Understanding the Likely Causes of the Zika Virus Congenital Syndrome

Newswise — The ongoing Zika virus epidemic in the Americas and the observed association with both fetal abnormalities (primary microcephaly) and adult autoimmune pathology (Guillain–Barré syndrome) has brought attention to this neglected pathogen. In “Zika Fetal Neuropathogenesis: Etiology of a Viral Syndrome,” published in the most recent PLOS Neglected Tropical Diseases, the authors analyze Zika fetal neuropathogenesis from a comparative pathology perspective. By drawing parallels to other viral infections of the fetus, the authors identify common themes and mechanisms that may illuminate the observed pathology.

The authors of the paper include: Zachary A. Klase (University of the Sciences), Svetlana Khakhina (University of the Sciences), Adriano De Bernardi Schneider (University of North Carolina at Charlotte), Michael V. Callahan (Massachusetts General Hospital and Zika Foundation), Jill Glasspool-Malone (Atheric Pharmaceutical and Global Clinical Scholars Research Training Program at the Harvard Medical School), and Robert Malone (Atheric Pharmaceutical and Global Clinical Scholars Research Training Program at the Harvard Medical School).

Author Robert Malone, M.D. places these findings in historical context of other infectious diseases, “Never before has the world health community encountered a pathogen like the version of Zika virus circulating in the Americas. The combination of enhanced viral stability, efficient sexual and mosquito borne transmission makes the Zika virus unique.” Pertaining to birth defects, Dr. Malone points out “Other viruses such as Rubella and West Nile virus can trigger similar birth defects; however, it is the frequency, relative risk, and severity of the congenital syndrome that makes Zika so unique as a disease.” Dr. Malone continues the discussion on the likely cells and tissues “Our analysis indicates that one of the most striking features of human Zika virus disease is the presence of virus in specific types of cells in the nervous system, as well as in various glands which produce key body fluids. Many of these cells and tissues are associated with stem cells which employ the Musashi-1 regulatory protein to control gene expression.”

Author Zachary A. Klase, Ph.D. notes, "When we began writing this review all that existed in the literature were case reports and theories. We decided to compile this paper to give a comprehensive overview of all the information and to use solid basic virology to draw conclusions."

Author Michael Callahan, M.D. discusses the health implications, “Unlike in Asia and Africa, Zika virus is a new arrival in the tropical Americas and so our patients are not immune. Also, Zika is now proving destructive to growing nerve cells with a spectrum of congenital abnormalities seen in intrauterine patients.” Pertaining to developing a Zika vaccine, Dr. Callahan raises the concern that “Antibodies to other local viruses such as dengue can make Zika infection worse. This point emphasizes that physicians must be very careful to ensure that any proposed vaccine does not increase the severity of a Zika infection or another viral infection by inducing harmful antibodies.”

In summary, the author’s meta-analysis reveals that Zika virus most likely triggers the Zika congenital birth defect syndrome by multiple mechanisms, which may act at different stages of pregnancy. While it is now clear that the Zika virus can directly damage fetal development including by directly infecting the brain, the analysis of available data suggests that the fetal damage is a multifactorial process. Interaction of many different events including time and level of infection during pregnancy, prior exposure to related pathogens such as Dengue, and possibly other environmental, toxin, drug and genetic factors may interact to determine the relative risk of birth defects when the fetus or the placenta are infected.

Funding: The authors received no specific funding for this work. Research reported in this publication was supported by a UNC Research Opportunities Initiative grant to UNC Charlotte, NC State University, and UNC-Chapel Hill. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing Interests: Drs. Robert Malone and Jill Glasspool-Malone are principal stockholders of Atheric Pharmaceutical, LLC. Robert Malone is the managing partner of Atheric Pharmaceutical. Dr. Michael Callahan is the Chief Medical Officer of the Zika Foundation.

Citation: Klase ZA, Khakhina S, Schneider ADB, Callahan MV, Glasspool-Malone J, Malone R (2016) Zika Fetal Neuropathogenesis: Etiology of a Viral Syndrome. PLOS Negl Trop Dis 10(8): e0004877. doi:10.1371/journal.pntd.0004877

Contacts:Robert W. Malone, M.D., [email protected], +1 (240) 994-3334Zachary A. Klase, Ph.D., [email protected], +1 (215) 596-8521

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About Atheric: Atheric Pharmaceutical LLC (Atheric) has been formed to address the global unmet need for the rapid development of drugs to prevent and treat emerging infectious disease. Atheric is an early-stage pharmaceutical company currently focused on the prevention and treatment of human flavivirus disease (e.g., West Nile, dengue, yellow fever, and Zika virus (ZIKV)) including associated neurological disorders (e.g., Guillain–Barré Syndrome (GBS)) and birth defects (e.g., congenital microcephaly) using re-purposed broad spectrum multidrug regimens. Although there is a longstanding need for anti-flavivirus drugs, Atheric is initially addressing the most pressing unmet medical needs caused by the Zika virus (ZIKV) outbreak in the Americas. For questions, please contact Jeffrey DiFrancesco, Chief Business Officer at [email protected], +1 (215) 275-1080 or visit Atheric.com.

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