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On Mechanisms of Zika Virus-Induced Microcephaly and Host Invasion [Version 2; Peer Review: 2 Approved, 1 Approved with Reservations, 1 Not Approved]

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On Mechanisms of Zika Virus-Induced Microcephaly and Host Invasion [Version 2; Peer Review: 2 Approved, 1 Approved with Reservations, 1 Not Approved] F1000Research 2017, 5:1919 Last updated: 30 JUL 2021 RESEARCH NOTE Predicted protein interactions of IFITMs may shed light on mechanisms of Zika virus-induced microcephaly and host invasion [version 2; peer review: 2 approved, 1 approved with reservations, 1 not approved] Previously titled: Predicted protein interactions of IFITMs which inhibit Zika virus infection Madhavi K. Ganapathiraju1,2, Kalyani B. Karunakaran3, Josefina Correa-Menéndez2 1Intelligent Systems Program, University of Pittsburgh, Pittsburgh, PA, USA 2Department of Biomedical Informatics, University of Pittsburgh, Pittsburgh, PA, USA 3Supercomputer Education and Research Centre, Indian Institute of Science, Bangalore, India v2 First published: 05 Aug 2016, 5:1919 Open Peer Review https://doi.org/10.12688/f1000research.9364.1 Latest published: 21 Nov 2017, 5:1919 https://doi.org/10.12688/f1000research.9364.2 Reviewer Status Invited Reviewers Abstract After the first reported case of Zika virus (ZIKV) in Brazil, in 2015, a 1 2 3 4 significant increase in the reported cases of microcephaly was observed. Microcephaly is a neurological condition in which the version 2 infant’s head is significantly smaller with complications in brain (revision) report report report development. Recently, two small membrane-associated interferon- 21 Nov 2017 inducible transmembrane proteins (IFITM1 and IFITM3) have been shown to repress members of the flaviviridae family which includes version 1 ZIKV. However, the exact mechanisms leading to the inhibition of the 05 Aug 2016 report report report virus are yet unknown. Here, we assembled an interactome of IFITM1 and IFITM3 with known protein-protein interactions (PPIs) collected from publicly available databases and novel PPIs predicted using the 1. Judith Klein-Seetharaman, University of High-confidence Protein-Protein Interaction Prediction (HiPPIP) Warwick, Warwick, UK model. We analyzed the functional and pathway associations of the interacting proteins, and found that there are several immunity 2. Nicholas Eyre, University of Adelaide, pathways (toll-like receptor signaling, cd28 signaling in T-helper cells, Adelaide, Australia crosstalk between dendritic cells and natural killer cells), neuronal pathways (axonal guidance signaling, neural tube closure and actin 3. Sandeep Chakraborty , University of cytoskeleton signaling) and developmental pathways (neural tube California, Davis, USA closure, embryonic skeletal system development) that are associated with these interactors. Our novel PPIs associate cilia dysfunction in 4. Rama Rao Damerla , Memorial Sloan ependymal cells to microcephaly, and may also shed light on potential Kettering Cancer Center, New York, USA targets of ZIKV for host invasion by immunosuppression and cytoskeletal rearrangements. These results could help direct future Any reports and responses or comments on the research in elucidating the mechanisms underlying host defense to ZIKV and other flaviviruses. Page 1 of 20 F1000Research 2017, 5:1919 Last updated: 30 JUL 2021 Keywords article can be found at the end of the article. Zika, , virus infection, protein interaction, interferon-inducible transmembrane proteins This article is included in the Disease Outbreaks gateway. This article is included in the Zika & Arbovirus Outbreaks collection. Corresponding author: Madhavi K. Ganapathiraju ([email protected]) Author roles: Ganapathiraju MK: Conceptualization, Data Curation, Formal Analysis, Funding Acquisition, Investigation, Methodology, Project Administration, Supervision, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing; Karunakaran KB: Investigation, Writing – Original Draft Preparation; Correa-Menéndez J: Writing – Original Draft Preparation Competing interests: No competing interests were disclosed. Grant information: MKG’s work is funded by Biobehavioral Research Awards for Innovative New Scientists (BRAINS) grant (R01MH094564) from National Institute of Mental Health of National Institutes of Health of USA. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Copyright: © 2017 Ganapathiraju MK et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. How to cite this article: Ganapathiraju MK, Karunakaran KB and Correa-Menéndez J. Predicted protein interactions of IFITMs may shed light on mechanisms of Zika virus-induced microcephaly and host invasion [version 2; peer review: 2 approved, 1 approved with reservations, 1 not approved] F1000Research 2017, 5:1919 https://doi.org/10.12688/f1000research.9364.2 First published: 05 Aug 2016, 5:1919 https://doi.org/10.12688/f1000research.9364.1 Page 2 of 20 F1000Research 2017, 5:1919 Last updated: 30 JUL 2021 Recently, it was discovered that two small membrane-associated REVISE D Amendments from Version 1 interferon inducible transmembrane proteins (IFITMs) IFITM1 In this revision, we have added additional details to the and IFITM3 play a protective role against ZIKV infection by Introduction and Methods sections, and added a substantial inhibiting replication of the virus and preventing cell death7. The Discussion section that presents 3 hypotheses about mechanisms IFITM protein family belongs to a group of small (10 – 15kDa)20 of Zika-virus induced microcephaly and host-invasion by the interferon stimulated genes (ISGs), which are in turn produced by virus, based on the functional significance of predicted interactors the interferon system21. The interferon system is the host’s primary of IFITMs. We have added 2 new authors, Kalyani B. Karunakaran and Josefina Correa-Menéndez who contributed to this revision. response against infection which restricts entry and fusion from late endosomes22, with some ISGs being involved in suppressing We have added a brief description about HiPPIP, the 21,23,24 computational method that was employed to predict protein- the early stages of viral replication . IFITMs are located at protein interactions. This method has been described in detail in the cell plasma and endosomal membranes, which are the means our prior publication (npj Schizophrenia 2, Article number: 16012, of entry of many viruses25. This protein family protects the host 2016, doi:10.1038/npjschz.2016.12). against viral infection by directly restricting entry and fusion from See referee reports late endosomes26. Flaviviruses depend on the intracellular membrane of their host throughout their lifecycle27–29. Mice that are lacking immune Introduction sensors, signaling pathways and effector molecules were found Zika virus (ZIKV) is a flavivirus that was initially isolated from to be susceptible to flavivirus infection highlighting the impor- rhesus monkeys in 1947 and was first reported in humans in tance of the host’s innate immune response to these viruses5,30,31. 19521. The flavivirus genus contains around 70 viruses belong- Recent literature has demonstrated that during ZIKV infection, the ing to the family Flaviviridiae, a family of positive sense, single- production of several types of interferon and ISGs is increased, stranded, enveloped RNA viruses2, that also include Dengue virus, and that IFITM1 and IFITM3 are involved in inhibiting ZIKV West nile virus (WNV), tick-borne encephalitis virus, Japanese infection during the early stages of pathogenesis7,30–33. Enveloped encephalitis virus, yellow fever virus, and Hepatitis C virus3. Until viruses, such as ZIKV, have a membrane of host cell lipids that recently, ZIKV reports had been limited to Africa and Asia4 but contains viral fusion proteins; these proteins mediate fusion it became a wide-spread ZIKV epidemic5. The virus spread rap- between the virus and the endosomal membrane of the host cell, idly across the Americas and was declared a ‘global emergency’ a necessary step for initiating infection21,34. The precise mecha- by the World Health Organization6. It is mostly transmitted by nisms by which IFITMs inhibit infection are yet to be described. mosquitoes and clinical manifestations include rash, mild fever, However, IFITM3 has been shown to impact the function of arthralgia, conjunctivitis, myalgia, and headaches. In addition, vesicle-associated membrane protein (VAMP)-associated the virus can be transmitted sexually, with the risk of infection protein A (VAPA) and oxysterol-binding protein (OSBP) by persisting for several months after initial contact7. While the directly interacting with VAPA. This leads to the accumula- symptoms of ZIKV can be mild1, the virus has been linked to tion of cholesterol in multivesicular bodies and late endosomes, two more serious afflictions: Guillen-Barré syndrome (GBS)8,9 preventing the fusion of the intraluminal virion-containing and microcephaly10–14, both of which are serious neurological vesicles with endosomal membranes35. Additionally, IFITM1 has conditions. Microcephaly results in reduced head circumference been shown to suppress cell to cell fusion (syncytia formation) by measurement in infants, exhibiting complications in brain devel- localizing to the plasma membrane after interferon induction21. opment. Of particular concern is the attribution of microcephaly to infection with ZIKV occurring between the first two trimesters There are additional reasons to explore the role of IFITMs in of pregnancy13,14. Evidence linking ZIKV to microcephaly includes ZIKV restriction. For
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