RESUMO
Infection with viruses, such as the lactate dehydrogenase-elevating virus (LDV), is known to trigger the onset of autoimmune anemia through the enhancement of the phagocytosis of autoantibody-opsonized erythrocytes by activated macrophages. Type I interferon receptor-deficient mice show enhanced anemia, which suggests a protective effect of these cytokines, partly through the control of type II interferon production. The development of anemia requires the expression of Fcγ receptors (FcγR) I, III, and IV. Whereas LDV infection decreases FcγR III expression, it enhances FcγR I and IV expression in wild-type animals. The LDV-associated increase in the expression of FcγR I and IV is largely reduced in type I interferon receptor-deficient mice, through both type II interferon-dependent and -independent mechanisms. Thus, the regulation of the expression of FcγR I and IV, but not III, by interferons may partly explain the exacerbating effect of LDV infection on anemia that results from the enhanced phagocytosis of IgG autoantibody-opsonized erythrocytes.
Assuntos
Anemia Hemolítica Autoimune/imunologia , Infecções por Arterivirus/imunologia , Interferons/metabolismo , Vírus Elevador do Lactato Desidrogenase/imunologia , Receptores de IgG/metabolismo , Anemia Hemolítica Autoimune/virologia , Animais , Infecções por Arterivirus/virologia , Interações Hospedeiro-Patógeno , Camundongos Endogâmicos C57BL , Camundongos Knockout , FagocitoseRESUMO
Equine arteritis virus (EAV) has the unique ability to establish long-term persistent infection in the reproductive tract of stallions and be sexually transmitted. Previous studies showed that long-term persistent infection is associated with a specific allele of the CXCL16 gene (CXCL16S) and that persistence is maintained despite the presence of local inflammatory and humoral and mucosal antibody responses. Here, we performed transcriptomic analysis of the ampullae, the primary site of EAV persistence in long-term EAV carrier stallions, to understand the molecular signatures of viral persistence. We demonstrated that the local CD8+ T lymphocyte response is predominantly orchestrated by the transcription factors eomesodermin (EOMES) and nuclear factor of activated T-cells cytoplasmic 2 (NFATC2), which is likely modulated by the upregulation of inhibitory receptors. Most importantly, EAV persistence is associated with an enhanced expression of CXCL16 and CXCR6 by infiltrating lymphocytes, providing evidence of the implication of this chemokine axis in the pathogenesis of persistent EAV infection in the stallion reproductive tract. Furthermore, we have established a link between the CXCL16 genotype and the gene expression profile in the ampullae of the stallion reproductive tract. Specifically, CXCL16 acts as a "hub" gene likely driving a specific transcriptional network. The findings herein are novel and strongly suggest that RNA viruses such as EAV could exploit the CXCL16/CXCR6 axis in order to modulate local inflammatory and immune responses in the male reproductive tract by inducing a dysfunctional CD8+ T lymphocyte response and unique lymphocyte homing in the reproductive tract.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/virologia , Equartevirus/imunologia , Equartevirus/patogenicidade , Animais , Infecções por Arterivirus/genética , Infecções por Arterivirus/imunologia , Infecções por Arterivirus/veterinária , Portador Sadio/imunologia , Portador Sadio/veterinária , Portador Sadio/virologia , Quimiocina CXCL16/genética , Quimiocina CXCL16/imunologia , Perfilação da Expressão Gênica , Genitália Masculina/imunologia , Genitália Masculina/patologia , Genitália Masculina/virologia , Doenças dos Cavalos/genética , Doenças dos Cavalos/imunologia , Doenças dos Cavalos/virologia , Cavalos , Interações entre Hospedeiro e Microrganismos/genética , Interações entre Hospedeiro e Microrganismos/imunologia , Masculino , Receptores CXCR6/genética , Receptores CXCR6/imunologia , Receptores Virais/imunologia , Fatores de Transcrição/imunologia , Eliminação de Partículas Virais/genética , Eliminação de Partículas Virais/imunologiaRESUMO
Simian hemorrhagic fever virus (SHFV) causes a fulminant and typically lethal viral hemorrhagic fever (VHF) in macaques (Cercopithecinae: Macaca spp.) but causes subclinical infections in patas monkeys (Cercopithecinae: Erythrocebus patas). This difference in disease course offers a unique opportunity to compare host responses to infection by a VHF-causing virus in biologically similar susceptible and refractory animals. Patas and rhesus monkeys were inoculated side-by-side with SHFV. Unlike the severe disease observed in rhesus monkeys, patas monkeys developed a limited clinical disease characterized by changes in complete blood counts, serum chemistries, and development of lymphadenopathy. Viral RNA was measurable in circulating blood 2 days after exposure, and its duration varied by species. Infectious virus was detected in terminal tissues of both patas and rhesus monkeys. Varying degrees of overlap in changes in serum concentrations of interferon (IFN)-γ, monocyte chemoattractant protein (MCP)-1, and interleukin (IL)-6 were observed between patas and rhesus monkeys, suggesting the presence of common and species-specific cytokine responses to infection. Similarly, quantitative immunohistochemistry of livers from terminal monkeys and whole blood flow cytometry revealed varying degrees of overlap in changes in macrophages, natural killer cells, and T-cells. The unexpected degree of overlap in host response suggests that relatively small subsets of a host's response to infection may be responsible for driving hemorrhagic fever pathogenesis. Furthermore, comparative SHFV infection in patas and rhesus monkeys offers an experimental model to characterize hostâ»response mechanisms associated with viral hemorrhagic fever and evaluate pan-viral hemorrhagic fever countermeasures.
Assuntos
Infecções por Arterivirus/veterinária , Arterivirus/patogenicidade , Febres Hemorrágicas Virais/veterinária , Interações Hospedeiro-Patógeno , Doenças dos Macacos/imunologia , Animais , Anticorpos Antivirais/sangue , Arterivirus/imunologia , Infecções por Arterivirus/imunologia , Citocinas/sangue , Erythrocebus , Feminino , Febres Hemorrágicas Virais/imunologia , Macaca , Macrófagos/virologia , Masculino , Doenças dos Macacos/virologia , RNA Viral , Replicação ViralRESUMO
Equine arteritis virus (EAV) has the ability to establish persistent infection in the reproductive tract of the stallion (carrier) and is continuously shed in its semen. We have recently demonstrated that EAV persists within stromal cells and a subset of lymphocytes in the stallion accessory sex glands in the presence of a significant local inflammatory response. In the present study, we demonstrated that EAV elicits a mucosal antibody response in the reproductive tract during persistent infection with homing of plasma cells into accessory sex glands. The EAV-specific immunoglobulin isotypes in seminal plasma included IgA, IgG1, IgG3/5, and IgG4/7. Interestingly, seminal plasma IgG1 and IgG4/7 possessed virus-neutralizing activity, while seminal plasma IgA and IgG3/5 did not. However, virus-neutralizing IgG1 and IgG4/7 in seminal plasma were not effective in preventing viral infectivity. In addition, the serological response was primarily mediated by virus-specific IgM and IgG1, while virus-specific serum IgA, IgG3/5, IgG4/7, and IgG6 isotype responses were not detected. This is the first report characterizing the immunoglobulin isotypes in equine serum and seminal plasma in response to EAV infection. The findings presented herein suggest that while a broader immunoglobulin isotype diversity is elicited in seminal plasma, EAV has the ability to persist in the reproductive tract, in spite of local mucosal antibody and inflammatory responses. This study provides further evidence that EAV employs complex immune evasion mechanisms during persistence in the reproductive tract that warrant further investigation.
Assuntos
Anticorpos Antivirais/análise , Infecções por Arterivirus/veterinária , Equartevirus/imunologia , Doenças dos Cavalos/imunologia , Imunidade nas Mucosas , Infecções do Sistema Genital/veterinária , Sêmen/imunologia , Animais , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Infecções por Arterivirus/imunologia , Infecções por Arterivirus/virologia , Doenças dos Cavalos/virologia , Cavalos , Evasão da Resposta Imune , Imunidade Humoral , Imunoglobulina G/análise , Imunoglobulina G/imunologia , Imunoglobulina M/análise , Imunoglobulina M/imunologia , Masculino , Infecções do Sistema Genital/imunologia , Infecções do Sistema Genital/virologia , ViremiaRESUMO
The aim of this study was to characterize the immune response of dendritic cells derived from monocytes (Mo-DCs) in the porcine peripheral blood following infection with porcine reproductive and respiratory syndrome virus (PRRSV). Viral load assays indicated that PRRSV efficiently infected Mo-DCs but failed to replicate, whereas PRRSV infection of Mo-DCs decreased the expression of SLA-I, SLA-II, CD80 and CD40 compared with those of mock Mo-DCs. Furthermore, we analyzed the cytokine profiles using quantitative RT-PCR and ELISA. Results indicated apparent changes in IL-10 and IL-12 p40 expression but not in IFN-γ and TNF-α among Mo-DCs infected with PRRSV and uninfected Mo-DCs. Additionally, flow cytometry analysis of the altered Mo-DCs together with IL-4 and GM-CSF induction for 7days revealed the typical morphology and phenotype with 91.73% purity before infection with PRRSV. Overall, our data demonstrate that PRRSV impaired the normal antigen presentation of Mo-DCs and led to inadequate adaptive immune response by down-regulating the expression of SLA-I,SLA-II, CD80 and CD40. Enhanced Th2 -type cytokine IL-10 secretion and reduced Th1-type cytokines IL-12p40,IFN-γ and TNF-α secretion results in Th1/Th2 imbalance.
Assuntos
Imunidade Adaptativa , Infecções por Arterivirus/imunologia , Arterivirus/fisiologia , Células Dendríticas/imunologia , Monócitos/imunologia , Animais , Apresentação de Antígeno , Diferenciação Celular , Células Cultivadas , Citocinas/genética , Citocinas/metabolismo , Células Dendríticas/virologia , Antígenos de Histocompatibilidade/metabolismo , Evasão da Resposta Imune , Suínos , Equilíbrio Th1-Th2 , Transcriptoma , Carga ViralRESUMO
UNLABELLED: Simian hemorrhagic fever (SHF) is a highly lethal disease in captive macaques. Three distinct arteriviruses are known etiological agents of past SHF epizootics, but only one, simian hemorrhagic fever virus (SHFV), has been isolated in cell culture. The natural reservoir(s) of the three viruses have yet to be identified, but African nonhuman primates are suspected. Eleven additional divergent simian arteriviruses have been detected recently in diverse and apparently healthy African cercopithecid monkeys. Here, we report the successful isolation in MARC-145 cell culture of one of these viruses, Kibale red colobus virus 1 (KRCV-1), from serum of a naturally infected red colobus (Procolobus [Piliocolobus] rufomitratus tephrosceles) sampled in Kibale National Park, Uganda. Intramuscular (i.m.) injection of KRCV-1 into four cynomolgus macaques (Macaca fascicularis) resulted in a self-limiting nonlethal disease characterized by depressive behavioral changes, disturbance in coagulation parameters, and liver enzyme elevations. In contrast, i.m. injection of SHFV resulted in typical lethal SHF characterized by mild fever, lethargy, lymphoid depletion, lymphoid and hepatocellular necrosis, low platelet counts, increased liver enzyme concentrations, coagulation abnormalities, and increasing viral loads. As hypothesized based on the genetic and presumed antigenic distance between KRCV-1 and SHFV, all four macaques that had survived KRCV-1 injection died of SHF after subsequent SHFV injection, indicating a lack of protective heterotypic immunity. Our data indicate that SHF is a disease of macaques that in all likelihood can be caused by a number of distinct simian arteriviruses, although with different severity depending on the specific arterivirus involved. Consequently, we recommend that current screening procedures for SHFV in primate-holding facilities be modified to detect all known simian arteriviruses. IMPORTANCE: Outbreaks of simian hemorrhagic fever (SHF) have devastated captive Asian macaque colonies in the past. SHF is caused by at least three viruses of the family Arteriviridae: simian hemorrhagic fever virus (SHFV), simian hemorrhagic encephalitis virus (SHEV), and Pebjah virus (PBJV). Nine additional distant relatives of these three viruses were recently discovered in apparently healthy African nonhuman primates. We hypothesized that all simian arteriviruses are potential causes of SHF. To test this hypothesis, we inoculated cynomolgus macaques with a highly divergent simian arterivirus (Kibale red colobus virus 1 [KRCV-1]) from a wild Ugandan red colobus. Despite being only distantly related to red colobuses, all of the macaques developed disease. In contrast to SHFV-infected animals, KRCV-1-infected animals survived after a mild disease presentation. Our study advances the understanding of an important primate disease. Furthermore, our data indicate a need to include the full diversity of simian arteriviruses in nonhuman primate SHF screening assays.
Assuntos
Infecções por Arterivirus/veterinária , Arterivirus/isolamento & purificação , Arterivirus/patogenicidade , Colobus/virologia , Febres Hemorrágicas Virais/veterinária , Macaca fascicularis/virologia , Doenças dos Macacos/virologia , Animais , Arterivirus/genética , Arterivirus/crescimento & desenvolvimento , Infecções por Arterivirus/imunologia , Infecções por Arterivirus/fisiopatologia , Infecções por Arterivirus/virologia , Linhagem Celular , Febres Hemorrágicas Virais/imunologia , Febres Hemorrágicas Virais/fisiopatologia , Febres Hemorrágicas Virais/virologia , Fígado/química , Fígado/enzimologia , Masculino , Doenças dos Macacos/imunologia , Doenças dos Macacos/fisiopatologia , Uganda , Carga ViralRESUMO
IgM anti-mouse platelet autoantibodies cause thrombocytopenia by mediating uptake of opsonized thrombocytes, whereas IgM anti-erythrocyte autoantibodies induce anemia through a phagocytosis-independent cell destruction. In this article, we show that infection with lactate dehydrogenase-elevating virus, a benign mouse arterivirus, exacerbates the pathogenicity of IgM anti-platelet, but not anti-erythrocyte autoantibodies. To define the role of Fcα/µ receptor (Fcα/µR) in IgM-mediated thrombocytopenia and anemia, we generated mice deficient for this receptor. These animals were resistant to IgM autoantibody-mediated thrombocytopenia, but not anemia. However, the lactate dehydrogenase-elevating virus-induced exacerbation of thrombocytopenia was not associated with enhanced Fcα/µR expression on macrophages. These results indicate that Fcα/µR is required for the pathogenicity of IgM anti-platelet autoantibodies but is not sufficient to explain the full extent of the disease in virally infected animals.
Assuntos
Autoanticorpos/imunologia , Plaquetas/imunologia , Eritrócitos/imunologia , Imunoglobulina M/imunologia , Receptores Fc/fisiologia , Animais , Infecções por Arterivirus/imunologia , Vírus Elevador do Lactato Desidrogenase , Camundongos , Camundongos Endogâmicos C57BL , Trombocitopenia/etiologiaRESUMO
The objective of this study was to investigate the effect of equine arteritis virus (EAV) on type I interferon (IFN) production. Equine endothelial cells (EECs) were infected with the virulent Bucyrus strain (VBS) of EAV and expression of IFN-ß was measured at mRNA and protein levels by quantitative real-time RT-PCR and IFN bioassay using vesicular stomatitis virus expressing the green fluorescence protein (VSV-GFP), respectively. Quantitative RT-PCR results showed that IFN-ß mRNA levels in EECs infected with EAV VBS were not increased compared to those in mock-infected cells. Consistent with quantitative RT-PCR, Sendai virus- (SeV-) induced type I IFN production was inhibited by EAV infection. Using an IFN-ß promoter-luciferase reporter assay, we subsequently demonstrated that EAV nsps 1, 2, and 11 had the capability to inhibit type I IFN activation. Of these three nsps, nsp1 exhibited the strongest inhibitory effect. Taken together, these data demonstrate that EAV has the ability to suppress the type I IFN production in EECs and nsp1 may play a critical role to subvert the equine innate immune response.
Assuntos
Infecções por Arterivirus/metabolismo , Infecções por Arterivirus/veterinária , Equartevirus/metabolismo , Imunidade Inata , Interferon beta/antagonistas & inibidores , Proteínas não Estruturais Virais/metabolismo , Animais , Infecções por Arterivirus/genética , Infecções por Arterivirus/imunologia , Cricetinae , Células Endoteliais , Equartevirus/genética , Equartevirus/imunologia , Células HEK293 , Cavalos , Humanos , Interferon beta/biossíntese , Interferon beta/genética , Interferon beta/imunologia , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , RNA Mensageiro/imunologia , Proteínas não Estruturais Virais/genéticaRESUMO
Simian hemorrhagic fever virus (SHFV) causes a fatal hemorrhagic fever in macaques but an asymptomatic, persistent infection in baboons. To investigate factors contributing to this differential infection outcome, the targets of SHFV infection, macrophages (MΦs) and myeloid dendritic cells (mDCs), were differentiated from macaque and baboon peripheral blood monocytes and used to compare viral replication and cell responses. SHFV replicated in >90% of macaque MΦs but in only â¼10% of baboon MΦs. Although SHFV infected â¼50% of macaque and baboon mDCs, virus replication was efficient in macaque but not in baboon mDCs. Both types of macaque cultures produced higher virus yields than baboon cultures. A more efficient type I interferon response and the production of proinflammatory cytokines, including interleukin-1ß (IL-1ß), IL-6, IL-12/23(p40), tumor necrosis factor alpha (TNF-α), and macrophage inflammatory protein 1α (MIP-1α), in response to SHFV infection were observed in macaque but not baboon cultures, suggesting less efficient counteraction of these responses by viral proteins in macaque cells. Baboon cultures produced higher levels of IL-10 than macaque cultures both prior to and after SHFV infection. In baboon but not macaque cell cultures, SHFV infection upregulated IL-10R1, a subunit of the IL-10 receptor (IL-10R), and also SOCS3, a negative regulator of proinflammatory cytokine production. Incubation of macaque cultures with human IL-10 before and/or after SHFV infection decreased production of IL-6, IL-1ß, and MIP-1α but not TNF-α, suggesting a role for IL-10 in suppressing SHFV-induced proinflammatory cytokine production in macaques.
Assuntos
Infecções por Arterivirus/imunologia , Arterivirus , Células Dendríticas/virologia , Resistência à Doença/imunologia , Macrófagos/virologia , Células Mieloides/virologia , Animais , Western Blotting , Citocinas/sangue , Primers do DNA/genética , Humanos , Macaca mulatta , Microscopia Confocal , Papio , Reação em Cadeia da Polimerase em Tempo Real , Especificidade da Espécie , Replicação Viral/fisiologiaRESUMO
Currently, little is known on the cellular pathogenesis of equine arteritis virus (EAV). The purpose of the present study was to identify the target cells in ponies experimentally inoculated with EAV 08P178 (EU, clade-1). EAV-target organs (respiratory tissues with associated lymphoid tissues and large intestines), collected at 3 and 7 days post inoculation (dpi) and with virus titers≥10(5.0) TCID50/g, were processed with double immunofluorescence staining for the simultaneous detection of EAV N-protein and one of the following cell markers: CD172a (myeloid cells), CD3 (T lymphocytes), IgM (B lymphocytes) and von Willebrand factor (endothelial cells). In the different analyzed organs, 31-58% and 47-63% of the EAV-positive cells were mononuclear leukocytes (mainly CD172a(+) followed by CD3(+)) at 3 and 7 dpi, respectively. EAV-positive endothelial cells were not detected in 3.200 large blood vessels (≥3 endothelial cells/vessel cross section). However, in terminal capillaries (1-2 endothelial cells/vessel cross section) of the different organs, 15-51% of the endothelial cells were EAV-positive. In conclusion, the present study demonstrates that EAV 08P178 (i) has a main tropism for CD172a(+) and CD3(+) mononuclear leukocytes and (ii) infects a large number of endothelial cells in terminal capillaries. EAV 08P178 infection in capillaries is most probably the cause of an increased vascular permeability leading to leakage of fluid (edema-serous exudate) but not to severe vasculitis and hemorrhages.
Assuntos
Infecções por Arterivirus/veterinária , Equartevirus/imunologia , Doenças dos Cavalos/imunologia , Doenças dos Cavalos/patologia , Leucócitos Mononucleares/imunologia , Linfócitos T/imunologia , Animais , Infecções por Arterivirus/imunologia , Infecções por Arterivirus/patologia , Complexo CD3/metabolismo , Feminino , Cavalos , Imunoglobulina M/metabolismo , Leucócitos Mononucleares/virologia , Masculino , Receptores Imunológicos/metabolismo , Linfócitos T/virologia , Proteínas Virais/metabolismo , Fator de von Willebrand/metabolismoRESUMO
Equine arteritis virus (EAV) is the causative agent of equine viral arteritis (EVA), a respiratory and reproductive disease of equids. There has been significant recent progress in understanding the molecular biology of EAV and the pathogenesis of its infection in horses. In particular, the use of contemporary genomic techniques, along with the development and reverse genetic manipulation of infectious cDNA clones of several strains of EAV, has generated significant novel information regarding the basic molecular biology of the virus. Therefore, the objective of this review is to summarize current understanding of EAV virion architecture, replication, evolution, molecular epidemiology and genetic variation, pathogenesis including the influence of host genetics on disease susceptibility, host immune response, and potential vaccination and treatment strategies.
Assuntos
Infecções por Arterivirus/veterinária , Equartevirus/fisiologia , Doenças dos Cavalos/virologia , Animais , Infecções por Arterivirus/imunologia , Infecções por Arterivirus/virologia , Equartevirus/genética , Equartevirus/imunologia , Genoma Viral/genética , Doenças dos Cavalos/imunologia , Cavalos , Interações Hospedeiro-Patógeno , Proteínas Virais/genética , Proteínas Virais/metabolismo , Vírion/fisiologiaRESUMO
Lactate dehydrogenase-elevating virus (LDV) is an apparently innocuous and persistent virus that can modify mouse immune reactions. We have shown that LDV-infected mice immunized with human growth hormone (hGH) showed a deep modification of the specificity of the anti-hGH antibodies (Ab) in CBA/Ht mice but not BALB/c animals. The aim of this work was to extend the previous observations to another mouse strain, C57BL/6, as well as to an antigen unrelated to hGH, ovalbumin (OVA), and to explore at the same time the production of various cytokines at serum and cellular levels. The amount of Ab directed to hGH or OVA native antigenic determinants versus the concentration of Ab to cryptic epitopes was evaluated by ELISA competition experiments. Results indicated that LDV infection affected Ab specificity solely in CBA/Ht mice. In CBA/Ht the virus infection was associated with a reduction of the Ab titers to hGH native epitopes and with a decrease of IL-13 and IL-17 serum levels, but Ab to native OVA epitopes were increased with a simultaneous increase of IL-17. Accordingly, only lymph node cells from infected CBA/Ht mice immunized with OVA were found to produce INF-γ, IL-13 and IL-17. Thus, a correlation of cytokine production with a change in Ab specificity after a viral infection was found, although this phenomenon was restricted to a given antigen and to the genetic background of immunized animals. These observations suggest that an apparent harmless virus can affect some immunological mechanisms, which could lead, for example, to inflammatory or autoimmune disorders.
Assuntos
Anticorpos Antivirais/imunologia , Especificidade de Anticorpos , Infecções por Arterivirus/imunologia , Citocinas/imunologia , Epitopos Imunodominantes/imunologia , Vírus Elevador do Lactato Desidrogenase/imunologia , Animais , Anticorpos Antivirais/sangue , Hormônio do Crescimento/imunologia , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Ovalbumina/imunologia , Especificidade da EspécieRESUMO
Regulatory T cells (T(regs)) are a subset of T cells that are responsible for maintaining peripheral immune tolerance and homeostasis. The hallmark of T(regs) is the expression of the forkhead box P3 (FoxP3) transcription factor. Natural regulatory T cells (nT(regs)) are a distinct population of T cells that express CD4 and FoxP3. nTregs develop in the thymus and function in maintaining peripheral immune tolerance. Other CD4(+), CD4(-)CD8(-), and CD8(+)CD28(-) T cells can be induced to acquire regulatory function by antigenic stimulation, depending on the cytokine milieu. Inducible (or adaptive) T(regs) frequently express high levels of the interleukin 2 receptor (CD25). Atypical T(regs) express FoxP3 and CD4 but have no surface expression of CD25. Type 1 regulatory T cells (Tr1 cells) produce IL-10, while T helper 3 cells (Th3) produce TGF-ß. The function of inducible T(regs) is presumably to maintain immune homeostasis, especially in the context of chronic inflammation or infection. Induction of T(regs) in coronaviral infections protects against the more severe forms of the disease attributable to the host response. However, arteriviruses have exploited these T cell subsets as a means to dampen the immune response allowing for viral persistence. T(reg) induction or activation in the pathogenesis of disease has been described in both porcine reproductive and respiratory syndrome virus, lactate dehydrogenase elevating virus, and mouse hepatitis virus. This review discusses the development and biology of regulatory T cells in the context of arteriviral and coronaviral infection.
Assuntos
Infecções por Arterivirus/imunologia , Infecções por Arterivirus/patologia , Arterivirus/patogenicidade , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/patologia , Coronavirus/patogenicidade , Linfócitos T Reguladores/imunologia , Animais , Arterivirus/imunologia , Coronavirus/imunologia , Modelos Animais de Doenças , Humanos , Timo/imunologiaRESUMO
Animal coronaviruses, such as infectious bronchitis virus (IBV), and arteriviruses, such as porcine reproductive and respiratory syndrome virus (PRRSV), are able to manifest highly contagious infections in their specific native hosts, thereby arising in critical economic damage to animal industries. This review discusses recent progress in studies of virus-host interactions during animal and human coronavirus and arterivirus infections, with emphasis on IBV-host cell interactions. These interactions may be directly involved in viral replication or lead to the alteration of certain signaling pathways, such as cell stress response and innate immunity, to facilitate viral replication and pathogenesis.
Assuntos
Infecções por Arterivirus/imunologia , Infecções por Arterivirus/metabolismo , Arterivirus/fisiologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/metabolismo , Coronavirus/fisiologia , Interações Hospedeiro-Patógeno , Animais , Apoptose , Ciclo Celular , Humanos , Imunidade Inata , Biossíntese de Proteínas , Transdução de SinaisRESUMO
Lactate dehydrogenase-elevating virus (LDV) exacerbates mouse susceptibility to endotoxin shock through enhanced tumour necrosis factor (TNF) production by macrophages exposed to lipopolysaccharide (LPS). However, the in vivo enhancement of TNF production in response to LPS induced by the virus largely exceeds that found in vitro with cells derived from infected animals. Infection was followed by a moderate increase of Toll-like receptor (TLR)-4/MD2, but not of membrane CD14 expression on peritoneal macrophages. Peritoneal macrophages from LDV-infected mice unresponsive to type I interferons (IFNs) did not show enhanced expression of TLR-4/MD2 nor of CD14, and did not produce more TNF in response to LPS than cells from infected normal counterparts, although the in vivo response of these animals to LPS was strongly enhanced. In contrast, the virus triggered a sharp increase of soluble CD14 and of LPS-binding protein serum levels in normal mice. However, production of these LPS soluble receptors was similar in LDV-infected type I IFN-receptor deficient mice and in their normal counterparts. Moreover, serum of LDV-infected mice that contained these soluble receptors had little effect if any on cell response to LPS. These results suggest that enhanced response of LDV-infected mice to LPS results mostly from mechanisms independent of LPS receptor expression.
Assuntos
Infecções por Arterivirus/veterinária , Vírus Elevador do Lactato Desidrogenase/fisiologia , Receptores de Lipopolissacarídeos/genética , Doenças dos Roedores/genética , Doenças dos Roedores/virologia , Proteínas de Fase Aguda/genética , Proteínas de Fase Aguda/imunologia , Animais , Infecções por Arterivirus/genética , Infecções por Arterivirus/imunologia , Infecções por Arterivirus/virologia , Proteínas de Transporte/genética , Proteínas de Transporte/imunologia , Células Cultivadas , Regulação para Baixo , Feminino , Vírus Elevador do Lactato Desidrogenase/imunologia , Receptores de Lipopolissacarídeos/metabolismo , Lipopolissacarídeos/imunologia , Antígeno 96 de Linfócito/genética , Antígeno 96 de Linfócito/imunologia , Macrófagos Peritoneais/imunologia , Macrófagos Peritoneais/virologia , Masculino , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Doenças dos Roedores/imunologia , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/imunologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologiaRESUMO
In a recent study, we demonstrated that the virulent Bucyrus strain (VBS) of EAV could infect in vitro a small population of CD3(+) T lymphocytes from some but not all horses. Furthermore, we have shown that a common haplotype is associated with this in vitro CD3(+) T cell susceptibility/resistance phenotype to EAV infection. In this study, we investigated whether the differences in the susceptibility or resistance of CD3(+) T cells in vitro correlate with the outcome and severity of clinical signs in vivo. Thus, horses were divided into two groups based on their CD3(+) T cell susceptible or resistant phenotype. Following experimental inoculation with the recombinant VBS of EAV, horses were assessed for presence and severity of clinical signs, duration and magnitude of virus shedding, as well as production of proinflammatory and immunomodulatory cytokines in peripheral blood mononuclear cells using real-time quantitative RT-PCR. The data showed that there was a significant difference between the two groups of horses in terms of cytokine mRNA expression and evidence of increased clinical signs in horses possessing the in vitro CD3(+) T cell resistant phenotype. This is the first study to provide direct evidence for a correlation between variation in host genotype and phenotypic differences in terms of the extent of viral replication, presence and severity of clinical signs and cytokine gene expression caused by infection with virulent EAV.
Assuntos
Infecções por Arterivirus/veterinária , Equartevirus/patogenicidade , Doenças dos Cavalos/imunologia , Cavalos/imunologia , Linfócitos T/imunologia , Animais , Infecções por Arterivirus/genética , Infecções por Arterivirus/imunologia , Complexo CD3/genética , Complexo CD3/imunologia , Citocinas/genética , Citocinas/imunologia , Suscetibilidade a Doenças , Equartevirus/imunologia , Feminino , Haplótipos , Doenças dos Cavalos/genética , Doenças dos Cavalos/virologia , Cavalos/virologia , Imunidade Inata/genética , Leucócitos Mononucleares/imunologia , Contagem de Linfócitos , Fenótipo , Eliminação de Partículas ViraisRESUMO
The innate immune response constitutes the first line of defense against viral infection and is extensively regulated through ubiquitination. The removal of ubiquitin from innate immunity signaling factors by deubiquitinating enzymes (DUBs) therefore provides a potential opportunity for viruses to evade this host defense system. It was previously found that specific proteases encoded by the unrelated arteri- and nairoviruses resemble the ovarian tumor domain-containing (OTU) family of DUBs. In arteriviruses, this domain has been characterized before as a papain-like protease (PLP2) that is also involved in replicase polyprotein processing. In nairoviruses, the DUB resides in the polymerase protein but is not essential for RNA replication. Using both in vitro and cell-based assays, we now show that PLP2 DUB activity is conserved in all members of the arterivirus family and that both arteri- and nairovirus DUBs inhibit RIG-I-mediated innate immune signaling when overexpressed. The potential relevance of RIG-I-like receptor (RLR) signaling for the innate immune response against arterivirus infection is supported by our finding that in mouse embryonic fibroblasts, the production of beta interferon primarily depends on the recognition of arterivirus RNA by the pattern-recognition receptor MDA5. Interestingly, we also found that both arteri- and nairovirus DUBs inhibit RIG-I ubiquitination upon overexpression, suggesting that both MDA5 and RIG-I have a role in countering infection by arteriviruses. Taken together, our results support the hypothesis that arteri- and nairoviruses employ their deubiquitinating potential to inactivate cellular proteins involved in RLR-mediated innate immune signaling, as exemplified by the deubiquitination of RIG-I.
Assuntos
Infecções por Arterivirus/imunologia , Arterivirus/enzimologia , RNA Helicases DEAD-box/imunologia , Endopeptidases/imunologia , Febre Hemorrágica da Crimeia/imunologia , Imunidade Inata , Nairovirus/enzimologia , Proteínas Virais/imunologia , Animais , Arterivirus/química , Arterivirus/genética , Infecções por Arterivirus/enzimologia , Infecções por Arterivirus/virologia , Linhagem Celular , Proteína DEAD-box 58 , RNA Helicases DEAD-box/genética , RNA Helicases DEAD-box/metabolismo , Endopeptidases/genética , Endopeptidases/metabolismo , Febre Hemorrágica da Crimeia/enzimologia , Febre Hemorrágica da Crimeia/metabolismo , Febre Hemorrágica da Crimeia/virologia , Humanos , Camundongos , Camundongos Transgênicos , Nairovirus/química , Nairovirus/genética , Estrutura Terciária de Proteína , Transdução de Sinais , Ubiquitina/metabolismo , Proteínas Virais/genética , Proteínas Virais/metabolismoRESUMO
Simian Hemorrhagic Fever Virus (SHFV) has caused sporadic outbreaks of hemorrhagic fevers in macaques at primate research facilities. SHFV is a BSL-2 pathogen that has not been linked to human disease; as such, investigation of SHFV pathogenesis in non-human primates (NHPs) could serve as a model for hemorrhagic fever viruses such as Ebola, Marburg, and Lassa viruses. Here we describe the pathogenesis of SHFV in rhesus macaques inoculated with doses ranging from 50 PFU to 500,000 PFU. Disease severity was independent of dose with an overall mortality rate of 64% with signs of hemorrhagic fever and multiple organ system involvement. Analyses comparing survivors and non-survivors were performed to identify factors associated with survival revealing differences in the kinetics of viremia, immunosuppression, and regulation of hemostasis. Notable similarities between the pathogenesis of SHFV in NHPs and hemorrhagic fever viruses in humans suggest that SHFV may serve as a suitable model of BSL-4 pathogens.
Assuntos
Infecções por Arterivirus , Arterivirus , Modelos Animais de Doenças , Febres Hemorrágicas Virais , Animais , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Arterivirus/imunologia , Arterivirus/patogenicidade , Infecções por Arterivirus/sangue , Infecções por Arterivirus/imunologia , Infecções por Arterivirus/patologia , Infecções por Arterivirus/virologia , Quimiocinas/sangue , Citocinas/sangue , Febres Hemorrágicas Virais/sangue , Febres Hemorrágicas Virais/imunologia , Febres Hemorrágicas Virais/patologia , Febres Hemorrágicas Virais/virologia , Tolerância Imunológica , Macaca mulatta , Fatores de RiscoRESUMO
Previously, we have shown that horses could be divided into susceptible and resistant groups based on an in vitro assay using dual-color flow cytometric analysis of CD3+ T cells infected with equine arteritis virus (EAV). Here, we demonstrate that the differences in in vitro susceptibility of equine CD3+ T lymphocytes to EAV infection have a genetic basis. To investigate the possible hereditary basis for this trait, we conducted a genome-wide association study (GWAS) to compare susceptible and resistant phenotypes. Testing of 267 DNA samples from four horse breeds that had a susceptible or a resistant CD3+ T lymphocyte phenotype using both Illumina Equine SNP50 BeadChip and Sequenom's MassARRAY system identified a common, genetically dominant haplotype associated with the susceptible phenotype in a region of equine chromosome 11 (ECA11), positions 49572804 to 49643932. The presence of a common haplotype indicates that the trait occurred in a common ancestor of all four breeds, suggesting that it may be segregated among other modern horse breeds. Biological pathway analysis revealed several cellular genes within this region of ECA11 encoding proteins associated with virus attachment and entry, cytoskeletal organization, and NF-κB pathways that may be associated with the trait responsible for the in vitro susceptibility/resistance of CD3+ T lymphocytes to EAV infection. The data presented in this study demonstrated a strong association of genetic markers with the trait, representing de facto proof that the trait is under genetic control. To our knowledge, this is the first GWAS of an equine infectious disease and the first GWAS of equine viral arteritis.