Most people are aware of some of the tools that help us fight pandemics: safe and effective vaccines, antiviral drugs and antibody treatments, and for respiratory infections like COVID, public health measures like masks.
But they overlooked one tool that could help us prevent the next pandemic: zombie viral genomes.
Zombie viruses are injured byproducts of a viral infection that cannot reproduce without help. They are interesting from a therapeutic point of view because they seem to do several things to reduce disease: they make the immune system work and, without adding to the diseases themselves, they suck out some of the mechanisms that their active counterparts use to copy themselves during infection. They also hide in the proteins that normally wrap viral genomes, resulting in virus-like particles which can indicate when their operational counterparts are distributed. A better understanding of how these zombies work could allow researchers like me to develop zombies as treatments so that when the next pandemic hits, we can give people medicinal zombies to keep them from getting really sick.
Viruses reproduce by multiplying at lightning speed inside the cells they infect. However, for the viral machinery that creates copies of the virus genome that are packaged into new particles, this rapid production can be disruptive. This is often because the machine lacks a proofreading mechanism that scans the copied genome for errors, but even viruses that can proofread make mistakes. When these malfunctions occur, the machine introduces mutations, such as those that led to the highly infectious variants of SARS-CoV-2, such as Delta and Omicron. But even bigger mistakes often happen, creating zombie genomes that lack the replication or packaging functions a virus needs to infect productively. So when a zombie’s genome is packaged and this crippled viral particle enters a healthy host cell, it appears dead, unable to copy itself and create new zombies.
But when the genome of a zombie virus is delivered to a cell that is already infected with a fully functional virus, then, like a zombie, it can come to life. It does this by rewiring the viral engineering of functional viruses to self-replicate, creating virus-like zombies that can grow and spread, often at the expense of the infectious virus. Thus, a zombie infects, co-opts the replication machinery of active viruses like a parasite, and at least does not appear to exacerbate an ongoing viral disease.
Take, for example, the flu virus. Molecular virologist Ana Falcon from the National Center for Biotechnology in Spain found the links between zombie virus genomes and disease severity. People with more zombie flu genomes avoided intensive care, while those with fewer zombie genomes suffered more severe illness, sometimes ending up in the hospital and dying. Having more zombie genomes can trigger protective immune responses, leading to less severe disease.
Zombie virus genomes associated with other respiratory infections are also associated with disease severity, but the results can be both good and bad. Immunologist Carolina Lopez of Washington University in St. Louis showed that the presence of zombie virus genomes in the early stages of respiratory syncytial virus infection, during the first three days of infection and one to two weeks, was associated with overall lower viral load and less severe disease. However, the continued presence of zombie virus genomes beyond 6 days post-infection was associated with higher total virus levels, greater activation of immune responses, and greater disease severity. Together, these results indicate a potentially complex role for zombie viruses in disease severity, depending on their effects on both virus production and immune activation.
What about zombie SARS-CoV-2, the RNA virus that causes COVID? So far, researchers have performed genetic analysis of countless nasal swabs from people with COVID around the world to discover Delta, Omicron and many other options. But to make these discoveries, the researchers sequenced full-length RNA genomes; defective or incomplete viral genomes can complicate assays, so they are usually ignored or discarded. For us zombie virus researchers, these defective genomes are a gold mine.
Genomics expert Chia-Lin Wei of the Jackson Laboratory in Connecticut has identified several hundred candidate zombie viral genomes found in swabs from people with COVID. Some zombie genomes carried deletions that were exclusively associated with symptomatic or asymptomatic COVID. Symptoms of the disease, such as tissue inflammation, can be associated with cellular defenses that cause virus-producing cells to kill themselves, so zombie viruses that cannot induce such defenses cannot cause inflammation either, and their infections are asymptomatic. For viruses, the ability to cause mild or asymptomatic disease can be useful, allowing its human hosts to interact with others on a daily basis and spread the virus more widely.
For now, such observations raise more questions than answers. How do SARS-CoV-2 zombie viruses arise and how do they affect the severity of COVID-19 in individuals? What role will zombie viruses play in the behavior of the current pandemic in the coming months or years? More broadly, what role might zombie viruses play in diseases caused by other viruses that can cause pandemics like Ebola, influenza, or Zika? And how can we use zombies to protect against future pandemics caused by new viruses?
Given the protection that zombie viruses can provide, it’s reasonable to believe that they could help treat COVID-19 or another viral infection of a future pandemic. Virus expert Leor Weinberger of the University of California, San Francisco recently developed SARS-CoV-2 zombie particles and showed their protective effect against infection in hamsters. Importantly, zombie particles reduced the severity of a COVID-like illness when given before or after infection. Longer-term studies have shown that such particles can protect against variants such as Delta, Omicron and others. Finally, virologist Raul Andino, also at UCSF, discovered this polio virus zombie genomes can stimulate immune responses in mice and protect the infected from infection not only with the polio virus, but also with influenza and SARS-CoV-2.
These findings provide exciting evidence for the holy grail of vaccine development: broad protection against a variety of viruses. To grow and spread, all viruses reprogram their host cells to make viral proteins; infected cells respond by activating defenses to slow or stop production of these proteins. Viruses contribute to the escalation of the arms race by inhibiting the signals cells use to slow or stop the production of proteins. Recent studies in mice show that zombie genomes can eventually give cells the upper hand by shutting down the production of proteins needed for viruses to grow and spread.
If zombie genomes can stimulate protective immune responses not only in mice but also in humans, a single dose may one day protect us from new variants of the flu virus, the coronavirus, or other viruses. More safety and efficacy studies will be needed to assess the ability of engineered zombie particles to treat or prevent disease before they can be considered for human use. At the moment, zombie viruses offer an interesting new idea to protect against future pandemics.
This is an opinion and analytical article and the views expressed by the author or authors do not necessarily reflect the Scientific American.
