Infection with Zika virus during pregnancy can result in various neurological disorders, fetal abnormalities, and even fetal death. However, until now, scientists have not fully understood how the virus manages to cross the placenta—a barrier that typically protects developing fetuses from harmful microorganisms and chemicals.
Researchers at Baylor College of Medicine, along with collaborators from Pennsylvania State University, recently reported in Nature Communications a novel strategy used by Zika virus to secretly spread within placental cells without raising significant alarm in the immune system. The virus transmits via mosquitoes and caused an epidemic in the Americas beginning in 2015, affecting approximately 30 million people by 2018.
“Understanding how Zika spreads through the human placenta is crucial for preventing or controlling this devastating condition,” Dr. Indira Mysorekar explained as co-senior author and E.I. Wagner Endowed Chair in Internal Medicine II, Chief of Basic and Translational Research, and Professor of Medicine – Infectious Diseases at Baylor College.
The researchers discovered that Zika virus constructs underground tunnels known as tunneling nanotubes. These tiny tubes enable the transfer of viral particles to adjacent uninfected cells. “The formation of these tiny tunnels is exclusively driven by a protein called NS1 from the Zika virus,” said first author Dr. Rafael T. Michita, postdoctoral research associate in Mysorekar’s lab.
“Exposure to this NS1 protein triggers tunnel formation within placental cells as they connect neighboring cells, creating pathways for the virus to invade new cells.” Unlike other viruses in its family such as dengue and West Nile that trigger tunnels only in specific cell types, Zika’s NS1 causes tunneling across multiple kinds of tissues.
Interestingly, these conduits not only facilitate viral spread but also transport RNA, proteins, and mitochondria from infected to uninfected cells. “We suggest that moving mitochondria through the tunnels could supply additional energy to virus-infected cells, promoting viral replication,” Tran Long B., a graduate student in Mysorekar’s lab.
“The tiny tunnels may allow Zika viruses to evade significant antiviral responses such as interferon lambda defenses deployed by the placenta,” added Dr. Michita. “Mutant strains of Zika that do not create these tunnels trigger strong IFN-lambda reactions, which can limit viral spread.”
Overall, the study reveals that Zika uses a tunneling strategy to stealthily infect the placenta while also hijacking mitochondria to aid in its replication and survival. The researchers propose this method shields the virus from immune responses too.
“These insights offer vital clues that could be used to develop therapies targeting this covert transmission mode,” said Dr. Mysorekar.
Steven J. Bark, Deepak Kumar at Baylor College of Medicine and Shay A. Toner, Joyce Jose along with co-senior author Anoop Narayanan from Pennsylvania State University were key members in the research team.
This work was supported by grants from NIH/NIAID (R01AI176505), NIH/NICHD (R01HD091218) and startup funds from Penn State. It also received support from Baylor’s Cytometry and Cell Sorting Core, funded by CPRIT Core Facility Support Award CPRIT-RP180672 and the NIH (CA125123 and RR024574).
