A Texas A&M-led team has identified a mouse strain that develops ALS-like damage long after a viral infection is cleared. The work could help explain why some people are more vulnerable to motor neuron disease than others.
A research team led by Texas A&M University has uncovered a powerful new clue to how devastating motor neuron diseases such as amyotrophic lateral sclerosis, or ALS, might begin.
In a study using genetically diverse mice, the scientists found that a particular strain, known as CC023, developed long-lasting, ALS-like damage after a viral infection — even after the virus itself had been cleared from the spinal cord.
The discovery offers rare experimental support for a long-debated idea in neurology: that a common viral infection, combined with a person’s genetic makeup, can set off a chain reaction that leads to permanent damage of motor neurons, the nerve cells that control movement.
“This is exciting because this is the first animal model that affirms the long-standing theory that a virus can trigger permanent neurological damage or disease — like ALS — long after the infection itself occurred,” corresponding author Candice Brinkmeyer-Langford, an associate professor at the Texas A&M School of Public Health who is a neurodegenerative disease expert, said in a news release.
ALS is a rapidly progressive and fatal disease that destroys motor neurons in the brain and spinal cord, leading to muscle weakness, paralysis and, eventually, respiratory failure. While a small fraction of cases are inherited, more than 90% are considered sporadic, with no clear family history. For those cases, scientists have long suspected that environmental triggers, including viral infections, might interact with genes to raise the risk of disease.
To explore that possibility, the Texas A&M-led team turned to Theiler’s murine encephalomyelitis virus, or TMEV, a virus commonly used in research to study how infections affect the nervous system. They infected five different strains of mice that had distinct genetic backgrounds, then followed them through the acute, subacute and chronic phases of infection.
The researchers tracked what happened in the spinal cord and muscles over time using several approaches. They compared spinal cord inflammation in infected and healthy mice at different time points, measured how much inflammation each strain developed, checked whether more inflammation was tied to worse paralysis and other physical symptoms, measured how much virus was present and tested whether higher viral levels were linked to more spinal cord inflammation.
Across all strains, the team saw early signs of trouble. Within the first two weeks after infection, every strain showed nerve damage in the lumbar region of the spine, and some mice began to show signs of illness as soon as four days after exposure to the virus.
Over the longer term, however, the strains diverged. In all of them, the virus was eventually cleared from the spinal cord. But in the CC023 mice, the damage did not resolve. Instead, they developed permanent muscle wasting and lesions in the spinal cord that closely resembled those seen in people with ALS.
The team also found that the immune system’s response shifted over time. Early in infection, immune cells in the spinal cord were highly active as they fought the virus. Once the virus was eliminated, that activity dropped off — but the damage that had been triggered in the spinal cord and muscles persisted, especially in the CC023 strain.
In other words, the initial infection spread to the lumbar spinal cord, sparked a strong immune reaction and produced lesions and clinical signs of disease. Even after the virus was gone, the CC023 mice continued to show ALS-like symptoms, suggesting that their genetic background made them especially vulnerable to long-term harm from the early inflammatory assault.
That combination of infection and genetics is key.
“This study gives us a new way to understand the various types of damage caused by a viral infection to the spinal cord and its nerves and muscles, especially since we now know that the initial viral infection triggers lasting, damaging reaction in susceptible individuals,” Brinkmeyer-Langford added.
The CC023 strain, she explained, offers researchers a kind of “test track” for probing how viral infections might set the stage for ALS and related conditions. By studying what happens in these mice immediately after infection, scientists may be able to identify early biomarkers — measurable signs in tissue or blood — that predict who is at higher risk for long-term motor neuron damage.
That, in turn, could open the door to earlier diagnosis and new treatment strategies, particularly for sporadic ALS. If doctors can one day recognize the biological fingerprints of a harmful post-viral response before symptoms appear, they might be able to intervene sooner, potentially slowing or preventing the progression of disease.
The study, published in the Journal of Neuropathology & Experimental Neurology, involved a large, multidisciplinary team from Texas A&M’s College of Veterinary Medicine and Biomedical Sciences, the College of Arts and Sciences, the College of Agriculture and Life Sciences, and the University of Wisconsin-Madison.
For now, the findings apply to animal models, not directly to patients. But by clearly linking a specific genetic background, a defined viral infection and ALS-like damage in the spinal cord, the Texas A&M team has created a powerful new platform for understanding how motor neuron diseases might begin — and how they might one day be stopped before they take hold.
Source: Texas A&M University