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Neurokinin-1 enables measles virus trans-synaptic spread in neurons
Nina R Makhortova1, Peter Askovich, Catherine E Patterson
1Division of Basic Science, The Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA.
Abstract:
Measles virus (MV), a morbillivirus that remains a significant human pathogen, can infect the central nervous system, resulting in rare but often fatal diseases, such as subacute sclerosing panencephalitis. Previous work demonstrated that MV was transmitted trans-synaptically and that, while a cellular receptor for the hemagglutinin (H) protein was required for MV entry, it was dispensable for subsequent cell-to-cell spread. Here, we explored what role the other envelope protein, fusion (F), played in trans-synaptic transport. We made the following observations: (1) MV-F expression in infected neurons was similar to that seen in infected fibroblasts; (2) fusion inhibitory peptide (FIP), an inhibitor of MV fusion, prevented both infection and spread in primary neurons; (3) Substance P, a neurotransmitter with the same active site as FIP, also blocked neuronal MV spread; and (4) both genetic deletion and pharmacological inhibition of the Substance P receptor, neurokinin-1 (NK-1), reduced infection of susceptible mice. Together, these data implicate a role for NK-1 in MV CNS infection and spread, perhaps serving as an MV-F receptor or co-receptor on neurons.
Insights
Measles virus (MV) spreads in the brain by utilizing the neurokinin-1 (NK-1) receptor. Targeting NK-1 may offer new strategies for treating MV central nervous system infections.
Area of Science:
- Neurovirology
- Central Nervous System Infections
- Morbillivirus Pathogenesis
Background:
- Measles virus (MV) is a significant human pathogen with the potential to infect the central nervous system (CNS).
- Previous studies established trans-synaptic transmission of MV, with the hemagglutinin (H) protein's receptor being crucial for entry but not cell-to-cell spread.
Purpose of the Study:
- To investigate the role of the measles virus fusion (F) protein in trans-synaptic transport within neurons.
- To identify potential receptors or co-receptors involved in MV spread in the CNS.
Main Methods:
- Examined MV-F protein expression in infected neurons and fibroblasts.
- Utilized a fusion inhibitory peptide (FIP) and Substance P to assess their impact on neuronal MV spread.
- Investigated the effect of genetic deletion and pharmacological inhibition of the neurokinin-1 (NK-1) receptor on MV infection in mice.
Main Results:
- MV-F expression patterns were consistent between infected neurons and fibroblasts.
- FIP and Substance P effectively inhibited neuronal MV infection and spread.
- Targeting the NK-1 receptor, either genetically or pharmacologically, significantly reduced MV infection in susceptible mice.
Conclusions:
- The neurokinin-1 (NK-1) receptor is implicated in measles virus CNS infection and spread.
- NK-1 may function as a receptor or co-receptor for the MV-F protein on neurons.
- These findings suggest NK-1 as a potential therapeutic target for MV-induced neurological diseases.
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