RESUMEN
BACKGROUND: Equine herpesvirus type 1 (EHV-1) is commonly associated with horse abortion. Currently, there are no reported cases of abortion resulting from EHV-1 infection in donkeys. RESULTS: This was the first survey-based study of Chinese donkeys. The presence of EHV-1 was identified by PCR. This survey was conducted in Chabuchar County, North Xinjiang, China, in 2020. A donkey EHV-1 strain (Chabuchar/2020) was successfully isolated in MDBK cells. Seventy-two of 100 donkey sera were able to neutralize the isolated EHV-1. Moreover, the ORF33 sequence of the donkey-origin EHV-1 Chabuchar/2020 strain showed high levels of similarity in both its nucleotide (99.7â100%) and amino acid (99.5â100%) sequences, with those of horse EHV-1 strains. EHV-1 Chabuchar/2020 showed significant consistency and was classified within cluster 1 of horse EHV-1 strains. Further, analysis of the expected ORF30 nucleotide sequence revealed that donkey EHV-1 strains contained guanine at position 2254, resulting in a change to aspartic acid at position 752 of the viral DNA polymerase. Therefore, these strains were classified as horse neuropathogenic strains. Lastly, a phylogenetic tree was constructed using the partial ORF68 nucleotide sequences, showing that the identified donkey EHV-1 strain and the EHV-1 strain found in aborted Yili horses in China comprised a novel independent VIII group. CONCLUSION: This study showed the first isolation and identification of EHV-1 as an etiological agent of abortions in donkeys. Further analysis of the ORF33, ORF30, and ORF68 sequences indicated that the donkey EHV-1 contained the neuropathogenic genotype of strains in the VIII group. It is thus important to be aware of EHV-1 infection in the donkey population, even though the virus has only been identified in donkey abortions in China.
Asunto(s)
Equidae , Infecciones por Herpesviridae , Herpesvirus Équido 1 , Pulmón , Filogenia , Animales , Equidae/virología , Herpesvirus Équido 1/aislamiento & purificación , Herpesvirus Équido 1/genética , Herpesvirus Équido 1/clasificación , China , Infecciones por Herpesviridae/veterinaria , Infecciones por Herpesviridae/virología , Pulmón/virología , Feto Abortado/virología , Femenino , ADN Viral/genética , Sistemas de Lectura Abierta , Análisis de Secuencia de ADN , Embarazo , Reacción en Cadena de la PolimerasaRESUMEN
BACKGROUND: Varicellovirus equidalpha1 (formerly Equid alphaherpesvirus 1, EqAHV-1) is among the most important viruses responsible for respiratory disease outbreaks among horses throughout the world. No reports to date have detailed the association between EqAHV-1 and respiratory disease among horses in China. This study described one such outbreak among a population of horses in north Xinjiang that occurred from April 2021 - May 2023. RESULTS: qPCR revealed that EqAHV-1 was detectable in all samples and this virus was identified as a possible source of respiratory disease, although a limited subset of these samples were also positive for EqAHV-2, EqAHV-4, and EqAHV-5. In total, three EqAHV-1 strains responsible for causing respiratory illness in horses were isolated successfully, and full-length ORF33 sequence comparisonsand phylogenetic analyses indicated that these isolates may have originated from EqAHV-1 strains detected in Yili horse abortions. ORF30 sequence data additionally suggested that these strains were neuropathic, as evidenced by the presence of a guanine residue at nucleotide position 2254 corresponding to the aspartic acid present at position 752 in the DNA polymerase encoded by this virus. CONCLUSION: This study is the first report of an outbreak of respiratory disease among horses in China caused by EqAHV-1. ORF30 sequence characterization revealed that these EqAHV-1 strains harbored a neuropathogenic genotype. Given the detection of this virus in horses suffering from respiratory disease, concern is warranted with respect to this neuropathogenic EqAHV-1 outbreak.
Asunto(s)
Infecciones por Herpesviridae , Herpesvirus Équido 1 , Enfermedades de los Caballos , Varicellovirus , Embarazo , Femenino , Caballos/genética , Animales , Filogenia , ADN Viral/genética , Herpesvirus Équido 1/genética , Brotes de Enfermedades/veterinaria , Enfermedades de los Caballos/epidemiología , Infecciones por Herpesviridae/epidemiología , Infecciones por Herpesviridae/veterinariaRESUMEN
Measles virus (MeV), the causative agent of measles, is an enveloped RNA virus of the family Paramyxoviridae, which remains an important cause of childhood morbidity and mortality. MeV has two envelope glycoproteins, the hemagglutinin (H) and fusion (F) proteins. During viral entry or virus-mediated fusion between infected cells and neighboring susceptible cells, the head domain of the H protein initially binds to its receptors, signaling lymphocytic activation molecule family member 1 (SLAM) and nectin-4, and then the stalk region of the H protein transmits the fusion-triggering signal to the F protein. MeV may persist in the human brain and cause a fatal neurodegenerative disease, subacute sclerosing panencephalitis (SSPE). Recently, we showed, using in vitro cell culture, that cell adhesion molecule (CADM) 1 and CADM2 are host factors that trigger hyperfusogenic mutant F proteins, causing cell-to-cell fusion and the transfer of the MeV genome between neurons. Unlike conventional receptors, CADM1 and CADM2 interact in cis (on the same membrane) with the H protein and then trigger membrane fusion. Here, we show that alanine substitutions in part of the stalk region (positions 171-175) abolish the ability of the H protein to mediate membrane fusion triggered by CADM1 and CADM2, but not by SLAM. The recombinant hyperfusogenic MeV carrying this mutant H protein loses its ability to spread in primary mouse neurons as well as its neurovirulence in experimentally infected suckling hamsters. These results indicate that CADM1 and CADM2 are key molecules for MeV propagation in the brain and its neurovirulence in vivo. IMPORTANCE Measles is an acute febrile illness with skin rash. Despite the availability of highly effective vaccines, measles is still an important cause of childhood morbidity and mortality in many countries. The World Health Organization estimates that more than 120,000 people died from measles worldwide in 2021. Measles virus (MeV), the causative agent of measles, can also cause a fatal progressive neurological disorder, subacute sclerosing panencephalitis (SSPE), several years after acute infection. There is currently no effective treatment for this disease. In this study, using recombinant MeVs with altered receptor usage patterns, we show that cell adhesion molecule (CADM) 1 and CADM2 are host factors critical for MeV spread in neurons and its neurovirulence. These findings further our understanding of the molecular mechanism of MeV neuropathogenicity.
Asunto(s)
Sarampión , Enfermedades Neurodegenerativas , Panencefalitis Esclerosante Subaguda , Cricetinae , Humanos , Ratones , Animales , Virus del Sarampión/fisiología , Panencefalitis Esclerosante Subaguda/genética , Hemaglutininas/metabolismo , Enfermedades Neurodegenerativas/metabolismo , Proteínas Virales de Fusión/genética , Proteínas Virales de Fusión/metabolismo , Moléculas de Adhesión Celular/genética , Moléculas de Adhesión Celular/metabolismo , Proteínas Recombinantes/metabolismo , Neuronas , Molécula 1 de Adhesión Celular/metabolismoRESUMEN
The canine distemper virus (CDV) is a morbillivirus that infects a broad range of terrestrial carnivores, predominantly canines, and is associated with high mortality. Similar to another morbillivirus, measles virus, which infects humans and nonhuman primates, CDV transmission from an infected host to a naïve host depends on two cellular receptors, namely, the signaling lymphocyte activation molecule (SLAM or CD150) and the adherens junction protein nectin-4 (also known as PVRL4). CDV can also invade the central nervous system by anterograde spread through olfactory nerves or in infected lymphocytes through the circulation, thus causing chronic progressive or relapsing demyelination of the brain. However, the absence of the two receptors in the white matter, primary cultured astrocytes, and neurons in the brain was recently demonstrated. Furthermore, a SLAM/nectin-4-blind recombinant CDV exhibits full cell-to-cell transmission in primary astrocytes. This strongly suggests the existence of a third CDV receptor expressed in neural cells, possibly glial cells. In this review, we summarize the recent progress in the study of CDV receptors, highlighting the unidentified glial receptor and its contribution to pathogenicity in the host nervous system. The reviewed studies focus on CDV neuropathogenesis, and neural receptors may provide promising directions for the treatment of neurological diseases caused by CDV. We also present an overview of other neurotropic viruses to promote further research and identification of CDV neural receptors.
Asunto(s)
Virus del Moquillo Canino , Moquillo , Animales , Moléculas de Adhesión Celular/metabolismo , Virus del Moquillo Canino/fisiología , Perros , Nectinas , Receptores Virales/metabolismoRESUMEN
BACKGROUND: EHV-1 is one of the most serious viral pathogens that frequently cause abortion in horses around the world. However, so far, relatively little information is available on EHV-1 infections as they occur in China. In January 2021, during an abortion storm which occurred in Yili horses at the Chinese State Studs of Zhaosu (North Xinjiang, China), 43 out of 800 pregnant mares aborted. RESULTS: PCR detection revealed the presence of EHV-1 in all samples as the possible cause of all abortions, although EHV-4, EHV-2 and EHV-5 were also found to circulate in the aborted fetuses. Furthermore, the partial ORF33 sequences of the 43 EHV-1 shared 99.3-100% and 99.0-100% similarity in nucleotide and amino acid sequences respectively. These sequences not only indicated a highly conserved region but also allowed the strains to group into six clusters. In addition, based on the predicted ORF30 nucleotide sequence, it was found that all the strains carried a guanine at the 2254 nucleotide position (aspartic acid at position 752 of the viral DNA polymerase) and were, therefore, identified as neuropathogenic strains. CONCLUSION: This study is the first one that establishes EHV-1 as the cause of abortions in Yili horses, of China. Further characterization of the ORF30 sequences revealed that all the EHV-1 strains from the study carried the neuropathogenic genotype. Totally, neuropathogenic EHV-1 infection in China's horse population should be concerned although the virus only detected in Yili horse abortions.
Asunto(s)
Infecciones por Herpesviridae , Herpesvirus Équido 1 , Herpesvirus Équido 4 , Enfermedades de los Caballos , Aborto Veterinario/epidemiología , Animales , Femenino , Infecciones por Herpesviridae/epidemiología , Infecciones por Herpesviridae/veterinaria , Herpesvirus Équido 1/genética , Enfermedades de los Caballos/epidemiología , Caballos , EmbarazoRESUMEN
Measles virus (MeV), an enveloped RNA virus in the family Paramyxoviridae, usually causes acute febrile illness with skin rash but in rare cases persists in the brain, causing a progressive neurological disorder, subacute sclerosing panencephalitis (SSPE). MeV bears two envelope glycoproteins, the hemagglutinin (H) and fusion (F) proteins. The H protein possesses a head domain that initially mediates receptor binding and a stalk domain that subsequently transmits the fusion-triggering signal to the F protein. We recently showed that cell adhesion molecule 1 (CADM1; also known as IGSF4A, Necl-2, and SynCAM1) and CADM2 (also known as IGSF4D, Necl-3, and SynCAM2) are host factors enabling cell-cell membrane fusion mediated by hyperfusogenic F proteins of neuropathogenic MeVs as well as MeV spread between neurons lacking the known receptors. CADM1 and CADM2 interact in cis with the H protein on the same cell membrane, triggering hyperfusogenic F protein-mediated membrane fusion. Multiple isoforms of CADM1 and CADM2 containing various lengths of their stalk regions are generated by alternative splicing. Here, we show that only short-stalk isoforms of CADM1 and CADM2 predominantly expressed in the brain induce hyperfusogenic F protein-mediated membrane fusion. While the known receptors interact in trans with the H protein through its head domain, these isoforms can interact in cis even with the H protein lacking the head domain and trigger membrane fusion, presumably through its stalk domain. Thus, our results unveil a new mechanism of viral fusion triggering by host factors. IMPORTANCE Measles, an acute febrile illness with skin rash, is still an important cause of childhood morbidity and mortality worldwide. Measles virus (MeV), the causative agent of measles, may also cause a progressive neurological disorder, subacute sclerosing panencephalitis (SSPE), several years after acute infection. The disease is fatal, and no effective therapy is available. Recently, we reported that cell adhesion molecule 1 (CADM1) and CADM2 are host factors enabling MeV cell-to-cell spread in neurons. These molecules interact in cis with the MeV attachment protein on the same cell membrane, triggering the fusion protein and causing membrane fusion. CADM1 and CADM2 are known to exist in multiple splice isoforms. In this study, we report that their short-stalk isoforms can induce membrane fusion by interacting in cis with the viral attachment protein independently of its receptor-binding head domain. This finding may have important implications for cis-acting fusion triggering by host factors.
Asunto(s)
Molécula 1 de Adhesión Celular/metabolismo , Células Gigantes/virología , Hemaglutininas Virales/metabolismo , Interacciones Huésped-Patógeno , Virus del Sarampión/fisiología , Sarampión/metabolismo , Sarampión/virología , Animales , Encéfalo/metabolismo , Encéfalo/virología , Molécula 1 de Adhesión Celular/genética , Células Cultivadas , Cricetinae , Modelos Biológicos , Unión Proteica , Isoformas de Proteínas , Proteínas Virales de Fusión/metabolismoRESUMEN
Subacute sclerosing panencephalitis (SSPE) is a rare fatal neurodegenerative disease caused by a measles virus (MV) variant, SSPE virus, that accumulates mutations during long-term persistent infection of the central nervous system (CNS). Clusters of mutations identified around the matrix (M) protein in many SSPE viruses suppress productive infectious particle release and accelerate cell-cell fusion, which are features of SSPE viruses. It was reported, however, that these defects of M protein function might not be correlated directly with promotion of neurovirulence, although they might enable establishment of persistent infection. Neuropathogenicity is closely related to the character of the viral fusion (F) protein, and amino acid substitution(s) in the F protein of some SSPE viruses confers F protein hyperfusogenicity, facilitating viral propagation in the CNS through cell-cell fusion and leading to neurovirulence. The F protein of an SSPE virus Kobe-1 strain, however, displayed only moderately enhanced fusion activity and required additional mutations in the M protein for neuropathogenicity in mice. We demonstrated here the mechanism for the M protein of the Kobe-1 strain supporting the fusion activity of the F protein and cooperatively inducing neurovirulence, even though each protein, independently, has no effect on virulence. The occurrence of SSPE has been estimated recently as one in several thousand in children who acquired measles under the age of 5 years, markedly higher than reported previously. The probability of a specific mutation (or mutations) occurring in the F protein conferring hyperfusogenicity and neuropathogenicity might not be sufficient to explain the high frequency of SSPE. The induction of neurovirulence by M protein synergistically with moderately fusogenic F protein could account for the high frequency of SSPE.
Asunto(s)
Encéfalo/virología , Virus SSPE/patogenicidad , Panencefalitis Esclerosante Subaguda/virología , Proteínas Virales de Fusión/metabolismo , Proteínas de la Matriz Viral/metabolismo , Animales , Línea Celular , Línea Celular Tumoral , Genes Virales , Células Gigantes/virología , Humanos , Fusión de Membrana , Ratones , Mutación , Neuronas/virología , Virus SSPE/genética , Proteínas Virales de Fusión/genética , Proteínas de la Matriz Viral/genéticaRESUMEN
Tick-borne encephalitis virus (TBEV) is a zoonotic virus in the genus Flavivirus, family Flaviviridae. TBEV is widely distributed in northern regions of the Eurasian continent, including Japan, and causes severe encephalitis in humans. Tick-borne encephalitis (TBE) was recently reported in central Hokkaido, and wild animals with anti-TBEV antibodies were detected over a wide area of Hokkaido, although TBEV was only isolated in southern Hokkaido. In this study, we conducted a survey of ticks to isolate TBEV in central Hokkaido. One strain, designated Sapporo-17-Io1, was isolated from ticks (Ixodes ovatus) collected in Sapporo city. Sequence analysis revealed that the isolated strain belonged to the Far Eastern subtype of TBEV and was classified in a different subcluster from Oshima 5-10, which had previously been isolated in southern Hokkaido. Sapporo-17-Io1 showed similar growth properties to those of Oshima 5-10 in cultured cells and mouse brains. The mortality rate of mice infected intracerebrally with each virus was similar, but the survival time of mice inoculated with Sapporo-17-Io1 was significantly longer than that of mice inoculated with Oshima 5-10. These results indicate that the neurovirulence of Sapporo-17-Io1 was lower than that of Oshima 5-10. Using an infectious cDNA clone, the replacement of genes encoding non-structural genes from Oshima 5-10 with those from Sapporo-17-Io1 attenuated the neuropathogenicity of the cloned viruses. This result indicated that the non-structural proteins determine the neurovirulence of these two strains. Our results provide important insights for evaluating epidemiological risk in TBE-endemic areas of Hokkaido.
Asunto(s)
Virus de la Encefalitis Transmitidos por Garrapatas/aislamiento & purificación , Encefalitis Transmitida por Garrapatas/virología , Ixodes/virología , Animales , Animales Salvajes/virología , Encéfalo/virología , Línea Celular , Virus de la Encefalitis Transmitidos por Garrapatas/genética , Femenino , Japón , Masculino , Ratones , Ratones Endogámicos BALB C , Proteínas no Estructurales Virales/genética , Virulencia/genéticaRESUMEN
Measles virus (MeV) is an enveloped RNA virus bearing two envelope glycoproteins, the hemagglutinin (H) and fusion (F) proteins. Upon receptor binding, the H protein triggers conformational changes of the F protein, causing membrane fusion and subsequent virus entry. MeV may persist in the brain, infecting neurons and causing fatal subacute sclerosing panencephalitis (SSPE). Since neurons do not express either of the MeV receptors, signaling lymphocytic activation molecule (SLAM; also called CD150) and nectin-4, how MeV propagates in neurons is unknown. Recent studies have shown that specific substitutions in the F protein found in MeV isolates from SSPE patients are critical for MeV neuropathogenicity by rendering the protein unstable and hyperfusogenic. Recombinant MeVs possessing the F proteins with such substitutions can spread in primary human neurons and in the brains of mice and hamsters and induce cell-cell fusion in cells lacking SLAM and nectin-4. Here, we show that receptor-blind mutant H proteins that have decreased binding affinities to receptors can support membrane fusion mediated by hyperfusogenic mutant F proteins, but not the wild-type F protein, in cells expressing the corresponding receptors. The results suggest that weak interactions of the H protein with certain molecules (putative neuron receptors) trigger hyperfusogenic F proteins in SSPE patients. Notably, where cell-cell contacts are ensured, the weak cis interaction of the H protein with SLAM on the same cell surface also could trigger hyperfusogenic F proteins. Some enveloped viruses may exploit such cis interactions with receptors to infect target cells, especially in cell-to-cell transmission.IMPORTANCE Measles virus (MeV) may persist in the brain, causing incurable subacute sclerosing panencephalitis (SSPE). Because neurons, the main target in SSPE, do not express receptors for wild-type (WT) MeV, how MeV propagates in the brain is a key question for the disease. Recent studies have demonstrated that specific substitutions in the MeV fusion (F) protein are critical for neuropathogenicity. Here, we show that weak cis and trans interactions of the MeV attachment protein with receptors that are not sufficient to trigger the WT MeV F protein can trigger the mutant F proteins from neuropathogenic MeV isolates. Our study not only provides an important clue to understand MeV neuropathogenicity but also reveals a novel viral strategy to expand cell tropism.
Asunto(s)
Moléculas de Adhesión Celular/metabolismo , Hemaglutininas Virales/metabolismo , Virus del Sarampión/metabolismo , Miembro 1 de la Familia de Moléculas Señalizadoras de la Activación Linfocitaria/metabolismo , Panencefalitis Esclerosante Subaguda/metabolismo , Proteínas Virales de Fusión/metabolismo , Animales , Moléculas de Adhesión Celular/genética , Línea Celular , Cricetinae , Hemaglutininas Virales/genética , Humanos , Virus del Sarampión/genética , Virus del Sarampión/patogenicidad , Ratones , Miembro 1 de la Familia de Moléculas Señalizadoras de la Activación Linfocitaria/genética , Panencefalitis Esclerosante Subaguda/genética , Panencefalitis Esclerosante Subaguda/patología , Proteínas Virales de Fusión/genéticaRESUMEN
Bluetongue virus (BTV) is neurotropic in nature, especially in ruminant fetuses and in-utero infection results in abortion and congenital brain malformations. The aim of the present study was to compare the neuropathogenicity of major Indian BTV serotypes 1, 2, 10, 16 and 23 by gross and histopathological lesions and virus distribution in experimentally infected neonatal BALB/c mice. Each BTV serotype (20 µl of inoculum containing 1 × 105 tissue culture infectious dose [TCID]50/ml of virus) was inoculated intracerebrally into 3-day-old mice, while a control group was inoculated with mock-infected cell culture medium. Infection with BTV serotypes 1, 2 and 23 led to 65-70% mortality at 7-9 days post infection (dpi) and caused severe necrotizing encephalitis with neurodegenerative changes in neurons, swelling and proliferation of vascular endothelial cells in the cerebral cortex, cerebellum, midbrain and brainstem. In contrast, infection with BTV serotypes 10 and 16 led to 25-30% mortality at 9-11 dpi and caused mild neuropathological lesions. BTV antigen was detected by immunohistochemistry, direct fluorescence antibody technique and confocal microscopy in the cytoplasm of neuronal cells of the hippocampus, grey matter of the cerebral cortex and vascular endothelial cells in the midbrain and brainstem of BTV-1, -2, -10, -16 and -23 infected groups from 3 to 20 dpi. BTV nucleic acid was detected in the infected brain tissues from as early as 24 h up to 20 dpi by VP7 gene segment-based one-step reverse transcriptase polymerase chain reaction. This study of the relative neurovirulence of BTV serotypes is likely to help design suitable vaccination and control strategies for the disease.
Asunto(s)
Lengua Azul/patología , Encéfalo/patología , Encéfalo/virología , Animales , Animales Recién Nacidos , Virus de la Lengua Azul , Modelos Animales de Enfermedad , Ratones , Ratones Endogámicos BALB C , SerogrupoRESUMEN
Neurological diseases caused by encephalitic flaviviruses are severe and associated with high levels of mortality. However, little is known about the detailed mechanisms of viral replication and pathogenicity in the brain. Previously, we reported that the genomic RNA of tick-borne encephalitis virus (TBEV), a member of the genus Flavivirus, is transported and replicated in the dendrites of neurons. In the present study, we analyzed the transport mechanism of the viral genome to dendrites. We identified specific sequences of the 5' untranslated region of TBEV genomic RNA that act as a cis-acting element for RNA transport. Mutated TBEV with impaired RNA transport in dendrites caused a reduction in neurological symptoms in infected mice. We show that neuronal granules, which regulate the transport and local translation of dendritic mRNAs, are involved in TBEV genomic RNA transport. TBEV genomic RNA bound an RNA-binding protein of neuronal granules and disturbed the transport of dendritic mRNAs. These results demonstrated a neuropathogenic virus hijacking the neuronal granule system for the transport of viral genomic RNA in dendrites, resulting in severe neurological disease.
Asunto(s)
Infecciones por Flavivirus/metabolismo , Infecciones por Flavivirus/fisiopatología , Flavivirus/patogenicidad , Animales , Transporte Biológico/fisiología , Encéfalo/patología , Dendritas/patología , Dendritas/fisiología , Virus de la Encefalitis Transmitidos por Garrapatas/fisiología , Encefalitis Transmitida por Garrapatas/virología , Genoma Viral , Neuronas/patología , ARN , Proteínas de Unión al ARN/genética , Garrapatas , Virulencia , Replicación ViralRESUMEN
This study aimed to investigate the neuropathogenesis of equine herpes virus 9 (EHV-9) by studying the effects of a single point mutation introduced in two different EHV-9 genes. The two EHV-9 mutants, 14R and 19R, were generated carrying a point mutation in two separate EHV-9 genes. These mutants, along with the wild-type EHV-9, were used to infect a hamster model. The EHV-9- and 19R-infected groups showed earlier and more severe clinical signs of infection than the 14R-infected group. The white blood cells (WBCs) count was significantly increased in both EHV-9- and 19R-infected groups compared to the 14R-infected group at the 4th day post infection (DPI). Viremia was also detected earlier in both EHV-9- and 19R-infected groups than 14R-infected group. There were differences in the anterograde transmission pattern of both EHV-9 and 19R compared to 14R inside the brain. Serum TNF-α, IL-6 and IFN-γ levels were significantly increased in both EHV-9- and 19R-infected groups compared to the 14R-infected group. Histopathological and immunohistochemical analyses revealed that the mean group scores for the entire brain were significantly higher in both EHV-9- and 19R- infected groups than 14R-infected group. Collectively, these results confirm that the gene product of Open Reading Frame 19 (ORF19) plays an important role in EHV-9 neuropathogenicity and that the mutation in ORF19 is responsible for the attenuation of EHV-9.
Asunto(s)
Infecciones del Sistema Nervioso Central/virología , Infecciones por Herpesviridae/virología , Mutación Puntual , Varicellovirus/genética , Animales , Cricetinae , Masculino , Varicellovirus/patogenicidadRESUMEN
Human astrocyte cells were exposed to HIV-Tat and/or epidermal growth factor (EGF), to monitor the expression of the neuropathogenic MSRV and Syncytin-1 elements of the HERV-W family of endogenous retroviruses and of TNFα. The results indicate that EGF counteracts Tat regulation of HERV-W/MSRVenv/Syncytin-1, throughout EGFR activation; this effect occurs by interfering with the induction of TNFα production by Tat. The novel effect of EGF counteraction of Tat-mediated regulation of the neuropathogenic HERV-Ws could be neuro-protective, but its actual role in the brain remains to be elucidated.
Asunto(s)
Astrocitos/virología , Retrovirus Endógenos/genética , Factor de Crecimiento Epidérmico/farmacología , Productos del Gen tat del Virus de la Inmunodeficiencia Humana/farmacología , Anticuerpos Monoclonales/farmacología , Astrocitos/efectos de los fármacos , Línea Celular , Retrovirus Endógenos/crecimiento & desarrollo , Retrovirus Endógenos/metabolismo , Receptores ErbB/genética , Receptores ErbB/metabolismo , Feto , Productos del Gen env/genética , Productos del Gen env/metabolismo , Anticuerpos Anti-VIH/farmacología , Humanos , Lipopolisacáridos/farmacología , Proteínas Gestacionales/genética , Proteínas Gestacionales/metabolismo , Factor de Necrosis Tumoral alfa/farmacología , Productos del Gen tat del Virus de la Inmunodeficiencia Humana/antagonistas & inhibidoresRESUMEN
A point mutation in the DNA polymerase gene in equine herpesvirus type 1 (EHV-1) is one determinant for the development of neurological disease in horses. Three recently conducted infection experiments using domestic horses and ponies failed to detect statistically significant differences in viral shedding between the neuropathogenic and non-neuropathogenic variants. These results were interpreted as suggesting the absence of a consistent selective advantage of the neuropathogenic variant and therefore appeared to be inconsistent with a systematic increase in the prevalence of neuropathogenic strains. To overcome potential problems of low statistical power related to small group sizes in these infection experiments, we integrated raw data from all three experiments into a single statistical analysis. The results of this combined analysis showed that infection with the neuropathogenic EHV-1 variant led to a statistically significant increase in viral shedding. This finding is consistent with the idea that neuropathogenic strains could have a selective advantage and are therefore systematically increasing in prevalence in domestic horse populations. However, further studies are required to determine whether a selective advantage indeed exists for neuropathogenic strains.
Asunto(s)
Herpesvirus Équido 1/genética , Herpesvirus Équido 1/patogenicidad , Mutación Puntual , Esparcimiento de Virus , Animales , Caballos , VirulenciaRESUMEN
Equine herpesvirus myeloencephalopathy (EHM) is a severe manifestation of equine herpesvirus 1 (EHV-1) infection. Prevention and treatment of EHM during EHV-1 outbreaks is critical, but no reliable and tested specific medication is available. Due to the thromboischemic nature of EHM and due to the fact that EHV-1 entry in cells is blocked by heparin, it was hypothesized that this compound may be useful in reduction of EHM incidence and severity. Therefore, during an acute EHV-1 outbreak with the neuropathogenic G2254/D752 Pol variant, metaphylactic treatment with heparin to prevent EHM was initiated. Clinical signs were present in 61 horses (fever n = 55; EHM n = 8; abortion n = 6). Heparin (25000 IU subcutaneously twice daily for 3 days) was given to 31 febrile horses from day 10 of the outbreak, while the first 30 horses exhibiting fever remained untreated. Treatment outcome was analyzed retrospectively. Heparin-treated horses showed a lower EHM incidence (1/31; 3.2%) than untreated horses (7/30; 23.3%; p = 0.03). Results indicate that heparin may be useful for prevention of EHM during an EHV-1 outbreak. These promising data highlight the need for randomized and possibly blinded studies for the use of heparin in EHV-1 outbreaks.
Asunto(s)
Antivirales/uso terapéutico , Brotes de Enfermedades/veterinaria , Heparina/uso terapéutico , Infecciones por Herpesviridae/veterinaria , Herpesvirus Équido 1 , Enfermedades de los Caballos/prevención & control , Animales , Brotes de Enfermedades/prevención & control , Infecciones por Herpesviridae/tratamiento farmacológico , Infecciones por Herpesviridae/prevención & control , Enfermedades de los Caballos/tratamiento farmacológico , Enfermedades de los Caballos/virología , Caballos , Estudios RetrospectivosRESUMEN
In addition to the env gene, a 0.3-kb fragment containing the R-U5-5' leader sequence is essential for the induction of spongiform neurodegeneration by Friend murine leukemia virus (Fr-MLV) clone A8 and it also influences expression of the Env protein. Kinetic studies were carried out using two recombinant viruses, R7f, carrying the A8 0.3-kb fragment, and Rec5, carrying the 0.3-kb fragment of the non-neuropathogenic Fr-MLV clone 57. These analyses suggested that the 0.3-kb fragment influenced the expression level of the Env protein by regulating the amount of spliced env-mRNA rather than the amount of total viral mRNA or viral production.