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1.
Am J Pathol ; 192(2): 195-207, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34767812

RESUMO

To catalyze severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) research, including development of novel interventive and preventive strategies, the progression of disease was characterized in a robust coronavirus disease 2019 (COVID-19) animal model. In this model, male and female golden Syrian hamsters were inoculated intranasally with SARS-CoV-2 USA-WA1/2020. Groups of inoculated and mock-inoculated uninfected control animals were euthanized at 2, 4, 7, 14, and 28 days after inoculation to track multiple clinical, pathology, virology, and immunology outcomes. SARS-CoV-2-inoculated animals consistently lost body weight during the first week of infection, had higher lung weights at terminal time points, and developed lung consolidation per histopathology and quantitative image analysis measurements. High levels of infectious virus and viral RNA were reliably present in the respiratory tract at days 2 and 4 after inoculation, corresponding with widespread necrosis and inflammation. At day 7, when the presence of infectious virus was rare, interstitial and alveolar macrophage infiltrates and marked reparative epithelial responses (type II hyperplasia) dominated in the lung. These lesions resolved over time, with only residual epithelial repair evident by day 28 after inoculation. The use of quantitative approaches to measure cellular and morphologic alterations in the lung provides valuable outcome measures for developing therapeutic and preventive interventions for COVID-19 using the hamster COVID-19 model.


Assuntos
COVID-19/patologia , Animais , COVID-19/virologia , Cricetinae , Modelos Animais de Doenças , Feminino , Pulmão/patologia , Masculino , Mesocricetus , SARS-CoV-2
2.
J Neurovirol ; 26(4): 511-519, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32488843

RESUMO

HIV-associated neuroinflammation is primarily driven by CNS macrophages including microglia. Regulation of these immune responses, however, remains to be characterized in detail. Using the SIV/macaque model of HIV, we evaluated CNS expression of triggering receptor expressed on myeloid cells 2 (TREM2) which is constitutively expressed by microglia and contributes to cell survival, proliferation, and differentiation. Loss-of-function mutations in TREM2 are recognized risk factors for neurodegenerative diseases including Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and Nasu-Hakola disease (NHD); recent reports have also indicated a role for TREM2 in HIV-associated neuroinflammation. Using in situ hybridization (ISH) and qRT-PCR, TREM2 mRNA levels were found to be significantly elevated in frontal cortex of macaques with SIV encephalitis compared with uninfected controls (P = 0.02). TREM2 protein levels were also elevated as measured by ELISA of frontal cortex tissue homogenates in these animals. Previously, we characterized the expression of CSF1R (colony-stimulating factor 1 receptor) in this model; the TREM2 and CSF1R promoters both contain a PU.1 binding site. While TREM2 and CSF1R mRNA levels in the frontal cortex were highly correlated (Spearman R = 0.79, P < 0.001), protein levels were not well correlated. In SIV-infected macaques released from ART to study viral rebound, neither TREM2 nor CSF1R mRNA increased with rebound viremia. However, CSF1R protein levels remained significantly elevated unlike TREM2 (P = 0.02). This differential expression suggests that TREM2 and CSF1R play unique, distinct roles in the pathogenesis of HIV CNS disease.


Assuntos
Encefalite Viral/genética , Macaca nemestrina/imunologia , Macrófagos/imunologia , Glicoproteínas de Membrana/genética , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/genética , Síndrome de Imunodeficiência Adquirida dos Símios/genética , Vírus da Imunodeficiência Símia/imunologia , Animais , Terapia Antirretroviral de Alta Atividade/métodos , Antivirais/farmacologia , Esquema de Medicação , Encefalite Viral/tratamento farmacológico , Encefalite Viral/imunologia , Encefalite Viral/virologia , Lobo Frontal/efeitos dos fármacos , Lobo Frontal/imunologia , Lobo Frontal/virologia , Regulação da Expressão Gênica , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Macaca nemestrina/genética , Macaca nemestrina/virologia , Macrófagos/efeitos dos fármacos , Macrófagos/virologia , Masculino , Glicoproteínas de Membrana/imunologia , Microglia/efeitos dos fármacos , Microglia/imunologia , Microglia/virologia , Regiões Promotoras Genéticas , Ligação Proteica , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/imunologia , RNA Mensageiro/genética , RNA Mensageiro/imunologia , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/tratamento farmacológico , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/virologia , Vírus da Imunodeficiência Símia/efeitos dos fármacos , Vírus da Imunodeficiência Símia/crescimento & desenvolvimento , Transativadores/genética , Transativadores/imunologia
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