Lethal human brain infection by measles virus: phylogeography and mechanisms

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A key question in virology is how pathogens adapt to different organs of their hosts, and cause disease. Subacute sclerosing panencephalitis (SSPE) is one of the best characterized diseases of the human central nervous system that is caused by a persistent viral infection. It typically occurs several years after an acute measles virus (MeV) infection, in about 1 in 10’000 children. Studies of SSPE have provided insights into MeV mutations favoring brain spread, which occurs through cell-cell fusion in the absence of virus particle budding. While most previous studies were limited to the analysis of viral RNA in a single specimen, we have obtained specimens from different locations of a SSPE patient brain autopsy. Our pilot deep-sequencing analyses, beside revealing very high levels of MeV transcripts in all specimens, documented extensive genomic diversity. Diversity is due to mutations introduced not only by the viral RNA polymerase, but also by a cellular RNA editing enzyme. We have already identified several candidate SSPE-driver mutations in the genes coding for the viral membrane fusion apparatus proteins. Our central hypothesis is that some of these mutations, in combination, caused lethal disease by accelerating cell-cell based viral spread. We will (aim 1) establish a spatiotemporal map of the spread of MeV genomic variants in this brain, and (aim 2) functionally characterize the relevance of candidate SSPE-driver mutations.