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Zika virus hijacks the host cell’s own defense mechanism to cause disease

How did Zika virus acquire the ability to infect the brain and reproductive tissue to cause its characteristic disease? The answer may lie in a newly observed ability of the virus to use a host cell’s own defense mechanisms as a disguise.

A team from The University of Texas Medical Branch at Galveston have published new research that shows the Zika virus evolved to use a host cellular enzyme for its own invasion, potentially explaining the mechanism by which the virus efficiently infects the brain and reproductive tissues, a potential explanation for how the Zika virus causes congenital neurological disorders like microcephaly, found in the newborns of infected mothers.

The findings are published in the journal Nature.

“One striking aspect of these findings is that Zika hijacks TRIM7, a cellular enzyme which usually functions as a ‘soldier’ or antiviral factor against the virus, and turns a molecule (ubiquitin) typically used for marking proteins for disposal, into camouflage for the virus to enter particular cells driving its unique pathology,” said Ricardo Rajsbaum, Associate Professor of Microbiology and Immunology at UTMB and senior author of the study. “This highlights the constant battle that takes place between the host cell and viruses, which drives virus evolution and adaptation.”

The host cellular ubiquitin system is best known for its function in marking unnecessary proteins for disposal. This machinery can also be used as a weapon against invading pathogens. However, Zika virus hijacks this system for its own use. A host enzyme, called TRIM7, which puts ubiquitin onto the virus’ surface, drives the tissue specificity of Zika virus. The presence of this ‘ubiquitin mark’ on the virus envelope allows the virus to bind more tightly to cells, and hence higher levels of infection in these tissues: the brain, testis, placenta and uterus. This specificity is dependent on TRIM7 activity. In contrast, mosquitoes, which transmit the virus, do not have TRIM7 and this ‘ubiquitin mark’ on the envelope protein does not provide an advantage for Zika infection.

“We also found that anti-ubiquitin antibodies can reduce the viral load in cells and animals infected with Zika, opening a potential new strategy for therapeutic treatment against Zika infections.” said Maria Giraldo, the UTMB postdoctoral fellow and lead author of the study. “More studies need to be done to demonstrate whether a strategy like this could work and be used in humans, especially in pregnant women infected with Zika”

“This is the first time scientists have clearly demonstrated that a mosquito-borne virus has the ability to camouflage itself using ubiquitin modification. The new information is critical for developing new diagnosis, vaccine, and therapeutics,” said Pei-Yong Shi, I.H. Kempner professor of Human Genetics at UTMB, who co-senior-authored the study.

“This finding was so exciting to us because it is not only Zika that uses this mechanism, dengue virus envelope can also be ubiquitinated suggesting that this could be a more general mechanism of virus entry,” Rajsbaum said. “Since TRIM7 belongs to a large family of ubiquitin enzymes, it will be interesting to see whether other TRIMs can function similarly to increase entry of other enveloped viruses, and whether targeting TRIMs could be developed as an antiviral strategy to multiple viruses”.

Other authors include UTMB’s Hongjie Xia who co-led the studies and Leopoldo Aguilera-Aguirre, graduate students Adam Hage, and Sarah van Tol; Chao Shan, Xuping Xie, Sasha Azar, Shannan Rossi, Michael Woodson, and Marc Morais. In additional to external collaborators Gail Sturdevant, Shelly Robertson, Kristin McNally, Kimberly Meade-White, and Sonja Best from Rocky Mountain Labs, NIH/NIAID; Wendy Maury from University of Iowa; Holly Ramage from University of Pennsylvania; Jeffrey Johnson and Nevan Krogan from the Icahn School of Medicine at Mount Sinai.

The UTMB team received grants from National Institutes of Health and philanthropic support from the John Sealy Memorial Endowment Fund for Biomedical Research; Sealy & Smith Foundation; Robert J. Kleberg, Jr. and Helen C. Kleberg Foundation; John S. Dunn Foundation; Amon G. Carter Foundation; Gillson Longenbaugh Foundation; Summerfield G. Roberts Foundation.