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Recent research suggests that a person’s unique genetic makeup may determine whether a temporary viral infection triggers a permanent, debilitating brain disease later in life. A team of scientists found that specific genetic strains of mice developed lasting spinal cord damage resembling amyotrophic lateral sclerosis (ALS) long after their immune systems had successfully cleared the virus. These findings were published in the Journal of Neuropathology & Experimental Neurology.
The origins of neurodegenerative diseases have puzzled medical experts for decades. Conditions such as ALS, often called Lou Gehrig’s disease, involve the progressive death of motor neurons. This leads to muscle weakness, paralysis, and eventually respiratory failure. While a small percentage of cases run in families, the vast majority are sporadic. This means they appear without a clear family history.
Researchers have hypothesized that environmental factors likely initiate these sporadic cases. Viral infections are a primary suspect. The theory suggests a “hit and run” mechanism. A virus enters the body and causes damage or alters the immune system. The body eventually eliminates the virus. However, the pathological process continues long after the pathogen is gone. Proving this connection has been difficult because by the time a patient develops ALS, the triggering virus is no longer detectable.
To investigate this potential link, the research team needed a better animal model. Standard laboratory mice are often genetically identical. This lack of diversity fails to mimic the human population. In humans, one person might catch a cold and recover quickly, while another might develop severe complications. Standard lab mice usually respond to infections in a uniform way.
To overcome this limitation, the researchers utilized the Collaborative Cross. This is a large panel of mouse strains bred to capture immense genetic diversity. The team, led by first author Koedi S. Lawley and senior author Candice Brinkmeyer-Langford from Texas A&M University, selected five distinct strains from this collection. They aimed to see if different genetic backgrounds would result in different disease outcomes following the exact same viral exposure.
The researchers infected these genetically diverse mice with Theiler’s murine encephalomyelitis virus (TMEV). This virus is a well-established tool in neurology research. It is typically used to study conditions like multiple sclerosis and epilepsy. In this context, the scientists used it to examine spinal cord damage. They compared the infected mice to a control group that received a placebo.
The team monitored the animals over a period of three months. They assessed the mice at four days, fourteen days, and ninety days post-infection. These time points represented the acute phase, the transition phase, and the chronic phase of the disease. The researchers utilized a variety of methods to track the health of the animals. They observed clinical signs of motor dysfunction. They also performed detailed microscopic examinations of spinal cord tissues.
In the acute phase, which occurred during the first two weeks, most of the infected mouse strains showed signs of illness. The virus actively replicated within the spinal cord. This triggered a strong immune response. The researchers tracked this response by staining for Iba-1, a marker for microglia and macrophages. These are the immune cells that defend the central nervous system. As expected, inflammation levels spiked as the bodies of the mice fought the invader.
The virus targeted the lumbar region of the spinal cord. This is the lower section of the back that controls the hind legs. Consequently, the mice displayed varying degrees of difficulty walking. Some developed paresis, which is partial weakness. Others developed paralysis. The severity of these early symptoms varied widely depending on the mouse strain. This confirmed that genetics played a major role in the initial susceptibility to the infection.
The most revealing data emerged at the ninety-day mark. By this time, the acute infection had long passed. The researchers used sensitive RNA testing to look for traces of the virus. They found that every single mouse had successfully cleared the infection. There was no detectable viral genetic material left in their spinal cords. In most strains, the inflammation had also subsided.
Despite the absence of the virus, the clinical outcomes diverged sharply. One specific strain, known as CC023, remained severely affected. These mice did not recover. Instead, they exhibited lasting symptoms that mirrored human ALS. They suffered from profound muscle atrophy, or wasting, particularly in the muscles controlled by the lumbar spinal cord. They also displayed kyphosis, a hunching of the back often seen in models of neuromuscular disease.
The microscopic analysis of the CC023 mice revealed the underlying cause of these symptoms. Even though the virus was gone, the damage to the motor neurons persisted. The researchers observed lesions in the ventral horn of the spinal cord. This is the specific area where motor neurons reside. The loss of these neurons disconnected the spinal cord from the muscles, leading to the observed atrophy.
This outcome stood in stark contrast to other strains. For instance, the CC027 strain proved to be highly resistant. These mice showed almost no clinical signs of disease despite being infected with the same amount of virus. Their genetic background seemingly provided a protective shield against the neurological damage that devastated the CC023 strain.
The researchers noted that the inflammation in the spinal cord did not persist at high levels into the chronic phase. At ninety days, the number of active immune cells had returned to near-normal levels. This is a critical observation. It suggests that the ongoing disease in the CC023 mice was not driven by chronic, active inflammation. Instead, the initial viral insult triggered a cascade of damage that continued independently.
These findings support the idea that a person’s genetic background dictates how their body handles the aftermath of an infection. In susceptible individuals, a virus might initiate a neurodegenerative process that outlasts the infection itself. The study provides a concrete example of a virus causing a “hit and run” injury that leads to an ALS-like condition.
Candice Brinkmeyer-Langford, the senior author, highlighted the importance of this discovery in a press release. She noted, “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.”
The identification of the CC023 mouse strain is a practical advancement for the field. Current mouse models for ALS often rely on artificial genetic mutations found in only a tiny fraction of human patients. The CC023 model represents a different pathway. It models sporadic disease triggered by an environmental event. This could allow scientists to test therapies designed to stop neurodegeneration in a context that more closely resembles the human experience.
There are caveats to the study. While the symptoms in the mice resemble ALS, mice are not humans. The biological pathways may differ. Additionally, the researchers have not yet identified the specific genes responsible for the susceptibility in the CC023 strain. Understanding exactly which genes failed to protect these mice is a necessary next step.
Future research will likely focus on pinpointing these genetic factors. The team plans to investigate why the immune response in the CC023 strain failed to prevent the lasting damage. They also aim to identify biomarkers that appear early in the infection. Such markers could potentially predict which individuals are at risk for developing long-term neurological complications following a viral illness.
The study, “The association between virus-induced spinal cord pathology and the genetic background of the host,” was authored by Koedi S. Lawley, Tae Wook Kang, Raquel R. Rech, Moumita Karmakar, Raymond Carroll, Aracely A. Perez Gomez, Katia Amstalden, Yava Jones-Hall, David W Threadgill, C. Jane Welsh, Colin R. Young, and Candice Brinkmeyer-Langford.
