Viruses: the Ugly, the Bad, and the Good

Some of these biological agents are being recruited  to combat bacterial infections.

Although this 3-D rendering shows a nerve cell being attacked by virus, scientists are finding viruses (bacteriophages) that can be targeted to compromise the defenses of infection-causing bacteria and make them less resistant to antibiotics.

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By every measure, viruses are the most successful inhabitants of the biosphere—abundance, environmental tolerance, biodiversity, reproductive capacity, and impact on organisms. Colleague and fellow evolutionary biologist Brian Wasik and I came to this conclusion some years ago, based on evidence from our own empirical studies with RNA viruses and on metrics that are, admittedly, difficult to assess, such as relative evolvability and persistence in the face of extinction. We reported these findings in a  paper, “On the Biological Success of Viruses,” in the June 28, 2013 Annual Review of Microbiology.

Bacteria and viruses compete for the title of being the oldest members of Earth's biosphere, roughly 3 to 4 billion years; however, the timing of the evolutionary origin of each is debated and hard to pinpoint. Although bacteria often achieve large population sizes in a wide variety of niches, numbering overall perhaps 1030 individuals at any one time, bacteria-specific viruses, alone—the bacteriophages, or “eaters of bacteria”—are numerically superior. In particular, surveys from aquatic environments (especially the oceans) demonstrate that viruses tend to exceed their unicellular hosts by at least an order of magnitude. Thus, just counting phages in the virosphere, there are perhaps 1031–1032 individual viral particles in the world. Eukaryote cells reproduce quickly, bacteria are faster, but viruses are the fastest. 

Viruses appear to occupy every possible environmental niche that can support life and seem very capable—if not more capable than cellular organisms—of adapting in the face of environmental changes. They are often challenged by host immune systems and evolving resistance and by environmental fluctuations in temperature, moisture, and other stressors. Despite these challenges, or perhaps because of them, viruses quickly adapt, and the novel viruses that readily emerge are increasingly problematic for humans and other hosts. The repercussions of this adaptability extend beyond the viral world. Owing to the prevalence of virus-host interactions, viruses can strongly impact which host types dominate populations and communities, in turn affecting all evels of biological organization, from host-genome composition to ecosystem function.

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Although primarily submicroscopic, some newly discovered viruses are larger than some of the smallest-size cells (e.g., Acanthamoeba polyphaga mimivirus compared to, say, Mycoplasma gallisepticum, which is a parasite that infects certain organs). In the past, macroscopic viruses had been overlooked because of the filtration process that researchers traditionally use. Anything that passed through a very small pore size was assumed to be a virus, and anything that was held back must be cellular or cellular debris. By increasing the pore size of the filters, these large-sized viruses have been found off the coast of Chile and in 30,000-year-old ice cores in Siberia, which indicates that they are nothing new.   

Viruses are not composed of cells; they are, therefore, not typically considered alongside other biological entities (e.g., on the universal tree of life). This omission is due to a dichotomy between fundamental body plans; a virus is generally composed of nucleic acid surrounded by a protein shell (capsid), whereas cellular life consists of ribosome-encoding organisms. Viruses may be “devolved” cellular ife, having evolved as parasites within cellular genomes, becoming simpler over time, and later gaining the ability to move between hosts. Whatever the history, viruses and cellular organisms play by the same evolutionary rules: the processes of spontaneous mutation, natural selection, genetic drift, etc. The relative simplicity of viral genomes and life cycles provides tractable opportunities to understand how evolution proceeds in response to selective challenges.

3,400-year-old Egyptian stele depicts a man known as Roma the Doorkeeper, whose shriveled leg suggests he was a survivor of paralytic polio. Roma is making an offering to the goddess Astarte for a decent burial of his spirit.

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There are no inherently good, bad, or ugly viruses. The drive behind all organisms is to live and propagate. The huge success of some viruses, however, has had a devastating impact on hosts and, in some instances, has changed the course of human history. Take the poliovirus, for example. Early evidence of the virus was found on a 3,400-year-old Egyptian stele that depicts a man with a shriveled leg, symptomatic of paralytic poliomyelitis [see “Polio’s Last Stand?” by Michael J. Toole, Natural History, September 2017]. Also, a medical examination of the remains of the Egyptian pharaoh Siptah (reign c.1197–1191 BCE) revealed a deformed left foot, presumedly from polio. The examiner determined that the pharaoh died at the age of sixteen.

Polio as an epidemic, however, wasn’t known to have occurred until the Industrial Revolution. The concentration of people in urban areas and, some contend, improved hygiene created conditions that helped the spread of the disease. The surge in the United States in the mid-twentieth century was stopped by the introduction of the Salk vaccine in 1955 and the Sabin vaccine in 1961. Yet, according to Toole, “in 1988 polio was endemic in more than 125 countries and paralyzed or killed 350,000 people, mainly children, every year.” In 2017, the number of new cases reported of naturally caused paralytic polio was down to eight. As tempting as it is to declare defeat over this “ugly” virus, it may be premature, given the survival success rate of viruses.

Historically, smallpox, caused by the variola virus, has perhaps been the most dreaded viral disease because of its high human death toll—one third of those infected—and because of its disfiguring effect on survivors. Another Egyptian pharaoh, Ramses V, (reign c.1150-1145 BCE) also died at a relatively early age, apparently from smallpox. There is evidence that the disease was in China, India, and northeastern Africa 3,000 years ago and in Europe 1,800 years ago [see “Stamping Out Smallpox” by William H. Foege, Natural History, September 2017]. The introduction of the disease to North and South America by Europeans decimated indigenous inhabitants who had no background immunity. Even though British medical practitioner Edward Jenner discovered in the late nineteenth century that people inoculated with the milder cowpox virus were immune to smallpox, the disease still killed over 300 million people in the twentieth century. Since an aggressive global eradication program was started by the World Health Organization (WHO) in 1959, the world is now free of any reported cases of smallpox. Samples of the live virus, however, are still in storage.

A research team in Liberia samples bats for Ebola.

COURTESY OF ECOHEALTH ALLIANCE

The line between ugly and bad viruses is sometimes blurred. The influenza epidemic of 1918-1920 was deadly, killing 20-100 million people worldwide. New strains of the influenza virus, types A, B, and C, evolve every year and the virus still takes its annual death toll, but through vaccines and better health care it has been stopped from reaching the mortality rates seen in the early 1900s. Likewise, the AIDS epidemic—which has afflicted 78 million people and killed half of them since it was recognized in 1981—is no longer a death sentence because a cocktail of drugs can now contain the HIV retrovirus from victims with the disease.

Despite human successes in combating some of our known viral enemies, unsuspecting viruses can “jump” directly, or indirectly—as has happened in the past—into humans from other host species and cause lethal diseases (e.g., the Zika virus transmitted by the Aedes aegypti mosquito from Rhesus macaques).

Probably the most successful viruses are those we categorize as bad; they generally don’t kill, but they can make us sick and they resist concerted attempts to control or eradicate. The 200 plus species of rhinovirus are the usual cause of the common cold. They thrive at the temperature inside our nose (31–33° Celsius)—thus, the name “rhino” from the Greek word for nose—and they cost sufferers billions of dollars in medications for cold symptom relief and work days lost.

For children under the age of five, rotavirus is the leading cause of severe diarrhea. Many children in the United States are infected at least once. The disease is untreatable, but there is a vaccine, and rehydration therapy is needed as the disease runs its course. Worldwide, however, rotavirus accounts for 450,000, or 5 percent, of childhood deaths. In sub-Saharan Africa, Pakistan, and Bangladesh—where there is lack of access to clean drinking water for rehydration therapy and to health care facilities to administer the therapy—the death rate is 100 to 1,000 deaths per 100,000. So, depending on your resources and where you raise your children, rotavirus is either bad or truly ugly.

The mumps virus protein called small hydrophobic protein (turquoise) can be seen here in the endoplasmic reticulum of a cultured cell. This is a region of the cell that processes proteins. This particular protein is possibly involved in determining how effectively the virus can infect people.

THE SCIENCE MUSEUM, LONDON

Good viruses have never received the recognition they deserve. While bacteria account for the bulk of microorganisms in our microbiome, there is a virus component, or virome, to our microbiome. The results of a recent study suggest that some of these viruses are interacting with our body to keep us healthy. For example, phages, which cannot infect our cells, can interact with our mucus layers and provide a barrier from bacterial infection. These phages are oriented in such a way that their tail fibers interact with bacteria and prevent them from getting to the mucus layer and transiting through to our cells. The phages provide a line of defense against the bacteria, because the phage will attach, replicate, kill the bacteria, and exit the cell. We don’t know whether this phage interaction with macroorganisms is an adaptation that has evolved, or whether it’s because phages are everywhere, and sometimes they’re in the right place to take advantage.

As an integral part of our body, versus being on or in our body, 8–18 percent of our DNA—segments of genetic material called transposons—are believed derived, in some cases, from viruses. We wouldn’t be who we are today if transposons hadn’t been able to jump from position to position within our genome and effect our evolutionary pathway. And none of us might be here if endogenous retrovirus genes (ERVs) didn’t enable us at the fetal stage to survive our mother’s immune system.

During pregnancy in viviparous mammals—which are all mammals except egg-laying monotremes—ERVs are activated and proliferate during the implantation of the embryo. They act as immunodepressors. Also, viral fusion proteins apparently cause the formation of the syncytium—the outer cell layer of the placenta—in order to limit the exchange of migratory cells between the developing embryo and the body of the mother (something an epithelium will not do sufficiently, as certain blood cells are specialized to be able to insert themselves between adjacent epithelial cells). ERVs are derived from viruses similar to HIV. The immunodepressive action was the initial normal behavior of the virus; similar to HIV, the fusion proteins were a way to spread the infection to other cells by simply merging them with the infected one (HIV does this too). It is believed that the ancestors of modern viviparous mammals evolved after an infection by this virus, enabling the fetus to survive the immune system of the mother. However, there is an ugly side to human relationships with the ERVs in our chromosomes: some ERVs may be contributing agents for such diseases as cancers, multiple sclerosis, and diabetes, although these possibilities are not yet confirmed and constitute active areas of ongoing research.

Viruses play a vital role controlling the balance of ecosystems. Half the oxygen in the atmosphere is produced by cyanobacteria in the ocean. Cyanophages, which live alongside cyanobacteria and outnumber them by about ten to one, prey on the bacteria, killing an estimated 20 percent each day. Not that long ago, it was discovered that cyanophages have genes that allow photosynthesis to occur, which is strange, because viruses don’t undergo metabolism. What are they doing with photosynthesis genes? It starts to make sense when we think about the virus life cycle and the necessity to keep cyanobacteria cells going and churning through their metabolism, while viruses are undergoing replication—a process that ultimately destroys the cyanobacteria. Bringing in photosynthesis genes to cyanobacteria cells is like adding fuel to the process. A net result: an estimated 5 percent of the oxygen in the atmosphere is indirectly produced by cyanophages.

Over the years, humans have exploited, or tried to exploit, viruses. A strain of the myxoma virus, which causes myxomatosis (“white blindness”), usually a disease fatal to rabbits, was introduced in Australia in the 1950s to control exploding wild rabbit populations. According to the World Organization for Animal Health, the virus “reduced the rabbit population from 600 million to 100 million in a period of two years. Since then, however, with natural selection of increasingly resistant animals, the mortality rate is below 50 percent, and the rabbit population in Australia has rebounded to 200 million.”

Recently, a group of scientists at Washington University School of Medicine in Saint Louis, MO and at the University of California, San Diego School of Medicine, and colleagues at other affiliated institutions found that the Zika virus “(ZIKV) preferentially infected and killed [the highly lethal brain cancer] glioblastoma stem cells relative to differentiated tumor progeny or normal neuronal cells.” The study’s findings were published in the 5 September 2017 issue of The Journal of Experimental Medicine. The researcher feel that if strains of the virus are genetically modified to further optimize safety, the virus “could have therapeutic efficacy for adult glioblastoma patients.”

Color enhanced transmission electron microscope image of T4 bacteriophages attacking host (Escherichia coli).

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A long-running and significant use of viruses—specifically, bacteriophages—started in the Soviet era in Russia and has been going on ever since—parallel to Western pursuits of antibiotics. According to Dmitriy Myelnikov, at the University of Manchester, in an October 12, 2018 paper “An Alternative Cure: The Adoption and Survival of Bacteriophage Therapy in the USSR, 1922–1955,” (Journal of the History of Medicine and Allied Sciences), Canadian microbiologist “Félix d’Hérelle coined the term bacteriophage in 1917 to characterize a hypothetical viral agent responsible for the mysterious phenomenon of rapid bacterial death. While the viral nature of the ‘phage’ was only widely accepted in the 1940s, attempts to use the phenomenon in treating infections started early. After raising hopes in the interwar years, by 1945 phage therapy had been abandoned almost entirely in the West, until the recent revival of interest in response to the crisis of antibiotic resistance.”

Part of the reason for the flagging interest in phage therapy in the West was due to the lack of English-language literature on results in Russia and in other Eastern European countries where the research was being conducted. Also, in the West where phage therapy was being tried, there was a lack of randomized control trials. Beginning in the late 1990s, however, Western interest in bacteriophage therapy has been steadily building and randomized control trials are now being carried out.

In my lab, we have focused on finding phages to combat multi-drug-resistant bacteria (MDR), which traditionally have been prevalent in hospitals, nursing homes, and among people with implants but are now becom-ing community-associated. We recognize that bacteria will inevitably develop phage resistance just as they are doing with antibiotics, but our strategy is to turn evolution in our favor—to force bacteria to make tradeoffs between their virulence and their resistance to phage attacks.

In 2016 in a lake in Connecticut, we discovered a phage, OMKO1, that binds to the efflux pumps of  Pseudomonas aeruginosa—a priority pathogen on the WHO list of antibiotic-resistant pathogens. According to the Centers for Disease Control and Prevention, “patients in hospitals, especially those on breathing machines, those with devices such as catheters, and patients with wounds from surgery or from burns are potentially at risk for serious, life-threatening infections.”

Visualization of OMKO1

MATT CIRIGLIANO
Efflux pumps are transport proteins in the cell membrane that expel toxic substances from the cell, including antibiotics. We devised a therapeutic mixture of phage OMKO1 with an antibiotic, which forced Pseudomonas aeruginosa to give up the efflux pump in order to resist an attack from OMKO1, thereby making the antibiotic more effective. Although we do not have approval by the Food and Drug Administration to conduct clinical trials, we do have their approval to provide experimental therapy as compassionate care for patients with life-threatening illness who have not responded to all other treatments.

To date, we have successfully treated eight patients with different phage antibiotic combinations. For one patient with an artificial aortic arch that was colonized by MDR P. aeruginosa, we used a cocktail of the antibiotic ceftazidime and phage OMKO1, directly administered nearby the bacterial infection. The patient recovered completely without side effects. We used a similar strategy, but as an inhaler in the second case to treat a patient with cystic fibrosis and failing lung function caused by infecting pan-drug-resistant P. aeruginosa. She saw radical improvement and stabilization in lung function coupled with re-sensitization of her predominant strain to most chemical antibiotics. For a patient with chronic obstructive pulmonary disease in the Medical Intensive Care Unit (MICU), we treated infecting MDR P. aeruginosa with phage H6 for ten days administered through a nebulizer, and saw quick response, allowing him to be transferred out of the MICU. And for a fire-fighter who was diagnosed with bronchiectasis following massive smoke inhalation in a building fire over 40 years ago, we used phage H6 plus antibiotics to cure him of his chronic (over six years) MDR P. aeruginosa infection.

In the future, we hope to develop phage therapy approaches for treating infections caused by all bacteria on the WHO list of priority pathogens. We continue to train students, researchers, and physicians around the world about developing new strategies for phage therapy, as we search with them for potentially useful phages in Haiti and other islands in the Caribbean, in East Africa, on refugee trails, and at sewage treatment plants in the United States.

--PET