Yadav, Kalpana

Measles virus (MeV) infection is mediated by two cellular receptors: signaling lymphocytic activation molecule family member 1 (SLAMF1, also known as CD150), expressed by immune cells, and nectin-4, expressed by epithelial cells. Infection of immune cells causes systemic disease and immune suppression, while infection of airway epithelial cells results in efficient transmission. In rare cases, MeV reaches the brain and slowly spreads in cells that do not express bona fide receptors, causing subacute sclerosing panencephalitis (SSPE). In the brains of persons with SSPE, multiple mutations of the MeV membrane fusion apparatus are selected that enable its triggering by host proteins acting as surrogate receptors. These mutations favor cell-to-cell spread, which promotes population-based MeV genome evolution and the formation of collective infectious units (CIUs). CIUs, which can rebalance their components and rapidly adapt to new environments, may support neuropathogenesis of other nonintegrating RNA viruses, in particular those with nonsegmented negative-strand genomes.

ABSTRACT Subacute sclerosing panencephalitis (SSPE) is a lethal neurological disorder occurring several years after measles. Reconstruction of the evolution of the measles virus (MeV) genome in an SSPE case suggested that the matrix (M) protein mutation M-F50S, when added to other mutations, drove neuropathogenesis. However, whether and how M-F50S would promote spread independently from other mutations was in question. We investigated here the cell specificity of MeV spread in this brain and documented that both neurons and astrocytes were heavily infected. We then generated recombinant MeV with individual mutations in the three proteins of the viral membrane fusion apparatus, M, fusion (F), and hemagglutinin (H). These viruses reached similar titers as the parental wild-type virus, kept the respective mutations upon passage, and infected cells expressing the tissue-specific MeV receptors SLAM and nectin-4 with similar efficiencies. However, after inoculation of receptor-negative neurons and astrocytes differentiated from human induced pluripotent stem cells, only MeV M-F50S spread with moderate efficiency; the parental virus and its derivatives coding for a hyperfusogenic F protein, or for a cytoplasmic tail-mutated H protein, did not spread. When delivered to primary mouse neurons by cell-mediated neurite overlay, MeV M-F50S frequently reached the cell bodies and occasionally formed small infectious centers, while the other MeV reached the cell bodies only sporadically. These results demonstrate that, in neuronal cell cultures, M-F50S can enable receptor-independent spread in the absence of other mutations, and validate the inference that this single amino acid change initiated ubiquitous MeV brain spread. IMPORTANCE Measles virus (MeV), a non-integrating negative-strand RNA virus, rarely causes subacute sclerosing panencephalitis (SSPE) several years after acute infection. During brain adaptation, the MeV genome acquires multiple mutations reducing the dependence of its membrane fusion apparatus (MFA) from an activating receptor. It was proposed that one of these mutations, matrix protein F50S, drove neuropathogenesis in an SSPE case. We report here that, in two types of neuronal cultures, a recombinant MeV with only this mutation gained receptor-independent spread, whereas viruses expressing MFA proteins with other mutations acquired during brain adaptation did not. Our results validate the inference that M-F50S initiated ubiquitous MeV brain spread resulting in lethal disease. They also prompt studies of the impact of analogous amino acid changes of the M proteins of other nonsegmented negative-strand RNA viruses on their interactions with membrane lipids and cytoskeletal components.