Virology

Mechanisms of Measles Virus Infection and Spread

Measles is a highly contagious and highly morbid, albeit vaccine preventable, disease caused by measles morbillivirus (MeV). MeV is a single-stranded, negative-sense, non-segmented RNA virus of the Orthoparamyxovirinae subfamily in the Paramyxoviridae family. Its genome consists of six coding regions (interspersed with non-coding segments) that code for six structural proteins and two non-structural proteins. The structural proteins include:

• nucleocapsid protein (N),
• phosphoprotein (P),
• matrix protein (M),
• fusion protein (F),
• hemagglutinin (H) and
• large protein (L).

Two non-structural proteins, V and C, are transcribed from different reading frames in the P gene and play a role in blocking the innate immune response; the C protein is also required for efficient replication of the viral genome. Based on differences in the N protein coding sequence, 24 genotypes of MeV have been identified, categorized into 8 clades (clades A through H).

The infection starts when the H protein, exposed at the surface of the virus, attaches to the host cell. Two types of cellular receptors can serve as attachment sites: the signaling lymphocytic activation molecule (SLAM or CD150) and nectin-4. The former is expressed on cells of the immune system, including immature thymocytes, activated and memory T cells, naïve and activated B cells, macrophages and dendritic cells. The latter is found on the basal surface of epithelial cells of the respiratory tract and in adherens junctions. When the H protein binds to the SLAM receptor, the F protein undergoes conformational changes that enable the fusion of the viral envelope and plasma membrane. The viral ribonucleoproteins are then released into the cytoplasm where replication occurs through the activity of the L protein (an RNA-dependent RNA polymerase); first, a positive-strand antigenome is generated, which then serves as a template for the synthesis of the negative-sense genome. Antigenome copies also serve as the template for translation, which is performed by the ribosomal machinery of the host. Newly translated H and F proteins are trafficked to the host cell surface, inducing the formation of syncytia between infected cells and neighboring cells.

Within the host, the virus primarily spreads by cell-to-cell contact. Infection of a new host occurs via inhalation of respiratory droplets and smaller aerosols, or direct contact with infected secretions. The cellular pathway of viral infection and spreading is shown in Figure 1-1.

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