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Scientists Identify Zika Proteins Causing Microcephaly

In the first research of its kind, an interdisciplinary group of scientists analyzed three Zika strains in second trimester fetal neural stem cells (fNSC) to identify which viral proteins cause congenital microcephaly. Since Zika causes significant neurological impairment, early diagnosis is imperative.

*Updated 8/18/2016 at 5:09 PM EST

In the first research of its kind, an interdisciplinary group of scientists analyzed three Zika strains in second trimester fetal neural stem cells (fNSC) to identify which viral proteins cause congenital microcephaly. These findings come as a separate team of researchers confirms that Zika virus causes neurological complications in adults. Together, these findings underscore the importance of proper diagnosis of Zika infection.

Tri-Plex Serological Test

Zika, dengue, and chikungunya are arboviral diseases transmitted primarily by the bite of an infected female Aedes aegypti mosquito. Infection with one virus can be easily mistaken for another. Recently, a multinational developer of raw diagnostics materials manufactured a tri-testing suite of proteins and antibodies that will help healthcare personnel differentiate between Zika, dengue, and chikungunya viruses to accurately diagnose Zika virus infection.

Previous research has proven that positive test results for dengue or chikungunya may lead healthcare professionals to rule out the possibility of a Zika infection, since symptoms for these diseases are similar. Yesterday, Aalto Bio Reagents (ABR) announced that its “Tri-Plex suite of proteins and antibodies” is now available to aid in the serodiagnosis of the three aforementioned arboviral diseases. The manufacturer notes that Tri-Plex, the first tri-testing suite, includes “Zika Virus (ZIKV) primary Envelope and NS1 proteins plus Chikungunya (CHIKV) E2 wildtype, E1 mutant and E1 wildtype proteins and a complete set of Dengue virus (DENV) proteins for serotypes 1-4.”

According to a press release, “Aalto has developed the Tri-Plex of CHIKV-DENV-ZIKV proteins and antibodies through 2015 and 2016 in order for the diagnostic testers at the point of impact to be able to truly sero diagnose positive cases and rule out any cross reactivity with similar viruses carried by the Aedes ageypti mosquito.”

Unlike dengue and chikungunya, congenital infection with the Zika virus is known to cause neurological impairments, such as microcephaly, which causes brain calcifications in developing fetuses.

Zika Proteins that Cause Microcephaly

Virologists and neurobiologists from the University of Southern California (USC) collaboratively identified the proteins that are responsible for these congenital complications. The interdisciplinary group of scientists analyzed three Zika strains in second trimester fetal neural stem cells (fNSC). Recently published in the journal Cell Stem Cell, their findings identified that two of the ten Zika proteins cause microcephaly: NS4A and NS4B.

In the article, the researchers wrote that infection with the Zika virus “augmented the death of fNSC in the neurospheres, in proportion to their size.” This led to a drop in fNSC proliferation, which is the process of cell growth and division that is imperative to fetal development. The researchers continued, “These results show that ZIKV infection not only induces the death of human fNSCs but also impairs their proliferation and clonal expansion in neurospheres.”

Additionally, the researchers found that Zika infection prompted the autophagy, or natural cell destruction, of fNSCs, leading to an increase of viral replication and thus a higher viral load. Together, NS4A and NS4B decreased fNSC proliferation by 64.7%. However, the researchers noted that expression of these proteins in fNSCs, either together or separately, do not lead to programmed cell death, meaning that the proteins are “not toxic to cells;" rather, “mitotic neurogenesis of fNSCs is selectively and substantially impaired by ZIKV NS4A and NS4B when these proteins are ectopically expressed individually and in combination.” The researchers noted that, while not toxic, the proteins inhibit Akt-mTOR signaling, which is critical for fNSC neurogenesis and autophagy induction.

In a USC news release, Zhen Zhao, PhD, corresponding co-author, assistant professor of research physiology and biophysics at USC, stated that future research involving NS4A and NS4B Zika proteins will focus on identifying a cure for Zika-related microcephaly. Jae Jung, PhD, senior corresponding author, distinguished professor and chair of the Department of Microbiology and Immunology, Keck School of Medicine at USC, added, “We now know the molecular pathway, so we made the first big step toward target therapy for Zika-induced microcephaly…Years from now, one shot or a series of shots could target the proteins NS4A and NS4B or their collaborators.”

Transmission Through Blood Transfusions

Although primarily transmitted by the mosquito vector, Zika, dengue and chikungunya can all be transmitted through blood transfusions in rare cases, according to the Centers for Disease Control and Prevention (CDC). Recent reports from Brazil indicate that a blood donor is suspected to have transmitted the infection to two hospital patients in late January: a 54-year-old patient with myelofibrosis, a bone marrow disorder, and a 14-year-old leukemia patient. The donor reported Zika-like symptoms two days after donating blood; the individual later tested positive for Zika. Further testing proved that the viral strain from the two patients matched that of the donor; however, neither patients exhibited any signs or symptoms of Zika infection.

Prior to these findings being published in the New England Journal of Medicine, US officials were aware of the possibility of infection through blood transfusion, and so, when active Zika transmission was suspected in Florida, the US Food and Drug Administration (FDA) urged blood establishments to cease blood collection in the areas with the non­—travel-related Zika-infected patients. Active transmission was later confirmed in Miami, Florida, and cases are currently up to 35, with one additional case locally infected in Miami and exported into Texas by the infected individual.

There are currently no FDA-approved Zika vaccines available to prevent infection, although several are in clinical trials. To avoid infection, the CDC recommends using DEET-containing mosquito repellents, covering exposed skin, and using window and door screens to avoid mosquito bites.