CADM1 and CADM2 Trigger Neuropathogenic Measles Virus-Mediated Membrane Fusion by Acting in cis

Abstract

Measles virus (MeV), an enveloped RNA virus in the family Paramyxoviridae , is still an important cause of childhood morbidity and mortality worldwide. MeV usually causes acute febrile illness with skin rash, but in rare cases persists in the brain, causing a progressive neurological disorder, subacute sclerosing panencephalitis (SSPE). The disease is fatal, and no effective therapy is currently available. Although trans-synaptic cell-to-cell transmission is thought to account for MeV propagation in the brain, neurons do not express the known receptors for MeV. Recent studies have shown that hyperfusogenic changes in the MeV fusion (F) protein play a key role in MeV propagation in the brain. However, how such mutant viruses spread in neurons remains unexplained. Here we show that cell adhesion molecule 1 (CADM1, also known as IGSF4A, Necl-2, SynCAM1) and CADM2 (also known as IGSF4D, Necl-3, SynCAM2) are host factors which enable MeV to cause membrane fusion in cells lacking the known receptors and to spread between neurons. During enveloped virus entry, a cellular receptor generally interacts in trans with the attachment protein on the envelope. However, CADM1 and CADM2 interact in cis with the MeV attachment protein on the same cell membrane, causing the fusion protein triggering and membrane fusion. Knockdown of CADM1 and CADM2 inhibits syncytium formation and virus transmission between neurons that are both mediated by hyperfusogenic F proteins. Thus, our results unravel the molecular mechanism (receptor-mimicking cis -acting fusion triggering) by which MeV spreads trans-synaptically between neurons, thereby causing SSPE. Importance Measles virus (MeV), an enveloped RNA virus, is the causative agent of measles, which is still an important cause of childhood morbidity and mortality worldwide. Persistent MeV infection in the brain causes a fatal progressive neurological disorder, subacute sclerosing panencephalitis (SSPE), several years after acute infection. However, how MeV spreads in neurons, which are mainly affected in SSPE, remains largely unknown. In this study, we demonstrate that cell adhesion molecule 1 (CADM1) and CADM2 are host factors enabling MeV spread between neurons. During enveloped virus entry, a cellular receptor generally interacts in trans with the attachment protein on the viral membrane (envelope). Remarkably, CADM1 and CADM2 interact in cis with the MeV attachment protein on the same membrane, triggering the fusion protein and causing membrane fusion, as viral receptors usually do in trans . Careful screening may lead to more examples of such “receptor mimicking cis -acting fusion triggering” in other viruses.

Comparable Infection Level and Tropism of Measles Virus and Canine Distemper Virus in Organotypic Brain Slice Cultures Obtained from Natural Host Species

“…In some cases the virus can obtain hyperfusogenic mutations allowing it to spread from microglia to neuron and subsequently from neuron to neuron. Spread into neurons can be facilitated independent of CD150 or nectin-4 by cis- interaction of CADM1 and CADM2 on infected neurons, allowing virus transmission to interacting neurons [ 54 ]. Alternatively, spread into neurons can be dependent of nectin-4 through transfers of cytoplasmic cargo from infected epithelial cells to nectin-1-expressing neurons [ 55 ].…”

Novel and classical morbilliviruses: Current knowledge of three divergent morbillivirus groups

“…In MeV infection, there is a late complication called subacute sclerosing encephalitis (SSPE) that arises from persistent infection in the brain, and viruses isolated from patients with SSPE have mutant fusion (F) proteins with high fusion ability. These mutant F proteins with high cell fusion ability are expressed on the same cells as cell adhesion molecule (CADM) 1 and 2 (called “cis” interactions), leading to cell fusion through the binding actions of these molecules 122,123 . Because these mutant F proteins differ in ability from the field strains, 124 it remains unclear whether natural morbillivirus infection in the CNS utilizes a similar mechanism.…”

“…These mutant F proteins with high cell fusion ability are expressed on the same cells as cell adhesion molecule (CADM) 1 and 2 (called "cis" interactions), leading to cell fusion through the binding actions of these molecules. 122,123 Because these mutant F proteins differ in ability from the field strains, 124 it remains unclear whether natural morbillivirus infection in the CNS utilizes a similar mechanism. However, experiments using F proteins isolated from patients with measles inclusion body encephalitis (F proteins containing a mutation for high cell fusion capacity) showed that MeV strains with these mutated F proteins caused CNS invasion through the respiratory route, 125 suggesting that the cell fusion capacity of the F protein is related to its neuropathogenic potential.…”

Molecular signatures in cetacean morbillivirus and host species proteomes: Unveiling the evolutionary dynamics of an enigmatic pathogen?

“…In addition, a novel molecular mechanism was described recently, where host cell adhesion molecules 1 (CADM1) and 2 (CADM2) interact in cis with MeV H in neurons as well as in other cells lacking SLAM and nectin-4, thereby allowing membrane fusion and cell-to-cell trans-synaptic spread. 33 Given that similar studies have not been conducted in CeMV-infected neurons, caution should be taken before crediting the striped dolphin BOFDI as a comparative model for human SSPE and SSPE-like neuropathies. Nonetheless, a detailed analysis of P, M, F, and H gene mutations in circulating CeMV isolates traceable to BOFDI cases will be helpful to shed light on how CeMV spreads and persists in the cetacean brain (Figure 1b).…”