RESUMEN
Rhesus macaques (Macaca mulatta) are amongst the most common nonhuman primate species used in biomedical research. These animals provide a precious resource for translational studies and opportunities to maximize rhesus data use are encouraged. Here we compile data produced from 10 years of investigator-driven pregnancy studies conducted at the Oregon National Primate Research Center (ONPRC). All pregnancies were generated within the consistent and reproducible protocols of the ONPRC time-mated breeding program. The data included are from control animals who did not experience in utero perturbations or experimental manipulations. A total of 86 pregnant rhesus macaques were delivered by cesarean section over a range of gestational days (G) 50 to G159 (where term is G165 ± 10 days in the rhesus macaque), with subsequent immediate tissue harvesting following standardized protocols. Fetal and placental growth measures, and all major organ weights are reported. All data are presented relative to gestational age for the entire cohort and in addition, data are stratified by fetal sex. The outcome is a large reference resource for use by laboratory animal researchers in future comparative fetal development studies.
Asunto(s)
Cesárea , Placenta , Embarazo , Animales , Femenino , Macaca mulatta , Desarrollo Fetal , Animales de LaboratorioRESUMEN
Rhesus and cynomolgus macaques are the most frequently used nonhuman primate (NHP) species for biomedical research and toxicology studies of novel therapeutics. In recent years, there has been a shortage of laboratory macaques due to a variety of competing factors. This was most recently exacerbated by the surge in NHP research required to address the severe acute respiratory syndrome (SARS)-coronavirus 2 pandemic. Continued support of these important studies has required the use of more varied cohorts of macaques, including animals with different origins, increased exposure to naturally occurring pathogens, and a wider age range. Diarrhea and diseases of the gastrointestinal tract are the most frequently occurring spontaneous findings in macaques of all origins and ages. The purpose of this review is to alert pathologists and scientists involved in NHP research to these findings and their impact on animal health and study endpoints, which may otherwise confound the interpretation of data generated using macaques.
Asunto(s)
COVID-19 , Animales , Tracto Gastrointestinal , Macaca fascicularis , Macaca mulattaRESUMEN
Pelizaeus-Merzbacher disease (PMD) is a severe hypomyelinating disorder of the central nervous system (CNS) linked to mutations in the proteolipid protein-1 (PLP1) gene. Although there are multiple animal models of PMD, few of them fully mimic the human disease. Here, we report three spontaneous cases of male neonatal rhesus macaques with the clinical symptoms of hypomyelinating disease, including intention tremors, progressively worsening motor dysfunction, and nystagmus. These animals demonstrated a paucity of CNS myelination accompanied by reactive astrogliosis, and a lack of PLP1 expression throughout white matter. Genetic analysis revealed that these animals were related to one another and that their parents carried a rare, hemizygous missense variant in exon 5 of the PLP1 gene. These animals therefore represent the first reported non-human primate model of PMD, providing a novel and valuable opportunity for preclinical studies that aim to promote myelination in pediatric hypomyelinating diseases.
Asunto(s)
Enfermedad de Pelizaeus-Merzbacher/patología , Animales , Apoptosis/efectos de los fármacos , Modelos Animales de Enfermedad , Gliosis , Macaca mulatta , Masculino , Trastornos del Movimiento/genética , Trastornos del Movimiento/fisiopatología , Mutación Missense , Proteína Proteolipídica de la Mielina , Vaina de Mielina/patología , Temblor/genética , Temblor/fisiopatología , Sustancia BlancaRESUMEN
Cryptococcus gattii was diagnosed in two female indoor-housed rhesus macaques. Gross and histopathologic findings included an isolated pulmonary cryptococcoma in a non-SIV-infected macaque and disseminated disease centered on the lungs of an SIV-infected macaque. Fungal yeast were positive with special stains, and the diagnoses were confirmed with a lateral flow assay and PCR.
Asunto(s)
Criptococosis/veterinaria , Cryptococcus gattii/aislamiento & purificación , Macaca mulatta , Enfermedades de los Monos/patología , Animales , Animales de Zoológico , Criptococosis/diagnóstico por imagen , Criptococosis/parasitología , Criptococosis/patología , Femenino , Enfermedades de los Monos/diagnóstico , Enfermedades de los Monos/parasitología , OregonRESUMEN
Colonic volvulus is an uncommon, often life-threatening condition, in non-human primates. Twenty-six cases of colonic volvulus in rhesus macaques (Macaca mulatta) were identified in necropsy records spanning 38 years at the Oregon National Primate Research Center (ONPRC). This report represents the largest collection of colonic volvuli in rhesus macaques.
Asunto(s)
Vólvulo Intestinal , Animales , Colon , Vólvulo Intestinal/diagnóstico , Vólvulo Intestinal/cirugía , Vólvulo Intestinal/veterinaria , Macaca mulatta , Oregon , Estudios RetrospectivosRESUMEN
Although IL-15 has been implicated in the pathogenic hyperimmune activation that drives progressive HIV and SIV infection, as well as in the generation of HIV/SIV target cells, it also supports NK and T cell homeostasis and effector activity, potentially benefiting the host. To understand the role of IL-15 in SIV infection and pathogenesis, we treated two cohorts of SIVmac239-infected rhesus macaques (RM; Macaca mulatta), one with chronic infection, the other with primary infection, with a rhesusized, IL-15-neutralizing mAb (versus an IgG isotype control) for up to 10 wk (n = 7-9 RM per group). In both cohorts, anti-IL-15 was highly efficient at blocking IL-15 signaling in vivo, causing 1) profound depletion of NK cells in blood and tissues throughout the treatment period; 2) substantial, albeit transient, depletion of CD8+ effector memory T cells (TEM) (but not the naive and central memory subsets); and 3) CD4+ and CD8+ TEM hyperproliferation. In primary infection, reduced frequencies of SIV-specific effector T cells in an extralymphoid tissue site were also observed. Despite these effects, the kinetics and extent of SIV replication, CD4+ T cell depletion, and the onset of AIDS were comparable between anti-IL-15- and control-treated groups in both cohorts. However, RM treated with anti-IL-15 during primary infection manifested accelerated reactivation of RM rhadinovirus. Thus, IL-15 support of NK cell and TEM homeostasis does not play a demonstrable, nonredundant role in SIV replication or CD4+ T cell deletion dynamics but may contribute to immune control of oncogenic γ-herpesviruses.
Asunto(s)
Interleucina-15/inmunología , Macaca mulatta/inmunología , Transducción de Señal/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Virus de la Inmunodeficiencia de los Simios/inmunología , Animales , Femenino , Masculino , Virus de la Inmunodeficiencia de los Simios/patogenicidadRESUMEN
Allogeneic hematopoietic stem cell transplantation (HSCT) and xenotransplantation are accompanied by viral reactivations and virus-associated complications resulting from immune deficiency. Here, in a Mauritian cynomolgus macaque model of fully MHC-matched allogeneic HSCT, we report reactivations of cynomolgus polyomavirus, lymphocryptovirus, and cytomegalovirus, macaque viruses analogous to HSCT-associated human counterparts BK virus, Epstein-Barr virus, and human cytomegalovirus. Viral replication in recipient macaques resulted in characteristic disease manifestations observed in HSCT patients, such as polyomavirus-associated hemorrhagic cystitis and tubulointerstitial nephritis or lymphocryptovirus-associated post-transplant lymphoproliferative disorder. However, in most cases, the reconstituted immune system, alone or in combination with short-term pharmacological intervention, exerted control over viral replication, suggesting engraftment of functional donor-derived immunity. Indeed, the donor-derived reconstituted immune systems of two long-term engrafted HSCT recipient macaques responded to live attenuated yellow fever 17D vaccine (YFV 17D) indistinguishably from untransplanted controls, mounting 17D-targeted neutralizing antibody responses and clearing YFV 17D within 14 days. Together, these data demonstrate that this macaque model of allogeneic HSCT recapitulates clinical situations of opportunistic viral infections in transplant patients and provides a pre-clinical model to test novel prophylactic and therapeutic modalities.
Asunto(s)
Modelos Animales de Enfermedad , Trasplante de Células Madre Hematopoyéticas , Infecciones Oportunistas , Virosis , Aloinjertos , Animales , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Macaca fascicularis , Infecciones Oportunistas/virologíaRESUMEN
Epidermolysis bullosa simplex (EBS) is an inherited skin disorder characterized by increased skin and mucous membrane fragility. Most cases are caused by mutations in keratin 5 (KRT5) and keratin 14 (KRT14). Mutations of these genes result in cytoskeletal disruption of the basal keratinocytes. Gross and histopathologic findings of 2 clinically affected homozygous rhesus macaques with an insertion variant mutation in KRT5 are described and compared with 6 deceased phenotypically normal animals that were heterozygous for the KRT5 insertion variant. Animals that were homozygous for the KRT5 insertion variant were stillborn and had widespread loss of the epidermis. Microscopic examination confirmed severe ulceration and basal cell vacuolation with basilar vesicle formation in the remaining intact epidermis. Immunohistochemistry for cytokeratin 5 demonstrated lack of epidermal immunoreactivity in homozygotes. DNA sequencing identified a 34-base pair insertion variant in exon 5 of the KRT5 gene. To our knowledge, this is the first report of epidermolysis bullosa in rhesus macaques.
Asunto(s)
Epidermólisis Ampollosa Simple/veterinaria , Variación Genética , Queratina-5/genética , Enfermedades de los Monos/diagnóstico , Animales , Modelos Animales de Enfermedad , Epidermólisis Ampollosa Simple/diagnóstico , Epidermólisis Ampollosa Simple/genética , Epidermólisis Ampollosa Simple/patología , Exones/genética , Femenino , Homocigoto , Humanos , Inmunohistoquímica/veterinaria , Queratinocitos/patología , Macaca mulatta , Masculino , Enfermedades de los Monos/genética , Enfermedades de los Monos/patología , Mutagénesis Insercional , Fenotipo , Piel/patología , Mortinato/veterinariaRESUMEN
The development of therapies for retinal disorders is hampered by a lack of appropriate animal models. Higher nonhuman primates are the only animals with retinal structure similar to humans, including the presence of a macula and fovea. However, few nonhuman primate models of genetic retinal disease are known. We identified a lineage of rhesus macaques with a frameshift mutation in exon 3 of the BBS7 gene c.160delG (p.Ala54fs) that is predicted to produce a non-functional protein. In humans, mutations in this and other BBS genes cause Bardet-Biedl syndrome, a ciliopathy and a syndromic form of retinitis pigmentosa generally occurring in conjunction with kidney dysfunction, polydactyly, obesity, and/or hypogonadism. Three full- or half-sibling monkeys homozygous for the BBS7 c.160delG variant, at ages 3.5, 4 and 6 years old, displayed a combination of severe photoreceptor degeneration and progressive kidney disease. In vivo retinal imaging revealed features of severe macular degeneration, including absence of photoreceptor layers, degeneration of the retinal pigment epithelium, and retinal vasculature atrophy. Electroretinography in the 3.5-year-old case demonstrated loss of scotopic and photopic a-waves and markedly reduced and delayed b-waves. Histological assessments in the 4- and 6-year-old cases confirmed profound loss of photoreceptors and inner retinal neurons across the posterior retina, with dramatic thinning and disorganization of all cell layers, abundant microglia, absent or displaced RPE cells, and significant gliosis in the subretinal space. Retinal structure, including presence of photoreceptors, was preserved only in the far periphery. Ultrasound imaging of the kidneys revealed deranged architecture, and renal histopathology identified distorted contours with depressed, fibrotic foci and firmly adhered renal capsules; renal failure occurred in the 6-year-old case. Magnetic resonance imaging obtained in one case revealed abnormally low total brain volume and unilateral ventricular enlargement. The one male had abnormally small testes at 4 years of age, but polydactyly and obesity were not observed. Thus, monkeys homozygous for the BBS7 c.160delG variant closely mirrored several key features of the human BBS syndrome. This finding represents the first identification of a naturally-occurring nonhuman primate model of BBS, and more broadly the first such model of retinitis pigmentosa and a ciliopathy with an associated genetic mutation. This important new preclinical model will provide the basis for better understanding of disease progression and for the testing of new therapeutic options, including gene and cell-based therapies, not only for BBS but also for multiple forms of photoreceptor degeneration.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Síndrome de Bardet-Biedl/diagnóstico , Ceguera/etiología , Proteínas del Citoesqueleto/genética , ADN/genética , Mutación del Sistema de Lectura , Retina/patología , Retinitis Pigmentosa/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Síndrome de Bardet-Biedl/complicaciones , Síndrome de Bardet-Biedl/genética , Encéfalo/patología , Proteínas del Citoesqueleto/metabolismo , Análisis Mutacional de ADN , Modelos Animales de Enfermedad , Electrorretinografía , Femenino , Angiografía con Fluoresceína/métodos , Fondo de Ojo , Inmunohistoquímica , Macaca mulatta , Imagen por Resonancia Magnética , Masculino , Tomografía de Coherencia Óptica/métodosRESUMEN
Naturally occurring neurologic disease in non-human primates may be attributable to a wide-range of causes, including infectious agents, congenital or acquired malformations, degenerative diseases, and, rarely, neoplasia. We report a case of ataxia and paresis in a juvenile rhesus macaque with ependymal-lined cerebral cysts.
Asunto(s)
Neoplasias Encefálicas/veterinaria , Quistes/veterinaria , Epéndimo/patología , Macaca mulatta , Enfermedades de los Monos/patología , Animales , Ataxia/etiología , Ataxia/veterinaria , Neoplasias Encefálicas/patología , Quistes/patología , Femenino , Paresia/etiología , Paresia/veterinariaRESUMEN
We have identified a natural Japanese macaque model of the childhood neurodegenerative disorder neuronal ceroid lipofuscinosis, commonly known as Batten Disease, caused by a homozygous frameshift mutation in the CLN7 gene (CLN7-/-). Affected macaques display progressive neurological deficits including visual impairment, tremor, incoordination, ataxia and impaired balance. Imaging, functional and pathological studies revealed that CLN7-/- macaques have reduced retinal thickness and retinal function early in disease, followed by profound cerebral and cerebellar atrophy that progresses over a five to six-year disease course. Histological analyses showed an accumulation of cerebral, cerebellar and cardiac storage material as well as degeneration of neurons, white matter fragmentation and reactive gliosis throughout the brain of affected animals. This novel CLN7-/- macaque model recapitulates key behavioral and neuropathological features of human Batten Disease and provides novel insights into the pathophysiology linked to CLN7 mutations. These animals will be invaluable for evaluating promising therapeutic strategies for this devastating disease.
Asunto(s)
Modelos Animales de Enfermedad , Proteínas de Transporte de Membrana/genética , Lipofuscinosis Ceroideas Neuronales/diagnóstico por imagen , Lipofuscinosis Ceroideas Neuronales/genética , Animales , Femenino , Técnicas de Inactivación de Genes/métodos , Locomoción/fisiología , Macaca , Masculino , Mutación Missense/genética , Lipofuscinosis Ceroideas Neuronales/fisiopatología , Equilibrio Postural/fisiología , Primates , Trastornos de la Visión/diagnóstico por imagen , Trastornos de la Visión/genética , Trastornos de la Visión/fisiopatologíaRESUMEN
Reproductive lesions have been described in various nonhuman primate species, including rhesus macaques ( Macaca mulatta), cynomolgus macaques ( Macaca fascicularis), baboons ( Papio spp.), squirrel monkeys ( Saimiri sciureus), and chimpanzees ( Pan spp.); however, there are few publications describing reproductive disease and pathology in Japanese macaques ( Macaca fuscata). A retrospective evaluation of postmortem reports for two captive M. fuscata populations housed within zoos from 1982 through 2015 was completed, comparing reproductive diseases diagnosed by gross pathology and histopathology. Disease prevalence, organs affected, and median age at death between the two institutions was also compared. Fifteen female captive M. fuscata, ranging in age from 15 to 29 yr were identified with reproductive tract lesions, including endometriosis, endometritis, leiomyoma, leiomyosarcoma, and adenomyosis. No significant differences were identified in disease prevalence, organs affected, and median age of death between the two institutions. Endometriosis was the most common disease process identified and was found in 10 of the 15 cases (66.7%), followed by leiomyoma (4 of 15; 26.7%). In four cases (26.7%), severe endometriosis and secondary hemorrhage was indicated as the cause of death or the primary reason for humane euthanasia. These findings were compared with a separate population of Japanese macaques managed within a research facility in the United States, with a prevalence of endometriosis of 7.6%. This study discusses possible risk factors and potential treatment options for the management of endometriosis in captive M. fuscata.
Asunto(s)
Macaca mulatta , Enfermedades de los Monos/patología , Enfermedades Uterinas/veterinaria , Factores de Edad , Animales , Animales de Zoológico , Femenino , Iowa , Minnesota , Enfermedades de los Monos/epidemiología , Prevalencia , Estudios Retrospectivos , Enfermedades Uterinas/epidemiología , Enfermedades Uterinas/patologíaRESUMEN
Bacterial infection of the laryngeal air sacs (air sacculitis) is infrequently reported in nonhuman primates, where it leads to chronic respiratory disease. It is particularly uncommon in macaques; however, we report here suppurative air sacculitis with extension to adjacent cervical tissues in three rhesus macaques and one Japanese macaque. Staphylococcus aureus, Streptococcus sp., and an anaerobic bacterium were isolated.
Asunto(s)
Sacos Aéreos/patología , Macaca , Enfermedades de los Monos/patología , Infecciones del Sistema Respiratorio/veterinaria , Infecciones Estafilocócicas/veterinaria , Infecciones Estreptocócicas/veterinaria , Sacos Aéreos/microbiología , Animales , Femenino , Macaca mulatta , Masculino , Enfermedades de los Monos/microbiología , Infecciones del Sistema Respiratorio/microbiología , Infecciones del Sistema Respiratorio/patología , Infecciones Estafilocócicas/microbiología , Infecciones Estafilocócicas/patología , Staphylococcus aureus/aislamiento & purificación , Infecciones Estreptocócicas/microbiología , Infecciones Estreptocócicas/patología , Streptococcus/aislamiento & purificaciónRESUMEN
Rhesus macaques experimentally infected with Simian Immunodeficiency Virus (SIV) experience immunosuppression and often opportunistic infection. Among the most common opportunistic infections are rhesus cytomegalovirus (RhCMV), a ubiquitous betaherpesvirus that undergoes continuous low-level replication in immunocompetent monkeys. Upon SIV-mediated immunodeficiency, RhCMV reactivates and results in lesions in numerous organ systems including the nervous and reproductive systems. We report the first case of cytomegaloviral hypophysitis in a SIV-immunocompromised rhesus macaque.
Asunto(s)
Citomegalovirus/aislamiento & purificación , Hipofisitis/inmunología , Huésped Inmunocomprometido , Macaca mulatta , Infecciones Oportunistas/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/complicaciones , Animales , Femenino , Hipofisitis/complicaciones , Hipofisitis/virología , Infecciones Oportunistas/complicaciones , Infecciones Oportunistas/virología , Virus de la Inmunodeficiencia de los Simios/fisiologíaRESUMEN
BACKGROUND: A juvenile rhesus macaque presented with blindness, ataxia, and head tilt. METHODS: Postmortem gross and microscopic examination, histochemical staining and bacterial culture were performed. RESULTS: Nocardia sp. was identified as the etiologic agent of a primary pneumonia with secondary cerebral abscessation. CONCLUSIONS: Nocardiosis should be a differential diagnosis for patients with neurologic disease.
Asunto(s)
Absceso Encefálico/diagnóstico , Enfermedades Pulmonares/diagnóstico , Macaca mulatta , Enfermedades de los Monos/diagnóstico , Nocardiosis/diagnóstico , Animales , Absceso Encefálico/microbiología , Absceso Encefálico/patología , Diagnóstico Diferencial , Resultado Fatal , Femenino , Enfermedades Pulmonares/complicaciones , Enfermedades Pulmonares/patología , Enfermedades de los Monos/microbiología , Enfermedades de los Monos/patología , Nocardia/aislamiento & purificación , Nocardiosis/microbiología , Nocardiosis/patologíaRESUMEN
Simian-human immunodeficiency virus (SHIV) models for human immunodeficiency virus (HIV) infection have been widely used in passive studies with HIV neutralizing antibodies (NAbs) to test for protection against infection. However, because SHIV-infected adult macaques often rapidly control plasma viremia and any resulting pathogenesis is minor, the model has been unsuitable for studying the impact of antibodies on pathogenesis in infected animals. We found that SHIVSF162P3 infection in 1-month-old rhesus macaques not only results in high persistent plasma viremia but also leads to very rapid disease progression within 12 to 16 weeks. In this model, passive transfer of high doses of neutralizing IgG (SHIVIG) prevents infection. Here, we show that at lower doses, SHIVIG reduces both plasma and peripheral blood mononuclear cell (PBMC)-associated viremia and mitigates pathogenesis in infected animals. Moreover, production of endogenous NAbs correlated with lower set-point viremia and 100% survival of infected animals. New SHIV models are needed to investigate whether passively transferred antibodies or antibodies elicited by vaccination that fall short of providing sterilizing immunity impact disease progression or influence immune responses. The 1-month-old rhesus macaque SHIV model of infection provides a new tool to investigate the effects of antibodies on viral replication and clearance, mechanisms of B cell maintenance, and the induction of adaptive immunity in disease progression.
Asunto(s)
Modelos Animales de Enfermedad , Inmunoglobulina G/inmunología , Linfocitos/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/prevención & control , Virus de la Inmunodeficiencia de los Simios/inmunología , Viremia/inmunología , Animales , Animales Recién Nacidos , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/inmunología , Citotoxicidad Celular Dependiente de Anticuerpos , Humanos , Inmunización Pasiva , Leucocitos Mononucleares , Linfocitos/virología , Macaca mulatta , Pruebas de Neutralización , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/virología , Virus de la Inmunodeficiencia de los Simios/patogenicidad , Tasa de Supervivencia , Carga Viral , Viremia/sangre , Viremia/virología , Replicación ViralRESUMEN
Ethanol consumption is associated with positive, negative, and neutral effects on the skeletal system. Our previous work using a nonhuman primate model of voluntary ethanol consumption showed that chronic ethanol use has an impact on skeletal attributes, most notably on biochemical markers of bone turnover. However, these studies were limited by small sample sizes and resulting lack of statistical power. Here, we applied a machine learning framework to integrate data from 155 monkeys (100 ethanol and 55 controls) to identify the bone features associated with chronic ethanol use. Specifically, we analyzed the influence of ethanol consumption on biomarkers of bone turnover and cancellous and cortical bone architecture in tibia. We hypothesized that chronic ethanol use for 6 months to 2.5 years would result in measurable changes to cancellous features and the biochemical markers compared to control animals. We observed a decrease in bone turnover in monkeys exposed to ethanol; however, we did not find that ethanol consumption resulted in measurable changes in bone architecture.
Asunto(s)
Consumo de Bebidas Alcohólicas , Biomarcadores , Remodelación Ósea , Etanol , Tibia , Animales , Tibia/efectos de los fármacos , Tibia/metabolismo , Tibia/diagnóstico por imagen , Remodelación Ósea/efectos de los fármacos , Biomarcadores/sangre , Etanol/farmacología , Etanol/administración & dosificación , Consumo de Bebidas Alcohólicas/sangre , Consumo de Bebidas Alcohólicas/efectos adversos , Masculino , Femenino , Macaca mulattaRESUMEN
Yellow fever virus (YFV) is endemic in >40 countries and causes viscerotropic disease with up to 20%-60% mortality. Successful live-attenuated yellow fever (YF) vaccines were developed in the mid-1930s, but their use is restricted or formally contraindicated in vulnerable populations including infants, the elderly, and people with compromised immune systems. In these studies, we describe the development of a next-generation hydrogen peroxide-inactivated YF vaccine and determine immune correlates of protection based on log neutralizing index (LNI) and neutralizing titer-50% (NT50) studies. In addition, we compare neutralizing antibody responses and protective efficacy of hydrogen peroxide-inactivated YF vaccine candidates to live-attenuated YFV-17D (YF-VAX) in a rhesus macaque model of viscerotropic YF. Our results indicate that an optimized, inactivated YF vaccine elicits protective antibody responses that prevent viral dissemination and lethal infection in rhesus macaques and may be a suitable alternative for vaccinating vulnerable populations who are not eligible to receive replicating live-attenuated YF vaccines.
Asunto(s)
Anticuerpos Neutralizantes , Anticuerpos Antivirales , Modelos Animales de Enfermedad , Peróxido de Hidrógeno , Macaca mulatta , Vacunas de Productos Inactivados , Vacuna contra la Fiebre Amarilla , Fiebre Amarilla , Virus de la Fiebre Amarilla , Animales , Vacunas de Productos Inactivados/inmunología , Vacuna contra la Fiebre Amarilla/inmunología , Fiebre Amarilla/prevención & control , Fiebre Amarilla/inmunología , Virus de la Fiebre Amarilla/inmunología , Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/inmunología , Vacunas Atenuadas/inmunología , Chlorocebus aethiops , Células Vero , HumanosRESUMEN
Pre-clinical research and development relies heavily upon translationally valid models of disease. A major difficulty in understanding the biology of, and developing treatments for, rare disease is the lack of animal models. It is important that these models not only recapitulate the presentation of the disease in humans, but also that they share functionally equivalent underlying genetic causes. Nonhuman primates share physiological, anatomical, and behavioral similarities with humans resulting from close evolutionary relationships and high genetic homology. As the post-genomic era develops and next generation sequencing allows for the resequencing and screening of large populations of research animals, naturally occurring genetic variation in nonhuman primates with clinically relevant phenotypes is regularly emerging. Here we review nonhuman primate models of multiple rare genetic diseases with a focus on the similarities and differences in manifestation and etiologies across species. We discuss how these models are being developed and how they can offer new tools and opportunities for researchers interested in exploring novel therapeutics for these and other genetic diseases. Modeling human genetic diseases in translationally relevant nonhuman primates presents new prospects for development of therapeutics and a better understanding of rare diseases. The post-genomic era offers the opportunity for the discovery and further development of more models like those discussed here.
Asunto(s)
Modelos Genéticos , Enfermedades Raras , Animales , Humanos , Enfermedades Raras/genética , Genómica , Secuenciación de Nucleótidos de Alto Rendimiento , Primates/genéticaRESUMEN
Passively administered monoclonal antibodies (mAbs) given before or after viral infection can prevent or blunt disease. Here, we examine the efficacy of aerosol mAb delivery to prevent infection and disease in rhesus macaques inoculated with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Delta variant via intranasal and intratracheal routes. SARS-CoV-2 human mAbs or a human mAb directed to respiratory syncytial virus (RSV) are nebulized and delivered using positive airflow via facemask to sedated macaques pre- and post-infection. Nebulized human mAbs are detectable in nasal, oropharyngeal, and bronchoalveolar lavage (BAL) samples. SARS-CoV-2 mAb treatment significantly reduces levels of SARS-CoV-2 viral RNA and infectious virus in the upper and lower respiratory tracts relative to controls. Reductions in lung and BAL virus levels correspond to reduced BAL inflammatory cytokines and lung pathology. Aerosolized antibody therapy for SARS-CoV-2 could be effective for reducing viral burden and limiting disease severity.