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1.
Gut ; 69(1): 133-145, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31409605

RESUMO

OBJECTIVE: The Fragile X mental retardation (FMR) syndrome is a frequently inherited intellectual disability caused by decreased or absent expression of the FMR protein (FMRP). Lack of FMRP is associated with neuronal degradation and cognitive dysfunction but its role outside the central nervous system is insufficiently studied. Here, we identify a role of FMRP in liver disease. DESIGN: Mice lacking Fmr1 gene expression were used to study the role of FMRP during tumour necrosis factor (TNF)-induced liver damage in disease model systems. Liver damage and mechanistic studies were performed using real-time PCR, Western Blot, staining of tissue sections and clinical chemistry. RESULTS: Fmr1null mice exhibited increased liver damage during virus-mediated hepatitis following infection with the lymphocytic choriomeningitis virus. Exposure to TNF resulted in severe liver damage due to increased hepatocyte cell death. Consistently, we found increased caspase-8 and caspase-3 activation following TNF stimulation. Furthermore, we demonstrate FMRP to be critically important for regulating key molecules in TNF receptor 1 (TNFR1)-dependent apoptosis and necroptosis including CYLD, c-FLIPS and JNK, which contribute to prolonged RIPK1 expression. Accordingly, the RIPK1 inhibitor Necrostatin-1s could reduce liver cell death and alleviate liver damage in Fmr1null mice following TNF exposure. Consistently, FMRP-deficient mice developed increased pathology during acute cholestasis following bile duct ligation, which coincided with increased hepatic expression of RIPK1, RIPK3 and phosphorylation of MLKL. CONCLUSIONS: We show that FMRP plays a central role in the inhibition of TNF-mediated cell death during infection and liver disease.


Assuntos
Proteína do X Frágil de Retardo Mental/fisiologia , Hepatite Viral Animal/imunologia , Fator de Necrose Tumoral alfa/imunologia , Animais , Infecções por Arenaviridae/imunologia , Infecções por Arenaviridae/patologia , Linfócitos T CD8-Positivos/imunologia , Morte Celular/efeitos dos fármacos , Morte Celular/imunologia , Morte Celular/fisiologia , Células Cultivadas , Colestase/imunologia , Colestase/metabolismo , Colestase/patologia , Proteína do X Frágil de Retardo Mental/metabolismo , Hepatite Viral Animal/patologia , Hepatite Viral Animal/prevenção & controle , Hepatócitos/patologia , Imidazóis/farmacologia , Imidazóis/uso terapêutico , Indóis/farmacologia , Indóis/uso terapêutico , Vírus da Coriomeningite Linfocítica , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína Serina-Treonina Quinases de Interação com Receptores/antagonistas & inibidores , Proteína Serina-Treonina Quinases de Interação com Receptores/fisiologia
2.
Avian Pathol ; 48(4): 352-361, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30982334

RESUMO

Duck hepatitis A virus type 1 (DHAV-1) causes acute hepatitis with high morbidity and mortality in ducklings of the genera Cairina and Anas and is characterized by ecchymotic haemorrhage and necrosis of the liver surface. Since September 2011, a new subtype of DHAV-1 (named pancreatitis-type DHAV-1) has been isolated. This new subtype is characterized by yellowish or haemorrhagic pancreatitis, but with no significant pathological changes in the liver. To further investigate the difference in pathogenicity between hepatitis-type DHAV-1 and pancreatitis-type DHAV-1, we infected Muscovy ducklings with a hepatitis-type DHAV-1 strain, FZ86, or a pancreatitis-type DHAV-1 strain, MPZJ1206, and then compared the resulting gross lesions, histopathological changes, viral distribution and cellular apoptosis in the liver and pancreas of Muscovy ducklings. The results suggested that FZ86 induced a more efficient viral propagation in the liver than MPZJ1206, and the gross and histopathological lesions were also limited to the liver. However, MPZJ1206 induced more effective viral replication in the pancreas than FZ86. The MPZJ1206-infected Muscovy ducklings showed an obviously yellowed and haemorrhagic pancreas, but with no significant pathological changes in the liver. Furthermore, FZ86 induced notable hepatocyte apoptosis and increased the expression of caspase-3 in the liver, whereas MPZJ1206 caused apoptosis in a large number of acinar epithelial cells and elevated the expression of caspase-3 in the pancreas. Taken together, these results demonstrated that pancreatitis-type DHAV-1 has many new pathogenic features which distinguish it from the hepatitis-type DHAV-1. RESEARCH HIGHLIGHTS Pancreatitis-type DHAV-1 (MPZJ1206) was characterized by pancreatic haemorrhage and yellow discolouration, but with no obvious haemorrhage and necrosis in the liver. Pancreatitis-type DHAV-1 (MPZJ1206) exhibits many new pathogenic features which distinguish it from the hepatitis-type DHAV-1 (FZ86).


Assuntos
Patos , Vírus da Hepatite do Pato/patogenicidade , Hepatite Viral Animal/virologia , Pancreatite Necrosante Aguda/veterinária , Infecções por Picornaviridae/veterinária , Doenças das Aves Domésticas/virologia , Animais , Vírus da Hepatite do Pato/classificação , Hepatite Viral Animal/patologia , Fígado/patologia , Pâncreas/patologia , Pancreatite Necrosante Aguda/patologia , Pancreatite Necrosante Aguda/virologia , Infecções por Picornaviridae/patologia , Infecções por Picornaviridae/virologia , Doenças das Aves Domésticas/patologia
3.
Poult Sci ; 98(7): 2765-2771, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-30815694

RESUMO

Hydropericardium-hepatitis syndrome (HHS) is characterized by pericardial effusion and hepatitis and causes huge economic losses in the poultry industry in China. In this study, a strain of fowl adenoviruses (FAdV-4) (GX-1) was isolated from liver samples of diseased chickens with HHS. Phylogenetic analysis based on complete genome gene revealed that GX-1 clustered with the C-type fowl adenovirus and was serotyped as FAdV-4. Pathogenicity testing showed that the GX-1 strain caused 100% mortality in 10-day-old specific pathogen-free chickens at a dose of 104 tissue culture infective doses (TCID50) within 3 d post-infection. A viral dose of 103 TCID50 resulted in a 16% survival rate before day 9 and at 102 TCID50 an 80% rate before day 6. At necropsy, livers from infected chickens were swollen and yellow brown with necrotic foci. The hearts were flabby with amber-colored and jelly-like fluid in the pericardial sacs. The kidneys were swollen and congested. Histologically eosinophilic intranuclear inclusion body could be seen in the hepatic cell. The result of histopathological examination also revealed that heart muscle fibers were fractured with extensive congestion and hemorrhaging. Other tissues like kidney, bursa of Fabricius, thymus, and spleen were observed degeneration and necrosis. Virus-specific antibodies appeared in serum beginning at day 14 and reached statistically significant levels at 21, 28, 35, and 42 dpi (P < 0.001). In conclusion, we identified a highly virulent FAdV-4 virus as causative agent of the HHS outbreak reported here. The FAdV-4 GX-1 strain will be valuable for vaccine evaluation and development to prevent and reduce the spread of HHS in the poultry industry.


Assuntos
Infecções por Adenoviridae/veterinária , Aviadenovirus/isolamento & purificação , Derrame Pericárdico/veterinária , Doenças das Aves Domésticas/virologia , Infecções por Adenoviridae/patologia , Infecções por Adenoviridae/virologia , Animais , Aviadenovirus/genética , Galinhas , China , Hepatite Viral Animal/patologia , Hepatite Viral Animal/virologia , Derrame Pericárdico/virologia , Pericárdio , Sorogrupo , Organismos Livres de Patógenos Específicos , Virulência
4.
Virus Res ; 263: 164-168, 2019 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-30711577

RESUMO

A 15-year-old female cockatiel (Nymphicus hollandicus) undergoing long term management for hepatopathy died and underwent necropsy. Microscopic findings were consistent with chronic liver disease characterized by distorted hepatic architecture, fibrosis and biliary proliferation. The additional finding of large intranuclear inclusion bodies within hepatocytes and renal tubular epithelium prompted diagnostic next generation sequencing. The assembled sequences isolated from pooled kidney and liver were related to siadenoviruses. The genus Siadenovirus, within the family Adenoviridae, includes several species of viruses that pathogenically infect avian species including hemorrhagic enteritis virus of turkeys and marble spleen virus of pheasants. Siadenoviruses have previously been reported in seven psittacine species: a plum-headed parakeet (Psittacula cyanocephala), an umbrella cockatoo (Cacatua alba) budgerigars (Melopsittacus undulates), an eastern rosella (Platycercus eximius), a scarlet chested parrot (Neophema splendida), a cockatiel (Nymphicus hollandicus), and a red-crowned parakeet (Cyanoramphus novaezelandiae). This report describes a novel siadenovirus in a cockatiel that is highly identical to budgerigar adenovirus 1 and distinct from PsAdV-2 in cockatiels. We report the clinical pathologic, gross, and histopathologic findings in a cockatiel with chronic hepatitis and a novel siadenovirus, PsAdV-5. The sequencing data is presented with a phylogenetic analysis.


Assuntos
Infecções por Adenoviridae/veterinária , Doenças das Aves/virologia , Cacatuas , Hepatite Viral Animal/virologia , Siadenovirus/classificação , Siadenovirus/isolamento & purificação , Infecções por Adenoviridae/virologia , Animais , Doenças das Aves/patologia , Feminino , Hepatite Viral Animal/patologia , Sequenciamento de Nucleotídeos em Larga Escala , Histocitoquímica , Túbulos Renais/patologia , Túbulos Renais/virologia , Fígado/patologia , Fígado/virologia , Filogenia , Homologia de Sequência , Siadenovirus/genética
5.
J Vet Intern Med ; 33(1): 258-265, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30520132

RESUMO

BACKGROUND: A novel equine parvovirus (EqPV-H) was recently discovered in the equine liver with Theiler's disease. OBJECTIVES: To determine the prevalence of EqPV-H infection in naturally occurring Theiler's disease cases and in-contact horses in the absence of historical equine biologic product administration. ANIMALS: Ten cases of Theiler's disease from 6 separate properties were included in the study, based on the criteria of acute onset of clinical signs of liver failure with laboratory or histopathologic findings characteristic of Theiler's disease and no history of receiving an equine biologic product within the preceding 4 months. In addition, 37 in-contact horses from 4 of the 6 properties were screened for EqPV-H infection and hepatitis. METHODS: In prospective case series, cases were diagnosed with Theiler's disease by the attending veterinarian and were tested for EqPV-H by PCR of liver or serum. In-contact horses were assessed via serum chemistry and PCR at the attending veterinarian's discretion. Hepatitis was defined as serum gamma-glutamyltransferase activity above reference interval. The association of EqPV-H with hepatitis was determined by Fisher's exact test. RESULTS: Nine of 10 (90%) Theiler's disease cases and 54% of tested in-contact horses were EqPV-H positive. Hepatitis was significantly associated with EqPV-H infection (P = .036). CONCLUSIONS AND CLINICAL IMPORTANCE: Although further study is required to identify EqPV-H as the causative agent of Theiler's disease, EqPV-H appears strongly associated with cases of fatal Theiler's disease and subclinical hepatitis in horses in contact with those cases. The prevalence of EqPV-H infection on affected properties can be high.


Assuntos
Hepatite Viral Animal/virologia , Doenças dos Cavalos/virologia , Infecções por Parvoviridae/veterinária , Animais , Produtos Biológicos/efeitos adversos , Feminino , Hepatite Viral Animal/patologia , Doenças dos Cavalos/patologia , Cavalos , Fígado/patologia , Fígado/virologia , Masculino , Parvovirus , Estudos Prospectivos , Reação em Cadeia da Polimerase em Tempo Real/veterinária
6.
J Vet Intern Med ; 33(1): 251-257, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30520162

RESUMO

BACKGROUND: Three flaviviruses (equine pegivirus [EPgV]; Theiler's disease-associated virus [TDAV]; non-primate hepacivirus [NPHV]) and equine parvovirus (EqPV-H) are present in equine blood products; the TDAV, NPHV, and EqPV-H have been suggested as potential causes of serum hepatitis. OBJECTIVE: To determine the prevalence of these viruses in horses with equine serum hepatitis. ANIMALS: Eighteen horses diagnosed with serum hepatitis, enrolled from US referral hospitals. METHODS: In the prospective case study, liver, serum, or both samples were tested for EPgV, TDAV, NPHV, and EqPV-H by PCR. RESULTS: Both liver tissue and serum were tested for 6 cases, serum only for 8 cases, and liver only for 4 cases. Twelve horses received tetanus antitoxin (TAT) 4-12.7 weeks (median = 8 weeks), 3 horses received commercial equine plasma 6-8.6 weeks, and 3 horses received allogenic stem cells 6.4-7.6 weeks before the onset of hepatic failure. All samples were TDAV negative. Two of 14 serum samples were NPHV-positive. Six of 14 serum samples were EPgV-positive. All liver samples were NPHV-negative and EPgV-negative. EqPV-H was detected in the serum (N = 8), liver (N = 4), or both samples (N = 6) of all 18 cases. The TAT of the same lot number was available for virologic testing in 10 of 12 TAT-associated cases, and all 10 samples were EqPV-H positive. CONCLUSIONS AND CLINICAL IMPORTANCE: We demonstrated EqPV-H in 18 consecutive cases of serum hepatitis. EPgV, TDAV, and NPHV were not consistently present. This information should encourage blood product manufacturers to test for EqPV-H and eliminate EqPV-H-infected horses from their donor herds.


Assuntos
Infecções por Flavivirus/veterinária , Hepatite C/veterinária , Hepatite Viral Animal/virologia , Doenças dos Cavalos/virologia , Infecções por Parvoviridae/veterinária , Animais , Feminino , Flavivirus , Infecções por Flavivirus/complicações , Infecções por Flavivirus/virologia , Hepacivirus , Hepatite C/complicações , Hepatite C/virologia , Hepatite Viral Animal/sangue , Hepatite Viral Animal/patologia , Doenças dos Cavalos/sangue , Doenças dos Cavalos/patologia , Cavalos , Fígado/patologia , Fígado/virologia , Masculino , Infecções por Parvoviridae/complicações , Infecções por Parvoviridae/virologia , Parvovirus , Estudos Prospectivos , Reação em Cadeia da Polimerase em Tempo Real/veterinária , Theilovirus
7.
Toxicol Lett ; 299: 129-136, 2018 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-30287270

RESUMO

Chlordecone is an organochlorine used in the 1970's as a pesticide in banana plantations. It has a long half-life in the soil and can potentially contaminate humans and animals through food. Chlordecone targets, and mainly accumulates in, the liver, leading to hepatomegaly and neurological signs in mammals. Chlordecone does not cause liver injuries or any inflammation by itself at low doses, but it can potentiate the hepatotoxic effects of other chemicals and drugs. We studied the impact of chlordecone on the progression of acute hepatitis in mouse models of co-exposure to chlordecone with Concanavalin A or murine hepatitis virus type 3. We examined the progression of these two types of hepatitis by measuring hepatic transaminase levels in the serum and inflammatory cells in the liver, liver histological studies. Amplified tremors presented in the MHV3- chlordecone mouse model had led us to study the expression of specific genes in the brain. We show that chlordecone amplifies the auto-immune hepatitis induced by Concanavalin A by increasing the number of liver NKT cells, which are involved in liver damage. Chlordecone also accelerated the death of mice infected by murine hepatitis virus and enhanced the entry of the virus into the cervical spinal cord in infected mice, leading to considerable neurological damage. In conclusion, chlordecone potentiates both the Concanavalin A-induced hepatitis and brain damage caused by an hepatotropic/neurotropic virus.


Assuntos
Encéfalo/virologia , Clordecona/toxicidade , Hepatite Autoimune/patologia , Hepatite Viral Animal , Inseticidas/toxicidade , Vírus da Hepatite Murina/patogenicidade , Doença Aguda , Animais , Concanavalina A/toxicidade , Modelos Animais de Doenças , Progressão da Doença , Hepatite Autoimune/etiologia , Hepatite Viral Animal/patologia , Hepatite Viral Animal/virologia , Fígado/efeitos dos fármacos , Fígado/imunologia , Fígado/patologia , Masculino , Camundongos Endogâmicos C57BL , Necrose
8.
Front Immunol ; 9: 1845, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30197639

RESUMO

Duck hepatitis A virus type 1 (DHAV-1) is one of the most common and lethal pathogens in young ducklings. Live-attenuated DHAV vaccine (CH60 strain) developed by passaging in chicken embryos provided effective immune protection for ducklings. However, the accurate mechanism for such adaption in chicken embryos is not fully revealed. Here, we utilize RNA-sequencing to perform global transcriptional analysis of DHAV-1-innoculated embryonated livers along with histopathological and ultrastructural analysis. This study revealed that infection with DHAV-1 strain CH60 is associated with enhanced type I and II interferon responses, activated innate immune responses, elevated levels of suppressor of cytokine signaling 1 and 3 (SOCS1 and SOCS3) accompanied with abnormalities in multiple metabolic pathways. Excessive inflammatory and innate immune responses induced by the CH60 strain are related to severe liver damage. Our study presents a comprehensive characterization of the transcriptome of chicken embryos infected with DHAV-CH60 and provides insight for in-depth exploration of viral adaption and virus-host interactions.


Assuntos
Vírus da Hepatite do Pato , Hepatite Viral Animal/genética , Hepatite Viral Animal/virologia , Transcriptoma , Animais , Apoptose , Embrião de Galinha , Biologia Computacional/métodos , Patos , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Vírus da Hepatite do Pato/imunologia , Hepatite Viral Animal/patologia , Imunidade Inata , Fígado/imunologia , Fígado/metabolismo , Fígado/patologia , Fígado/virologia , Metilação , Fenótipo , Infecções por Picornaviridae/veterinária , Proteína 3 Supressora da Sinalização de Citocinas/metabolismo
9.
Arch Virol ; 163(5): 1187-1193, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29387970

RESUMO

To establish an animal model for the newly identified Marmota Himalayana hepatovirus, MHHAV, so as to develop a better understanding of the infection of hepatitis A viruses. Five experimental woodchucks (Marmota monax) were inoculated intravenously with the purified MHHAV from wild woodchuck feces. One animal injected with PBS was defined as a control. Feces and blood were routinely collected. After the animals were subjected to necropsy, different tissues were collected. The presence of viral RNA and negative sense viral RNA was analyzed in all the samples and histopathological and in situ hybridization analysis was performed for the tissues. MHHAV infection caused fever but no severe symptoms or death. Virus was shed in feces beginning at 2 dpi, and MHHAV RNA persisted in feces for ~2 months, with a biphasic increase, and in blood for ~30 days. Viral RNA was detected in all the tissues, with high levels in the liver and spleen. Negative-strand viral RNA was detected only in the liver. Furthermore, the animals showed histological signs of hepatitis at 45 dpi. MHHAV can infect M. monax and is associated with hepatic disease. Therefore, this animal can be used as a model of HAV pathogenesis and to evaluate antiviral and anticancer therapeutics.


Assuntos
Modelos Animais de Doenças , Vírus da Hepatite A/patogenicidade , Hepatite A , Hepatite Viral Animal , Marmota , Animais , Fezes/virologia , Hepatite A/patologia , Hepatite A/fisiopatologia , Hepatite A/virologia , Vírus da Hepatite A/genética , Vírus da Hepatite A/isolamento & purificação , Vírus da Hepatite A/fisiologia , Hepatite Viral Animal/patologia , Hepatite Viral Animal/fisiopatologia , Hepatite Viral Animal/virologia , Fígado/patologia , Fígado/virologia , RNA Viral/isolamento & purificação , Baço/patologia , Baço/virologia
10.
Mol Immunol ; 95: 30-38, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29407574

RESUMO

Duck virus hepatitis caused by duck hepatitis A virus (DHAV) is an acute and contagious disease. To better understand the pathogenic mechanism of DHAV-3 in ducklings, an infection experiment was performed. Our results showed that typical symptoms were observed in the infected ducklings. DHAV-3 could infect many tissues, leading to pathological lesions, especially on the livers and spleen, and the host immune responses are activated in infection. Real-time quantitative PCR demonstrated that expression of many innate immune-related genes was mostly up-regulated in the livers and spleen, and antiviral innate immune response was established, but not sufficient to restrict the virus replication of lethal dose. Many major pattern recognition receptors (PRRs) (RIG-1, MDA5, and TLR7) are involved in the host immune response to DHAV-3, and the expression of interferon (IFNα, IFNß and IFNγ) and antiviral proteins (MX, OAS and PKR) are also up-regulated in the liver and spleen. The expression of most cytokines (IL-1ß, IL-2 and IL-6) was also up-regulated to different degrees and was various; the expression of IL-2 increased most significantly in liver. Our data provide a foundation for further study of the pathogenicity of duck virus hepatitis and extend our understanding of the immune responses of ducklings to DHAV-3 infection.


Assuntos
Patos , Vírus da Hepatite do Pato/patogenicidade , Imunidade Inata , Infecções por Picornaviridae/imunologia , Animais , Patos/imunologia , Patos/virologia , Vírus da Hepatite do Pato/imunologia , Hepatite Viral Animal/imunologia , Hepatite Viral Animal/mortalidade , Hepatite Viral Animal/patologia , Hepatite Viral Animal/virologia , Infecções por Picornaviridae/mortalidade , Infecções por Picornaviridae/veterinária , Infecções por Picornaviridae/virologia , Doenças das Aves Domésticas/imunologia , Doenças das Aves Domésticas/mortalidade , Doenças das Aves Domésticas/patologia , Doenças das Aves Domésticas/virologia , Virulência/imunologia
11.
Mol Neurobiol ; 55(8): 6558-6571, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29327203

RESUMO

Mouse hepatitis virus (MHV) infection causes meningoencephalitis by disrupting the neuro-glial and glial-pial homeostasis. Recent studies suggest that MHV infection alters gap junction protein connexin 43 (Cx43)-mediated intercellular communication in brain and primary cultured astrocytes. In addition to astrocytes, meningeal fibroblasts also express high levels of Cx43. Fibroblasts in the meninges together with the basal lamina and the astrocyte endfeet forms the glial limitans superficialis as part of the blood-brain barrier (BBB). Alteration of glial-pial gap junction intercellular communication (GJIC) in MHV infection has the potential to affect the integrity of BBB. Till date, it is not known if viral infection can modulate Cx43 expression and function in cells of the brain meninges and thus affect BBB permeability. In the present study, we have investigated the effect of MHV infection on Cx43 localization and function in mouse brain meningeal cells and primary meningeal fibroblasts. Our results show that MHV infection reduces total Cx43 levels and causes its intracellular retention in the perinuclear compartments reducing its surface expression. Reduced trafficking of Cx43 to the cell surface in MHV-infected cells is associated with loss functional GJIC. Together, these data suggest that MHV infection can directly affect expression and cellular distribution of Cx43 resulting in loss of Cx43-mediated GJIC in meningeal fibroblasts, which may be associated with altered BBB function observed in acute infection.


Assuntos
Conexina 43/deficiência , Fibroblastos/patologia , Fibroblastos/virologia , Junções Comunicantes/metabolismo , Hepatite Viral Animal/metabolismo , Hepatite Viral Animal/patologia , Meninges/patologia , Vírus da Hepatite Murina/fisiologia , Animais , Células Cultivadas , Conexina 43/metabolismo , Retículo Endoplasmático/metabolismo , Fibroblastos/metabolismo , Inflamação/patologia , Camundongos Endogâmicos C57BL , Agregados Proteicos , Vimentina/metabolismo
12.
Front Immunol ; 9: 2935, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30619295

RESUMO

Background: Fulminant hepatitis (FH) is a serious threat to human life, accompanied by massive and rapid necroinflammation. Kupffer cells, the major immune cell population involved in innate immune responses, are considered to be central for FH. Fibrinogen-like protein 2 (Fgl2) is a pro-coagulant protein that is substantially induced in macrophages upon viral infection, and Fgl2 depletion represses murine hepatitis virus strain 3 (MHV-3) infection. Clara cell 10 kDa (CC10) protein is a secretory protein with anti-inflammatory properties in allergic rhinitis and asthma. However, its mechanisms of action and pathogenic roles in other disease are still unclear. In this study, we aimed to determine the role of CC10 in FH and the regulation of Fgl2 by CC10. Methods: A mouse FH model was established by peritoneal injection of MHV-3. The mice received CC10 protein through tail vein injection before viral infection. Survival rate, liver function, liver histology, fibrin deposition, and necrosis were examined. The regulatory effect of CC10 on Fgl2 expression was investigated using THP-1 cells and mouse peritoneal macrophages in vitro. Results: In the mouse FH model induced by MHV-3, the survival rate increased from 0 to 12.5% in the CC10 group compared to that in the saline-only control group. Meanwhile, the levels of ALT and AST in serum were significantly decreased and liver damage was reduced. Furthermore, hepatic Fgl2, TNF-α, and IL-1ß expression was obviously downregulated together with fibrin deposition, and hepatocyte apoptosis was reduced after administration of CC10 protein. In vitro, CC10 was found to significantly inhibit the expression of Fgl2 in IFN-γ-treated THP-1 cells and MHV-3-infected mouse peritoneal macrophages by western blot and real-time PCR. However, there was no direct interaction between CC10 and Fgl2 as shown by co-immunoprecipitation. Microarray investigations suggested that HMG-box transcription factor 1 (HBP1) was significantly low in CC10-treated and IFN-γ-primed THP-1 cells. HBP1-siRNA treatment abrogated the inhibitory effect of CC10 on Fgl2 expression in Human Umbilical Vein Endothelial cells (HUVECs). Conclusion:CC10 protects against MHV-3-induced FH via suppression of Fgl2 expression in macrophages. Such effects may be mediated by the transcription factor HBP1.


Assuntos
Infecções por Coronavirus/imunologia , Fibrinogênio/metabolismo , Hepatite Viral Animal/imunologia , Falência Hepática Aguda/imunologia , Uteroglobina/metabolismo , Animais , Células CHO , Infecções por Coronavirus/mortalidade , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Cricetulus , Modelos Animais de Doenças , Feminino , Fibrinogênio/genética , Hepatite Viral Animal/mortalidade , Hepatite Viral Animal/patologia , Hepatite Viral Animal/virologia , Proteínas de Grupo de Alta Mobilidade/metabolismo , Células Endoteliais da Veia Umbilical Humana , Humanos , Fígado/imunologia , Fígado/patologia , Fígado/virologia , Falência Hepática Aguda/mortalidade , Falência Hepática Aguda/patologia , Falência Hepática Aguda/virologia , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Vírus da Hepatite Murina/imunologia , Vírus da Hepatite Murina/patogenicidade , Necrose/imunologia , Necrose/patologia , Necrose/virologia , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Proteínas Repressoras/metabolismo , Taxa de Sobrevida , Células THP-1 , Uteroglobina/genética
13.
Emerg Microbes Infect ; 6(11): e103, 2017 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-29184155

RESUMO

Fowl adenovirus (FAdV) has caused significant losses in chicken flocks throughout China in recent years. However, the current understanding of the genetic and pathogenic characteristics of the FAdV epidemic in southwestern China remains poorly understood. In this study, a total of 22 strains were isolated from liver samples of diseased chickens from farms in southwestern China. Phylogenetic analysis based on the hexon loop-1 gene showed that the 22 isolates were clustered into four distinct serotypes: FAdV serotype 4 (FAdV-4) (86.4%, 19/22), FAdV-2 (4.5%, 1/22), FAdV-8a (4.5%, 1/22), and FAdV-8b (4.5%, 1/22). FAdV-4 was the predominant serotype in southwestern China. Pathogenicity testing showed that the FAdV-4 serotype strain CH/GZXF/1602 and FAdV-8a strain CH/CQBS/1504 were pathogenic to chickens, with mortality rates reaching as high as 80% and 20%, respectively. The primary clinical feature observed following infection with strain CH/GZXF/1602 (FAdV-4) was hepatitis-hydropericardium syndrome, and that of strain CH/CQBS/1504 (FAdV-8a) was inclusion body hepatitis. Conversely, the FAdV-2 serotype strain CH/GZXF/1511 and FAdV-8b serotype strain CH/CQBS/1512 was not observed to be pathogenic in chickens. Then, CH/GZXF/1602 (FAdV-4) was selected for the preparation of an inactivated oil-emulsion vaccine. Immune studies on Partridge Shank broilers showed that a single dose immunization at 17 days of age could not only protect against homologous challenge with virulent FAdV-4 but also provided protection against clinical disease following challenge with the heterologous FAdV-8b virulent strain until 70 days of age. The characterization of newly prevalent FAdV strains provides a valuable reference for the development of an efficacious control strategy.


Assuntos
Infecções por Adenoviridae/veterinária , Aviadenovirus/classificação , Aviadenovirus/genética , Variação Genética , Doenças das Aves Domésticas/virologia , Infecções por Adenoviridae/epidemiologia , Infecções por Adenoviridae/prevenção & controle , Infecções por Adenoviridae/virologia , Animais , Aviadenovirus/isolamento & purificação , Aviadenovirus/patogenicidade , Proteínas do Capsídeo/genética , Galinhas , China/epidemiologia , Genótipo , Hepatite Viral Animal/patologia , Hepatite Viral Animal/prevenção & controle , Hepatite Viral Animal/virologia , Fígado/virologia , Filogenia , Doenças das Aves Domésticas/epidemiologia , Doenças das Aves Domésticas/prevenção & controle , Sorogrupo , Análise de Sobrevida , Vacinas de Produtos Inativados/administração & dosagem , Vacinas de Produtos Inativados/imunologia , Vacinas de Produtos Inativados/isolamento & purificação , Vacinas Virais/administração & dosagem , Vacinas Virais/imunologia , Vacinas Virais/isolamento & purificação
15.
Virology ; 512: 187-193, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28982029

RESUMO

Hepatitis E virus (HEV) causes severe hepatitis in pregnant women, with associated poor fetal outcomes. To study HEV viral pathogenesis, pregnant rabbits were infected with low- and high-dose rabbit HEV at 2 weeks gestation. HEV was identified in the serum, feces, and liver tissue of infected rabbits, and dose-dependent fetal mortality rates ranging from 67% to 80% were observed. The aspartate transaminase (AST)/alanine transaminase ratio was significantly higher (P < 0.01) in high-dose infected rabbits than low-dose infected and negative control rabbits 14 days post infection (dpi). Tumor necrosis factor-α (TNF-α) was significantly higher in low-dose (P < 0.01) and high-dose infected rabbits (P < 0.001) than in negative controls 7 dpi. High-dose HEV-infected rabbits produced significantly more interferon-γ (IFN-γ; P < 0.05) than negative control rabbits at 7 and 14 dpi. High levels of AST, TNF-α, and IFN-γ may substantially influence adverse fetal outcomes in pregnant rabbits infected with high-dose HEV.


Assuntos
Vírus da Hepatite E/classificação , Hepatite E/virologia , Hepatite Viral Animal/patologia , Complicações Infecciosas na Gravidez/virologia , Coelhos/anormalidades , Animais , Anticorpos Antivirais/sangue , Citocinas/genética , Citocinas/metabolismo , Feminino , Regulação da Expressão Gênica/imunologia , Hepatite E/patologia , Vírus da Hepatite E/patogenicidade , Gravidez , Complicações Infecciosas na Gravidez/patologia , Organismos Livres de Patógenos Específicos , Replicação Viral
16.
Virology ; 512: 48-55, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28915405

RESUMO

Despite drug advances for Hepatitis C virus (HCV), re-infections remain prevalent in high-risk populations. Unfortunately, the role of preexisting viral immunity and how it modulates re-infection is unclear. GBV-B infection of common marmosets is a useful model to study tissue immune responses in hepacivirus infections, and in this study we re-challenged 4 animals after clearance of primary viremia. Although only low-to-absent viremia was observed following re-challenge, GBV-B viral RNA was detectable in liver, confirming re-infection. Microscopic hepatic lesions indicated severe-to-mild lymphocyte infiltration and fibrosis in 3 out of 4 animals. Further, GBV-B-specific T cells were elevated in animals with moderate-to-severe hepatopathology, and up to 3-fold increases in myeloid dendritic and activated natural killer cells were observed after infection. Our data indicate that occult hepacivirus re-infections occur and that new liver pathology is possible even in the presence of anti-hepacivirus T cells and in the absence of high viremia.


Assuntos
Infecções por Flaviviridae/imunologia , Vírus GB B/fisiologia , Hepatite Viral Animal/imunologia , Animais , Callithrix , Infecções por Flaviviridae/patologia , Hepatite Viral Animal/patologia , Imunidade Inata/fisiologia , Fígado/patologia , Fígado/virologia , Linfócitos T/fisiologia , Carga Viral , Viremia
17.
Vet Microbiol ; 207: 1-6, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28757007

RESUMO

Hepatitis E virus (HEV) is an increasingly important zoonotic infection in humans with HEV genotypes 3 and 4 being recognized as zoonotic pathogens. The relatively recently isolated genotype 3 rabbit HEV (rHEV-3) and the more well known genotype 3 isolates from humans and swine (hsHEV-3) have all been confirmed experimentally to be capable of infecting both non-human primates and specific-pathogen free (SPF) pigs. In a previous study rHEV-3 was shown to cause acute hepatitis in experimentally infected rabbits. However, whether hsHEV-3 can productively infect rabbits remained unclear. The objective of this study was to investigate the experimental infection of rabbits with human HEV-3 (hHEV-3, JRC-HE3), to compare it to that with rHEV-3 (CHN-BJ-rb14) and to further characterise the pathogenesis of the two isolates. All animals inoculated with rHEV-3 (CHN-BJ-rb14) became infected, exhibiting an intermittent viremia, elevated liver enzymes, and persistent fecal virus shedding throughout the 15 week study period. Liver histopathology showed acute inflammation and both positive- and negative-stranded viral RNA was detected in various tissues from necropsied rabbits. By contrast, neither sero-conversion nor alanine aminotransferase (ALT) elevation was observed in most rabbits inoculated with hHEV-3 (JRC-HE3). In addition, rHEV-3 (CHN-BJ-rb14) but not hHEV-3 (JRC-HE3) recovered from primary infected rabbits was transmissible to naive rabbits. These results showed that SPF rabbits are readily susceptible to infection with rHEV-3 (CHN-BJ-rb14) but not hHEV-3 (JRC-HE3), which might indicate the influence of viral genomic organization on its pathogenicity.


Assuntos
Suscetibilidade a Doenças/veterinária , Vírus da Hepatite E/genética , Vírus da Hepatite E/patogenicidade , Hepatite E/veterinária , Hepatite Viral Animal/virologia , Animais , Hepatite E/patologia , Hepatite E/virologia , Vírus da Hepatite E/classificação , Hepatite Viral Animal/patologia , Humanos , Fígado/patologia , Fígado/virologia , Coelhos , Organismos Livres de Patógenos Específicos
18.
Hepatobiliary Pancreat Dis Int ; 16(3): 245-256, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28603092

RESUMO

BACKGROUND: Liver inflammation or hepatitis is a result of pluripotent interactions of cell death molecules, cytokines, chemokines and the resident immune cells collectively called as microenvironment. The interplay of these inflammatory mediators and switching of immune responses during hepatotoxic, viral, drug-induced and immune cell-mediated hepatitis decide the fate of liver pathology. The present review aimed to describe the mechanisms of liver injury, its relevance to human liver pathology and insights for the future therapeutic interventions. DATA SOURCES: The data of mouse hepatic models and relevant human liver diseases presented in this review are systematically collected from PubMed, ScienceDirect and the Web of Science databases published in English. RESULTS: The hepatotoxic liver injury in mice induced by the metabolites of CCl4, acetaminophen or alcohol represent necrotic cell death with activation of cytochrome pathway, formation of reactive oxygen species (ROS) and mitochondrial damage. The Fas or TNF-alpha induced apoptotic liver injury was dependent on activation of caspases, release of cytochrome c and apoptosome formation. The ConA-hepatitis demonstrated the involvement of TRAIL-dependent necrotic/necroptotic cell death with activation of RIPK1/3. The alpha-GalCer-induced liver injury was mediated by TNF-alpha. The LPS-induced hepatitis involved TNF-alpha, Fas/FasL, and perforin/granzyme cell death pathways. The MHV3 or Poly(I:C) induced liver injury was mediated by natural killer cells and TNF-alpha signaling. The necrotic ischemia-reperfusion liver injury was mediated by hypoxia, ROS, and pro-inflammatory cytokines; however, necroptotic cell death was found in partial hepatectomy. The crucial role of immune cells and cell death mediators in viral hepatitis (HBV, HCV), drug-induced liver injury, non-alcoholic fatty liver disease and alcoholic liver disease in human were discussed. CONCLUSIONS: The mouse animal models of hepatitis provide a parallel approach for the study of human liver pathology. Blocking or stimulating the pathways associated with liver cell death could unveil the novel therapeutic strategies in the management of liver diseases.


Assuntos
Comunicação Celular , Doença Hepática Induzida por Substâncias e Drogas/imunologia , Hepatite Viral Animal/imunologia , Fígado/imunologia , Animais , Apoptose , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Citocinas/metabolismo , Modelos Animais de Doenças , Proteína Ligante Fas/metabolismo , Hepatite Viral Animal/metabolismo , Hepatite Viral Animal/patologia , Hepatite Viral Animal/virologia , Interações Hospedeiro-Patógeno , Humanos , Mediadores da Inflamação/metabolismo , Fígado/metabolismo , Fígado/patologia , Fígado/virologia , Camundongos , Necrose , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Especificidade da Espécie
19.
PLoS One ; 12(4): e0175495, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28394931

RESUMO

The principal target organ of duck hepatitis A virus type 1 (DHAV-1) is duckling liver, which is an energy-intensive organ and plays important roles in body's energy metabolism and conversion. As the "power house" of the hepatocytes, mitochondria provide more than 90% of the energy. However, mitochondria are much vulnerable to the oxidative stress for their rich in polyunsaturated fatty acids. Although previous researches have demonstrated that DHAV-1 could induce the oxidative stress in the serum of the infected ducklings, no related study on the mitochondria during the pathological process of DVH has been reported by far. To address this issue, we examined the HE stained tissue pathological slices, detected the hepatic SOD, CAT and GPX activities and MDA contents and analyzed the ATP content, mitochondrial ultrastructure and the mitochondrial SOD, GPX activities and MDA content in the liver tissues. The results showed that the hepatic redox status was significantly disturbed so that causing the mitochondrial dysfunction, ATP depletion and mitochondrial oxidative stress during the process of the DHAV-1 infection, and a prescription formulated with Hypericum japonicum flavone, Radix Rehmanniae Recens polysaccharide and Salvia plebeia flavone (HRS), which had been demonstrated with good anti-oxidative activity in serum, could effectively alleviate the hepatic injury and the oxidative stress in liver tissue induced by DHAV-1 thus alleviating the mitochondrial injury and oxidative stress. In a word, this research discovers the oxidative stress induced mitochondrial dysfunction and oxidative stress during the DVH pathological process and demonstrates HRS exerts good anti-oxidative activity in liver tissue to protect mitochondria against reactive oxygen species (ROS).


Assuntos
Antivirais/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Vírus da Hepatite do Pato , Hepatite Viral Animal/tratamento farmacológico , Mitocôndrias/efeitos dos fármacos , Infecções por Picornaviridae/tratamento farmacológico , Trifosfato de Adenosina/metabolismo , Animais , Patos , Flavonas/farmacologia , Glutationa Peroxidase/metabolismo , Hepatite Viral Animal/metabolismo , Hepatite Viral Animal/mortalidade , Hepatite Viral Animal/patologia , Peroxidação de Lipídeos/efeitos dos fármacos , Peroxidação de Lipídeos/fisiologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Malondialdeído/metabolismo , Mitocôndrias/metabolismo , Mitocôndrias/ultraestrutura , Estresse Oxidativo/efeitos dos fármacos , Infecções por Picornaviridae/metabolismo , Infecções por Picornaviridae/mortalidade , Infecções por Picornaviridae/patologia , Polissacarídeos/farmacologia , Distribuição Aleatória , Superóxido Dismutase/metabolismo , Resultado do Tratamento
20.
J Vet Med Sci ; 79(5): 917-920, 2017 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-28413174

RESUMO

In June 2015, a highly fatal and acute disease broke out in a duckling farm in Hyogo Prefecture, Japan. The birds exhibited poor growth, reduced movement, lying in a dorsal recumbent position, depression, lethargy, ataxia and opisthotonus, with a high mortality rate of approximately 76%. By performing a reverse transcription-polymerase chain reaction (RT-PCR) using primers specific for duck hepatitis A virus type 1 (DHAV-1), we obtained the PCR products of a predicted size. The nucleotide sequences of the PCR products showed a >96% identity with that of the DHAV-1, HB02 strain, which was isolated in China. To our knowledge, this is the first time that the DHAV-1 virus has been isolated since its outbreak in Japan in 1963.


Assuntos
Surtos de Doenças/veterinária , Vírus da Hepatite A , Hepatite A/veterinária , Hepatite Viral Animal/epidemiologia , Doenças das Aves Domésticas/epidemiologia , Animais , Patos/virologia , Hepatite A/epidemiologia , Hepatite A/virologia , Vírus da Hepatite A/genética , Hepatite Viral Animal/patologia , Hepatite Viral Animal/virologia , Japão/epidemiologia , Fígado/patologia , Filogenia , Doenças das Aves Domésticas/patologia , Doenças das Aves Domésticas/virologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa/veterinária
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