RESUMO
SARS-CoV-2-induced hypercytokinemia and inflammation are critically associated with COVID-19 severity. Baricitinib, a clinically approved JAK1/JAK2 inhibitor, is currently being investigated in COVID-19 clinical trials. Here, we investigated the immunologic and virologic efficacy of baricitinib in a rhesus macaque model of SARS-CoV-2 infection. Viral shedding measured from nasal and throat swabs, bronchoalveolar lavages, and tissues was not reduced with baricitinib. Type I interferon (IFN) antiviral responses and SARS-CoV-2-specific T cell responses remained similar between the two groups. Animals treated with baricitinib showed reduced inflammation, decreased lung infiltration of inflammatory cells, reduced NETosis activity, and more limited lung pathology. Importantly, baricitinib-treated animals had a rapid and remarkably potent suppression of lung macrophage production of cytokines and chemokines responsible for inflammation and neutrophil recruitment. These data support a beneficial role for, and elucidate the immunological mechanisms underlying, the use of baricitinib as a frontline treatment for inflammation induced by SARS-CoV-2 infection.
Assuntos
Anti-Inflamatórios/administração & dosagem , Azetidinas/administração & dosagem , Tratamento Farmacológico da COVID-19 , COVID-19/imunologia , Macaca mulatta , Infiltração de Neutrófilos/efeitos dos fármacos , Purinas/administração & dosagem , Pirazóis/administração & dosagem , Sulfonamidas/administração & dosagem , Animais , COVID-19/fisiopatologia , Morte Celular/efeitos dos fármacos , Degranulação Celular/efeitos dos fármacos , Modelos Animais de Doenças , Inflamação/tratamento farmacológico , Inflamação/genética , Inflamação/imunologia , Janus Quinases/antagonistas & inibidores , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/patologia , Ativação Linfocitária/efeitos dos fármacos , Macrófagos Alveolares/imunologia , SARS-CoV-2/fisiologia , Índice de Gravidade de Doença , Linfócitos T/imunologia , Replicação Viral/efeitos dos fármacosRESUMO
A combination of vaccination approaches will likely be necessary to fully control the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. Here, we show that modified vaccinia Ankara (MVA) vectors expressing membrane-anchored pre-fusion stabilized spike (MVA/S) but not secreted S1 induced strong neutralizing antibody responses against SARS-CoV-2 in mice. In macaques, the MVA/S vaccination induced strong neutralizing antibodies and CD8+ T cell responses, and conferred protection from SARS-CoV-2 infection and virus replication in the lungs as early as day 2 following intranasal and intratracheal challenge. Single-cell RNA sequencing analysis of lung cells on day 4 after infection revealed that MVA/S vaccination also protected macaques from infection-induced inflammation and B cell abnormalities and lowered induction of interferon-stimulated genes. These results demonstrate that MVA/S vaccination induces neutralizing antibodies and CD8+ T cells in the blood and lungs and is a potential vaccine candidate for SARS-CoV-2.
Assuntos
Vacinas contra COVID-19/imunologia , COVID-19/prevenção & controle , Vetores Genéticos/genética , SARS-CoV-2/imunologia , Vacinas de DNA/imunologia , Vaccinia virus/genética , Animais , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Antígenos Virais/genética , Antígenos Virais/imunologia , COVID-19/imunologia , COVID-19/patologia , COVID-19/virologia , Vacinas contra COVID-19/genética , Modelos Animais de Doenças , Expressão Gênica , Ordem dos Genes , Imunofenotipagem , Pulmão/imunologia , Pulmão/patologia , Pulmão/virologia , Macaca , Macrófagos Alveolares/imunologia , Macrófagos Alveolares/metabolismo , Macrófagos Alveolares/patologia , Camundongos , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/imunologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Vacinação/métodos , Vacinas de DNA/genéticaRESUMO
Most cancer vaccines target peptide antigens, necessitating personalization owing to the vast inter-individual diversity in major histocompatibility complex (MHC) molecules that present peptides to T cells. Furthermore, tumours frequently escape T cell-mediated immunity through mechanisms that interfere with peptide presentation1. Here we report a cancer vaccine that induces a coordinated attack by diverse T cell and natural killer (NK) cell populations. The vaccine targets the MICA and MICB (MICA/B) stress proteins expressed by many human cancers as a result of DNA damage2. MICA/B serve as ligands for the activating NKG2D receptor on T cells and NK cells, but tumours evade immune recognition by proteolytic MICA/B cleavage3,4. Vaccine-induced antibodies increase the density of MICA/B proteins on the surface of tumour cells by inhibiting proteolytic shedding, enhance presentation of tumour antigens by dendritic cells to T cells and augment the cytotoxic function of NK cells. Notably, this vaccine maintains efficacy against MHC class I-deficient tumours resistant to cytotoxic T cells through the coordinated action of NK cells and CD4+ T cells. The vaccine is also efficacious in a clinically important setting: immunization following surgical removal of primary, highly metastatic tumours inhibits the later outgrowth of metastases. This vaccine design enables protective immunity even against tumours with common escape mutations.
Assuntos
Síndromes Mielodisplásicas , Neoplasias , Dermatopatias Genéticas , Vacinas , Antígenos de Histocompatibilidade Classe I , Humanos , Células Matadoras Naturais , Subfamília K de Receptores Semelhantes a Lectina de Células NK/metabolismo , Neoplasias/prevenção & controleRESUMO
A 57-year-old female chimpanzee presented with a brief history of increasing lethargy and rapidly progressive lower-limb weakness that culminated in loss of use. Postmortem examination revealed no significant gross lesions in the nervous system or other organ systems. Histological analysis revealed round, basophilic to amphophilic polyglucosan bodies (PGBs) in the white and gray matter of the cervical, thoracic, lumbar, and coccygeal regions of spinal cord. Only rare PGBs were observed in forebrain samples. The lesions in the spinal cord were polymorphic, and they were positively stained with hematoxylin, periodic acid Schiff, Alcian blue, toluidine blue, Bielschowsky silver, and Grocott-Gomori methenamine-silver methods, and they were negative for von Kossa and Congo Red stains. Immunohistochemical evaluation revealed reactivity with antibodies to ubiquitin, but they were negative for glial fibrillary acidic protein, neuron-specific enolase, neurofilaments, tau protein, and Aß protein. Electron microscopy revealed non-membrane-bound deposits composed of densely packed filaments within axons and in the extracellular space. Intra-axonal PGBs were associated with disruption of the axonal fine structure and disintegration of the surrounding myelin sheath. These findings are the first description of PGBs linked to neurological dysfunction in a chimpanzee. Clinicopathologically, the disorder resembled adult PGB disease in humans.
Assuntos
Pan troglodytes , Prata , Adulto , Feminino , Animais , Humanos , Idoso , Pessoa de Meia-Idade , Pan troglodytes/metabolismo , Axônios , Glucanos/metabolismoRESUMO
Amitriptyline is a tricyclic antidepressant commonly prescribed in humans for pain and sleep disorders and in non-human primates for self-injurious behaviors. Here, we report a clinical case on the teratogenic effect of maternal-fetal amitriptyline exposure.
Assuntos
Amitriptilina/efeitos adversos , Antidepressivos Tricíclicos/efeitos adversos , Macaca mulatta/anormalidades , Teratogênese , Teratogênicos , Animais , Feminino , Exposição MaternaRESUMO
The detection of viral dynamics and localization in the context of controlled HIV infection remains a challenge and is limited to blood and biopsies. We developed a method to capture total-body simian immunodeficiency virus (SIV) replication using immunoPET (antibody-targeted positron emission tomography). The administration of a poly(ethylene glycol)-modified, (64)Cu-labeled SIV Gp120-specific antibody led to readily detectable signals in the gastrointestinal and respiratory tract, lymphoid tissues and reproductive organs of viremic monkeys. Viral signals were reduced in aviremic antiretroviral-treated monkeys but detectable in colon, select lymph nodes, small bowel, nasal turbinates, the genital tract and lung. In elite controllers, virus was detected primarily in foci in the small bowel, select lymphoid areas and the male reproductive tract, as confirmed by quantitative reverse-transcription PCR (qRT-PCR) and immunohistochemistry. This real-time, in vivo viral imaging method has broad applications to the study of immunodeficiency virus pathogenesis, drug and vaccine development, and the potential for clinical translation.
Assuntos
Antirretrovirais/uso terapêutico , Tomografia por Emissão de Pósitrons/métodos , Vírus da Imunodeficiência Símia , Imagem Corporal Total/métodos , Adenina/análogos & derivados , Adenina/uso terapêutico , Animais , Radioisótopos de Cobre , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Emtricitabina , Imuno-Histoquímica , Masculino , Glicoproteínas de Membrana/metabolismo , Naftiridinas/uso terapêutico , Organofosfonatos/uso terapêutico , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Sensibilidade e Especificidade , Tenofovir , Proteínas do Envelope Viral/metabolismo , Viremia , Replicação ViralRESUMO
BACKGROUND: Rhesus and cynomologus macaques are valuable animal models for the study of human immunodeficiency virus (HIV) prevention strategies. However, for such studies focused on the vaginal route of infection, differences in vaginal environment may have deterministic impact on the outcome of such prevention, providing the rationale for this study. METHODS: We tested the vaginal environment of rhesus and cynomolgus macaques longitudinally to characterize the normal microflora based on Nugent scores and pH. This evaluation was extended after colonization of the vaginal space with Lactobacilli in an effort to recreate NHP models representing the healthy human vaginal environment. RESULTS AND CONCLUSION: Nugent scores and pH differed significantly between species, although data from both species were suggestive of stable bacterial vaginosis. Colonization with Lactobacilli was successful in both species leading to lower Nugent score and pH, although rhesus macaques appeared better able to sustain Lactobacillus spp over time.
Assuntos
Lactobacillus/fisiologia , Macaca fascicularis/microbiologia , Macaca mulatta/microbiologia , Vagina/microbiologia , Animais , Modelos Animais de Doenças , Feminino , Infecções por HIV/prevenção & controle , Humanos , Valores de ReferênciaRESUMO
The physiology of the oxytocin receptor has increasingly become a focus of scientific investigation due to its connection with social behavior and psychiatric disorders with impairments in social funciton. Experimental utilization of small molecule and peptide antagonists for the oxytocin receptor has played a role in deciphering these biological and social behavior connections in rodents. Described herein is the evaluation of a potent and selective oxytocin receptor antagonist, ALS-I-41, and details to consider for its use in nonhuman primate behavioral pharmacology experiments utilizing intranasal or intramuscular administration. The central nervous system penetration and rate of metabolism of ALS-I-41 was investigated via mass spectroscopy analysis of cerebrospinal fluid and plasma in the rhesus macaque after intranasal and intramuscular administration. Positron emission tomography was also utilized with [18F] ALS-I-41 in a macaque to verify observed central nervous system (CNS) penetration and to further evaluate the effects of administration rate on CNS penetration of Sprague-Dawley rats in comparison to previous studies.
Assuntos
Encéfalo/metabolismo , Quinolonas/farmacologia , Compostos Radiofarmacêuticos/farmacologia , Receptores de Ocitocina/antagonistas & inibidores , Sulfonamidas/farmacologia , Administração Intranasal , Animais , Feminino , Radioisótopos de Flúor , Injeções Intramusculares , Macaca fascicularis , Macaca mulatta , Masculino , Tomografia por Emissão de Pósitrons , Quinolonas/sangue , Quinolonas/líquido cefalorraquidiano , Quinolonas/síntese química , Compostos Radiofarmacêuticos/sangue , Compostos Radiofarmacêuticos/líquido cefalorraquidiano , Compostos Radiofarmacêuticos/síntese química , Ratos Sprague-Dawley , Sulfonamidas/sangue , Sulfonamidas/líquido cefalorraquidiano , Sulfonamidas/síntese químicaRESUMO
Type I interferons (IFN-I) are critical mediators of innate control of viral infections but also drive the recruitment of inflammatory cells to sites of infection, a key feature of severe coronavirus disease 2019. Here, IFN-I signaling was modulated in rhesus macaques (RMs) before and during acute SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection using a mutated IFN-α2 (IFN-modulator; IFNmod), which has previously been shown to reduce the binding and signaling of endogenous IFN-I. IFNmod treatment in uninfected RMs was observed to induce a modest up-regulation of only antiviral IFN-stimulated genes (ISGs); however, in SARS-CoV-2-infected RMs, IFNmod reduced both antiviral and inflammatory ISGs. IFNmod treatment resulted in a potent reduction in SARS-CoV-2 viral loads both in vitro in Calu-3 cells and in vivo in bronchoalveolar lavage (BAL), upper airways, lung, and hilar lymph nodes of RMs. Furthermore, in SARS-CoV-2-infected RMs, IFNmod treatment potently reduced inflammatory cytokines, chemokines, and CD163+ MRC1- inflammatory macrophages in BAL and expression of Siglec-1 on circulating monocytes. In the lung, IFNmod also reduced pathogenesis and attenuated pathways of inflammasome activation and stress response during acute SARS-CoV-2 infection. Using an intervention targeting both IFN-α and IFN-ß pathways, this study shows that, whereas early IFN-I restrains SARS-CoV-2 replication, uncontrolled IFN-I signaling critically contributes to SARS-CoV-2 inflammation and pathogenesis in the moderate disease model of RMs.
Assuntos
COVID-19 , Interferon Tipo I , Animais , Interferon Tipo I/farmacologia , SARS-CoV-2 , Macaca mulatta , Replicação Viral , Antivirais/farmacologia , Antivirais/uso terapêutico , Inflamação/tratamento farmacológicoRESUMO
Type-I interferons (IFN-I) are critical mediators of innate control of viral infections, but also drive recruitment of inflammatory cells to sites of infection, a key feature of severe COVID-19. Here, and for the first time, IFN-I signaling was modulated in rhesus macaques (RMs) prior to and during acute SARS-CoV-2 infection using a mutated IFNα2 (IFN-modulator; IFNmod), which has previously been shown to reduce the binding and signaling of endogenous IFN-I. In SARS-CoV-2-infected RMs, IFNmod reduced both antiviral and inflammatory ISGs. Notably, IFNmod treatment resulted in a potent reduction in (i) SARS-CoV-2 viral load in Bronchoalveolar lavage (BAL), upper airways, lung, and hilar lymph nodes; (ii) inflammatory cytokines, chemokines, and CD163+MRC1-inflammatory macrophages in BAL; and (iii) expression of Siglec-1, which enhances SARS-CoV-2 infection and predicts disease severity, on circulating monocytes. In the lung, IFNmod also reduced pathogenesis and attenuated pathways of inflammasome activation and stress response during acute SARS-CoV-2 infection. This study, using an intervention targeting both IFN-α and IFN-ß pathways, shows that excessive inflammation driven by type 1 IFN critically contributes to SARS-CoV-2 pathogenesis in RMs, and demonstrates the potential of IFNmod to limit viral replication, SARS-CoV-2 induced inflammation, and COVID-19 severity.
RESUMO
Understanding viral rebound in pediatric HIV-1 infection may inform the development of alternatives to lifelong antiretroviral therapy (ART) to achieve viral remission. We thus investigated viral rebound after analytical treatment interruption (ATI) in 10 infant macaques orally infected with SHIV.C.CH505 and treated with long-term ART. Rebound viremia was detected within 7 to 35 days of ATI in 9 of 10 animals, with posttreatment control of viremia seen in 5 of 5 Mamu-A*01+ macaques. Single-genome sequencing revealed that initial rebound virus was similar to viral DNA present in CD4+ T cells from blood, rectum, and lymph nodes before ATI. We assessed the earliest sites of viral reactivation immediately following ATI using ImmunoPET imaging. The largest increase in signal that preceded detectable viral RNA in plasma was found in the gastrointestinal (GI) tract, a site with relatively high SHIV RNA/DNA ratios in CD4+ T cells before ATI. Thus, the GI tract may be an initial source of rebound virus, but as ATI progresses, viral reactivation in other tissues likely contributes to the composition of plasma virus. Our study provides potentially novel insight into the features of viral rebound in pediatric infection and highlights the application of a noninvasive technique to monitor areas of HIV-1 expression in children.
Assuntos
Antirretrovirais/uso terapêutico , Síndrome de Imunodeficiência Adquirida dos Símios/virologia , Viremia/etiologia , Animais , Feminino , Macaca , Masculino , Viremia/patologiaRESUMO
Ongoing SARS-CoV-2 vaccine development is focused on identifying stable, cost-effective, and accessible candidates for global use, specifically in low and middle-income countries. Here, we report the efficacy of a rapidly scalable, novel yeast expressed SARS-CoV-2 specific receptor-binding domain (RBD) based vaccine in rhesus macaques. We formulated the RBD immunogen in alum, a licensed and an emerging alum adsorbed TLR-7/8 targeted, 3M-052-alum adjuvants. The RBD+3M-052-alum adjuvanted vaccine promoted better RBD binding and effector antibodies, higher CoV-2 neutralizing antibodies, improved Th1 biased CD4+T cell reactions, and increased CD8+ T cell responses when compared to the alum-alone adjuvanted vaccine. RBD+3M-052-alum induced a significant reduction of SARS-CoV-2 virus in respiratory tract upon challenge, accompanied by reduced lung inflammation when compared with unvaccinated controls. Anti-RBD antibody responses in vaccinated animals inversely correlated with viral load in nasal secretions and BAL. RBD+3M-052-alum blocked a post SARS-CoV-2 challenge increase in CD14+CD16++ intermediate blood monocytes, and Fractalkine, MCP-1, and TRAIL in the plasma. Decreased plasma analytes and intermediate monocyte frequencies correlated with reduced nasal and BAL viral loads. Lastly, RBD-specific plasma cells accumulated in the draining lymph nodes and not in the bone marrow, contrary to previous findings. Together, these data show that a yeast expressed, RBD-based vaccine+3M-052-alum provides robust immune responses and protection against SARS-CoV-2, making it a strong and scalable vaccine candidate.
Assuntos
Adjuvantes Imunológicos/administração & dosagem , Compostos de Alúmen/administração & dosagem , Vacinas contra COVID-19 , COVID-19/prevenção & controle , SARS-CoV-2 , Saccharomycetales/genética , Glicoproteína da Espícula de Coronavírus/genética , Administração por Inalação , Administração Intranasal , Animais , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , COVID-19/imunologia , COVID-19/patologia , COVID-19/virologia , Linhagem Celular , Citocinas/imunologia , Humanos , Imunoglobulina G/imunologia , Pulmão/patologia , Macaca mulatta , Masculino , Ligação Proteica , Domínios Proteicos , Glicoproteína da Espícula de Coronavírus/imunologia , Carga ViralRESUMO
A Chinese rhesus macaque infected with the pathogenic CCR5-tropic clade C simian-human immunodeficiency virus, SHIV-1157ipd3N4, had persistent viremia, depletion of CD4(+) T cells to <200 cells/µl, opportunistic infections, coagulopathy, and gradual development of bilateral blindness. MRI revealed marked thickening of both optic nerves. Histopathological evaluation showed diffuse cellular infiltration at necropsy and a focus of SHIV-infected cells. This is the first report of CNS pathology following chronic infection with an obligate R5 SHIV.
Assuntos
HIV-1/genética , Macaca mulatta , Doenças dos Macacos/virologia , Neurite Óptica/veterinária , Síndrome de Imunodeficiência Adquirida dos Símios/virologia , Vírus da Imunodeficiência Símia/genética , Infecções Oportunistas Relacionadas com a AIDS/veterinária , Infecções Oportunistas Relacionadas com a AIDS/virologia , Animais , Feminino , Neurite Óptica/virologia , ViremiaRESUMO
Effective therapeutics aimed at mitigating COVID-19 symptoms are urgently needed. SARS-CoV-2 induced hypercytokinemia and systemic inflammation are associated with disease severity. Baricitinib, a clinically approved JAK1/2 inhibitor with potent anti-inflammatory properties is currently being investigated in COVID-19 human clinical trials. Recent reports suggest that baricitinib may also have antiviral activity in limiting viral endocytosis. Here, we investigated the immunologic and virologic efficacy of baricitinib in a rhesus macaque model of SARS-CoV-2 infection. Viral shedding measured from nasal and throat swabs, bronchoalveolar lavages and tissues was not reduced with baricitinib. Type I IFN antiviral responses and SARS-CoV-2 specific T cell responses remained similar between the two groups. Importantly, however, animals treated with baricitinib showed reduced immune activation, decreased infiltration of neutrophils into the lung, reduced NETosis activity, and more limited lung pathology. Moreover, baricitinib treated animals had a rapid and remarkably potent suppression of alveolar macrophage derived production of cytokines and chemokines responsible for inflammation and neutrophil recruitment. These data support a beneficial role for, and elucidate the immunological mechanisms underlying, the use of baricitinib as a frontline treatment for severe inflammation induced by SARS-CoV-2 infection.
RESUMO
Increased vulnerability to psychosocial stressors likely predisposes individuals to decreased immune function and inability to control pathogens. While many factors influence the susceptibility to psychosocial stress, genetic polymorphisms may modify individual reactivity to environmental stressors. The present study evaluated how immune function was altered by the interaction of in polymorphisms in the gene that encodes the serotonin reuptake transporter (5HTT) and the psychosocial stress imposed by social subordination in adult female rhesus monkeys. Subjects were dominant and subordinate females that carried both alleles of the long promoter variant (l/l) of the 5HTT gene, and dominant and subordinate that had at least one allele for the short promoter length variant (l/s or s/s, s-variant). Plasma cortisol was higher in subordinate females in response to a social separation paradigm, confirming their increased reactivity to psychosocial stressors. Subordinate females exhibited increased T-cell activation and proliferation regardless of genotype. Despite these higher levels of T-cell proliferation and activation, subordinate females showed significantly lower frequency of T-cells. This latter finding may be due to an increased susceptibility to cell death, as indicated by higher levels of annexin-V+ CD4+ and CD8+ T-cells in s-variant subordinate compared to dominant females. These findings indicate that subordinate rhesus monkeys with the s-variant 5HTT genotype exhibit decreased T-cell numbers perhaps compromising their ability to mount an immune response to pathogens. These data underscore the importance for considering gene polymorphisms that influence emotional reactivity to better understand susceptibility to disease.
Assuntos
Dominação-Subordinação , Polimorfismo Genético , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Estresse Psicológico/genética , Estresse Psicológico/imunologia , Linfócitos T/imunologia , Animais , Anexina A5/metabolismo , Antígenos CD4/metabolismo , Antígenos CD8/metabolismo , Morte Celular , Proliferação de Células , Feminino , Citometria de Fluxo , Variação Genética , Glucocorticoides/sangue , Macaca mulatta , Fenótipo , Regiões Promotoras Genéticas , Meio Social , Isolamento Social/psicologia , Estresse Psicológico/fisiopatologia , Linfócitos T/metabolismoRESUMO
The neurodegeneration associated with Huntington disease (HD) leads to the onset of motor and cognitive impairment and their advancement with increased age in humans. In children at risk for HD, body measurement growth abnormalities include a reduction in BMI, weight, height, and head circumference. The transgenic HD NHP model was first reported in 2008, and progressive decline in cognitive behaviors and motor impairment have been reported. This study focuses on longitudinal body measurements in HD macaques from infancy through adulthood. The growth of HD macaques was assessed through head circumference, sagittal and transverse head, and crown-to-rump ('height') measurements and BMI. The animals were measured monthly from 0 to 72 mo of age and every 3 mo from 72 mo of age onward. A mixed-effect model was used to assess subject-specific effects in our nonlinear serial data. Compared with WT controls, HD macaques displayed different developmental trajectories characterized by increased BMI, head circumference, and sagittal head measurements beginning around 40 mo of age. The physiologic comparability between NHP and humans underscores the translational utility of our HD macaques to evaluate growth and developmental patterns associated with HD.
Assuntos
Pesos e Medidas Corporais , Doença de Huntington/patologia , Animais , Estatura , Índice de Massa Corporal , Peso Corporal , Cabeça/anatomia & histologia , Humanos , Estudos Longitudinais , Macaca mulatta , MasculinoRESUMO
An adult rhesus macaque developed seizures after the induction of ischemic stroke. Initially, on the day of surgery, a focal ischemic lesion was present exclusively in the right caudate nucleus. By 48 h after stroke induction, the lesion had extended into the putamen, when a seizure was observed. Our report highlights the temporal changes in infarction of unilateral basal ganglia after acute stroke and the accompanying clinical symptoms. This unusual case may provide additional information regarding the involvement of the basal ganglia in seizures, given that prior case reports and studies usually have not described the temporal and spatial evolution of the lesion before clinical symptoms emerge.
Assuntos
Gânglios da Base/diagnóstico por imagem , Macaca mulatta , Doenças dos Macacos/diagnóstico por imagem , Convulsões/veterinária , Acidente Vascular Cerebral/veterinária , Animais , Imageamento por Ressonância Magnética , Convulsões/diagnóstico por imagem , Acidente Vascular Cerebral/diagnóstico por imagemRESUMO
West Nile virus (WNV) surfaced as an emerging infectious disease in the northeastern United States in 1999, gradually spread across the continent, and is now endemic throughout North America. Outdoor-housed nonhuman primates at the Tulane National Primate Research Center (TNPRC) in Louisiana were documented with a relatively high prevalence (36%) of antibodies to West Nile virus. We examined the prevalence of antibodies to WNV in a nonhuman primate population housed in outdoor colonies at the Yerkes National Primate Research Center Field Station located near Atlanta, Georgia. We screened rhesus macaques (Macaca mulatta) and sooty mangabeys (Cercocebus atys) that were at least 3 y old by serum neutralization for antibodies to WNV and confirmed these results by hemagglutination-inhibition assay. None of the 45 rhesus monkeys had antibodies to WNV, but 3 of the 45 mangabeys (6.6%) were positive by both serum neutralization and hemagglutination-inhibition tests. The ratio of seroprevalences in the TNPRC and Yerkes primate populations was similar to the ratio of WNV incidences in people in Louisiana and Georgia from 2002 to 2004. The difference in the exposure of nonhuman primates (and possibly humans) to WNV between these 2 regions is consistent with the difference in the abundance of mammal-biting WNV-infectious mosquitoes, which was 23 times lower near Yerkes than around TNPRC in 2003 and 33 times lower in 2004.
Assuntos
Animais de Laboratório/virologia , Cercocebus atys , Culex , Macaca mulatta , Doenças dos Macacos/epidemiologia , Doenças dos Macacos/virologia , Febre do Nilo Ocidental/veterinária , Vírus do Nilo Ocidental/imunologia , Animais , Anticorpos Antivirais/sangue , Georgia/epidemiologia , Testes de Inibição da Hemaglutinação , Abrigo para Animais , Louisiana/epidemiologia , Testes de Neutralização , Densidade Demográfica , Estudos Soroepidemiológicos , Febre do Nilo Ocidental/epidemiologiaRESUMO
Transgenic nonhuman primate models are an increasingly popular model for neurologic and neurodegenerative disease because their brain functions and neural anatomies closely resemble those of humans. Transgenic Huntington's disease monkeys (HD monkeys) developed clinical features similar to those seen in HD patients, making the monkeys suitable for a preclinical study of HD. However, until HD monkey colonies can be readily expanded, their use in preclinical studies will be limited. In the present study, we confirmed germline transmission of the mutant huntingtin (mHTT) transgene in both embryonic stem cells generated from three male HD monkey founders (F0) and in second-generation offspring (F1) produced via artificial insemination by using intrauterine insemination technique. A total of five offspring were produced from 15 females that were inseminated by intrauterine insemination using semen collected from the three HD founders (5 of 15, 33%). Thus far, sperm collected from the HD founder (rHD8) has led to two F1 transgenic HD monkeys with germline transmission rate at 100% (2 of 2). mHTT expression was confirmed by quantitative real-time polymerase chain reaction using skin fibroblasts from the F1 HD monkeys and induced pluripotent stem cells established from one of the F1 HD monkeys (rHD8-2). Here, we report the stable germline transmission and expression of the mHTT transgene in HD monkeys, which suggest possible expansion of HD monkey colonies for preclinical and biomedical research studies.