Catching the Cold

© OCEAN/CORBISThe common cold is usually nothing more than a temporary nuisance. Except for people who are highly immunosuppressed or have other serious conditions, colds—most commonly caused by very small RNA viruses known as rhinoviruses—are usually restricted to the cells lining the upper respiratory tract and tend to be limited in duration and symptoms. Nevertheless, with a global population exceeding one billion trillion (1021), rhinoviruses are arguably the most successful rapidly infecting viruses on Earth today. Despite their abundance, rhinoviruses have been relatively understudied by virologists and largely ignored by epidemiologists and virus modelers. Many mathematical methods for studying virus evolution and spread have provided key insights into the control of epidemics, but these efforts have concentrated on viruses such as HIV and influenza, and cannot be directly applied to the study of rhinoviruses. Unlike these more dangerous viruses, rhinoviruses did not jump recently from other animals to humans. They are human specialists that almost certainly evolved several times from the equally specialized enteroviruses that infect the gut. This means that rhinoviruses are highly adapted to humans, possibly explaining their low virulence—because they have had a chance to evolve efficient ways of spreading to many individuals without harming their hosts—and their high abundance as a consequence of this efficiency. Their expert ability to infect humans makes rhinoviruses a good model for understanding the process of adaptation. Indeed, a handful of recent studies of rhinovirus evolution have yielded insights into how the viruses manipulate the immune system and cause only limited damage to their hosts. Such information will not only help researchers understand one of the most common of all viral infections, but will also shed light on the emergence of deadlier diseases that likely share rhinoviruses’ mechanisms of evolutionary change. The evolving virus Studying population dynamics and evolution in plants and animals can require many years. With viruses, everything happens fast. Mutation rates are roughly 100,000 times higher than in humans,1 and population sizes, as we have seen, can be enormous. These factors combine to make ecological and evolutionary timescales converge, such that major evolutionary changes can occur during a single season—or even a single infection. QUICK AND DIRTY: Rhinoviruses are rapidly infecting viruses that are highly adapted to their human hosts, possibly explaining their low virulence and high abundance.© VISUALS UNLIMITED, INC./CAROL & MIKE WERNEREvolution in an RNA virus is also distinct from that of more traditionally studied organisms because of its tiny genome of single-stranded RNA. Rhinoviruses, for example, carry just 10 genes. Because viruses cannot survive and reproduce on their own, they are especially dependent on their environment, which for rhinoviruses is the epithelial cell of a host’s throat. This home provides not just resources and protection, but also an “extended genotype” of host genes that do most of the virus’s work for it. These special characteristics of small RNA viruses have many consequences beyond speeding evolution. These viruses show an odd mix of carefulness and carelessness. They have tidy genomes with no “junk DNA,” and thus a much higher probability that mutations will have a noticeable effect. This high-stakes evolution, in which a single bad mutation can mean the end, is counterbalanced by huge populations that can tolerate many individual failures. A swarm of viruses probably explores more evolutionary space than any other evolving entity, as seen in the rapid evolution of resistance to antiviral therapies in patients with HIV. In fact, there may well be more viruses in a single common cold infection than there have been primates in the entire history of life on Earth. There may well be more viruses in a single common cold infection than there have been primates in the entire history of life on Earth. Finally, the simplicity that stems from the small physical size of viruses also changes how we think about the process of evolution. A mutation in a virus, as in all organisms, changes one molecule. Understanding the fitness effects of a mutation requires understanding how the biochemical change translates into survival and reproduction. Because small viruses like rhinovirus are little more than a few molecules themselves, it is far simpler to track the consequences of mutation than those of, say, a single nucleotide change in a neurotransmitter in the brain of a large, intelligent social mammal. Rhinoviruses thus provide a tractable and quickly evolving system by which researchers can probe the evolution of host and pathogen—and the coevolution of the two. The rhinovirus switch The jump from enteroviruses, which cause acute infections in the human gut, to rhinoviruses that are specialized in attacking the upper respiratory tract involved a series of biochemical changes to the capsid proteins encasing the mature virion. These changes rendered the gut-resident viruses sensitive to the low pH of the digestive tract, most likely forcing the subset that became the rhinoviruses into a new niche. It is unclear when these transitions occurred, due to the viruses’ high mutation rates and the obvious lack of a fossil record even in preserved human remains. Indeed, how long rhinoviruses and their ancestors have been causing misery to humans is almost impossible to establish. It may be that rhinoviruses are a pathogen of civilization, previously unable to persist in the small and relatively isolated groups that predated agriculture and urbanization. Alternatively, rhinoviruses may have been infecting humans since before the dawn of Homo sapiens sapiens. There are roughly 100 different rhinovirus serotypes that, until a couple of years ago, were thought to comprise only two species: HRV-A and HRV-B. Recent genetic testing revealed a new species of rhinovirus, however, called HRV-C, which fails to grow in cell culture and thus could not be detected using earlier methods.2 Rhinoviruses can also be categorized by the receptors they use to enter cells. The major group, which consists of about 90 members and includes all HRV-B and the majority of HRV-A serotypes, binds to the cell surface receptor ICAM-1 for entry, while the minor group, which consists of just 12 or so HRV-A viral serotypes, binds to the unrelated low density lipoprotein (LDL) receptor. (It is not yet known which receptors HRV-C viruses bind to enter host cells.) Minor-group viruses appear to have evolved from major-group viruses, and then diversified. Since this initial diversification, however, the number of minor-group serotypes and the frequency of minor-group virus infections has remained fairly constant over the decades. This is despite—or perhaps because of—the fact that minor-group viruses interact quite differently with the immune system. (See illustration below.) RHINOVIRUSES AND THE IMMUNE SYSTEM View full size JPG | PDFTHE SCIENTIST STAFFIn addition to the epithelial cells targeted by rhinoviruses, the ICAM-1 molecule used by major-group rhinoviruses is expressed on many other types of human cells, including macrophages and dendritic cells, which play critical roles in initiating, amplifying, and controlling the immune response. The major-group viruses don’t actually infect these host immune cells, but they can alter the cells’ behavior just by attaching to the ICAM-1 receptor, which is upregulated when the immune response begins.3 Viral attachment stimulates these immune cells to produce anti-inflammatory signals, and also makes them travel more slowly to the lymph nodes where they activate the T cells that fight the invaders. Major-group rhinoviruses thus delay a full-on immune attack. These viruses also create delayed and ambiguous signals, slowing and reducing the production of antibodies and memory B and T cells that protect the host against reinfection. Minor-group rhinoviruses, on the other hand, do not, in any way that we know, suppress the immune system. On the contrary, infections with minor-group viruses involve a more enhanced immune response. For example, when we reanalyzed antibody levels recorded in 1985 by John Fox and colleagues at the University of Washington in Seattle 1 year after initial infection,4 we found that major-group viruses induced antibodies in only a fraction of infected individuals, while most patients produced antibodies in response to infections with minor-group viruses. By eliciting a stronger immune response, minor-group viruses should be at a distinct competitive disadvantage. The phylogeny indicates, however, that the minor-group strategy has arisen at least three times within the HRV-A species, indicating some counterintuitive selective advantage. It’s possible that if multiple infections are sufficiently common, minor-group viruses might capitalize on the ability of major-group viruses to suppress the immune response. Alternatively, minor-group viruses may escape immune attacks by evolving more rapidly than major-group viruses. Indeed, amino-acid changes have occurred most commonly among minor-group serotypes, and often close to places in the genome that encode the regions of capsid receptor proteins where antibodies bind, presumably allowing the viruses to evade antibody detection.5 The common cold has proven stubbornly resistant to treatment and prevention. Furthermore, because the symptoms of infection are predominantly caused by the immune system’s reaction, rather than by the viruses themselves, the fact that minor-group viruses elicit a stronger immune response could mean they are more virulent. Although no data yet exist to examine this in detail, high virulence could lead to more effective transmission as a result of the damage inflicted on the host. One new approach to better understand viral infections is to model the experience from our own perspective—namely, the progression of symptoms—rather than that of the virus. To date, only a few models have attempted to predict the symptoms produced by acute upper respiratory tract viruses, and those have focused on influenza. Similar models of rhinovirus infections could quantify the components of host damage and the host immune system that lead to particular symptoms, and thus could pave the way to study a whole range of questions: How do partial immunity, coinfection, and prior infection alter symptoms? What treatments might be most effective in alleviating symptoms, and what effects might those treatments have on viral reproduction and transmission? Because they are so common, rhinovirus infections could serve as a natural experiment to test these models, and could eventually inspire new treatments that direct the immune system into more effective response pathways. Swapping out receptors Rhinoviruses may also shed light on the sometimes shadowy link between microevolution and macroevolution. Some small changes, of perhaps a single amino acid in a viral protease, might do little more than alter the rate of viral replication. Others, like the target receptor change that characterizes the switch from major to minor group, alter the very way that viruses overcome one of their central challenges—entering a host cell. We have seen that all members of HRV-B bind the same ICAM-1 receptor, while minor group members of HRV-A bind the alternative LDL receptor. This is quite different from the rest of the enterovirus genus, which as a group uses a panoply of receptors. FROM GUT TO THROAT: Rhinoviruses evolved from gut-specialized enteroviruses to infect the upper respiratory tract (artistically illustrated here) of its human hosts.© DAVID MACK/SCIENCE SOURCEReceptor usage plays a central role in determining the course of infection. Some members of the human enterovirus C species use the ICAM-1 receptor for entry, much like major-group rhinoviruses, and the two groups follow a similar course of infection despite their somewhat distant relationship. Other enteroviruses, such as the polioviruses, use the receptor CD155, which determines the type of cells these potentially deadly viruses are able to attack. It has been speculated that the eradication of polio could open up a niche, and favor one of the virus’s close relatives to make the same receptor switch.6 As we have seen with the minor-group rhinoviruses, receptor switches might provide opportunities for new adaptive radiations. In addition to understanding how these particular viruses evolve to inhabit different regions of the human body, tracking changes in the viruses’ targeted receptors may also provide insight into how the virus switches species. Specialized as enteroviruses and rhinoviruses are today, changes in host surely occurred at some point in the distant past, and those jumps were likely supported by changes of the receptor to which the viruses bind. While host species switches are rare and isolated events, and thus notoriously difficult to study, receptor switches are relatively common events within the enterovirus family and appear to parallel host switches. Indeed, in both host and receptor switches, we expect some degree of initial maladaptation—first creating severe symptoms that in no way aid viral transmission. But should these viruses succeed in making the change, whether it be to a new host organism or a new target receptor, they will then rapidly adapt and diversify, possibly accruing changes in virulence. Where next? Although neglected in comparison with viruses causing more severe infections, such as influenza and HIV, rhinovirus infections do create a serious public-health burden, forcing people to miss work, leading to wrongly prescribed antibiotics, and occasionally resulting in medical complications. And in the modern era, the common cold has proven stubbornly resistant to treatment and prevention. In spite of vast changes in science and society, the frequency of colds has remained pretty much constant over the last half century. The promising drug pleconaril, originally developed by the pharmaceutical company Sanofi-Aventis in 1995, caused a modest reduction in the duration of symptoms in rhinovirus and enterovirus patients during Phase II trials, but was not used widely after 2002 because of side effects and interactions with other drugs.7 Given rhinoviruses’ high diversity and low medical profile, developing a vaccine seems quixotic at best and dangerous at worst, because it has been speculated that rhinovirus infections early in life could play a role in inhibiting infection by more-severe upper respiratory tract viruses or in training the immune system.8 Asthma is probably the most important clinical side effect of rhinovirus infection; the virus is implicated in two ways. First, severe rhinovirus infections that cause wheezing in infants predict later asthma, although the causal factor appears more likely to be allergic sensitivity, which may increase the risks of both infection and asthma.9 Second, rhinovirus infections trigger many asthma exacerbations in children. Patients with cystic fibrosis are also highly sensitive to rhinovirus infections. These patients suffer from chronic bacterial lung infections, and the immunosuppressive effects of rhinovirus could release the bacteria from control.10 In both cases, understanding the ways in which rhinovirus manipulates the immune system is crucial. Modern genetic techniques are making it possible to sequence the entire rhinovirus genome from individual patients, and to link viral sequences with symptoms collected using Internet-based tools. In combination with mathematical models, this places us in a position to look in detail at the way small changes in the viral genome translate into consistent patterns of symptoms. If we can figure out which rhinovirus serotypes cause the most severe pathology, and link those to genetic mechanisms, we will have new targets for controlling the worst infections. Fred Adler is a professor of biology and mathematics at the University of Utah. References 1. J.W. Drake, J.J. Holland, “Mutation rates among RNA viruses,” PNAS, 96:13910-13, 1999. 2. K.E. Arden, I.M. Mackay, “Newly identified human rhinoviruses: molecular methods heat up the cold viruses,” Rev Med Virol, 20:156-76, 2010. 3. S. Kirchberger et al., “Modulation of the immune system by human rhinoviruses,” Int Arch Allergy Immunol, 142:1-10, 2007. 4. J.P. Fox et al., “Rhinoviruses in Seattle families, 1975-1979,” Am J Epidemiol, 122:830-46, 1985. 5. N. Lewis-Rogers et al., “Phylogenetic relationships and molecular adaptation dynamics of human rhinoviruses,” Mol Biol Evol, 26:969-81, 2009. 6. E. Rieder et al., “Will the polio niche remain vacant?” Dev Biol (Basel), 105:111-22, 2001. 7. W.G. Nichols et al., “Respiratory viruses other than influenza virus: impact and therapeutic advances,” Clin Microbiol Rev, 21:274-90, 2008. 8. R.M. Greer et al., “Do rhinoviruses reduce the probability of viral co-detection during acute respiratory tract infections?” J Clin Virol, 45:10-15, 2009. 9. D.J. Jackson et al., “Evidence for a causal relationship between allergic sensitization and rhinovirus wheezing in early life,” Am J Respir Crit Care Med, 185:281-85, 2012. 10. M. Vareille et al., “Impaired type I and type III interferon induction and rhinovirus control in human cystic fibrosis airway epithelial cells,” Thorax, 67:517-25, 2012.

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