HLA-A, HSPA5, IGFBP5 and PSMA2 Are Restriction Factors for Zika Virus Growth in Astrocytic Cells.

(1) Background: Zika virus (ZIKV), an arbo-flavivirus, is transmitted via Aeges aegyptii mosquitoes Following its major outbreaks in 2013, 2014 and 2016, WHO declared it a Public Health Emergency of International Concern. Symptoms of ZIKV infection include acute fever, conjunctivitis, headache, muscle & joint pain and malaise. Cases of its transmission also have been reported via perinatal, sexual and transfusion transmission. ZIKV pathologies include meningo-encephalitis and myelitis in the central nervous system (CNS) and Guillain-Barré syndrome and acute transient polyneuritis in the peripheral nervous system (PNS). Drugs like azithromycin have been tested as inhibitors of ZIKV infection but no vaccines or treatments are currently available. Astrocytes are the most abundant cells in the CNS and among the first cells in CNS infected by ZIKV; (2) Methods: We previously used SOMAScan proteomics to study ZIKV-infected astrocytic cells. Here, we use mass spectrometric analyses to further explain dysregulations in the cellular expression profile of glioblastoma astrocytoma U251 cells. We also knocked down (KD) some of the U251 cellular proteins using siRNAs and observed the impact on ZIKV replication and infectivity; (3) Results & Conclusions: The top ZIKV dysregulated cellular networks were antimicrobial response, cell death, and energy production while top dysregulated functions were antigen presentation, viral replication and cytopathic impact. Th1 and interferon signaling pathways were among the top dysregulated canonical pathways. siRNA-mediated KD of HLA-A, IGFBP5, PSMA2 and HSPA5 increased ZIKV titers and protein synthesis, indicating they are ZIKV restriction factors. ZIKV infection also restored HLA-A expression in HLA-A KD cells by 48 h post-infection, suggesting interactions between this gene product and ZIKV.

The roles of apoptosis, autophagy and unfolded protein response in arbovirus, influenza virus, and HIV infections.

Virus infection induces different cellular responses in infected cells. These include cellular stress responses like autophagy and unfolded protein response (UPR). Both autophagy and UPR are connected to programed cell death I (apoptosis) in chronic stress conditions to regulate cellular homeostasis via Bcl2 family proteins, CHOP and Beclin-1. In this review article we first briefly discuss arboviruses, influenza virus, and HIV and then describe the concepts of apoptosis, autophagy, and UPR. Finally, we focus upon how apoptosis, autophagy, and UPR are involved in the regulation of cellular responses to arboviruses, influenza virus and HIV infections. Abbreviation: AIDS: Acquired Immunodeficiency Syndrome; ATF6: Activating Transcription Factor 6; ATG6: Autophagy-specific Gene 6; BAG3: BCL Associated Athanogene 3; Bak: BCL-2-Anatagonist/Killer1; Bax; BCL-2: Associated X protein; Bcl-2: B cell Lymphoma 2x; BiP: Chaperon immunoglobulin heavy chain binding Protein; CARD: Caspase Recruitment Domain; cART: combination Antiretroviral Therapy; CCR5: C-C Chemokine Receptor type 5; CD4: Cluster of Differentiation 4; CHOP: C/EBP homologous protein; CXCR4: C-X-C Chemokine Receptor Type 4; Cyto c: Cytochrome C; DCs: Dendritic Cells; EDEM1: ER-degradation enhancing-a-mannosidase-like protein 1; ENV: Envelope; ER: Endoplasmic Reticulum; FasR: Fas Receptor;G2: Gap 2; G2/M: Gap2/Mitosis; GFAP: Glial Fibrillary Acidic Protein; GP120: Glycoprotein120; GP41: Glycoprotein41; HAND: HIV Associated Neurodegenerative Disease; HEK: Human Embryonic Kidney; HeLa: Human Cervical Epithelial Carcinoma; HIV: Human Immunodeficiency Virus; IPS-1: IFN-ß promoter stimulator 1; IRE-1: Inositol Requiring Enzyme 1; IRGM: Immunity Related GTPase Family M protein; LAMP2A: Lysosome Associated Membrane Protein 2A; LC3: Microtubule Associated Light Chain 3; MDA5: Melanoma Differentiation Associated gene 5; MEF: Mouse Embryonic Fibroblast; MMP: Mitochondrial Membrane Permeabilization; Nef: Negative Regulatory Factor; OASIS: Old Astrocyte Specifically Induced Substrate; PAMP: Pathogen-Associated Molecular Pattern; PERK: Pancreatic Endoplasmic Reticulum Kinase; PRR: Pattern Recognition Receptor; Puma: P53 Upregulated Modulator of Apoptosis; RIG-I: Retinoic acid-Inducible Gene-I; Tat: Transactivator Protein of HIV; TLR: Toll-like receptor; ULK1: Unc51 Like Autophagy Activating Kinase 1; UPR: Unfolded Protein Response; Vpr: Viral Protein Regulatory; XBP1: X-Box Binding Protein 1.

Zika Virus Infection Disrupts Astrocytic Proteins Involved in Synapse Control and Axon Guidance.

The first human Zika virus (ZIKV) outbreak was reported in Micronesia in 2007, followed by one in Brazil in 2015. Recent studies have reported cases in Europe, Oceania and Latin America. In 2016, ZIKV transmission was also reported in the US and the World Health Organization declared it a Public Health Emergency of International Concern. Because various neurological conditions are associated with ZIKV, such as microcephaly, Guillain-Barré syndrome, and other disorders of both the central and peripheral nervous systems, including encephalopathy, (meningo)encephalitis and myelitis, and because of the lack of reliable patient diagnosis, numerous ongoing studies seek to understand molecular mechanisms underlying ZIKV pathogenesis. Astrocytes are one of the most abundant cells in the CNS. They control axonal guidance, synaptic signaling, neurotransmitter trafficking and maintenance of neurons, and are targeted by ZIKV. In this study, we used a newly developed multiplexed aptamer-based technique (SOMAScan) to examine > 1300 human astrocyte cell proteins. We identified almost 300 astrocyte proteins significantly dysregulated by ZIKV infection that span diverse functions and signaling pathways, including protein translation, synaptic control, cell migration and differentiation.

TAPP Adaptors Control B Cell Metabolism by Modulating the Phosphatidylinositol 3-Kinase Signaling Pathway: A Novel Regulatory Circuit Preventing Autoimmunity.

Class I PI3K enzymes play critical roles in B cell activation by phosphorylating plasma membrane lipids to generate two distinct phosphoinositide (PI) products, PI(3,4,5)P3 and PI(3,4)P2. These PIs each bind distinct but overlapping sets of intracellular proteins that control cell survival, cytoskeletal reorganization, and metabolic activity. The tandem PH domain containing proteins (TAPPs) bind with high specificity to PI(3,4)P2, and their genetic uncoupling from PI(3,4)P2 in TAPP knock in (KI) mice was previously found to cause chronic B cell activation, abnormal germinal centers (GCs), and autoimmunity. In this article, we find that TAPPs provide feedback regulation affecting PI3K signaling and metabolic activation of B cells. Upon activation, TAPP KI B cells show enhanced metabolic activity associated with increased extracellular acidification rate, increased expression of glucose transporter GLUT1, and increased glucose uptake. TAPP KI B cells show markedly increased activation of the PI3K-regulated kinases Akt, GSK3ß, and p70-S6K. Conversely, overexpression of the C-terminal TAPP PH domains in B cells can inhibit Akt phosphorylation by a mechanism requiring the TAPP PI(3,4)P2-binding pocket. Inhibition of the PI3K pathway in TAPP KI B cells reduced GLUT1 expression and glucose uptake, whereas inhibition of Akt alone was not sufficient to normalize these responses. TAPP KI GC B cells also show increased GLUT1 and glucose uptake, and treatment with the inhibitor of glycolysis 2-deoxy-D-glucose reduced chronic GC responses and autoantibody production within these mice. Our findings show that TAPP-PI(3,4)P2 interaction controls activation of glycolysis and highlights the significance of this pathway for B cell activation, GC responses, and autoimmunity.