratory infections in infants and young children, and there is also a positive interaction between metapneumovirus and respiratory syncytial virus, which are easy to infect young children. Negative interactions between B virus and adenovirus, and between rhinovirus and influenza A virus, show negative interactions.
Rhinovirus infection is the cause of common colds, but studies have proven that it can block other viral infections. The team of Renee Chan, a cell biologist at the University of Chinese in Hong Kong, has studied the interaction between rhinovirus and influenza virus at the population, individual and cellular levels, proving that there is a negative interaction between the two. [10]
Effective virus detection tools allow us to see clearer patterns of viral off-peak outbreaks, and the development of organoid models provides a new platform for understanding the mechanisms of viral interference. Ellen Foxman's team, an immunologist at Yale University School of Medicine, used this technique to differentiate stem cells into tissues to form human airway epithelial cell organoids and conduct viral experiments. In papers published in 2020 and 2021 [11, 12], they reported their experimental method of infecting organoids with rhinovirus first, which can induce a rapid and powerful innate immune response. Foxman explains, "The perceptual factors produced by the body are able to detect structures common to many viruses and ignore specific details. Specifically, the immune system detects viral RNA, which prompts infected cells to secrete interferons, which act like alarms that warn surrounding cells that there is a virus nearby; Next, interferon upregulates interferon-stimulating genes (ISGs), which encode antiviral proteins, some of which "stop the virus from invading the cell," others "stop the virus from escaping the cell," and some simply shut down all cellular mechanisms so that the virus cannot proliferate.
Based on experimental and mathematical models, the researchers also proposed another theory [13]. They believe that viruses compete for infected cells, cell surface receptors or cell sources, and that direct competition between these viruses may also promote viral interference. In the host, such competition may be related to the immune response: the faster a virus replicates, the faster it can bring the host into an antiviral state, truly restricting the entry of the second and third viruses into and infecting the cellular environment, thereby gaining a real advantage in the competition.
In addition, whether one virus interferes with a second infection with other viruses depends on many other factors, some of which are related to the immune response itself: how the "offender" virus triggers the interferon response, how they respond, in addition to the timing of infection and the host's ability to make an innate immune response.
First, the innate immune response tends to be weak in people with poor physical conditions, such as pregnant women or older people, which raises another question: whether these groups are more likely to have concurrent infections.
Second, the timing of infection is also important: suppose someone gets the flu, the virus enters the lungs, and some tissues suffer damage as a result. Once all interferon effects have disappeared and the second virus has unfortunately been infected, the damaged tissue may still be in the recovery period. In this way, a second infection can make the situation worse, because weak tissues are more vulnerable.
Patterns and effects of virus interactions in the context of the new crown
Based on multiple existing findings, scientists agree that it is important to understand the mechanisms of viral interactions. Hana Dobrovolny, a computer biophysicist who studies viral infections at Texas Christian University, suggests that doctors and public health experts should track concurrent infections more closely because evidence suggests that concurrent infections do affect how the virus behaves in the human body and how severe the disease is. By understanding the frequency of concurrent infections and the associated clinical outcomes, scientists can use this information to improve and create new and effective interventions and treatment strategies
Therefore, tackling the co-transmission of the new coronavirus and other respiratory infections has always been a top priority in public health this winter. Given that the pandemic is only a two-year affair, we know very little about co-infections involving the coronavirus. But now that virus disruption experts are watching the topic closely, Murica said: "Until now, we didn't have particularly strong epidemiological data. "Prevention and control measures such as wearing masks and avoiding large crowds reduce the opportunity for scientists to observe the interference of the virus.
However, the angle of interferon, one of the immune markers, can provide scientists with some ideas. On the one hand, the new coronavirus itself has evolved many defenses to reduce the secretion of interferons type I and III in patients [14, 15], on the other hand, accumulating data also show that those with insufficient interferon secretion are particularly susceptible to infection with the new coronavirus, and the inflammatory response after infection intensifies and develops severe disease. [16-19] Based on this, the researchers wanted to further understand whether patients with a weak interferon response were more likely to develop concurrent infections, or whether their condition was more severe if they did.
Some epidemiological data and animal studies have shown that there may indeed be an interaction between influenza virus and the new coronavirus, affecting the clinical manifestations of patients. For example, a 2020 study published in the journal Clinical Infectious Diseases conducted animal experiments on Syrian golden hamsters infected with both the new coronavirus and influenza viruses, and found that the hamsters with concurrent infections lost more weight, had more severe inflammatory damage to the lungs, and expressed more cytokines/chemokines in tissues [20]. Subsequently, another study published in May 2021 in the International Journal of Epidemiology also showed that even though researchers observed a lower risk of influenza infection in patients with the new coronavirus, the clinical symptoms were much more severe if they were actually infected with both viruses at the same time than if they were infected with either virus alone [21]. However, Foxman's team [22] and Morica's team [23] started with rhinovirus, and found that infection with rhinovirus first, and then infection with the new coronavirus, accelerates the ISG response, thereby inhibiting the viral replication kinetics of the new coronavirus.
However, the number of such related studies is still small and the conclusions are mixed, so scientists have not yet fully understood the interaction between the new coronavirus and other viruses in real life and its consequences. This year is likely to be the first winter in the northern hemisphere to encounter the co-infection of the new coronavirus and other viruses, and the scientific team will need to continue to closely track the infection of the same population for the next many seasons to truly observe a clear pattern of the interaction between the various viruses.
Immunologists caution that this winter, viruses interfering with this mechanism may not have much protection against highly transmitted respiratory viruses. If it does, it could mean that "we are not peaking at the same time for each virus," and they may be peaking at each other. In any case, effective precautions need to continue to be taken, because as long as you are infected with any virus, you will get sick.
bibliography
[1] https://bestpractice.bmj.com/topics/zh-cn/1165
[2] https://www.who.int/publications/m/item/influenza-update-n-435
[3] https://www.cdc.gov/flu/weekly/index.htm
[4] https://www.zj.gov.cn/art/2022/11/2/art_1228996605_59924035.html
[5] https://www.science.org/content/article/competition-between-respiratory-viruses-may-hold-tripledemic-winter?cookieSet=1
[6] https://www.the-scientist.com/news-opinion/what-happens-when-you-catch-more-than-one-virus-70817
[7] https://www.eurosurveillance.org/content/10.2807/ese.14.40.19354-en
[7] https://www.pnas.org/doi/10.1073/pnas.1911083116
[9] https://www.pnas.org/doi/10.1073/pnas.1911083116
[10] https://www.sciencedirect.com/science/article/pii/S266651742200044X
[11] https://www.sciencedirect.com/science/article/pii/S2666524720301142
[12] https://rupress.org/jem/article/218/8/e20210583/212380/Dynamic-innate-immune-response-determines
[13] https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0155589
[14] https://www.sciencedirect.com/science/article/pii/S009286742030489X
[15] https://www.science.org/doi/full/10.1126/science.abc6027?cookieSet=1
[16] https://www.cell.com/med/fulltext/S2666-6340(20)30029-5?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS2666634020300295%3Fshowall%3Dtrue
[17] https://www.nature.com/articles/s41467-022-34895-1
[18] https://www.science.org/doi/10.1126/science.abd4570
[19] https://www.frontiersin.org/articles/10.3389/fimmu.2022.888897/full
[20] https://academic.oup.com/cid/article/72/12/e978/5995847?login=false
[21] https://academic.oup.com/ije/article/50/4/1124/6263422?login=false
[22] https://rupress.org/jem/article/218/8/e20210583/212380/Dynamic-innate-immune-response-determines
[23] https://academic.oup.com/jid/article/224/1/31/6179975?login=false
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