A new study reveals the biological secret of the infectious success of the Zika virus: Zika uses the “self -care” system of host cells to clean the useless molecules to suppress the host proteins that the virus has used to enter those cells first.
While these cell surface proteins are valuable for viral entry, they also have roles in the production of an antiviral response. Before that may happen, the virus manipulates a process that cells use to stay healthy to reduce protein activity, clearing the way for a viral infection without restrictions.
Although it is known that other viruses, such as HIV, silencing guest receptors that allow them to enter cells, Zika is unusual to have at least three of their own proteins that the work can do, said Shan-Lu Liu, principal author of the study and professor of virology in the department of veterinary biosciences at the State University of Ohio.
“That is the most interesting part: it is surprising that not only one, but several Zika proteins can do this,” said Liu, a professor in the department of microbial infection and immunity. “We observed two strains of the Zika virus and we examined three types of physiologically relevant cells. With both strains, we could see the negative regulation in the three types of cells. It seems that this is an important mechanism.”
The study was published on May 23 in Proceedings of the National Academy of Sciences.
The Zika virus, transmitted to humans mainly by Aedes aegypti Mosquitoes have caused infectious outbreaks in Africa, America, Asia and Pacific since 2007, according to the World Health Organization. Although cases have decreased worldwide since 2017, the transmission of the virus continues at low levels in the Americas and other endemic regions.
A great epidemic in Brazil in 2015 led to the confirmation of a link between Zika infection during pregnancy and babies born with congenital problems that include microcephaly, or head size smaller than normal. Although most infected people develop not or only mild symptoms, the virus is also associated with Guillain-Barra syndrome, neuropathy and myelitis (inflammation of the spinal cord) in adults and older children.
Previous investigations have shown that specific proteins of the cell surface known as PS receptors are important entry points for many viruses, including Zika. This study focused on two of these proteins, known as AXL and Tim-1, which had previously been related to Zika infection. In this work, Liu and his colleagues set out to explain how Zika holds the infection after obtaining the entrance through AXL and Tim-1.
The team completed cell culture experiments using African and Asian Zika virus strains in three types of cells related to respiratory, reproductive and neurological systems directed by the pathogen: human cells that border the lungs, cells that support embryos called trophoblasts and cells of glioblastoma brain cancer.
The experiments showed that both AXL and Tim-1 were negatively regulated in the three types of cells after Zika infection. The researchers expected this suppression to occur through two common protein degradation processes, but instead discovered that the Zika virus uses a cellular self-preservation routine: autophagy.
“Autophagy is a fundamental physiological mechanism to conserve cellular processes by degrading the components of the host. It is also called selfish: the host needs to eliminate its own damaged organelles or proteins poorly folds because they are not good for the associated institute program of the Ohio state of the state of Ohio, the associated director of the state of Ohio.
In this case, the infectious process of the virus manipulated the host cells to suppress their own protective proteins, a viral adaptive tactic that allows Zika to control their own destination.
Without this suppression, AXL and Tim-1 would begin to produce inflammatory molecules as part of an antiviral response. Its normal level of facilitating viral entry could also allow more Zika particles to access already infected cells, establishing a competitive scenario called superinfection, something that viruses want to avoid because overcrowding threatens to kill cells, which kills infected pathogens.
Other experiments identified three Zika proteins that drive the autophagy of host cells, all of which are found in the virus membrane.
“Normally, these proteins mediate viral entry or are involved in viral replication, but they are also responsible for this negative regulation, a kind of new function, which is not so surprising because viruses encode something important for them, either for their own replication or to modulate the guest,” Liu said.
Although more research is needed to know with certainty, there is the possibility that this mechanism is relevant to the Ebola virus, which uses the Tim-1 protein to access guest cells, or for other pathogens in the same family of Flavivirus as Zika, including western Nile, yellow fever and dengue viruses.
“The conclusion is that this speaks of the coevolution of viral interactions-Hiés. The more important a host factor for a virus, the more a virus will do to take control,” Liu said. “Understanding these mechanisms is an important part of being prepared for emerging or re -emerging viruses that cause infectious diseases.”
This work was mainly done by Jingyou Yu, a former student graduated in the Liu laboratory and now a principal researcher in the National Laboratory of Guangzhou in China. Yi-Min Zheng, a main scientist, and Pei Li, a postdoctoral fellow at the Liu laboratory. This work was mainly supported by a state Ohio Fund and the National Health Institutes.
The additional co -authors are Megan Sheridan, Toshihiko Ezashi and R. Michael Roberts of the University of Missouri.