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Alphavirus Infection

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Irene Salinas – One of the best experts on this subject based on the ideXlab platform.

  • Effects of ploidy and salmonid Alphavirus Infection on the skin and gill microbiome of Atlantic salmon (Salmo salar).
    PloS one, 2021
    Co-Authors: Ryan M. Brown, Sonal Patel, Lindsey Moore, Amir Mani, Irene Salinas
    Abstract:

    The microbial communities that live in symbiosis with the mucosal surfaces of animals provide the host with defense strategies against pathogens. These microbial communities are largely shaped by the environment and the host genetics. Triploid Atlantic salmon (Salmo salar) are being considered for aquaculture as they are reproductively sterile and thus cannot contaminate the natural gene pool. It has not been previously investigated how the microbiome of triploid salmon compares to that of their diploid counterparts. In this study, we compare the steady-state skin and gill microbiome of both diploid and triploid salmon, and determine the effects of salmonid Alphavirus 3 experimental Infection on their microbial composition. Our results show limited differences in the skin-associated microbiome between triploid and diploid salmon, irrespective of Infection. In the gills, we observed a high incidence of the bacterial pathogen Candidatus Branchiomonas, with higher abundance in diploid compared to triploid control fish. Diploid salmon infected with SAV3 showed greater histopathological signs of epitheliocystis compared to controls, a phenomenon not observed in triploid fish. Our results indicate that ploidy can affect the alpha diversity of the gills but not the skin-associated microbial community. Importantly, during a natural outbreak of Branchiomonas sp. the gill microbiome of diploid Atlantic salmon became significantly more dominated by this pathogen than in triploid animals. Thus, our results suggest that ploidy may play a role on Atlantic salmon gill health and provide insights into co-Infection with SAV3 and C. Branchiomonas in Atlantic salmon.

  • Salmonid Alphavirus Infection causes skin dysbiosis in Atlantic salmon (Salmo salar L.) post-smolts.
    PLOS ONE, 2017
    Co-Authors: Kristin M. Reid, Sonal Patel, Aaron J Robinson, Lijing Bu, Jiraporn Jarungsriapisit, L.j. Moore, Irene Salinas
    Abstract:

    Interactions among host, microbiota and viral pathogens are complex and poorly understood. The goal of the present study is to assess the changes in the skin microbial community of Atlantic salmon (Salmo salar L.) in response to experimental Infection with salmonid Alphavirus (SAV). The salmon skin microbial community was determined using 16S rDNA pyrosequencing in five different experimental groups: control, 7 days after Infection with low-dose SAV, 14 days after Infection with low-dose SAV, 7 days after Infection with high-dose SAV, and 14 days after Infection with high-dose SAV. Both Infection treatment and time after Infection were strong predictors of the skin microbial community composition. Skin samples from SAV3 infected fish showed an unbalanced microbiota characterized by a decreased abundance of Proteobacteria such as Oleispira sp. and increased abundances of opportunistic taxa including Flavobacteriaceae, Streptococcaceae and Tenacibaculum sp. These results demonstrate that viral Infections can result in skin dysbiosis likely rendering the host more susceptible to secondary bacterial Infections.

Diane E. Griffin – One of the best experts on this subject based on the ideXlab platform.

  • stress granule formation disassembly and composition are regulated by Alphavirus adp ribosylhydrolase activity
    Proceedings of the National Academy of Sciences of the United States of America, 2021
    Co-Authors: Aravinth Kumar Jayabalan, Diane E. Griffin, Srivathsan Adivarahan, Aakash Koppula, Rachy Abraham, Mona Batish, Daniel Zenklusen, Anthony K L Leung
    Abstract:

    While biomolecular condensates have emerged as an important biological phenomenon, mechanisms regulating their composition and the ways that viruses hijack these mechanisms remain unclear. The mosquito-borne Alphaviruses cause a range of diseases from rashes and arthritis to encephalitis, and no licensed drugs are available for treatment or vaccines for prevention. The Alphavirus virulence factor nonstructural protproteina> (nsP3) suppresses the formation of stress granules (SGs)-a class of cytoplasmic condensates enriched with translation initiation factors and formed during the early stage of Infection. nsP3 has a conserved N-terminal macrodomain that hydrolyzes ADP-ribose from ADP-ribosylated proteins and a C-terminal hypervariable domain that binds the essential SG component G3BP1. Here, we show that macrodomain hydrolase activity reduces the ADP-ribosylation of G3BP1, disassembles virus-induced SGs, and suppresses SG formation. Expression of nsP3 results in the formation of a distinct class of condensates that lack translation initiation factors but contain G3BP1 and other SG-associated RNA-bindbinding proteins. Expression of ADP-ribosylhydrolase-deficient nsP3 results in condensates that retain translation initiation factors as well as RNA-bindbinding proteins, similar to SGs. Therefore, our data reveal that ADP-ribosylation controls the composition of biomolecular condensates, specifically the localization of translation initiation factors, during Alphavirus Infection.

  • interferon gamma modulation of the local t cell response to Alphavirus encephalomyelitis
    Viruses, 2020
    Co-Authors: Victoria K. Baxter, Diane E. Griffin
    Abstract:

    Infection of mice with Sindbis virus (SINV) provides a model for examining the role of the immune response to Alphavirus Infection of the central nervous system (CNS). Interferon-gamma (IFN-γ) is an important component of this response, and we show that SINV-infected differentiated neurons respond to IFN-γ in vitro by induction of antiviral genes and suppression of virus replication. To determine the in vivo effects of IFN-γ on SINV clearance and T cell responses, C57BL/6 mice lacking IFN-γ or IFN-γ receptor-1 were compared to wild-type (WT) mice after intracranial SINV Infection. In WT mice, IFN-γ was first produced in the CNS by natural killer cells and then by CD4+ and CD8+ T cells. Mice with impaired IFN-γ signaling initiated clearance of viral RNA earlier than WT mice associated with CNS entry of more granzyme B-producing CD8+ T cells. However, these mice established fewer CD8+ tissue-resident memory T (TRM) cells and were more likely to experience reactivation of viral RNA synthesis late after Infection. Therefore, IFN-γ suppresses the local development of granzyme B-expressing CD8+ T cells and slows viral RNA clearance but promotes CD8+ TRM cell establishment.

  • death and gastrointestinal bleeding complicate encephalomyelitis in mice with delayed appearance of cns igm after intranasal Alphavirus Infection
    Journal of General Virology, 2018
    Co-Authors: Elizabeth M Troisi, Victoria K. Baxter, Nathan M Pate, Julia N Zhao, Diane E. Griffin
    Abstract:

    Central nervous system (CNS) Infection of C57BL/6 mice with the TE strain of Sindbis virus (SINV) provides a valuable animal model for studying the pathogenesis of Alphavirus encephalomyelitis. While SINV TE inoculated intracranially causes little mortality, 20–30 % of mice inoculated intranasally (IN) died 8 to 11 days after Infection, the period during which immune cells typically infiltrate the brain and clear infectious virus. To examine the mechanism behind the mortality, mice infected IN with SINV TE were monitored for evidence of neurological disease, and those with signs of severe disease (moribund) were sacrificed and tissues collected. Mice showing the usual mild signs of encephalomyelitis were concurrently sacrificed to serve as time-matched controls (sick). Sixty-eight per cent of the moribund mice, but none of the sick mice, showed upper gastrointestinal bleeding due to gastric ulceration. Clinical disease and gastrointestinal pathology could not be attributed to direct viral Infection of tissues outside of the CNS, and brain pathology and inflammation were comparable in sick and moribund mice. However, more SINV antigen was present in the brains of moribund mice, and clearance of infectious virus from the CNS was delayed compared to sick mice. Lower levels of SINV-specific IgM and fewer B220+ B cells were present in the brains of moribund mice compared to sick mice, despite similar levels of antiviral IgM and IgG in serum. These findings highlight the importance of the local antibody response in determining the outcome of viral encephalomyelitis and offer a model system for understanding individual variation in this response.

William B Klimstra – One of the best experts on this subject based on the ideXlab platform.

  • applications of minimally invasive multimodal telemetry for continuous monitoring of brain function and intracranial pressure in macaques with acute viral encephalitis
    PLOS ONE, 2020
    Co-Authors: Jeneveve D Lundy, Emily L Cottle, Katherine J Omalley, Anita Trichel, William B Klimstra, Amy L Hartman, Douglas S Reed, Tobias Teichert
    Abstract:

    Alphaviruses such as Venezuelan equine encephalitis virus (VEEV) and Eastern equine encephalitis virus (EEEV) are arboviruses that can cause severe zoonotic disease in humans. Both VEEV and EEEV are highly infectious when aerosolized and can be used as biological weapons. Vaccines and therapeutics are urgently needed, but efficacy determination requires animal models. The cynomolgus macaque (Macaca fascicularis) provides a relevant model of human disease, but questions remain whether vaccines or therapeutics can mitigate CNS Infection or disease in this model. The documentation of Alphavirus encephalitis in animals relies on traditional physiological biomarkers and behavioral/neurological observations by veterinary staff; quantitative measurements such as electroencephalography (EEG) and intracranial pressure (ICP) can recapitulate underlying encephalitic processes. We detail a telemetry implantation method suitable for continuous monitoring of both EEG and ICP in awake macaques, as well as methods for collection and analysis of such data. We sought to evaluate whether changes in EEG/ICP suggestive of CNS penetration by virus would be seen after aerosol exposure of naive macaques to VEEV IC INH9813 or EEEV V105 strains compared to mock-Infection in a cohort of twelve adult cynomolgus macaques. Data collection ran continuously from at least four days preceding aerosol exposure and up to 50 days thereafter. EEG signals were processed into frequency spectrum bands (delta: [0.4 – 4Hz); theta: [4 – 8Hz); alpha: [8-12Hz); beta: [12-30] Hz) and assessed for viral encephalitis-associated changes against robust background circadian variation while ICP data was assessed for signal fidelity, circadian variability, and for meaningful differences during encephalitis. Results indicated differences in delta, alpha, and beta band magnitude in infected macaques, disrupted circadian rhythm, and proportional increases in ICP in response to Alphavirus Infection. This novel enhancement of the cynomolgus macaque model offers utility for timely determination of onset, severity, and resolution of encephalitic disease and for the evaluation of vaccine and therapeutic candidates.

  • Macromolecular Synthesis Shutoff Resistance by Myeloid Cells Is Critical to IRF7-Dependent Systemic Interferon Alpha/Beta Induction after Alphavirus Infection.
    Journal of virology, 2019
    Co-Authors: Nishank Bhalla, Christina L. Gardner, Sierra N Downs, Matthew D. Dunn, Chengqun Sun, William B Klimstra
    Abstract:

    Alphavirus Infection of fibroblastic cell types in vitro inhibits host cell translation and transcription, leading to suppression of interferon alpha/beta (IFN-α/β) production. However, the effect of Infection upon myeloid cells, which are often the first cells encountered by Alphaviruses in vivo, is unclear. Previous studies demonstrated an association of systemic IFN-α/β production with myeloid cell Infection efficiency. Murine Infection with wild-type Venezuelan equine encephalitis virus (VEEV), a highly myeloid-cell-tropic Alphavirus, results in secretion of very high systemic levels of IFN-α/β, suggesting that stress responses in responding cells are active. Here, we infected myeloid cell cultures with VEEV to identify the cellular source of IFN-α/β, the timing and extent of translation and/or transcription inhibition in infected cells, and the transcription factors responsible for IFN-α/β induction. In contrast to fibroblast Infection, myeloid cell cultures infected with VEEV secreted IFN-α/β that increased until cell death was observed. VEEV inhibited translation in most cells early after Infection ( 6 h p.i.). Furthermore, the interferon regulatory factor 7 (IRF7), but not IRF3, transcription factor was critical for IFN-α/β induction in vitro and in sera of mice. We identified a subset of infected Raw 264.7 myeloid cells that resisted VEEV-induced translation inhibition and secreted IFN-α/β despite virus Infection. However, in the absence of IFN receptor signaling, the size of this cell population was diminished. These results indicate that IFN-α/β induction in vivo is IRF7 dependent and arises in part from a subset of myeloid cells that are resistant, in an IFN-α/β-dependent manner, to VEEV-induced macromolecular synthesis inhibition.IMPORTANCE Most previous research exploring the interaction of Alphaviruses with host cell antiviral responses has been conducted using fibroblast lineage cell lines. Previous studies have led to the discovery of virus-mediated activities that antagonize host cell antiviral defense pathways, such as host cell translation and transcription inhibition and suppression of STAT1 signaling. However, their relevance and impact upon myeloid lineage cell types, which are key responders during the initial stages of Alphavirus Infection in vivo, have not been well studied. Here, we demonstrate the different abilities of myeloid cells to resist VEEV Infection compared to nonmyeloid cell types and begin to elucidate the mechanisms by which host antiviral responses are upregulated in myeloid cells despite the actions of virus-encoded antagonists.

  • macromolecular synthesis shutoff resistance by myeloid cells is critical to irf7 dependent systemic interferon alpha beta induction after Alphavirus Infection
    Journal of Virology, 2019
    Co-Authors: Nishank Bhalla, Christina L. Gardner, Sierra N Downs, Matthew D. Dunn, Chengqun Sun, William B Klimstra
    Abstract:

    Alphavirus Infection of fibroblastic cell types in vitro inhibits host cell translation and transcription, leading to suppression of interferon alpha/beta (IFN-α/β) production. However, the effect of Infection upon myeloid cells, which are often the first cells encountered by Alphaviruses in vivo, is unclear. Previous studies demonstrated an association of systemic IFN-α/β production with myeloid cell Infection efficiency. Murine Infection with wild-type Venezuelan equine encephalitis virus (VEEV), a highly myeloid-cell-tropic Alphavirus, results in secretion of very high systemic levels of IFN-α/β, suggesting that stress responses in responding cells are active. Here, we infected myeloid cell cultures with VEEV to identify the cellular source of IFN-α/β, the timing and extent of translation and/or transcription inhibition in infected cells, and the transcription factors responsible for IFN-α/β induction. In contrast to fibroblast Infection, myeloid cell cultures infected with VEEV secreted IFN-α/β that increased until cell death was observed. VEEV inhibited translation in most cells early after Infection ( 6 h p.i.). Furthermore, the interferon regulatory factor 7 (IRF7), but not IRF3, transcription factor was critical for IFN-α/β induction in vitro and in sera of mice. We identified a subset of infected Raw 264.7 myeloid cells that resisted VEEV-induced translation inhibition and secreted IFN-α/β despite virus Infection. However, in the absence of IFN receptor signaling, the size of this cell population was diminished. These results indicate that IFN-α/β induction in vivo is IRF7 dependent and arises in part from a subset of myeloid cells that are resistant, in an IFN-α/β-dependent manner, to VEEV-induced macromolecular synthesis inhibition.IMPORTANCE Most previous research exploring the interaction of Alphaviruses with host cell antiviral responses has been conducted using fibroblast lineage cell lines. Previous studies have led to the discovery of virus-mediated activities that antagonize host cell antiviral defense pathways, such as host cell translation and transcription inhibition and suppression of STAT1 signaling. However, their relevance and impact upon myeloid lineage cell types, which are key responders during the initial stages of Alphavirus Infection in vivo, have not been well studied. Here, we demonstrate the different abilities of myeloid cells to resist VEEV Infection compared to nonmyeloid cell types and begin to elucidate the mechanisms by which host antiviral responses are upregulated in myeloid cells despite the actions of virus-encoded antagonists.

Dennis Brown – One of the best experts on this subject based on the ideXlab platform.

  • insect response to Alphavirus Infection establishment of Alphavirus persistence in insect cells involves inhibition of viral polyprotein cleavage
    Virus Research, 2010
    Co-Authors: Usharani Mudiganti, Raquel Hernandez, Dennis Brown
    Abstract:

    Abstract Alphavirus persistence in the insect vector is an essential element in the vector–host transmission cycle of the virus and provides a model to study the biochemical and molecular basis for virus–vector coexistence. The prototype Alphavirus Sindbis (SV) establishes persistent Infections in invertebrate cell cultures which are characterized by low levels of virus production. We hypothesized that antiviral factors may be involved in decreasing the virus levels as virus persistence is established in invertebrate cells. Transcription profiles in Drosophila S2 cells at 5 days post-Infection with SV identified families of gene products that code for factors that can explain previous observations seen in insect cells infected with Alphaviruses. Genomic array analysis identified up-regulation of gene products involved in intracellular membmembrane vesicle formation, cell growth rate changes and immune-related functions in S2 cells infected with SV. Transcripts coding for factors involved in different aspects of the Notch signaling pathway had increased in expression. Increased expression of ankyrin, plap, syx13 , unc-13 , csp, rab1 and rab8 may aid in formation of virus containing vesicles and in intracellular transport of viral structural proteins. Possible functions of these gene products and relevant hypotheses are discussed. We confirmed the up-regulation of a wide-spectrum protease inhibitor, Thiol-ester containing Protein (TEP) II. We report inhibition of the viral polyprotein cleavage at 5 days post-Infection (dpi) and after superInfection of SV-infected cells at 5 dpi. We propose that inefficient cleavage of the polyprotein may, at least in part, lead to reduced levels of virus seen as persistence is established.

  • The distribution of Sindbis virus proteins in mosquito cells as determined by immunofluorescence and immunoelectron microscopy.
    Journal of General Virology, 1993
    Co-Authors: Mary L. Miller, Dennis Brown
    Abstract:

    Two Aedes albopictus (mosquito) subclones, C7–10 and C6/36, were examined by immunofluorescence and immunoelectron microscopy for the distribution of Sindbis virus structural and non-structural proteins. Both the viral glycoproteins, E1 and E2, and the non-structural proteins, nsP1 and nsP2, were found within vesicles and electron-dense, amorphous matrices associated with Sindbis virus Infection. The labelling patterns indicated that both replication of viral RNA and production of virus particles were localized within the same structures in the infected cell. The data support previous reports that Alphavirus Infection is contained within specific structures in the cytoplasm and provide additional evidence that the C6/36 and C7–10 subclones may represent different tissue types in the adult insect.

  • Alphavirus Infection in Cultured Tissue Cells
    Advances in Disease Vector Research, 1991
    Co-Authors: Mary L. Miller, Dennis Brown
    Abstract:

    Mosquitoes have been recognized since the early 1900s as vectors of a variety of pathogenic viruses that have plagued humans and domestic animals for centuries. Thorough understanding of the life cycles of these pathogens is essential for developing methods for their control. Epidemiological studies have yielded information on the vector species of many of these disease-causing agents and entomological studies have provided details regarding how arboviruses (arthropod-borne viruses) are cycled in nature through their insect and vertebrate hosts. As a result, eradication measures such as mosquito population control and physical barriers to hematophagous insects have developed, which have proven reasonably effective in certain regions of the world. However, the fact that many vectored phatogens are still responsible for disease outbreaks reaching epidemic proportions and remain a threat to the domestic livestock industry necessitates further research on their control.

Victoria K. Baxter – One of the best experts on this subject based on the ideXlab platform.

  • Immunopathogenesis of Alphaviruses.
    Advances in virus research, 2020
    Co-Authors: Victoria K. Baxter, Mark T. Heise
    Abstract:

    Abstract Alphaviruses, members of the enveloped, positive-sense, single-stranded RNA Togaviridae family, represent a reemerging public health threat as mosquito vectors expand into new geographic territories. The Old World Alphaviruses, which include chikungunya virus, Ross River virus, and Sindbis virus, tend to cause a clinical syndrome characterized by fever, rash, and arthritis, whereas the New World Alphaviruses, which consist of Venezuelan equine encephalitis virus, eastern equine encephalitis virus, and western equine encephalitis virus, induce encephalomyelitis. Following recovery from the acute phase of Infection, many patients are left with debilitating persistent joint and neurological complications that can last for years. Clues from human cases and studies using animal models strongly suggest that much of the disease and pathology induced by Alphavirus Infection, particularly atypical and chronic manifestations, is mediated by the immune system rather than directly by the virus. This review discusses the current understanding of the immunopathogenesis of the arthritogenic and neurotropic Alphaviruses accumulated through both natural Infection of humans and experimental Infection of animals, particularly mice. As treatment following Alphavirus Infection is currently limited to supportive care, understanding the contribution of the immune system to the disease process is critical to developing safe and effective therapies.

  • interferon gamma modulation of the local t cell response to Alphavirus encephalomyelitis
    Viruses, 2020
    Co-Authors: Victoria K. Baxter, Diane E. Griffin
    Abstract:

    Infection of mice with Sindbis virus (SINV) provides a model for examining the role of the immune response to Alphavirus Infection of the central nervous system (CNS). Interferon-gamma (IFN-γ) is an important component of this response, and we show that SINV-infected differentiated neurons respond to IFN-γ in vitro by induction of antiviral genes and suppression of virus replication. To determine the in vivo effects of IFN-γ on SINV clearance and T cell responses, C57BL/6 mice lacking IFN-γ or IFN-γ receptor-1 were compared to wild-type (WT) mice after intracranial SINV Infection. In WT mice, IFN-γ was first produced in the CNS by natural killer cells and then by CD4+ and CD8+ T cells. Mice with impaired IFN-γ signaling initiated clearance of viral RNA earlier than WT mice associated with CNS entry of more granzyme B-producing CD8+ T cells. However, these mice established fewer CD8+ tissue-resident memory T (TRM) cells and were more likely to experience reactivation of viral RNA synthesis late after Infection. Therefore, IFN-γ suppresses the local development of granzyme B-expressing CD8+ T cells and slows viral RNA clearance but promotes CD8+ TRM cell establishment.

  • death and gastrointestinal bleeding complicate encephalomyelitis in mice with delayed appearance of cns igm after intranasal Alphavirus Infection
    Journal of General Virology, 2018
    Co-Authors: Elizabeth M Troisi, Victoria K. Baxter, Nathan M Pate, Julia N Zhao, Diane E. Griffin
    Abstract:

    Central nervous system (CNS) Infection of C57BL/6 mice with the TE strain of Sindbis virus (SINV) provides a valuable animal model for studying the pathogenesis of Alphavirus encephalomyelitis. While SINV TE inoculated intracranially causes little mortality, 20–30 % of mice inoculated intranasally (IN) died 8 to 11 days after Infection, the period during which immune cells typically infiltrate the brain and clear infectious virus. To examine the mechanism behind the mortality, mice infected IN with SINV TE were monitored for evidence of neurological disease, and those with signs of severe disease (moribund) were sacrificed and tissues collected. Mice showing the usual mild signs of encephalomyelitis were concurrently sacrificed to serve as time-matched controls (sick). Sixty-eight per cent of the moribund mice, but none of the sick mice, showed upper gastrointestinal bleeding due to gastric ulceration. Clinical disease and gastrointestinal pathology could not be attributed to direct viral Infection of tissues outside of the CNS, and brain pathology and inflammation were comparable in sick and moribund mice. However, more SINV antigen was present in the brains of moribund mice, and clearance of infectious virus from the CNS was delayed compared to sick mice. Lower levels of SINV-specific IgM and fewer B220+ B cells were present in the brains of moribund mice compared to sick mice, despite similar levels of antiviral IgM and IgG in serum. These findings highlight the importance of the local antibody response in determining the outcome of viral encephalomyelitis and offer a model system for understanding individual variation in this response.