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Zika Virus
- 1. ZIKA VIRUS & EMBRYONIC DEVELOPMENT Presented By: Hadiah Bassam Al Mahdi PhD. Student in Genetics Faculty of Science , King Adulaziz University Developmental Genetics Course Bio707
- 2. OUTLINE What Is Zika Virus And Its History. Transmissions Of Zika Virus. Congenital Zika Syndrome Molecular Mechanism Of Microcephaly Role of the Immune System in the Development of the CNS Diagnosis
- 3. ZIKA VIRUS Zika virus (ZIKV) is a mosquito-borne arbovirus of Flaviviridae family. Aedes aegypti mosquito is a vector in human. ZIKV is an enveloped virus with an approximately 10.8-kb positive-sense RNA genome. The genome RNA of a +ssRNA virus contains only the genes needed for the infectious cycle and is simultaneously a messenger RNA. (Rombi et al., 2020)
- 5. TRANSMISSION Mosquito Primarily spread by Aedes aegypti mosquito which is active mostly in the daytime. Sexual transmission Zika can be transmitted from men and women to their sexual partners; most cases involve transmission from men to women ZIKV can persist in semen for several months. Blood transfusion Pregnancy Zika virus can spread by vertical transmission, during pregnancy or at delivery. Tissue tropism (Rather et al., 2017) (Gorshkov et al., 2019)
- 6. GENERAL SYMPTOMS ZIKV infection frequently goes unnoticed or is asymptomatic in approximately 80% of cases and most patients present with only mild symptoms. (Jain et al.)
- 7. VERTICALLY TRANSMITTED ZIKV and the invasion of viral particles through dermal fibroblasts, epidermal keratinocytes, and immature dendritic cells via an infected mosquito. The infected mother to the fetus by infecting placental trophoblasts and macrophages (Hofbauer cells) and crossing the placental barrier. (Faizan et al., 2016)
- 8. ZIKV as TERATOGENS Teratogens are substances or other factors that can cause congenital abnormalities, which are also called birth defects. Usually abnormalities arise in the third to eighth weeks of pregnancy, when the major organ systems are forming (Wen et al., 2017) (Gilbert, 2000)
- 9. CONGENITAL ZIKA SYNDROME The first trimester of pregnancy is crucial for neurological development It characterized with 5 distinctive features that focus on brain development abnormalities (microcephaly and brain calcifications), retinal manifestations, and defects on extremities including congenital contractures and hypertonia. (Musso et al., 2019)
- 10. ZIKA VIRUS INDUCE MICROCEPHELY o Microcephaly is a congenital defect in which the head size is smaller than normal. o Two types of microcephaly are recognized. The first : the brain fails to grow into appropriate size during pregnancy at around 32 weeks of the gestation period The second: caused by a gradual decrease in the neuron production. (CDC, 2018)
- 11. WHY ARE NEURONS SUSCEPTIBLE TO ZIKA VIRUS Axl receptor mediates ZIKA Virus entry in Human progenitor cell (hNPCs) and Modulates Innate Immune Responses. MSI1 an RNA-binding protein called Musashi-1 (MSI1), which is highly expressed in neural progenitor cells and binds to 3′UTR Zika's RNA genome (Meertens et al., 2017) (Griffin, 2017)
- 12. MOLECULAR MECHANISM OF MICROCEPHALY IN NPCS (Rombi et al., 2020) (Gharbaran and Somenarain, 2017) (Wen et al., 2017)
- 13. RECEPTOR TYROSINE KINASE MEDIATING INFLAMMATORY PROCESSES STAT2 to inhibit type I interferon signaling The Akt-mTOR signalling pathway to regulate various processes in NPCs Inhibit RIG-I-like receptor signalling, supressing type I IFN induction (Wen et al., 2017)
- 14. ROLE OF THE IMMUNE SYSTEM IN THE DEVELOPMENT OF THE CNS The central nervous system (CNS) and the immune system are both intricate and highly organized systems that regulate the entire body, with both sharing certain common features in developmental mechanisms and operational modes. The innate immunity-related molecules, such as cytokines, toll-like receptors, the complement family, and acquired immunity-related molecules are also expressed in the brain and play important roles in brain development. The brain has been regarded as an immune-privileged site, it is known to contain lymphatic vessels. Not only microglia but also lymphocytes regulate cognition and play a vital role in the formation of neuronal circuits. List of sharing genes and their functions
- 15. MOLECULAR MECHANISM OF MICROCEPHALY IN NPCS MCPH1 and CDK6 (MCPH12) are an association genes with Congenital Microcephaly. MSI1-expressing cell, Zika virus competes for available MSI1, decreasing MSI1 interaction with its normal targets. Targets include messenger RNAs (mRNAs) encoding proteins that promote the expression of microcephalin (MCPH1) for fetal brain development and cyclin- dependent kinase 6 (CDK6) for cell division cycle. (Chavali et al., 2017)
- 17. DIAGNOSIS (Musso and Gubler, 2016)
- 18. PREVENTION
- 19. REFERENCES o CHAVALI, P. L., STOJIC, L., MEREDITH, L. W., JOSEPH, N., NAHORSKI, M. S., SANFORD, T. J., SWEENEY, T. R., KRISHNA, B. A., HOSMILLO, M. & FIRTH, A. E. 2017. Neurodevelopmental protein Musashi-1 interacts with the Zika genome and promotes viral replication. Science, 357, 83-88. o FAIZAN, M. I., ABDULLAH, M., ALI, S., NAQVI, I. H., AHMED, A. & PARVEEN, S. 2016. Zika virus-induced microcephaly and its possible molecular mechanism. Intervirology, 59, 152-158. o GHARBARAN, R. & SOMENARAIN, L. 2017. Insights into the molecular roles of Zika virus in human reproductive complications and congenital neuropathologies. Pathology, 49, 707-714. o GILBERT, S. F. 2000. An Introduction to Early Developmental Processes. Developmental Biology. 6th edition. Sinauer Associates. o GORSHKOV, K., SHIRYAEV, S. A., FERTEL, S., LIN, Y.-W., HUANG, C.-T., PINTO, A., FARHY, C., STRONGIN, A. Y., ZHENG, W. & TERSKIKH, A. V. 2019. Zika virus: origins, pathological action, and treatment strategies. Frontiers in Microbiology, 9, 3252. o GRIFFIN, D. E. 2017. Why are neurons susceptible to Zika virus? Science, 357, 33- 34.
- 20. o JAIN, H., PATEL, K., RAJPUT, Z., JANI, P. & TANDEL, H. ZIKA VIRUS INFECTION: THREAT TO HUMAN LIFE. o MEERTENS, L., LABEAU, A., DEJARNAC, O., CIPRIANI, S., SINIGAGLIA, L., BONNET-MADIN, L., LE CHARPENTIER, T., HAFIRASSOU, M. L., ZAMBORLINI, A. & CAO-LORMEAU, V.-M. 2017. Axl mediates ZIKA virus entry in human glial cells and modulates innate immune responses. Cell reports, 18, 324-333. o MUSSO, D. & GUBLER, D. J. 2016. Zika virus. Clinical microbiology reviews, 29, 487-524. o MUSSO, D., KO, A. I. & BAUD, D. 2019. Zika virus infection—after the pandemic. New England Journal of Medicine, 381, 1444-1457. o RATHER, I. A., KUMAR, S., BAJPAI, V. K., LIM, J. & PARK, Y.-H. 2017. Prevention and control strategies to counter ZIKA epidemic. Frontiers in microbiology, 8, 305. o ROMBI, F., BAYLISS, R., TUPLIN, A. & YEOH, S. 2020. The journey of Zika to the developing brain. Molecular Biology Reports, 1-19. o WEN, Z., SONG, H. & MING, G.-L. 2017. How does Zika virus cause microcephaly? Genes & development, 31, 849-861. REFERENCES
Editor's Notes
- https://link.springer.com/article/10.1007/s11033-020-05349-y https://jvi.asm.org/content/90/10/4864 The genome RNA of a +ssRNA virus contains only the genes needed for the infectious cycle and is simultaneously a messenger RNA The genome of ZIKV encodes a single polyprotein that is post-translationally cleaved by host and viral proteases into three structural proteins (capsid [C], premembrane [prM], and envelope [E]) and seven nonstructural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5) https://www.youtube.com/watch?v=0rPJS32ir2I
- https://www.who.int/emergencies/zika-virus/timeline/en/
- https://www.researchgate.net/figure/ZIKA-transmission-cycle-in-humans_fig3_314112380 https://www.frontiersin.org/articles/10.3389/fmicb.2018.03252/full https://www.nejm.org/doi/full/10.1056/nejmcibr1605445 ZIKV is most commonly transmitted from the bite of a mosquito, where initial infection most likely occurs in human skin cells directly affecting permissive human dermal fibroblasts, epidermal keratinocytes, and immature dendritic cells Tissue tropism is the cells and tissues of a host which support growth of a particular virus or bacteria.
- https://www.researchgate.net/figure/Symptoms-of-zika-virus-infection-Guillain-Barr-syndrome-has-been-reported-in-patients_fig2_309770875
- /https://doi.org/10.1159/000452950 [VII] A diagrammatic representation of hNPCs showing the proposed molecular mechanism of microcephaly. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5458753/ vertically transmitted from the infected mother to the fetus by infecting placental trophoblasts and macrophages (Hofbauer cells) and crossing the placental barrier trophoblast combines with the maternal endometrium to form the placenta in eutherian mammals. Blastocyst: The blastocyst possesses an inner cell mass from which the embryo will develop, and an outer layer of cells, called the trophoblast, which will eventually form the placenta
- كتاب GILLBIRT https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5392600/ Chart shows the gestational timing of maternal infection and fetal phenotype. Based on current knowledge,(18,21,22,64) if vertical transmission of Zika infection occurs, the possible risks to the pregnancy and fetus associated with a particular gestational timing of the maternal infection are summarised. The absolute risks to the fetus during each of these window periods remain to be determined, but overall, they are believed to be relatively low, with the highest risk in the first(19) and early second trimesters.(53) The light grey boxes indicate the timing of maternal infection (in gestational weeks), while the dark grey boxes show the resultant anomalies for each time period. The text in italics represents retrospective information on the presumed timing of the maternal infection, which is less accurate.(48) CNS: central nervous system. Chemical perturbation of redox states alters developmental programming causing malformation. https://www.sciencedirect.com/science/article/abs/pii/S0890623812002985
- The first trimester of pregnancy is crucial for neurological development. Zika viral infection in the mother during this period is more likely to affect the central nervous system A congenital Zika syndrome (CZS) has been characterized with 5 distinctive features that focus on brain development abnormalities (including microcephaly and brain calcifications), retinal manifestations, and defects on extremities including congenital contractures and hypertonia.
- The other relates to a normal brain size at birth but failure to grow subsequently due to the loss of dendritic connections. Brain and Nervous System A study by Nayak et al 2016 using mouse models identified radial glial cells, a type of neural progenitor cells as the primary target of ZIKV in fetal mouse brains. In this study the Asian ZIKV strain was injected into immunosupprescent mice and the effects were observed. Upon injection ZIKV was shown to target neural progenitor cells. They were also shown to prevent the proliferation and differentiation of cortical neural progenitor cells. Although genes that regulate organ development were shown to be downregulated, a gene analysis also showed that genes involved in apoptosis pathways and immune response such as cytokine production were upregulated. This study demonstrated the persistent replication of ZIKV up to twenty eight days after the initial infection (Nayak et al 2016). An infected cell is characterised by rounding, pyknosis and caspase activation. Several molecular pathways have been put together to explain the mechanisms of ZIKV infection one of which includes the cytokine receptor AXL which has been shown to mediate ZIKV infection. Most cells in the body are enriched with AXL kinases especially the cells along the pathway of ZIKV infection which includes the skin, the lymph node, micro-capillaries, microglial and cortical astrocytes. This enables the rapid expansion of ZIKV. ZIkV then signals the upregulation of AXL kinases resulting in reduced neural cell proliferation and cell death. ZIKV has also been shown to upregulate genes associated with autophagy and apoptosis such as Bmf1, Casp6 and can activate toll-like receptor 3 (TLR3) in human embryonic stem cell derived organoids which leads to the disregulation of genes involved in neurogenesis and apoptotic pathways resulting in the manifestation of clinical neurological symptoms (Nayak et al 2016).
- https://www.sciencedirect.com/science/article/pii/S2211124716317521 https://science.sciencemag.org/content/357/6346/33?rss%253D1= Binding of viral particles with the hNPCs via the AXL receptor facilitates viral entry with the formation of the endosome. Neural progenitors are cells that are capable of dividing a limited number of times and have the capacity to differentiate into a restricted repertoire of neuronal and glial cell types Neural stem cells (NSCs) are a group of ectodermal progenitor cells Interaction between the Zika virus RNA genome and an RNA-binding protein (MSI1) that is highly expressed in neural progenitor cells may explain why infection leads to fewer neural precursors and microcephaly Notch signaling promotes proliferative signaling during neurogenesis, and its activity is inhibited by Numb to promote neural differentiation. It plays a major role in the regulation of embryonic development
- Mechanisms underlying impaired brain development upon ZIKV infection. ZIKV directly targets NPCs in the developing brain and activates innate immune response, which could lead to dysregulation of genes involved in cell cycle, neurogenesis, and apoptosis, resulting in increased cell death, disrupted cell cycle progression, reduced proliferation, and premature differentiation. On the other hand, infection of ZIKV in placenta and glial cells, including astrocytes and microglia, could lead to placental insufficiency and activation of immune response (inflammation), which may elicit non-cell-autonomous effects on NPCs, neurons, and vasculature, resulting in impaired neurogenesis and microcephaly. Autography : is the natural, regulated mechanism of the cell that removes unnecessary or dysfunctional components https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5458753/ https://link.springer.com/article/10.1007/s11033-020-05349-y https://www.pathologyjournal.rcpa.edu.au/article/S0031-3025(17)30098-3/abstract second pic) Third https://link.springer.com/article/10.1007/s11033-020-05349-y
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5458753/ Study of ZIKV infection in multiple cell types indicated that ZIKV gains entry into host cells through the interaction of the virus envelope glycoprotein with cell surface receptors DC-SIGN, AXL, TYRO3, and TIM-1 and that AXL, a receptor tyrosine kinase mediating inflammatory processes, appears to play a major role here are both cell-autonomous and non-cell-autonomous effects The Akt-mTOR signalling pathway plays a crucial role in regulating various processes in NPCs, including cellular development, proliferation, survival and inhibition of autophagy https://link.springer.com/article/10.1007/s11033-020-05349-y
- The viral envelope degrades due to a decrease in pH and release of virion into the cytoplasm. Some viral RNA released in the cytoplasm replicates and forms the viral proteins using the host cell machinery. The viral RNA and proteins form progeny virions which are released from the host cell. The viral RNA also binds to the TLR3 receptors present on the surface of the endosome. Hyperactivation of TLR3-mediated innate immune response occurs with the binding of viral RNA. Subsequent dysregulation in transcription occurs due to downregulation of about 41 specific genes responsible for NPC differentiation. This leads to impaired neurogenesis and activation of the proapoptotic pathway. Consequently, the downregulation of neurogenesis and upregulation of apoptosis leads to impaired brain growth culminating in microcephaly
- The central nervous system (CNS) and the immune system are both intricate and highly organized systems that regulate the entire body, with both sharing certain common features in developmental mechanisms and operational modes. It is known that innate immunity-related molecules, such as cytokines, toll-like receptors, the complement family, and acquired immunity-related molecules, such as the major histocompatibility complex and antibody receptors, are also expressed in the brain and play important roles in brain development. Moreover, although the brain has previously been regarded as an immune-privileged site, it is known to contain lymphatic vessels. Not only microglia but also lymphocytes regulate cognition and play a vital role in the formation of neuronal circuits. This review provides an overview of the function of immune cells and immune molecules in the CNS, with particular emphasis on their effect on neural developmental processes. Certain sites of the human body have immune privilege, meaning they are able to tolerate the introduction of antigens without eliciting an inflammatory immune response. https://www.frontiersin.org/articles/10.3389/fnins.2019.00916/full
- Zika's RNA genome binds to an RNA-binding protein called Musashi-1 (MSI1), which is highly expressed in neural progenitor cells. These progenitors are precursors for neurons and astrocytes (2), cells required for cortical development. The interaction between Zika viral RNA and MSI1 may explain why these precursor cells are targets for infection. binds to the of Zika viral RNA and promotes its translation into the polyprotein that then facilitates viral replication. In an MSI1-expressing cell, Zika virus competes for available MSI1, decreasing MSI1 interaction with its normal targets. These targets include messenger RNAs (mRNAs) encoding proteins that promote the expression of microcephalin (MCPH1) and cyclin-dependent kinase 6 (CDK6). In an MSI1-expressing cell, Zika virus competes for available MSI1, decreasing MSI1 interaction with its normal targets. These targets include messenger RNAs (mRNAs) encoding proteins that promote the expression of microcephalin (MCPH1) and cyclin-dependent kinase 6 (CDK6). MCPH1 is expressed during human fetal brain development, and mutations in the encoding gene can cause microcephaly, a smaller brain size. CDK6 is a serine-threonine kinase that controls the cell division cycle, and thus, cell proliferation. MSI1 also represses the translation of mRNAs encoding the proteins Numb and p21, both of which maintain proliferation of neural precursors and cortical development https://www.researchgate.net/publication/317590663_Neurodevelopmental_protein_Musashi_1_interacts_with_the_Zika_genome_and_promotes_viral_replication https://science.sciencemag.org/content/357/6346/33
- https://cmr.asm.org/content/29/3/487 RT-PCR Reverse transcriptase