Most people know of some of the tools that help us fight pandemics: safe and effective vaccines, antiviral and antibody treatments, and for respiratory infections such as COVID, public-health measures such as masks.
But they have overlooked one tool that might help us prevent the next pandemic: zombie viral genomes.
Zombie viruses are the crippled byproducts of viral infection that can’t reproduce without help. They are intriguing from a therapeutic perspective because they seem to do several things to lessen disease: they prompt the immune system to act, and, without adding to disease themselves, they suck up some of the machinery that their active counterparts use to copy themselves during an infection. They also cloak themselves in proteins that normally wrap around viral genomes, resulting in viruslike particles that can tag along when their operational counterparts spread. A better understanding of how these zombies work could allow researchers like me to engineer zombies as treatments so that when the next pandemic virus hits, we can give people medicinal zombies to keep them from getting really sick.
Viruses multiply by replicating themselves with lightning-fast speed inside the cells they infect. For the viral machinery that makes copies of the virus’s genome that get packed into new particles, however, this speedy production can be glitchy. This is often because the machinery lacks a proofreading mechanism that scans that copied genome for mistakes, but even the viruses that can proofread make mistakes. When these glitches happen, the machinery introduces mutations, like ones that gave rise to highly contagious SARS-CoV-2 variants such as Delta and Omicron. But even bigger gaffes often occur, creating zombie genomes that lack the replication or packaging functions a virus needs for productive infection. So when the zombie genome is packaged and that crippled viral particle enters a healthy host cell, it appears dead, unable to copy itself and make new zombies.
But when a zombie viral genome is delivered into a cell that is already infected by a fully functional virus, then—like a zombie—it can spring to life. It does this by diverting the viral machinery of functional viruses to replicate itself, making virus-like zombies that can grow and spread, often at the expense of infectious virus. So, the zombie infects, co-opts the replication machinery of active viruses like a parasite, and at a minimum, seems to not make the ongoing viral illness worse.
Take the influenza virus, for example. Molecular virologist Ana Falcón at the National Center for Biotechnology in Spain has found links between zombie viral genomes and the severity of disease. People who carried more influenza zombie genomes avoided intensive care units, while those who carried fewer zombie genomes suffered from more severe disease, sometimes ending up in the hospital and dying. Having more zombie genomes can trigger protective immune responses, leading to less severe disease.
Zombie viral genomes associated with other respiratory infections are also linked to disease severity, but the outcomes can be good or bad. Immunologist Carolina López at Washington University in St. Louis showed that the presence of zombie viral genomes early in respiratory syncytial virus infection, during the first three days of a one- to two-week infection, was linked to overall lower virus levels and less severe disease. Yet the prolonged presence of zombie viral genomes, beyond six days of infection, has been associated with higher overall virus levels, greater activation of immune responses, and greater severity of disease. Together, these results indicate potentially complex roles of zombie viruses in the severity of disease, depending on their effects on both virus production and immune activation.
What about zombies of SARS-CoV-2, the RNA virus that causes COVID? By now, researchers have genetically analyzed countless nasal swabs from people with COVID across the globe to reveal Delta, Omicron and many other variants. But to make these discoveries, the researchers have sequenced full-length RNA genomes; defective or incomplete viral genomes can complicate analyses, so they are typically ignored or discarded. For us zombie virus researchers, these defective genomes are a goldmine.
Genomics expert Chia-Lin Wei of the Jackson Laboratory in Connecticut has discovered several hundred candidate zombie viral genomes occurring in swabs from people with COVID. Some zombie genomes carried deletions that were linked exclusively to either symptomatic or asymptomatic COVID. Disease symptoms like tissue inflammation can be linked to cell-level defenses that trigger virus-producing cells to kill themselves, so zombie viruses that fail to trigger such defenses also fail to cause inflammation, and their infections are asymptomatic. For viruses, the ability to cause mild or asymptomatic disease can be beneficial, allowing its human hosts to go about their daily interactions with others and more widely spread the virus.
For now, such observations raise more questions than answers. How do zombie viruses of SARS-CoV-2 arise, and how do they affect the severity of COVID-19 in individual people? What roles will zombie viruses play in the behavior of the current pandemic in the coming months or years? More broadly, what roles might zombie viruses play in diseases caused by other viruses that could cause pandemics, like Ebola, influenza or Zika? And how might we harness zombies to protect against future pandemics caused by novel viruses?
Given the protection zombie viruses might provide, it’s reasonable to think they could help treat COVID-19 or other infection by future pandemic viruses. Virus expert Leor Weinberger of the University of California, San Francisco, has recently engineered zombie particles of SARS-CoV-2 and showed their protective effects against infection in hamsters. Importantly, zombie particles suppressed the severity of COVID-like disease when given before or after infection. Longer-term studies showed such particles might protect against variants like Delta, Omicron or others. Finally, virologist Raul Andino, also at U.C. S.F., has discovered that poliovirus zombie genomes can stimulate mouse immune responses and protect those infected from catching not only poliovirus, but also influenza and SARS-CoV-2.
These findings provide exciting evidence for the holy grail of vaccine development: broad protection against diverse viruses. To grow and spread, all viruses re-program their host cells to make virus proteins; infected cells respond by activating defenses to slow or stop making those proteins. Viruses escalate the arms race by inhibiting the signals cells used to slow or stop making proteins. The recent studies in mice suggest how zombie genomes may ultimately give the upper hand to the cells, shutting down production of proteins viruses need to grow and spread.
If zombie genomes can stimulate protective immune responses in not only mice but also humans, a single dose might someday protect us from new variants of influenza virus, coronavirus or other viruses. More safety and efficacy studies will be needed to assess the capacity of engineered zombie particles to treat or prevent disease before they can be considered for human use. For now, zombie viruses offer an interesting new idea in protecting us against future pandemics.
This is an opinion and analysis article, and the views expressed by the author or authors are not necessarily those of Scientific American.
