Weak cis and trans Interactions of the Hemagglutinin with Receptors Trigger Fusion Proteins of Neuropathogenic Measles Virus Isolates

Abstract

Measles virus (MeV) is an enveloped RNA virus bearing two envelope glycoproteins, the hemagglutinin (H) and fusion (F) proteins. Upon receptor binding, the H protein triggers conformational changes of the F protein, causing membrane fusion and subsequent virus entry. MeV may persist in the brain, infecting neurons and causing fatal subacute sclerosing panencephalitis (SSPE). Since neurons do not express either of the MeV receptors, signaling lymphocytic activation molecule (SLAM; also called CD150) and nectin-4, how MeV propagates in neurons is unknown. Recent studies have shown that specific substitutions in the F protein found in MeV isolates from SSPE patients are critical for MeV neuropathogenicity by rendering the protein unstable and hyperfusogenic. Recombinant MeVs possessing the F proteins with such substitutions can spread in primary human neurons and in the brains of mice and hamsters and induce cell-cell fusion in cells lacking SLAM and nectin-4. Here, we show that receptor-blind mutant H proteins that have decreased binding affinities to receptors can support membrane fusion mediated by hyperfusogenic mutant F proteins, but not the wild-type F protein, in cells expressing the corresponding receptors. The results suggest that weak interactions of the H protein with certain molecules (putative neuron receptors) trigger hyperfusogenic F proteins in SSPE patients. Notably, where cell-cell contacts are ensured, the weak cis interaction of the H protein with SLAM on the same cell surface also could trigger hyperfusogenic F proteins. Some enveloped viruses may exploit such cis interactions with receptors to infect target cells, especially in cell-to-cell transmission. IMPORTANCE Measles virus (MeV) may persist in the brain, causing incurable subacute sclerosing panencephalitis (SSPE). Because neurons, the main target in SSPE, do not express receptors for wild-type (WT) MeV, how MeV propagates in the brain is a key question for the disease. Recent studies have demonstrated that specific substitutions in the MeV fusion (F) protein are critical for neuropathogenicity. Here, we show that weak cis and trans interactions of the MeV attachment protein with receptors that are not sufficient to trigger the WT MeV F protein can trigger the mutant F proteins from neuropathogenic MeV isolates. Our study not only provides an important clue to understand MeV neuropathogenicity but also reveals a novel viral strategy to expand cell tropism.

Measles Encephalitis: Towards New Therapeutics

“…Alternatively, there is no proof that such a virus would be able to attach to any cell in absence of H and thus go through the first event allowing the entry in the CNS. Additionally, other hyperfusogenic mutants more stable and also observed in encephalitis cases were shown to conserve there dependence on H for F triggering [40], reinforcing the idea that at least a low affinity neural receptor should allow the initial entry in a CNS cell [186].…”

Multiple Receptors Involved in Invasion and Neuropathogenicity of Canine Distemper Virus: A Review

“…Specifically, the T461I substitution in the F protein conferred enhanced fusion activity and contributed to MeV spread in neurons. This hyperfusogenic virus spread in cells lacking SLAM and nectin-4 [ 62 ] and infected the CNS, causing lethal disease [ 63 ]. The above studies open up new avenues for researching as yet unidentified CDV receptors and the underlying neuropathogenesis mechanism(s).…”

“…Despite viral spread, there is little evidence of MeV-induced cell death, syncytium formation, or infectious virus production in neurons, while MeV RNA continues to persist in the CNS [ 61 , 69 ]. Since neurons, which are important cell targets affected in SSPE, express neither SLAM nor nectin-4, CDV is thought to exploit a different infection mechanism that does not involve these two receptors [ 62 ]. Early research on the spread of MeV between neurons indicated that MeV adopts a trans-synaptic mode of spread and does not require CD46 expression [ 61 , 70 ].…”

“…MeV isolated from SSPE patients harbors a fusion-enhancing T461I substitution in the F protein that contributes to MeV spread in human neurons and NT2N cells lacking SLAM and nectin-4. The H protein is also required for the spread of the hyperfusogenic MeV between neurons, indicating the presence of other neuronal receptors concentrated at synapses that interact with the MeV H protein [ 61 , 62 ]. We speculate that this hyperfusogenic F-protein-dependent mechanism of invasion and spread in the CNS via neuronal receptors may also be applicable to CDV.…”

Collective fusion activity determines neurotropism of an en bloc transmitted enveloped virus

“…The H protein binds to receptors on the human cells and subsequently triggers the conformational changes of the trimeric F protein from the prefusion form to the postfusion form, leading to virus-to-cell or cell-to-cell membrane fusion. While the wild-type (WT) F protein cannot induce membrane fusion in neurons lacking MeV receptors [signaling lymphocytic activation molecule family member 1 (SLAMF1) and nectin-4], hyperfusogenic mutant F proteins from SSPE patientderived MeV strains can do so by using cell adhesion molecule 1 (CADM1) and CADM2 as "cis-acting receptors" (host factors triggering fusion in cis) (12)(13)(14). The H protein interacts with CADM1 and CADM2 in cis on the same membrane, triggering the conformational changes of the hyperfusogenic mutant F proteins but not of the WT F protein.…”