Neurokinin-1 enables measles virus trans-synaptic spread in neurons

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.

The SI Strain of Measles Virus Derived from a Patient with Subacute Sclerosing Panencephalitis Possesses Typical Genome Alterations and Unique Amino Acid Changes That Modulate Receptor Specificity and Reduce Membrane Fusion Activity

“…Analyses using animal models have demonstrated that MV uses a transsynaptic route to spread between neurons (24,27,35,40). The data indicated that receptors for the H protein are not required for the transsynaptic transmission (27,70).…”

“…The data indicated that receptors for the H protein are not required for the transsynaptic transmission (27,70). It has been suggested that the F protein causes microfusion between neurons without the support of the H protein (27,70).…”

Bst2/Tetherin Is Induced in Neurons by Type I Interferon and Viral Infection but Is Dispensable for Protection against Neurotropic Viral Challenge

“…Primary hippocampal neurons were obtained from day 14 to 16 mouse embryos and cultured in Neurobasal medium (Gibco) supplemented with L-glutamine in the absence of an astrocyte feeder layer, as described previously (26)(27)(28). Neurons were plated on 15-mm glass coverslips or in 12-well plates coated with poly-L-lysine (Sigma-Aldrich) at a density of 2 ϫ 10 5 cells/well, unless otherwise noted.…”

“…Because mice are not normally permissive to MV infection, we can use this model to restrict viral replication to CNS neurons. MV spread within primary neurons that are obtained from these mice occurs through synaptic connections in the absence of extracellular viral release, distinct from the productive and lytic infection it causes in nonneuronal cells (23,27,28). Functional clearance of MV from the CNS of NSE-CD46 ϩ mice is noncytolytic and dependent on both T cells and gamma interferon (IFN-␥) (29,30).…”

Subacute Sclerosing Pan-Encephalitis (SSPE) – Past and Present

“…After entering the cell the viral matrix protein undergoes mutations and cannot be recognized by the immune system. This is followed by virus replication and persistence within the infected cell without being eradicated by the immune system (Makhortova et al, 2007). In addition, a truncated protein F receptor may also play a causative role.…”