Thought only to infect the respiratory tract, new research has proved for the first time that the respiratory syncytial virus (RSV), very common in young children, can also penetrate nerve cells directly, triggering excessive inflammation and potentially leading to nerve damage. The findings underscore the potential long-term effects of RSV and highlight the importance of preventive measures.
Infecting up to 90% of children in the first two years of life, RSV is highly contagious, causing mild, cold-like symptoms. In older adults, the virus is an important cause of acute respiratory illness, particularly in those who are frail or have co-morbidities. Entering the body through the upper respiratory tract, RSV was thought to affect only the respiratory system, but growing evidence has suggested that the virus can spread to non-respiratory tissues, particularly the nervous system, disrupting its function.
The virus has previously been detected in the cerebrospinal fluid (CSF) of children with seizures or other neurological symptoms, and around 40% of RSV-positive children under two have shown acute encephalopathy, brain damage that can result in confusion, memory loss or cognitive difficulties. But, despite this clinical data, the cellular mechanisms underlying RSV’s effects on the nervous system have remained unclear. Now, a new study by researchers at Tulane University in New Orleans has confirmed a link between RSV and the neurological symptoms reported in children.
“This is the most common respiratory virus in the first years of life as well as an impactful virus among the elderly,” said Giovanni Piedimonte, corresponding author of the study. “This [study] adds a new dimension to the importance of RSV vaccines for both the elderly and mothers to protect their babies.”
The researchers applied a stain that fluoresces bright red in the presence of viral replication to 3D peripheral nerve tissue cultures grown from human stem cells and rat embryos. After observing that the virus could infect the cells, the researchers observed that RSV induced the release of chemokines, proteins critical to the innate immune system that control the migration and positioning of immune cells, causing significant inflammation.
At a low viral load, RSV primarily infected macrophages, induced moderate expression of proinflammatory chemokines, and caused transient peripheral nerve hyperexcitability. Higher viral loads infected a greater number of neurons and macrophages, which induced a robust expression of chemokines, loss of macrophages and neurons, and progressive neurotoxicity.
“Until this study, the theory was that the inflammatory response was indirectly activating the nerves,” Piedimonte said. “This study shows that not only does that happen, but the virus can penetrate directly into the nerves.”
The researchers hypothesize that the transient nerve hyperexcitability is more likely due to chemokines than direct neuronal infection. Neuronal hyperexcitability in the respiratory system promotes the recruitment of innate immune effectors via inflammatory chemokines and cytokines, potentially resulting in chronic airway hyperreactivity. This may explain why children with RSV are more likely to develop asthma later. If future studies can identify the specific chemokines responsible for RSV-induced neuronal hypersensitivity, it could lead to more precise therapies for bronchiolitis, asthma, and chronic obstructive pulmonary disease (COPD).
They also found that RSV could enter the spinal cord via peripheral nerves despite being unable to enter the spinal neurons directly. More research is needed to ascertain this mechanism, but the researchers posit that by using the peripheral nerves to enter the spinal cord, the virus can bypass the blood-brain barrier, enter the central nervous system, and infect the brain. If confirmed by further research, it could indicate a connection between RSV and other neurological or developmental disorders, the researchers said.
“If indeed it’s confirmed in future studies that viruses like this are able to access the central nervous system, that opens a huge Pandora’s box,” said Piedimonte.
The study’s findings underscore the potential long-term impacts of RSV infection and highlight the importance of preventative measures. They’re especially important considering the increase in RSV infections reported in the US, UK, and Australia during 2023 and thought to be a ‘rebound activity’ caused by lifting COVID-19 control measures, which had interrupted the virus’ usual seasonal – fall and winter – activity.
In mid-2023, the FDA approved two new preventative tools for RSV: nirsevimab (Beyfortus), a long-acting monoclonal antibody to protect infants and some young children at increased risk for severe RSV disease, and RSVPreF3 (Arexvy) and RSVpreF (Abrysvo), recombinant protein vaccines for adults aged 60 and over to prevent RSV-associated lower respiratory tract disease (LRTD). Later that year, the FDA approved Abrysvo for use in pregnant women during weeks 32 through 36 of gestation for the prevention of RSV-associated LRTD in infants from birth through six months of age. Also, in late 2023, UK regulators approved Abrysvo for pregnant women and adults over 60. There are currently no vaccines to protect against RSV available in Australia.
The study was published in The Journal of Infectious Diseases.
Source: Tulane University