Tissue Trafficking Kinetics of Rhesus Macaque Natural Killer Cells Measured by Serial Intravascular Staining

The in vivo tissue distribution and trafficking patterns of natural killer (NK) cells remain understudied. Animal models can help bridge the gap, and rhesus macaque (RM) primates faithfully recapitulate key elements of human NK cell biology. Here, we profiled the tissue distribution and localization patterns of three NK cell subsets across various RM tissues. We utilized serial intravascular staining (SIVS) to investigate the tissue trafficking kinetics at steady state and during recovery from CD16 depletion. We found that at steady state, CD16+ NK cells were selectively retained in the vasculature while CD56+ NK cells had a shorter residence time in peripheral blood. We also found that different subsets of NK cells had distinct trafficking kinetics to and from the lymph node as well as other lymphoid and non-lymphoid tissues. Lastly, we found that following administration of CD16-depleting antibody, CD16+ NK cells and their putative precursors retained a high proportion of continuously circulating cells, suggesting that regeneration of the CD16 NK compartment may take place in peripheral blood or the perivascular compartments of tissues.

Immunogenicity of a Candidate DTacP-sIPV Combined Vaccine and Its Protection Efficacy against Pertussis in a Rhesus Macaque Model

The research and development of a pertussis-combined vaccine using a novel inactivated poliovirus vaccine made from the Sabin strain (sIPV) is of great significance in the polio eradication project and to address the recent resurge in pertussis. In the present study, we compared the immunogenicity and efficacy of a candidate DTacP-sIPV with those of a commercial DTacP-wIPV/Hib, DTaP/Hib, pertussis vaccine, and aluminum hydroxide adjuvant control in the rhesus macaque model with a 0-, 1-, and 2-month immunization schedule. At day 28 after the third dose, rhesus macaques were challenged with aerosol pertussis and the antibody and cellular response together with pertussis clinical symptoms were determined. The production of anti-PT, anti-PRN, anti-FHA, anti-DT, anti-TT, and polio type I, II, III antibodies was induced by the candidate DTacP-sIPV, which was as potent as commercial vaccines. In comparison with the control group that showed typical pertussis symptoms of humans after the aerosol challenge, the DTacP-sIPV group did not exhibit obvious clinical pertussis symptoms and had higher neutralization titers of anti-PT, anti-PRN, and anti-FHA. In conclusion, the DTacP-sIPV vaccine was able to induce immunity in rhesus macaques to prevent pertussis infections after immunization. The developed vaccine was as efficient as other commercial vaccines.

PDE4D And HCN1 Ultrastructure In Rhesus Macaque Entorhinal Cortex: Relevance For Aging And Alzheimer's Disease

Tau pathology emerges in a distinct spatial and temporal pattern in Alzheimer’s Disease (AD). Anatomical studies in AD subjects and rhesus macaques show earliest signs of tau pathology in the stellate cell islands in entorhinal cortex (ERC) layer II. However, the molecular mechanisms that confer vulnerability to ERC layer II cells early in AD is unknown. cAMP-PKA magnification of calcium release has been seen in prefrontal cortex, associated with HCN channel opening to dynamically regulate synaptic strength. This process is regulated by phosphodiesterases (PDE), regulation that is lost with age. The current study examined whether this “signature of flexibility” could also be seen in layer II ERC, underlying vulnerability to tau pathology with aging. We used high-spatial resolution immunoEM to localize PDE4D and HCN1 in young rhesus macaque (7-10y) ERC layer II. Our results suggest that PDE4D was concentrated on the SER-spine apparatus and in postsynaptic density, and HCN1 expressed in the membrane near excitatory synapses in dendritic spines. Within dendritic shafts, PDE4D labeling was observed along microtubules and near mitochondria, whereas HCN1 was organized in discrete clusters along the plasma membrane. These data suggest that PDE4D is optimally positioned to modulate cAMP microdomains and control calcium extrusion from the SER. HCN1 channels are localized in subcompartments to facilitate dynamic physiological representation of sensory experience and visual space governed by cAMP-PKA signaling. The anatomical patterns in ERC layer II corroborate our findings in vulnerable glutamatergic circuits in prefrontal cortex, suggesting conserved molecular features in association cortices most susceptible in AD.

Alteration of the gut microbiota in rhesus monkey with spontaneous osteoarthritis

Background The spontaneous osteoarthritis (OA) in rhesus macaque is similar to OA in human, which maintains an upright body posture and shows very similar biomechanical properties of bones to humans. At present, there is no good treatment for OA. This study aims to explore relationship between OA and intestinal microbiota, and provide a reference for the treatment of clinical OA. Results We collected colonic contents of the 20 rhesus macaque (6–15 years old, female) for intestinal microbiota analysis by metagenomics sequencing, of which 10 were spontaneous OA monkeys and 10 were normal monkeys. Our results showed the diversity of gut microbiota in monkeys with OA was decreased compared to the normal monkeys (p = 0.16). Mollicutes, Tenericutes, Coprobacillus and Faecalitalea may be biomarkers for the monkeys of OA. Lactobacillus found significantly increased in OA monkeys. Prevotella and Ruminococcus were higher in the normal group than OA group. Zinc/manganese transport system permease protein (p = 0.0011) and Cyclopropane-fatty-acyl-phospholipid synthase (p = 0.0012) are a microbiota metabolic pathway related to cartilage production. Conclusions Our results indicate that the diversity and composition of intestinal microbiota in monkeys with OA are different compared to the normal monkeys. we have found microbes that may be a biomarker for the diagnosis of osteoarthritis. Functional analysis of the microbiota also predicts cartilage damage in the monkeys with osteoarthritis. Non-human primates are closely related to humans, so this study can provide a reference for the development of drugs for the treatment of OA.

Hierarchical organization of rhesus macaque behavior

Primatologists, psychologists and neuroscientists have long hypothesized that primate behavior is highly structured. However, fully delineating that structure has been impossible due to the difficulties of precision behavioral tracking. Here we analyzed a dataset consisting of continuous measures of the 3D position of fifteen body landmarks from two male rhesus macaques (Macaca mulatta) performing three different tasks in a large unrestrained environment over many hours. Using an unsupervised embedding approach on the tracked joints, we identified commonly repeated pose patterns, which we call postures. We found that macaques' behavior is characterized by 49 distinct identifiable postures, lasting an average of 0.6 seconds each. We found evidence that behavior is hierarchically organized, in that transitions between poses tend to occur within larger modules, which correspond to intuitively identifiably actions; these actions are in turn organized hierarchically. Our behavioral decomposition allows us to identify universal (cross-individual and cross-task) and unique (specific to each individual and task) principles of behavior. These results demonstrate the hierarchical nature of primate behavior and provide a method for the automated "ethogramming" of primate behavior.

Pilot Study Assessing the Impact of Intrathecal Administration of Variants AAV-PHP.B and AAV-PHP.eB on Brain Transduction in Adult Rhesus Macaques

Adeno-associated virus (AAV) vectors are increasingly used as an effective and safe approach to deliver genetic material to the central nervous system (CNS). The AAV9-derived variants, AAV-PHP. B and AAV-PHP.eB, reportedly broadly transduce cells throughout the CNS compared to the original serotype 9, AAV9. As non-human primate data are scarce, we here evaluated the CNS transduction efficiencies after lumbar intrathecal bolus delivery of identical doses of either AAV-PHP. B:CAG-EGFP or AAV-PHP. eB:CAG-EGFP in rhesus macaque monkeys. AAV-PHP.eB achieved a more efficient and widespread CNS transduction compared to AAV-PHP.B. We report a strong neuronal and oligodendroglial tropism for both variants in the putamen and in the hippocampus. This proof-of-concept experiment highlights the potential value of intrathecal infusions of AAV-PHP.eB to distribute genetic material in the CNS with cell-type specificity and introduces a new opportunity to model brain diseases in rhesus macaque monkeys and further develop gene therapies targeting the CNS in humans.