Mechanisms of infection with dengue and zika virus and connection with microcephaly


New perspectives on how the dengue virus and zika cause diseases reveal shared and other mechanisms specific to each virus. An international and multidisciplinary team led by researchers at the University of California, San Francisco and Baylor College of Medicine in Houston, United States, reports in the scientific publication Cell that these viruses combat the immune defense mechanisms in mosquitoes and humans. In addition, viruses sequester host proteins to produce new viruses. The scientists also found that the Zika virus causes microcephaly in fruit flies, an experimental animal, by disrupting the function of ANKLE2, a protein involved in the development of the brain in both mosquitoes and humans. These findings open up new possibilities for planning therapies to combat these widespread and serious infectious diseases.

"In this study, we collaborated with Dr. Nevan J. Krogan and Dr. Priya Shah of the University of California, San Francisco, to expand our understanding of the mechanisms of infection of Dengue and Zika viruses," said one of the authors . corresponding authors, Dr. Hugo Bellen, professor of human and molecular genetics and neuroscience at Baylor College of Medicine. Dr. Bellen is also a research fellow at the Howard Hughes Medical Institute.

The researchers conducted systematic comparative analyzes of the interactions of dengue and zika virus proteins with host proteins, both mosquitoes and humans. They have discovered new strategies that viruses use to cause disease. For example, they found that viral proteins neutralize the genes of the interferon-like response, a defense mechanism in mosquitoes and humans, and that other viral proteins sequester host proteins and redirect their activities to reproduce the virus.

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Hugo Bellen. (Photo: Baylor College of Medicine)

In addition, the researchers combined their systematic comparative analysis with experiments with the fruit fly and discovered a new mechanism that may explain the childhood microcephaly associated with maternal infection by zika.

The Bellen laboratory combines the versatility of the fruit fly with modern molecular biology techniques to answer important questions about genes and diseases. This technology has enabled scientists to determine the role played by a gene and the corresponding protein in cells expressing the gene, and whether genetic loss could be associated with human disease.

"We changed thousands of mosquitoes and systematically characterized the expression and function of genes in detail." In a previous study, we combined this strategy with the analysis of genes not yet connected to human diseases. We found that mutations in the ANKLE2 gene can cause microcephaly in both people and fruit flies Microcephalus caused by the lack of ANKLE2, called hereditary microcephaly, is very similar to that caused by the Zika virus, "said Bellen, who is also a member of Jan and Dan Duncan Neurological Research Institute of Children's Hospital of Texas.

In this study, the researchers found that the Zika protein called NS4A binds to ANKLE2, the human protein associated with microcephaly.

"We found that if we exaggerated NS4A in normal mosquitoes, the result is mosquitoes with small brains," said first author, Dr. Nichole Link, a postdoctoral associate in the Bellen laboratory. "Together, the evidence suggests that when the NS4A protein of the Zika virus interacts with the ANKLE2, it disrupts its function in the development of the brain in order to result in microcephaly."

Dr. Link adds that "these findings also suggest that if we could find a drug that would prevent NS4A from adhering to ANKLE2, perhaps we could prevent the Zika virus from causing microcephaly." (Photo: Baylor College of Medicine)


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