Measles Encephalitis: Towards New Therapeutics

Abstract

Measles remains a major cause of morbidity and mortality worldwide among vaccine preventable diseases. Recent decline in vaccination coverage resulted in re-emergence of measles outbreaks. Measles virus (MeV) infection causes an acute systemic disease, associated in certain cases with central nervous system (CNS) infection leading to lethal neurological disease. Early following MeV infection some patients develop acute post-infectious measles encephalitis (APME), which is not associated with direct infection of the brain. MeV can also infect the CNS and cause sub-acute sclerosing panencephalitis (SSPE) in immunocompetent people or measles inclusion-body encephalitis (MIBE) in immunocompromised patients. To date, cellular and molecular mechanisms governing CNS invasion are still poorly understood. Moreover, the known MeV entry receptors are not expressed in the CNS and how MeV enters and spreads in the brain is not fully understood. Different antiviral treatments have been tested and validated in vitro, ex vivo and in vivo, mainly in small animal models. Most treatments have high efficacy at preventing infection but their effectiveness after CNS manifestations remains to be evaluated. This review describes MeV neural infection and current most advanced therapeutic approaches potentially applicable to treat MeV CNS infection.

Keywords: central nervous system; measles virus; treatments; tropism.

Figure 1

Measles Virus (MeV) replication cycle. (A) In order to infect a susceptible and permissive cell, MeV binds to its entry receptors on the cell surface (1) and initiates the virus-cell membrane fusion (2), as described in detail in (B). Virus and cell membranes fusion leads to genome delivery into the cytoplasm (3). Viral RNA is transcribed in mRNA (4) that is further translated into viral proteins (5). Viral glycoproteins maturate during their transport to the cell surface (6). The replication of positive stranded anti-genomic RNA starts in the cytoplasm (7) and serves as a template for synthesis of new negative stranded genomic RNA (8). Viral proteins assemble at the cell surface, leading either to budding of new virions (9) or cell-to-cell fusion (10). (B) The haemagglutinin (H) protein binds to the MeV receptor at the cell surface, allowing the triggering of fusion (F) which reaches a metastable conformation. Then, F protein anchors its fusion peptide in the target cell membrane, F undergoes serial conformational changes bringing the two membranes close enough to merge and form a pore throughout which the viral ribonucleocapsid (RNP) is delivered to the cytoplasm.

Figure 2

Course of MeV infection leading to measles encephalitis. (A) Initially, MeV infects myeloid cells in the respiratory tract. Then, MeV-infected lymphocytes disseminate the infection via the lymphatic and vascular systems. As a consequence of transient immunosuppression or autoimmunity, patients can develop acute post-infectious measles encephalitis (APME) shortly after exposure without systematic central nervous system (CNS) infection. However, measles inclusion-body encephalitis (MIBE) and subacute sclerosing panencephalitis (SSPE) are associated with MeV infection of the CNS. (B) The occurrence of MeV encephalitis may range from one day to 15 years following initial infection.

Figure 3

MeV F gene mutations related to CNS infection. (A) Schematic of MeV genome showing the most common mutations found in SSPE cases. (B) Details of MeV mutations in F protein leading to a hyperfusogenic phenotype and/or CNS infection.

Figure 4

MeV central nervous system infection. Lesion areas are found in the brain of SSPE and MIBE patients but the specific areas associated with RNA detection are still poorly documented (A). Generally, MeV infects neurons and oligodendrocytes in humans (B). Occasionally, MeV RNA is also found in astrocytes (C) and microglia (D).

Figure 5

Wild-type and hyperfusogenic MeV growth in organotypic cerebellar cultures (OCC). OCC from suckling SLAM-IFNARKO mice (A), IFNARKO mice (B), wild-type C57BL/6 mice (C), and Syrian Hamster (D) were prepared as described elsewhere [189] and infected on the day of slicing with 10³ PFU per slice with MeV-IC323-eGFP-F-wild-type (left side images), MeV-IC323-eGFP-F-L454W (right side images) and MeV-IC323-eGFP-F-T461I (middle images). Pictures were taken at day three post infection (dpi) and reconstituted using the Stitching plug-in with ImageJ software [191]. Scale bars, 1 mm.

Figure 6

MeV F heptad repeats at the C terminal domain (HRC)-derived peptide. Following its engagement with any MeV receptor, H triggers F which inserts its fusion peptide in the host membrane (A). Then, F undergoes serial conformational changes to reach its post fusion state, bringing the two membranes close enough to form a fusion pore (B). MeV F HRC-derived peptides interact with MeV F HRN and catch the intermediate states of MeV F to block the fusion, regardless of the insertion of the fusion peptide in the host membrane (C,D).