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1.
Elife ; 102021 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-34515026

RESUMO

The immune cells of macaques fed a Western-like diet adopt a pro-inflammatory profile.


Assuntos
Dieta Ocidental , Dieta , Animais , Macaca fascicularis
2.
Nat Commun ; 12(1): 5000, 2021 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-34404805

RESUMO

The successive emergences and accelerating spread of novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) lineages and evolved resistance to some ongoing clinical therapeutics increase the risks associated with the coronavirus disease 2019 (COVID-19) pandemic. An urgent intervention for broadly effective therapies to limit the morbidity and mortality of COVID-19 and future transmission events from SARS-related coronaviruses (SARSr-CoVs) is needed. Here, we isolate and humanize an angiotensin-converting enzyme-2 (ACE2)-blocking monoclonal antibody (MAb), named h11B11, which exhibits potent inhibitory activity against SARS-CoV and circulating global SARS-CoV-2 lineages. When administered therapeutically or prophylactically in the hACE2 mouse model, h11B11 alleviates and prevents SARS-CoV-2 replication and virus-induced pathological syndromes. No significant changes in blood pressure and hematology chemistry toxicology were observed after injections of multiple high dosages of h11B11 in cynomolgus monkeys. Analysis of the structures of the h11B11/ACE2 and receptor-binding domain (RBD)/ACE2 complexes shows hindrance and epitope competition of the MAb and RBD for the receptor. Together, these results suggest h11B11 as a potential therapeutic countermeasure against SARS-CoV, SARS-CoV-2, and escape variants.


Assuntos
Enzima de Conversão de Angiotensina 2/efeitos dos fármacos , Enzima de Conversão de Angiotensina 2/imunologia , Anticorpos Neutralizantes/administração & dosagem , COVID-19/tratamento farmacológico , SARS-CoV-2/efeitos dos fármacos , Animais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/imunologia , Anticorpos Neutralizantes/imunologia , COVID-19/imunologia , COVID-19/mortalidade , COVID-19/virologia , Chlorocebus aethiops , Modelos Animais de Doenças , Epitopos , Feminino , Células HEK293 , Haplorrinos , Humanos , Macaca fascicularis , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Pandemias , SARS-CoV-2/imunologia , SARS-CoV-2/isolamento & purificação , Células Vero , Ativação Viral
3.
Front Cell Infect Microbiol ; 11: 701930, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34336723

RESUMO

We performed a detailed analysis of immunophenotypic features of circulating leukocytes and spleen cells from cynomolgus macaques that had been naturally infected with Trypanosoma cruzi, identifying their unique and shared characteristics in relation to cardiac histopathological lesion status. T. cruzi-infected macaques were categorized into three groups: asymptomatic [CCC(-)], with mild chronic chagasic cardiopathy [CCC(+)], or with moderate chronic chagasic cardiopathy [CCC(++)]. Our findings demonstrated significant differences in innate and adaptive immunity cells of the peripheral blood and spleen compartments, by comparison with non-infected controls. CCC(+) and CCC(++) hosts exhibited decreased frequencies of monocytes, NK and NKT-cell subsets in both compartments, and increased frequencies of activated CD8+ T-cells and GranA+/GranB+ cells. While a balanced cytokine profile (TNF/IL-10) was observed in peripheral blood of CCC(-) macaques, a predominant pro-inflammatory profile (increased levels of TNF and IFN/IL-10) was observed in both CCC(+) and CCC(++) subgroups. Our data demonstrated that cardiac histopathological features of T. cruzi-infected cynomolgus macaques are associated with perturbations of the immune system similarly to those observed in chagasic humans. These results provide further support for the validity of the cynomolgus macaque model for pre-clinical research on Chagas disease, and provide insights pertaining to the underlying immunological mechanisms involved in the progression of cardiac Chagas disease.


Assuntos
Doença de Chagas , Trypanosoma cruzi , Animais , Linfócitos T CD8-Positivos , Humanos , Macaca fascicularis , Baço
5.
Viruses ; 13(8)2021 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-34452537

RESUMO

The post-acute phase of SARS-CoV-2 infection was investigated in rhesus (Macaca mulatta) and cynomolgus macaques (Macaca fascicularis). During the acute phase of infection, SARS-CoV-2 was shed via the nose and throat, and viral RNA was occasionally detected in feces. This phase coincided with a transient change in systemic immune activation. Even after the alleged resolution of the infection, computed tomography (CT) and positron emission tomography (PET)-CT revealed pulmonary lesions and activated tracheobronchial lymph nodes in all animals. Post-mortem histological examination of the lung tissue revealed mostly marginal or resolving minimal lesions that were indicative of SARS-CoV-2 infection. Evidence for SARS-CoV-2-induced histopathology was also found in extrapulmonary tissue samples, such as conjunctiva, cervical, and mesenteric lymph nodes. However, 5-6 weeks after SARS-CoV-2 exposure, upon necropsy, viral RNA was still detectable in a wide range of tissue samples in 50% of the macaques and included amongst others the heart, the respiratory tract and surrounding lymph nodes, salivary gland, and conjunctiva. Subgenomic messenger RNA was detected in the lungs and tracheobronchial lymph nodes, indicative of ongoing virus replication during the post-acute phase. These results could be relevant for understanding the long-term consequences of COVID-19 in humans.


Assuntos
COVID-19/patologia , COVID-19/virologia , Pulmão/patologia , SARS-CoV-2/fisiologia , Animais , Anticorpos Antivirais/sangue , COVID-19/imunologia , Citocinas/sangue , Modelos Animais de Doenças , Humanos , Pulmão/virologia , Linfonodos/patologia , Linfonodos/fisiopatologia , Macaca fascicularis , Macaca mulatta , RNA Mensageiro/análise , RNA Viral/análise , Sistema Respiratório/patologia , Sistema Respiratório/virologia , SARS-CoV-2/imunologia , Replicação Viral
6.
Nat Commun ; 12(1): 4911, 2021 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-34389710

RESUMO

The mammalian sensory neocortex consists of hierarchically organized areas reciprocally connected via feedforward (FF) and feedback (FB) circuits. Several theories of hierarchical computation ascribe the bulk of the computational work of the cortex to looped FF-FB circuits between pairs of cortical areas. However, whether such corticocortical loops exist remains unclear. In higher mammals, individual FF-projection neurons send afferents almost exclusively to a single higher-level area. However, it is unclear whether FB-projection neurons show similar area-specificity, and whether they influence FF-projection neurons directly or indirectly. Using viral-mediated monosynaptic circuit tracing in macaque primary visual cortex (V1), we show that V1 neurons sending FF projections to area V2 receive monosynaptic FB inputs from V2, but not other V1-projecting areas. We also find monosynaptic FB-to-FB neuron contacts as a second motif of FB connectivity. Our results support the existence of FF-FB loops in primate cortex, and suggest that FB can rapidly and selectively influence the activity of incoming FF signals.


Assuntos
Biorretroalimentação Psicológica/fisiologia , Macaca fascicularis/fisiologia , Neurônios/fisiologia , Córtex Visual/fisiologia , Vias Visuais/fisiologia , Animais , Feminino , Corpos Geniculados/citologia , Corpos Geniculados/fisiologia , Modelos Neurológicos , Reflexo Monosináptico/fisiologia , Córtex Visual/citologia
7.
Cytogenet Genome Res ; 161(5): 243-248, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34265761

RESUMO

A female cynomolgus monkey (Macaca fascicularis) with facial features characteristic of Down syndrome showed abnormal behavior, unwariness toward humans, and poor concentration. The number of metaphase chromosomes in blood lymphocytes was examined and found to be 43, which indicated one extra chromosome to the normal diploid number (2n = 42). We then used Q-banding and multicolor FISH techniques to identify the extra chromosome. The results revealed an additional chromosome 17, with no other chromosomal rearrangements, such as translocations. Since no mosaicism or heterozygous variant chromosomes were observed, full trisomy 17 was assessed in this female cynomolgus monkey. Chromosome 17 corresponds to human chromosome 13, and human trisomy 13, known as Patau syndrome, results in severe clinical signs and, often, a short life span; however, this individual has reached an age of 10 years with only mild clinical signs. Although genomic differences exist between human and macaques, this individual's case could help to reveal the pathological and genetic mechanisms of Patau syndrome.


Assuntos
Cromossomos de Mamíferos/ultraestrutura , Macaca fascicularis/genética , Animais , Bandeamento Cromossômico , Cromossomos Humanos Par 13 , Cromossomos Humanos Par 17 , Feminino , Humanos , Hibridização in Situ Fluorescente , Cariotipagem , Macaca fascicularis/anormalidades , Mosaicismo/veterinária , Especificidade da Espécie , Trissomia , Síndrome da Trissomia do Cromossomo 13/genética , Síndrome da Trissomia do Cromossomo 13/patologia
9.
Life Sci ; 282: 119811, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34256039

RESUMO

AIMS: Age-related macular degeneration (AMD) and high myopia are frequent causes of progressive visual impairment, so it is critical to identify animal models with resembling human retinal physiology, AMD and high myopia pathological features for therapeutic studies. MAIN METHODS: We screened elderly cynomolgus monkeys for fundus lesions by slit-lamp biomicroscope combined with fundus pre-set lens and further examined positive cases by color fundus photography (CFP), optical coherence tomography (OCT), fundus fluorescein angiography (FFA), streak retinoscopy, and A-scan ultrasonography. KEY FINDINGS: Among the 156 animals examined, 10 males and 5 females (30 eyes) exhibited fundus abnormalities (9.6% prevalence). Multi-modal imaging revealed drusen in 20 eyes of 11 animals (prevalence rate of 7.1%), tessellated fundus in 22 eyes of 11 animals, and myopia choroidal neovascularization (CNV) in 4 eyes of 3 animals. SIGNIFICANCE: Aged cynomolgus monkeys exhibit spontaneous fundus lesions resembling human AMD and high myopia, which could be an ideal model for clinical research.


Assuntos
Angiofluoresceinografia , Fundo de Olho , Degeneração Macular/diagnóstico por imagem , Miopia/diagnóstico por imagem , Tomografia de Coerência Óptica , Animais , Modelos Animais de Doenças , Feminino , Macaca fascicularis , Masculino
10.
Zool Res ; 42(4): 469-477, 2021 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-34213093

RESUMO

Mutations of PTEN-induced kinase I (PINK1) cause early-onset Parkinson's disease (PD) with selective neurodegeneration in humans. However, current PINK1 knockout mouse and pig models are unable to recapitulate the typical neurodegenerative phenotypes observed in PD patients. This suggests that generating PINK1 disease models in non-human primates (NHPs) that are close to humans is essential to investigate the unique function of PINK1 in primate brains. Paired single guide RNA (sgRNA)/Cas9-D10A nickases and truncated sgRNA/Cas9, both of which can reduce off-target effects without compromising on-target editing, are two optimized strategies in the CRISPR/Cas9 system for establishing disease animal models. Here, we combined the two strategies and injected Cas9-D10A mRNA and two truncated sgRNAs into one-cell-stage cynomolgus zygotes to target the PINK1 gene. We achieved precise and efficient gene editing of the target site in three newborn cynomolgus monkeys. The frame shift mutations of PINK1 in mutant fibroblasts led to a reduction in mRNA. However, western blotting and immunofluorescence staining confirmed the PINK1 protein levels were comparable to that in wild-type fibroblasts. We further reprogramed mutant fibroblasts into induced pluripotent stem cells (iPSCs), which showed similar ability to differentiate into dopamine (DA) neurons. Taken together, our results showed that co-injection of Cas9-D10A nickase mRNA and sgRNA into one-cell-stage cynomolgus embryos enabled the generation of human disease models in NHPs and target editing by pair truncated sgRNA/Cas9-D10A in PINK1 gene exon 2 did not impact protein expression.


Assuntos
Modelos Animais de Doenças , Macaca fascicularis/genética , Doença de Parkinson/veterinária , Proteínas Quinases/metabolismo , Animais , Animais Recém-Nascidos , Proteína 9 Associada à CRISPR/genética , Proteína 9 Associada à CRISPR/metabolismo , Técnicas de Cultura Embrionária , Transferência Embrionária , Fibroblastos/fisiologia , Mutação da Fase de Leitura , Regulação da Expressão Gênica , Macaca fascicularis/embriologia , Doenças dos Macacos/genética , Mutação , Doença de Parkinson/genética , Proteínas Quinases/genética , RNA Guia
11.
Nat Commun ; 12(1): 4219, 2021 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-34244505

RESUMO

Streptococcus pyogenes (Spy) Cas9 has potential as a component of gene therapeutics for incurable diseases. One of its limitations is its large size, which impedes its formulation and delivery in therapeutic applications. Smaller Cas9s are an alternative, but lack robust activity or specificity and frequently recognize longer PAMs. Here, we investigated four uncharacterized, smaller Cas9s and found three employing a "GG" dinucleotide PAM similar to SpyCas9. Protein engineering generated synthetic RNA-guided nucleases (sRGNs) with editing efficiencies and specificities exceeding even SpyCas9 in vitro and in human cell lines on disease-relevant targets. sRGN mRNA lipid nanoparticles displayed manufacturing advantages and high in vivo editing efficiency in the mouse liver. Finally, sRGNs, but not SpyCas9, could be packaged into all-in-one AAV particles with a gRNA and effected robust in vivo editing of non-human primate (NHP) retina photoreceptors. Human gene therapy efforts are expected to benefit from these improved alternatives to existing CRISPR nucleases.


Assuntos
Proteína 9 Associada à CRISPR/genética , Sistemas CRISPR-Cas/genética , Edição de Genes/métodos , RNA Guia/genética , Staphylococcus/enzimologia , Animais , Proteína 9 Associada à CRISPR/isolamento & purificação , Linhagem Celular Tumoral , Modelos Animais de Doenças , Terapia Genética/métodos , Vetores Genéticos/administração & dosagem , Vetores Genéticos/genética , Células HEK293 , Humanos , Macaca fascicularis , Masculino , Camundongos , Parvovirinae/genética , Engenharia de Proteínas , Ribonucleases , Staphylococcus/genética , Especificidade por Substrato , Síndromes de Usher/genética , Síndromes de Usher/terapia
12.
Eur J Pharm Sci ; 165: 105928, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34265405

RESUMO

Conjugation with polyethylene glycol (PEG), PEGylation, has been considered a useful tool to improve drug-like properties of novel small molecules and biologics in drug discovery. PEG40 or 40 kDa PEG is a double-branched PEG, routinely employed to improve the pharmacokinetics (PK) of therapeutics, including successful marketed products such as Pegasys® and Omontys®. However, less is known about the extent of contribution of PEG40 to the overall PK of the PEGylated product. Considering the half-life of PEG40 conjugated PEGylated products ranges from 1 to 14 days in human, this information is immensely valuable. After successfully developing a high sensitivity NMR based analytical method to quantitate PEG40 in mice serum after intravenous (IV) administration (Khandelwal et al., 2019), here, we extend its application to measure PEG40 in serum after IV administration and subcutaneous (SC) absorption in routinely employed non-clinical species in drug discovery, namely, mice, rats and cynomolgus monkeys. We utilized non-compartmental analysis and compartmental modeling to characterize the PK of PEG40 in these non-clinical species. Finally, we employed allometric scaling and Wajima (MRT-Css) method to predict the PK of PEG40 in human after IV administration and SC absorption. In general, our data shows that intrinsic PK parameters of PEG40 in mice, rats and cynomolgus monkeys are in the range of published literature values for PEG40-conjugated products, unless saturable clearance mechanisms are involved. We observed a bioavailability (F) of ~68% in CD-1 mice after SC administration of PEG40. In rats, the clearance (CL) and volume of distribution at steady state (Vss) after IV infusion of PEG40 were 0.079 mL/min/kg and 0.19 L/kg, respectively; and SC bioavailability was ~20%. In cynomolgus monkeys, after IV infusion, CL and Vss of PEG40 were 0.037 mL/min/kg and 0.20 L/kg, respectively; and SC bioavailability was ~69%. In addition, our findings indicate flip-flop kinetics of PEG40 in rodents, but not in cynomolgus monkeys. Finally, in human, intrinsic CL and Vss of PEG40 were projected to be 0.02 mL/min/kg (0.084 L/h) and 0.22 L/kg, respectively. This comprehensive report of PK of PEG40 in non-clinical species and its subsequent prediction in humans is expected to be useful to drug discovery and development scientists for efficient decision-making and optimal resource utilization.


Assuntos
Polietilenoglicóis , Administração Intravenosa , Animais , Disponibilidade Biológica , Meia-Vida , Humanos , Macaca fascicularis , Camundongos , Ratos
13.
J Gen Virol ; 102(7)2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34242156

RESUMO

Bactrian camel hepatitis E virus (HEV) is a novel HEV belonging to genotype 8 (HEV-8) in the Orthohepevirus A species of the genus Hepevirus in the family Hepeviridae. HEV-8 cross-transmits to cynomolgus monkeys and has a potential risk for zoonotic infection. Until now, neither a cell-culture system to grow the virus nor a reverse genetics system to generate the virus has been developed. To generate replication-competent HEV-8 and to establish a cell-culture system, we synthesized capped genomic HEV-8 RNAs by in vitro transcription and used them to transfect into PLC/PRF/5 cells. A HEV-8 strain, HEV-8M2, was recovered from the capped HEV-8 RNA-transfected cell-culture supernatants and subsequently passaged in the cells, demonstrating that PLC/PRF/5 cells were capable of supporting the replication of the HEV-8, and that a cell-culture system for HEV-8 was successfully established. In addition to PLC/PRF/5 cells, A549 and Caco-2 cells appeared to be competent for the replication, but HepG2 C3/A, Vero, Hela S3, HEp-2C, 293T and GL37 cells were incompetent. The HEV-8M2 strain was capable of infecting cynomolgus monkeys by an intravenous inoculation, indicating that HEV-8 was infectious and again carried a risk for zoonotic infection. In contrast, HEV-8 did not infect nude rats and BALB/c nude mice, suggesting that the reservoir of HEV-8 was limited. In addition, the replication of the HEV-8M2 strain was efficiently abrogated by ribavirin but not by favipiravir, suggesting that ribavirin is a drug candidate for therapeutic treatment of HEV-8-induced hepatitis. The infectious HEV-8 produced by a reverse genetics system would be useful to elucidate the mechanisms of HEV replication and the pathogenesis of type E hepatitis.


Assuntos
Vírus da Hepatite E/genética , Vírus da Hepatite E/fisiologia , Hepatite E/virologia , Genética Reversa , Amidas/farmacologia , Animais , Antivirais/farmacologia , Proteínas do Capsídeo/análise , Linhagem Celular , Feminino , Genoma Viral , Vírus da Hepatite E/efeitos dos fármacos , Vírus da Hepatite E/patogenicidade , Humanos , Macaca fascicularis , Masculino , Camundongos , Camundongos Nus , Pirazinas/farmacologia , RNA Viral/genética , Ratos , Ribavirina/farmacologia , Transfecção , Replicação Viral/efeitos dos fármacos
14.
Methods Mol Biol ; 2320: 295-302, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34302666

RESUMO

Recent evidence has provided exciting proof of concepts for the use of pluripotent stem cell-derived cardiomyocytes (PSC-CMs) for cardiac repair; however, large animal studies, which better reflect human disease, are required for clinical application. Here, we describe how to create myocardial infarction in cynomolgus monkey followed by transplantation of PSC-CMs. This method ensures the establishment of a myocardial infarction model and enables reliable PSC-CM transplantation.


Assuntos
Modelos Animais de Doenças , Células-Tronco Pluripotentes Induzidas/citologia , Macaca fascicularis , Infarto do Miocárdio/terapia , Miócitos Cardíacos/transplante , Anestesia por Inalação/métodos , Anestesia por Inalação/veterinária , Animais , Atropina/uso terapêutico , Bradicardia/tratamento farmacológico , Bradicardia/prevenção & controle , Células Cultivadas , Complicações Intraoperatórias/tratamento farmacológico , Complicações Intraoperatórias/prevenção & controle , Ligadura
15.
ACS Infect Dis ; 7(8): 2264-2276, 2021 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-34255474

RESUMO

Neutrophilic inflammation correlates with severe tuberculosis (TB), a disease caused by Mycobacterium tuberculosis (Mtb). Granulomas are lesions that form in TB, and a PET probe for following neutrophil recruitment to granulomas could predict disease progression. We tested the formyl peptide receptor 1 (FPR1)-targeting peptide FLFLF in Mtb-infected macaques. Preliminary studies in mice demonstrated specificity for neutrophils. In macaques, 64Cu-FLFLF was retained in lung granulomas and analysis of lung granulomas identified positive correlations between 64Cu-FLFLF and neutrophil and macrophage numbers (R2 = 0.8681 and 0.7643, respectively), and weaker correlations for T cells and B cells (R2 = 0.5744 and 0.5908, respectively), suggesting that multiple cell types drive 64Cu-FLFLF avidity. By PET/CT imaging, we found that granulomas retained 64Cu-FLFLF but with less avidity than the glucose analog 18F-FDG. These studies suggest that neutrophil-specific probes have potential PET/CT applications in TB, but important issues need to be addressed before they can be used in nonhuman primates and humans.


Assuntos
Neutrófilos , Receptores de Formil Peptídeo , Animais , Granuloma/diagnóstico por imagem , Pulmão/diagnóstico por imagem , Macaca fascicularis , Macrófagos , Camundongos , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada
16.
PLoS Pathog ; 17(7): e1009668, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34280241

RESUMO

SARS-CoV-2 infection presents clinical manifestations ranging from asymptomatic to fatal respiratory failure. Despite the induction of functional SARS-CoV-2-specific CD8+ T-cell responses in convalescent individuals, the role of virus-specific CD8+ T-cell responses in the control of SARS-CoV-2 replication remains unknown. In the present study, we show that subacute SARS-CoV-2 replication can be controlled in the absence of CD8+ T cells in cynomolgus macaques. Eight macaques were intranasally inoculated with 105 or 106 TCID50 of SARS-CoV-2, and three of the eight macaques were treated with a monoclonal anti-CD8 antibody on days 5 and 7 post-infection. In these three macaques, CD8+ T cells were undetectable on day 7 and thereafter, while virus-specific CD8+ T-cell responses were induced in the remaining five untreated animals. Viral RNA was detected in nasopharyngeal swabs for 10-17 days post-infection in all macaques, and the kinetics of viral RNA levels in pharyngeal swabs and plasma neutralizing antibody titers were comparable between the anti-CD8 antibody treated and untreated animals. SARS-CoV-2 RNA was detected in the pharyngeal mucosa and/or retropharyngeal lymph node obtained at necropsy on day 21 in two of the untreated group but undetectable in all macaques treated with anti-CD8 antibody. CD8+ T-cell responses may contribute to viral control in SARS-CoV-2 infection, but our results indicate possible containment of subacute viral replication in the absence of CD8+ T cells, implying that CD8+ T-cell dysfunction may not solely lead to viral control failure.


Assuntos
Linfócitos T CD8-Positivos/imunologia , COVID-19/veterinária , Macaca fascicularis/imunologia , Macaca fascicularis/virologia , Doenças dos Macacos/imunologia , Doenças dos Macacos/virologia , SARS-CoV-2/imunologia , SARS-CoV-2/fisiologia , Animais , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , COVID-19/imunologia , COVID-19/virologia , Modelos Animais de Doenças , Feminino , Humanos , Cinética , Depleção Linfocítica/veterinária , Masculino , RNA Viral/genética , RNA Viral/metabolismo , SARS-CoV-2/genética , Replicação Viral/imunologia
17.
Emerg Infect Dis ; 27(8): 2187-2191, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34287122

RESUMO

We detected the simian malaria parasites Plasmodium knowlesi, P. cynomolgi, P. inui, P. coatneyi, P. inui-like, and P. simiovale among forest fringe-living indigenous communities from various locations in Malaysia. Our findings underscore the importance of using molecular tools to identify newly emergent malaria parasites in humans.


Assuntos
Malária , Parasitos , Plasmodium cynomolgi , Plasmodium knowlesi , Plasmodium , Animais , Humanos , Macaca fascicularis , Malária/diagnóstico , Malária/epidemiologia , Malásia/epidemiologia , Plasmodium/genética , Plasmodium cynomolgi/genética , Plasmodium knowlesi/genética
18.
Acta Cir Bras ; 36(5): e360503, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34161432

RESUMO

PURPOSE: As a classical xenotransplantation model, porcine kidneys have been transplanted into the lower abdomen of non-human primates. However, we have improved upon this model by using size-matched grafting in the orthotopic position. The beneficial aspects and surgical details of our method are reported herein. METHODS: Donors were two newborn pigs (weighting 5 to 6 kg) and recipients were two cynomolgus monkeys (weighting, approximately, 7 kg). After bilateral nephrectomy, kidneys were cold-transported in Euro-Collins solution. The porcine kidney was transplanted to the site of a left nephrectomy and fixed to the peritoneum. RESULTS: Kidneys transplanted to the lower abdomen by the conventional method were more susceptible to torsion of the renal vein (two cases). In contrast, early-stage blood flow insufficiency did not occur in orthotopic transplants of theleft kidney. CONCLUSIONS: Size-matched porcine-primate renal grafting using our method of transplanting tothe natural position of the kidneys contributes to stable post-transplant blood flow to the kidney.


Assuntos
Transplante de Rim , Transplantes , Animais , Sobrevivência de Enxerto , Rim/cirurgia , Macaca fascicularis , Nefrectomia , Suínos
19.
Nat Nanotechnol ; 16(8): 942-951, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34140674

RESUMO

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has grown into a global pandemic, and only a few antiviral treatments have been approved to date. Angiotensin-converting enzyme 2 (ACE2) plays a fundamental role in SARS-CoV-2 pathogenesis because it allows viral entry into host cells. Here we show that ACE2 nanodecoys derived from human lung spheroid cells (LSCs) can bind and neutralize SARS-CoV-2 and protect the host lung cells from infection. In mice, these LSC-nanodecoys were delivered via inhalation therapy and resided in the lungs for over 72 h post-delivery. Furthermore, inhalation of the LSC-nanodecoys accelerated clearance of SARS-CoV-2 mimics from the lungs, with no observed toxicity. In cynomolgus macaques challenged with live SARS-CoV-2, four doses of these nanodecoys delivered by inhalation promoted viral clearance and reduced lung injury. Our results suggest that LSC-nanodecoys can serve as a potential therapeutic agent for treating COVID-19.


Assuntos
COVID-19/tratamento farmacológico , Lesão Pulmonar/prevenção & controle , Nanoestruturas/administração & dosagem , SARS-CoV-2/efeitos dos fármacos , Administração por Inalação , Enzima de Conversão de Angiotensina 2/metabolismo , Animais , COVID-19/virologia , Micropartículas Derivadas de Células/metabolismo , Micropartículas Derivadas de Células/transplante , Modelos Animais de Doenças , Humanos , Lesão Pulmonar/virologia , Macaca fascicularis , Camundongos , Ligação Proteica , SARS-CoV-2/metabolismo , Esferoides Celulares/metabolismo , Glicoproteína da Espícula de Coronavírus/metabolismo , Carga Viral/efeitos dos fármacos
20.
Sci Transl Med ; 13(597)2021 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-34108251

RESUMO

A safe and protective Lassa virus vaccine is crucially needed in Western Africa to stem the recurrent outbreaks of Lassa virus infections in Nigeria and the emergence of Lassa virus in previously unaffected countries, such as Benin and Togo. Major challenges in developing a Lassa virus vaccine include the high diversity of circulating strains and their reemergence from 1 year to another. To address each of these challenges, we immunized cynomolgus monkeys with a measles virus vector expressing the Lassa virus glycoprotein and nucleoprotein of the prototypic Lassa virus strain Josiah (MeV-NP). To evaluate vaccine efficacy against heterologous strains of Lassa virus, we challenged the monkeys a month later with heterologous strains from lineage II or lineage VII, finding that the vaccine was protective against these strains. A second cohort of monkeys was challenged 1 year later with the homologous Josiah strain, finding that a single dose of MeV-NP was sufficient to protect all vaccinated monkeys. These studies demonstrate that MeV-NP can generate both long-lasting immune responses and responses that are able to protect against diverse strains of Lassa virus.


Assuntos
Febre Lassa , Vacinas Virais/imunologia , África Ocidental , Animais , Febre Lassa/prevenção & controle , Vírus Lassa , Macaca fascicularis , Nucleoproteínas
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