Alphavirus interactions with cellular receptors are likely to play a major role determining viral tropism and driving virus-induced disease. However, the viral receptors that mediate alphavirus entry are poorly understood. A genome wide screen using Sindbis virus identified NRAMP as a potential alphavirus entry receptor in insect cells. Additional studies suggest that NRAMP is also an entry receptor for Venezuelan Equine Encephalitis virus. Furthermore, in mammalian cells the ubiquitously expressed homolog, NRAMP2, can mediate infection of these alphaviruses. Our long-term goal is to dissect the role of NRAMPs in infectivity and pathogenesis of alphaviruses with the goal of developing strategies to combat these pathogens. We will study this important interaction from both the perspective of the viruses and their varied hosts, including studies to determine whether additional alphaviruses use NRAMP as a receptor and to define the regions of the viral glycoproteins that mediate NRAMP binding. Since mammals have two homologous genes, NRAMP1 and NRAMP2, we will also test whether NRAMP1 and NRAMP2 can functionally substitute for one another as alphavirus entry receptors and test whether one or both of these molecules is required for alphavirus infection in primary cells from diverse lineages and in vivo. We will take advantage of powerful assays that we have developed to study alphavirus entry and infection both in insect and mammalian cells and extend these studies to mice and adult flies to explore the role of NRAMPs in viral pathogenesis and spread. Our central hypothesis is that dissecting the interactions of these medically important arboviruses with their receptor will reveal mechanisms that will aid in the development of antiviral treatments against these understudied pathogens for which there are no vaccines or therapeutics.
Alphaviruses are a significant cause of human disease and understanding how alphavirus receptors regulate viral tropism and pathogenesis is likely to result in the development of new therapies against these human pathogens. The studies outlined in this proposal will evaluate the role of NRAMP1 and NRAMP2 as entry receptors for alphaviruses in insects and vertebrate hosts, with the ultimate goal of elucidating how NRAMP/alphavirus interactions impact viral pathogenesis.
|Panda, Debasis; Pascual-Garcia, Pau; Dunagin, Margaret et al. (2014) Nup98 promotes antiviral gene expression to restrict RNA viral infection in Drosophila. Proc Natl Acad Sci U S A 111:E3890-9|
|Shapiro, Jillian S; Schmid, Sonja; Aguado, Lauren C et al. (2014) Drosha as an interferon-independent antiviral factor. Proc Natl Acad Sci U S A 111:7108-13|
|Moy, Ryan H; Gold, Beth; Molleston, Jerome M et al. (2014) Antiviral autophagy restrictsRift Valley fever virus infection and is conserved from flies to mammals. Immunity 40:51-65|
|Xu, Jie; Cherry, Sara (2014) Viruses and antiviral immunity in Drosophila. Dev Comp Immunol 42:67-84|
|Yasunaga, Ari; Hanna, Sheri L; Li, Jianqing et al. (2014) Genome-wide RNAi screen identifies broadly-acting host factors that inhibit arbovirus infection. PLoS Pathog 10:e1003914|
|Petersen, Josiah; Drake, Mary Jane; Bruce, Emily A et al. (2014) The major cellular sterol regulatory pathway is required for Andes virus infection. PLoS Pathog 10:e1003911|
|Moy, Ryan H; Cole, Brian S; Yasunaga, Ari et al. (2014) Stem-loop recognition by DDX17 facilitates miRNA processing and antiviral defense. Cell 158:764-77|
|Hopkins, Kaycie C; McLane, Laura M; Maqbool, Tariq et al. (2013) A genome-wide RNAi screen reveals that mRNA decapping restricts bunyaviral replication by limiting the pools of Dcp2-accessible targets for cap-snatching. Genes Dev 27:1511-25|
|Xu, Jie; Hopkins, Kaycie; Sabin, Leah et al. (2013) ERK signaling couples nutrient status to antiviral defense in the insect gut. Proc Natl Acad Sci U S A 110:15025-30|
|Panda, Debasis; Rose, Patrick P; Hanna, Sheri L et al. (2013) Genome-wide RNAi screen identifies SEC61A and VCP as conserved regulators of Sindbis virus entry. Cell Rep 5:1737-48|
Showing the most recent 10 out of 12 publications