Browsing by Subject "Arenavirus"

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    Arenavirus-Host Interactions: Roles of Viral Glycoprotein and Nucleoprotein in Mediating Cell Entry and Host Immune Suppression
    (2018-06) Shao, Junjie
    Several mammalian arenaviruses can infect humans and non-human primates and can cause severe and deadly hemorrhagic fever diseases. There are currently no FDA-approved vaccines available for the prevention of infection by any of these pathogenic arenaviruses and treatment options for the infections are extremely limited. Arenavirus is an enveloped, bi-segmented, single-stranded RNA virus. Its genome encodes four viral proteins: the RNA-dependent RNA polymerase L, the nucleoprotein NP, the glycoprotein complex GPC, and the matrix protein Z. Arenaviral GPC plays critical roles in the first step of virus infection (i.e, cell entry), which involves receptor recognition and virus-host membrane fusion activity. Arenaviral NP is a multifunctional protein, which is involved in the formation of the viral ribonucleoprotein (RNP) complex needed for viral genome replication and transcription, and in host immunosuppression. Arenaviral L protein, together with NP, is responsible for genome replication and transcription. Arenaviral Z protein is the driving force of virion budding from the membrane of the infected cells and is also involved in mediating immune suppression. My study focused on the roles of arenaviral GPC and NP in mediating cell entry and host immune suppression. Arenaviral GPC is synthesized as a single polypeptide and is post-translationally processed by the cellular signal peptidase and S1P cellular protease into stable signal peptide (SSP), the receptor-binding GP1 and transmembrane GP2 subunits. My thesis focused on characterizing (1) the role of the glycoprotein SSP in mediating entry of the Pichinde virus (PICV) into cells in culture and its role in disease pathogenesis in guinea pigs, (2) the role of several conserved amino acids residues in the glycoprotein GP2 C-terminal domain (CTD) of PICV in mediating virus entry in vitro, and (3) the role of NP in mediating immune suppression via the PACT-RIG-I innate immune pathway.
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    Pichinde virus infection of outbred Hartley guinea pigs and mice as small animal models of human Lassa fever
    (2022-05) Brisse, Morgan
    Arenaviruses are viruses that can cause severe and deadly hemorrhagic fever infections in Africa and South America, including Lassa virus that causes Lassa fever in several countries in west Africa. There are currently no vaccines and very limited therapeutics available for Lassa fever. There are also several under-addressed complications of Lassa fever such as high infant mortality during pregnancy infection and sensorineural hearing loss. An aspect of Lassa virus that makes it difficult to study is its designation as a highly pathogenic human virus that requires its handling in strict bio-containment laboratory (BSL4 level laboratory), which significantly limits the scope of studies to understand the host immune responses to this virus infection and disease pathology and pathogenesis. This thesis describes two studies that use two different small animal models of infection with the Pichinde virus as surrogate models of human Lassa fever that can be carried out in a conventional (BSL2 level) laboratory, as Pichinde virus is non-pathogenic in humans. The first study uses mice that are genetically engineered to be deficient in the viral RNA-sensing pathway, as the result of genetic ablation of the host proteins RIG-I and MDA5. This study was carried out to determine the importance of RIG-I and MDA5 in providing innate immune protection against Pichinde virus in mice, which may shed important light on virus-host interactions in the natural rodent reservoirs of Lassa virus and in human infection by this deadly virus. The second investigates whether outbred Hartley guinea pigs experienced hearing loss in addition to other disease signs that are similar in human Lassa fever. Taken together, these studies help establish Pichinde virus infection of small animals (mice and guinea pigs) as a useful and relevant model for human Lassa fever that can be used for future vaccine and/or therapeutic testing to benefit human patients.