RESUMEN
COVID-19 can cause neurological symptoms such as fever, dizziness, and nausea. However, such neurological symptoms of SARS-CoV-2 infection have been hardly assessed in mouse models. In this study, we infected two commonly used wild-type mouse lines (C57BL/6J and 129/SvEv) and a 129S calcitonin gene-related peptide (αCGRP) null-line with mouse-adapted SARS-CoV-2 and demonstrated neurological signs including fever, dizziness, and nausea. We then evaluated whether a CGRP receptor antagonist, olcegepant, a "gepant" antagonist used in migraine treatment, could mitigate acute neuroinflammatory and neurological signs of SARS-COV-2 infection. First, we determined whether CGRP receptor antagonism provided protection from permanent weight loss in older (>18 m) C57BL/6J and 129/SvEv mice. We also observed acute fever, dizziness, and nausea in all older mice, regardless of treatment. In both wild-type mouse lines, CGRP antagonism reduced acute interleukin 6 (IL-6) levels with virtually no IL-6 release in mice lacking αCGRP. These findings suggest that migraine inhibitors such as those blocking CGRP receptor signaling protect against acute IL-6 release and subsequent inflammatory events after SARS-CoV-2 infection, which may have repercussions for related pandemic or endemic coronavirus outbreaks.IMPORTANCECoronavirus disease (COVID-19) can cause neurological symptoms such as fever, headache, dizziness, and nausea. However, such neurological symptoms of severe acute respiratory syndrome CoV-2 (SARS-CoV-2) infection have been hardly assessed in mouse models. In this study, we first infected two commonly used wild-type mouse lines (C57BL/6J and 129S) with mouse-adapted SARS-CoV-2 and demonstrated neurological symptoms including fever and nausea. Furthermore, we showed that the migraine treatment drug olcegepant could reduce long-term weight loss and IL-6 release associated with SARS-CoV-2 infection. These findings suggest that a migraine blocker can be protective for at least some acute SARS-CoV-2 infection signs and raise the possibility that it may also impact long-term outcomes.
Asunto(s)
COVID-19 , Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina , Modelos Animales de Enfermedad , Interleucina-6 , Ratones Endogámicos C57BL , Trastornos Migrañosos , SARS-CoV-2 , Pérdida de Peso , Animales , Ratones , Interleucina-6/metabolismo , COVID-19/virología , SARS-CoV-2/efectos de los fármacos , Pérdida de Peso/efectos de los fármacos , Trastornos Migrañosos/tratamiento farmacológico , Trastornos Migrañosos/virología , Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina/farmacología , Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina/uso terapéutico , Quinazolinas/farmacología , Quinazolinas/uso terapéutico , Tratamiento Farmacológico de COVID-19 , Péptido Relacionado con Gen de Calcitonina/metabolismo , Masculino , Humanos , Femenino , PiperazinasRESUMEN
A 26-y-old, male, captive Humboldt penguin (Spheniscus humboldti) was euthanized following a 3.5-mo history of weakened elimination mechanics, recurrent tenesmus, intermittent hemorrhagic droppings, and a cloacal mass. Blepharospasm, of unknown cause, of the right eye was present for ~3 mo before euthanasia. Autopsy revealed a cloacal adenocarcinoma with localized coelomic carcinomatosis and distant metastases to the liver and lungs. On histopathology, a 2.6 × 1.2 × 0.5-mm, well-demarcated mass was found surrounding the right optic nerve, expanding the subdural space and wrapping the leptomeninges. The mass was composed of neoplastic spindle-to-polygonal cells consistent with a meningioma, meningothelial subtype. No evidence of neoplasia was found in the optic chiasm or brain, indicating a primary retrobulbar meningioma. Immunohistochemistry for cytokeratin AE1/AE3, vimentin, and S100 revealed robust and consistent immunoreactivity to vimentin, and weak and variable immunoreactivity to cytokeratin and S100, supporting the diagnosis. Meningiomas have been described only rarely in avian species, and we found no reports of optic nerve meningiomas in any avian species to date. The optic nerve meningioma in this case was considered a clinically incidental finding.
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Adenocarcinoma , Neoplasias Meníngeas , Meningioma , Spheniscidae , Masculino , Animales , Meningioma/veterinaria , Meningioma/patología , Vimentina , Adenocarcinoma/veterinaria , Nervio Óptico/patología , Neoplasias Meníngeas/veterinaria , Neoplasias Meníngeas/patología , QueratinasRESUMEN
Equine parvovirus-hepatitis (EqPV-H) is the causative agent of Theiler's disease, or severe acute hepatic necrosis, in horses. However, it is poorly understood whether EqPV-H is associated with other histologic findings in horses with clinical liver disease. The objective of this study was to examine the prevalence and severity of EqPV-H infections in diagnostic liver samples. Archived formalin-fixed, paraffin-embedded (FFPE) liver samples (n = 98) from Cornell University and University of California, Davis, collected between 2007 and 2022 were evaluated for 15 individual histologic features and by EqPV-H in situ hybridization. EqPV-H was detected in 48% (n = 47) of samples. The most common histologic features of EqPV-H-positive samples included individual hepatocyte death (n = 40, 85%), lobular infiltrates (n = 38, 80%), portal infiltrates (n = 35, 74%), and ductular reaction (n = 33, 70%). Centrilobular necrosis, portal infiltrate, and individual hepatocyte death were positively associated with high viral load. Neutrophil infiltrates, bridging fibrosis, and portal edema were negatively associated with a high viral load. Only 4 of 49 tested samples were positive for equine hepacivirus by polymerase chain reaction (PCR), but the PCR assay was unreliable for FFPE tissues. In summary, this study demonstrates that EqPV-H is common in a variety of liver pathologies and should be considered as a differential diagnosis in cases of hepatitis other than Theiler's disease.
RESUMEN
Pathology studies of SARS-CoV-2 Omicron variants of concern (VOC) are challenged by the lack of pathogenic animal models. While Omicron BA.1 and BA.2 replicate in K18-hACE2 transgenic mice, they cause minimal to negligible morbidity and mortality, and less is known about more recent Omicron VOC. Here, we show that in contrast to Omicron BA.1, BA.5-infected mice exhibited high levels of morbidity and mortality, correlating with higher early viral loads. Neither Omicron BA.1 nor BA.5 replicated in brains, unlike most prior VOC. Only Omicron BA.5-infected mice exhibited substantial weight loss, high pathology scores in lungs, and high levels of inflammatory cells and cytokines in bronchoalveolar lavage fluid, and 5- to 8-month-old mice exhibited 100% fatality. These results identify a rodent model for pathogenesis or antiviral countermeasure studies for circulating SARS-CoV-2 Omicron BA.5. Further, differences in morbidity and mortality between Omicron BA.1 and BA.5 provide a model for understanding viral determinants of pathogenicity.
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COVID-19 , Animales , Ratones , Virulencia , SARS-CoV-2 , Antivirales , Ratones TransgénicosRESUMEN
BACKGROUND: Theiler's disease, a.k.a. equine serum hepatitis, is a devastating, highly fatal disease of horses. Equine parvovirus-hepatitis (EqPV-H) has been identified as the likely cause of this disease. While the incidence of Theiler's disease is low, the prevalence of EqPV-H DNA in horses is high, with up to 37% in some regions, suggesting that subclinical or persistent infection is common. METHODS: To determine the prevalence and pathogenicity of EqPV-H infection at New York racetracks, DNA was extracted from archived formalin-fixed, paraffin-embedded liver tissues from racehorses submitted for necropsy to the Animal Health Diagnostic Center as part of the New York State Gaming Commission-Cornell University postmortem examination program. A total of 191 liver samples from horses between 2 and 13 years old were evaluated. Extracted DNA was tested for EqPV-H using PCR and gel electrophoresis. PCR-positive samples were further assessed for tissue morphology using histology and detection of viral nucleic acid using in situ hybridization. RESULTS: Forty-two samples were PCR positive (22%). Of those, 31 samples had positive viral nucleic acid hybridization in hepatocytes with 11 samples showing positive hybridization in necrotic hepatocytes associated with inflammatory cells, indicating active hepatitis. Both individual hepatocyte necrosis and hepatitis were positively associated with EqPV-H detection (p < 0.0001 and p = 0.0005, respectively). CONCLUSION: These findings indicate that presence of EqPV-H in the liver and parvoviral-associated hepatitis are prevalent in racehorses from New York racetracks, thus warranting additional studies examining potential associations between EqPV-H infection and racehorse performance.
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Hepatitis Viral Animal , Hepatitis , Enfermedades de los Caballos , Parvovirinae , Parvovirus , Caballos , Animales , Prevalencia , New York , Enfermedades de los Caballos/epidemiologíaRESUMEN
Equid herpesvirus 1 (EHV-1) outbreaks occur when virus spreads from infected horses to in-contact horses, primarily via nasal shedding. This study evaluated the efficacy of factors secreted by equine peripheral blood derived mesenchymal stromal cells (PB-MSCs), collectively named the secretome, to inhibit the growth of EHV-1 in (i) 2D epithelial cell cultures (RK-13) in vitro, (ii) 3D equine nasal explants in vitro and (iii) an EHV-1 infection mouse model in vivo. The PB-MSC secretome was found to inhibit EHV-1 in RK-13 cells as well as in the epithelium of equine nasal explants. Although the PB-MSC secretome did not decrease overall severity of EHV-1 infection in mice, as determined by weight loss and viral titers in lungs, histological analyses indicated local reduction of EHV-1 infection in nasal epithelium. These results indicate that the PB-MSC secretome inhibits EHV-1 in epithelial cells in a context-dependent manner.
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Infecciones por Herpesviridae , Herpesvirus Équido 1 , Herpesvirus Équido 4 , Enfermedades de los Caballos , Células Madre Mesenquimatosas , Enfermedades de los Roedores , Animales , Células Epiteliales , Infecciones por Herpesviridae/veterinaria , Caballos , Ratones , Mucosa Nasal , SecretomaRESUMEN
In line with the Latin expression "sed parva forti" meaning "small but mighty," the family Parvoviridae contains many of the smallest known viruses, some of which result in fatal or debilitating infections. In recent years, advances in metagenomic viral discovery techniques have dramatically increased the identification of novel parvoviruses in both diseased and healthy individuals. While some of these discoveries have solved etiologic mysteries of well-described diseases in animals, many of the newly discovered parvoviruses appear to cause mild or no disease, or disease associations remain to be established. With the increased use of animal parvoviruses as vectors for gene therapy and oncolytic treatments in humans, it becomes all the more important to understand the diversity, pathogenic potential, and evolution of this diverse family of viruses. In this review, we discuss parvoviruses infecting vertebrate animals, with a special focus on pathogens of veterinary significance and viruses discovered within the last four years.
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Infecciones por Parvoviridae , Parvoviridae , Parvovirus , Animales , Metagenómica , Parvoviridae/genética , Infecciones por Parvoviridae/veterinaria , Parvovirus/genética , FilogeniaRESUMEN
BACKGROUND: Equine parvovirus-hepatitis (EqPV-H) has been proposed as the aetiological cause of Theiler's disease, also known as serum hepatitis. EqPV-H-associated Theiler's disease has not been previously reported in Europe. OBJECTIVES: To determine whether EqPV-H infection was associated with a 2018-2019 outbreak of Theiler's disease in four horses on a studfarm. STUDY DESIGN: Descriptive case series. METHODS: The medical records of four horses from the same farm diagnosed with fatal Theiler's disease were examined retrospectively. Information collected included a clinical history, physical examination findings, tetanus antitoxin exposure, serum biochemistry and necropsy reports. Liver tissue from all four horses was tested for EqPV-H using PCR and in situ hybridisation (ISH) assays. RESULTS: Three of the horses had a history of recent (7-11 weeks) tetanus antitoxin administration. Liver tissue from all four horses tested positive for EqPV-H with PCR. In situ hybridisation revealed a widespread distribution of viral nucleic acid in hepatocytes in one case, and a more sporadic distribution in the remaining three cases. MAIN LIMITATIONS: Case controls were not available from the farm in question given the retrospective nature of analysis. CONCLUSIONS: This case series documents the first reported EqPV-H-associated Theiler's disease in Europe and the first use of ISH to visualise the viral nucleic acid in liver tissues of horses with Theiler's disease.
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Hepatitis , Enfermedades de los Caballos/epidemiología , Enfermedades de los Caballos/etiología , Infecciones por Parvoviridae/veterinaria , Parvovirus , Animales , Europa (Continente)/epidemiología , Caballos , Estudios RetrospectivosRESUMEN
Canid alphaherpesvirus 1 (CHV) causes morbidity and mortality in susceptible puppies. While the neuropathology of experimentally infected puppies has been detailed, characterization of naturally acquired infections is limited. The aim of this study was to describe the histologic, immunohistochemical, and in situ hybridization features of CHV encephalitis in the dog. Six female and 11 male puppies ranging in age from stillborn to 57 days old were included. Histologically, lesions included multifocal glial nodules (16/17, 94%), meningeal infiltrates (15/17, 88%), and cerebellar cortical necrosis (6/9, 67%); however, robust inflammation was not a significant feature in any of the cases. Immunohistochemistry for CD3, CD20, MAC387, and Iba1 was performed. Although T cells predominated over B cells, the overall number of cells was small in all cases both within the glial nodules and the meninges. In 16 of 16 (100%) cases, glial nodules were diffusely immunoreactive for Iba1; however, limited or no immunoreactivity for MAC387 was present. In situ hybridization directed at the CHV thymidine kinase gene revealed CHV nucleic acid in the granule neurons of the cerebellar folia (8/9; 89%), endothelial cells in the meninges and parenchyma (12/17, 71%), and individual randomly distributed neurons (6/17, 35%). These results clarify the pathology of naturally acquired CHV infection and indicate that developing cerebellar granule neurons are an important site of viral replication.