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A UC San Francisco-led research team has detected the immunological remnants of a common seasonal virus in spinal fluid from dozens of patients diagnosed with acute flaccid myelitis (AFM)—a polio-like illness that causes permanent, sometimes life-threatening paralysis in young children. The findings provide the clearest evidence to date that AFM is caused by an enterovirus (EV) that invades and impairs the central nervous system. The study was published October 21, 2019 in Nature Medicine. AFM, which begins with cold-like symptoms and progresses to limb weakness and paralysis in a matter of days, was first documented in 2012. Since then, AFM outbreaks have occurred every other year, with more than 500 confirmed cases recorded so far. But because scientists have had trouble pinpointing a cause, AFM has been the subject of contentious debate within the medical community.
Mounting evidence implicated EVs as the likely culprit—specifically the so-called D68 and A71 strains of the virus. EV outbreaks are common and normally cause nothing more severe than cold-like symptoms or the rash-producing hand, foot and mouth disease. Scientists started to notice, however, that EV outbreaks coincided with spikes in AFM. They also found that respiratory samples from children diagnosed with AFM often tested positive for EVs. Plus, laboratory studies found that these strains caused paralysis in mice. But many experts remained skeptical of the enterovirus hypothesis, instead proposing that AFM is an autoimmune disorder or is caused by some other, as-yet-undiscovered virus. These EV skeptics argued that that the evidence linking the virus to AFM was circumstantial, because the virus could not be found in 98 percent of AFM patients who had their spinal fluid tested. They maintained that until there was ample evidence of the virus invading the human nervous system, the link between EVs and AFM remained unproven.....
To find evidence of the missing virus, Wilson and his collaborators—researchers at the Chan Zuckerberg Biohub, the Centers for Disease Control and Prevention, the California Department of Public Health, the University of Colorado, Boston Children's Hospital and the University of Ottawa—used an enhanced version of a virus-hunting tool called VirScan, first developed at Harvard Medical School in the laboratory of Stephen J. Elledge, Ph.D. VirScan, which is a customized version of a Nobel Prize-winning technique called phage (rhymes with "beige") display, allowed Wilson's team to probe the spinal fluid of AFM patients for signs of an immune response against enterovirus and thousands of other viruses simultaneously. "When there's an infection in the spinal cord, antibody-making immune cells travel there and make more antibodies. We think finding antibodies against enterovirus in the spinal fluid of AFM patients means the virus really does go to the spinal cord. This helps us lay the blame on these viruses," said Ryan Schubert, MD, a clinical fellow in UCSF's Department of Neurology, a member of Wilson's Lab, and lead author of the new study.
The researchers created molecular libraries consisting of nearly 500,000 small chunks of every protein found in the over 3,000 viruses known to infect vertebrates (including humans), as well as those that infect mosquitoes and ticks (an effort to rule out disease transmission through their bites). They then exposed these molecular libraries to spinal fluid obtained from 42 children with AFM and, as a control, 58 who were diagnosed with other neurological diseases. Any chunks of viral protein cross-reacting with any antibodies present in the spinal fluid would provide evidence for a viral infection in the central nervous system.
Antibodies against enterovirus were found in the spinal fluid of nearly 70 percent of AFM patients; less than 7 percent of non-AFM patients tested positive for these antibodies. Furthermore, because spinal fluid from AFM patients did not contain antibodies against any other virus, every other known virus could be eliminated as a possible culprit. These results were confirmed using more conventional lab techniques....
Published In Nature Medicine on October 21, 2019:
https://doi.org/10.1038/s41591-019-0613-1
