Zika Virus Proteins Linked to Fetal Microcephaly through Activation of Autophagy Pathway

Two Zika virus (ZIKV) proteins have been implicated in causing microcephaly by inhibiting a molecular pathway required for normal fetal brain development.

The current widespread outbreak of ZIKV infection has been linked to severe clinical birth defects, particularly microcephaly, warranting urgent study of the molecular mechanisms underlying ZIKV pathogenesis.

To this end, investigators at the University of Southern California (Los Angeles, USA) examined the ability of each of the 10 ZIKV proteins collected from three strains of the virus growing in second trimester human fetal neural stem cells (fNSCs) to inhibit the Akt-mTOR molecular pathway. Akt-mTOR signaling is one of the key cellular pathways essential for brain development and autophagy regulation.

Autophagy is a self-degradative cellular process that is important for balancing sources of energy at critical times in development and in response to nutrient stress. Autophagy also plays a housekeeping role in removing misfolded or aggregated proteins, clearing damaged organelles, such as mitochondria, endoplasmic reticulum and peroxisomes, as well as eliminating intracellular pathogens. Thus, autophagy is generally thought of as a survival mechanism, although its deregulation has been linked to non-apoptotic cell death. Autophagy can be either non-selective or selective in the removal of specific organelles, ribosomes, and protein aggregates, although the mechanisms regulating aspects of selective autophagy are not fully understood.

The investigators reported in the August 11, 2016, online edition of the journal Cell Stem Cell that ZIKV infection of human fNSCs caused inhibition of the Akt-mTOR pathway, leading to defective neurogenesis and aberrant activation of autophagy. By screening the three structural proteins and seven nonstructural proteins present in ZIKV, they found that two, NS4A and NS4B, cooperatively suppressed the Akt-mTOR pathway and led to cellular dysregulation.

The action of the two proteins depressed the growth of fNSCs by 65% while reducing differentiation of neural stem cells into mature brain cells, such as neurons and astrocytes, by up to 51%. Corresponding proteins from the closely related dengue virus did not have the same effect on neurogenesis.

“Zika loves and needs autophagy,” said senior author Dr. Jae Jung, professor of molecular microbiology and immunology at the University of Southern California. “Zika raises the activity in this recycling factory so they can use the energy and nutrients there to replicate. It is possible that since Zika is using most of the energy, the neuronal stem cells are left with metabolic deficits. Thus, the chances for them to differentiate and mature into neurons and other brain cell types are much lower.”

“We now know the molecular pathway, so we made the first big step toward target therapy for Zika-induced microcephaly,” said Dr. Jung. “Years from now, one shot or a series of shots could target the proteins NS4A and NS4B or their collaborators.”

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