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Zika and microcephaly:
a deep dive into host RNA metabolism

In 2014, a surge in cases of microcephaly and other neurodevelopmental disorders in newborns in Brazil and Latin America was linked to an outbreak of the Zika virus, a mosquito-borne RNA virus, and cousin of the hepatitis C virus (HCV). Leveraging our longstanding expertise in HCV, we rapidly focused on the interaction of ZIKV with the nonsense-mediated mRNA decay (NMD) pathway, a target of HCV and known regulator of brain size in mice.

NMD pathway: An arms race between host and virus

The NMD pathway destroys faulty transcripts containing premature termination codons — and is required for normal brain size in mice. We found that NMD restricts ZIKV infection in healthy neural precursor cellsin vitro. Reciprocally, ZIKV has evolved a strategy to dampen the NMD response to infection by down-regulating UPF1, a member of the NMD complex. We are now exploring the impact of UPF1 downregulation on neuronal development.

Sexual transmission of Zika Virus

While ZIKV is a mosquito-borne virus, primarily infecting people through the bloodstream, it is also transmitted through sexual intercourse. Work with our collaborator Shomiseh Sanjab has shown that the lower female reproductive tract mounts a weak innate immune response to RNA viruses such as ZIKV because it expresses low levels of the RNA sensors that would normally be involved in detecting viral RNA. This exceptional vulnerability allows ZIKV to proliferate, and may explain the male to female sexual transmission observed during ZIKV infection. 

Kristoffer Leon, Ryan Flynn, Mir M. Khalid, Krystal A. Fontaine, Tom Nguyen, G. Renuka Kumar, Camille R Simoneau, Sakshi Tomar, David Jimenez-Morales, Mariah Dunlap, Julia Kaye, Priya S Shah, Steven Finkbeiner, Nevan J Krogan, Carolyn Bertozzi, Jan E. Carette, Melanie Ott. doi:

ZIKA | The Ott Lab Team