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Microvascular dysfunction and no-reflow are considered a major cause of secondary damage despite revascularization in acute ischemic stroke (AIS), ultimately affecting patient outcomes. We used quantitative PET-MRI imaging to characterize early microvascular damages in a preclinical non-human primate model mimicking endovascular mechanical thrombectomy (EVT). During occlusion, PET perfusion and MRI diffusion were used to measure ischemic and lesion core volumes respectively. Following revascularization, multiparametric PET-MRI included perfusion, diffusion, blood-brain barrier (BBB) permeability MRI, and 15 O-oxygen metabolism PET. Lesion growth on MRI was evaluated at one week, and the neurological score was assessed daily; a poor outcome was defined as a score>6 (0-normal, 60-death) after one week. Early after recanalization, the gold-standard PET ischemic threshold (<0.2 ​mL/min/g) identified post-EVT hypoperfusion in 67 ​% of the cases (14/21) located in the occlusion acute lesion. Acquired 110 ​min post-EVT, the area of MRI Tmax hypoperfusion was larger and even more frequent (18/20) and was also located within the acute lesion. Eight of the total cases (38 ​%) had a poor outcome, and all of them had no-reflow (7/8 MRI no-reflow and 6/8 ​PET no-reflow). Diffusion ADC alterations and post-EVT oxygen extraction fraction (OEF) values were significantly different in PET no-reflow cases compared to those without no-reflow, exhibiting an inverse correlation. Independently of no-reflow, long perfusion Tmax and post-EVT high BBB Ktrans in the lesion core were the hallmarks of poor outcome and infarct growth. This early quantitative imaging signature may predict infarct growth and poor outcome and help to identify neuroprotection targets., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Canet Soulas reports financial support was provided by French National Research Agency. Lucie Chalet reports a relationship with Olea Medical that includes: employment. Timothe Boutelier reports a relationship with Olea Medical that includes: employment. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025. Published by Elsevier Inc.)

Non-human primate studies are unique in translational research, especially in neurosciences where neuroimaging approaches are the preferred methods used for cross-species comparative neurosciences. In this regard, neuroimaging database development and sharing are encouraged to increase the number of subjects available to the community, while limiting the number of animals used in research. Here we present a simultaneous positron emission tomography (PET)/magnetic resonance (MR) dataset of 20 Macaca fascicularis images structured according to the Brain Imaging Data Structure standards. This database contains multiple MR imaging sequences (anatomical, diffusion and perfusion imaging notably), as well as PET perfusion and inflammation imaging using respectively [ 15 O]H 2 O and [ 11 C]PK11195 radiotracers. We describe the pipeline method to assemble baseline data from various cohorts and qualitatively assess all the data using signal-to-noise and contrast-to-noise ratios as well as the median of intensity and the pseudo-noise-equivalent-count rate (dynamic and at maximum) for PET data. Our study provides a detailed example for quality control integration in preclinical and translational PET/MR studies with the aim of increasing reproducibility. The PREMISE database is stored and available through the PRIME-DE consortium repository., (© 2023. The Author(s).)

SARS-CoV-2 emerged in December 2019 and quickly spread worldwide, continuously striking with an unpredictable evolution. Despite the success in vaccine production and mass vaccination programs, the situation is not still completely controlled, and therefore accessible second-generation vaccines are required to mitigate the pandemic. We previously developed an adjuvanted vaccine candidate coded PHH-1V, based on a heterodimer fusion protein comprising the RBD domain of two SARS-CoV-2 variants. Here, we report data on the efficacy, safety, and immunogenicity of PHH-1V in cynomolgus macaques. PHH-1V prime-boost vaccination induces high levels of RBD-specific IgG binding and neutralizing antibodies against several SARS-CoV-2 variants, as well as a balanced Th1/Th2 cellular immune response. Remarkably, PHH-1V vaccination prevents SARS-CoV-2 replication in the lower respiratory tract and significantly reduces viral load in the upper respiratory tract after an experimental infection. These results highlight the potential use of the PHH-1V vaccine in humans, currently undergoing Phase III clinical trials., Competing Interests: Authors indicated as “1” are employees of HIPRA, a private pharmaceutical company that develops and manufactures biological medicines such as vaccines. IrsiCaixa, UPF, Cynbiose, CIRI, VirNext, and CReSA have received financial support from HIPRA. Several patent applications have been filed by HIPRA Scientific S.L.U. and Laboratorios HIPRA, S.A. on different SARS-CoV-2 vaccine candidates and SARS-CoV-2 subunit vaccines, including the novel recombinant RBD fusion heterodimer PHH-1V. A.B., A.P., L.G., L.F., E.P., J.P., T.P., and C.G. are the inventors of these patent applications., (© 2023 The Authors.)

Reperfusion therapies in acute ischemic stroke have demonstrated their efficacy in promoting clinical recovery. However, ischemia/reperfusion injury and related inflammation remain a major challenge in patient clinical management. We evaluated the spatio-temporal evolution of inflammation using sequential clinical [ 11 C]PK11195 PET-MRI in a non-human primate (NHP) stroke model mimicking endovascular thrombectomy (EVT) with a neuroprotective cyclosporine A (CsA) treatment. The NHP underwent a 110-min transient endovascular middle cerebral artery occlusion. We acquired [ 11 C]PK11195 dynamic PET-MR imaging at baseline, 7 and 30 days after intervention. Individual voxel-wise analysis was performed thanks to a baseline scan database. We quantified [ 11 C]PK11195 in anatomical regions and in lesioned areas defined on per-occlusion MR diffusion-weighted imaging and perfusion [ 15 O 2 ]H 2 OPET imaging. [ 11 C]PK11195 parametric maps showed a clear uptake overlapping the lesion core at D7, which further increased at D30. Voxel-wise analysis identified individuals with significant inflammation at D30, with voxels located within the most severe diffusion reduction area during occlusion, mainly in the putamen. The quantitative analysis revealed that thalamic inflammation lasted until D30 and was significantly reduced in the CsA-treated group compared to the placebo. In conclusion, we showed that chronic inflammation matched ADC decrease at occlusion time, a region exposed to an initial burst of damage-associated molecular patterns, in an NHP stroke model mimicking EVT. We described secondary thalamic inflammation and the protective effect of CsA in this region. We propose that major ADC drop in the putamen during occlusion may identify individuals who could benefit from early personalized treatment targeting inflammation., (© 2023. The Author(s).)

Bacteriophages have been identified as a potential treatment option to treat lung infection in the context of antibiotic resistance. We performed a preclinical study to predict the efficacy of delivery of bacteriophages against Pseudomonas aeruginosa (PA) when administered via nebulization during mechanical ventilation (MV). We selected a mix of four anti-PA phages containing two Podoviridae and two Myoviridae, with a coverage of 87.8% (36/41) on an international PA reference panel. When administered via nebulization, a loss of 0.30-0.65 log of infective phage titers was measured. No difference between jet, ultrasonic and mesh nebulizers was observed in terms of loss of phage viability, but a higher output was measured with the mesh nebulizer. Interestingly, Myoviridae are significantly more sensitive to nebulization than Podoviridae since their long tail is much more prone to damage. Phage nebulization has been measured as compatible with humidified ventilation. Based on in vitro measurement, the lung deposition prediction of viable phage particles ranges from 6% to 26% of the phages loaded in the nebulizer. Further, 8% to 15% of lung deposition was measured by scintigraphy in three macaques. A phage dose of 1 × 10 9 PFU/mL nebulized by the mesh nebulizer during MV predicts an efficient dose in the lung against PA, comparable with the dose chosen to define the susceptibility of the strain.

Experimental autoimmune encephalitis (EAE) is a well-recognized model for the study of human acquired demyelinating diseases (ADD), a group of inflammatory disorders of the central nervous system (CNS) characterized by inflammation, myelin loss, and neurological impairment of variable severity. In rodents, EAE is typically induced by active immunization with a combination of myelin-derived antigen and a strong adjuvant as complete Freund's adjuvant (CFA), containing components of the mycobacterial wall, while myelin antigen alone or associated with other bacterial components, as lipopolysaccharides (LPS), often fails to induce EAE. In contrast to this, EAE can be efficiently induced in non-human primates by immunization with the recombinant human myelin oligodendrocyte glycoprotein (rhMOG), produced in Escherichia coli (E. coli), purified and formulated with incomplete Freund's adjuvant (IFA), which lacks bacterial elements. Here, we provide evidence indicating how trace amounts of bacterial contaminants within rhMOG may influence the course and severity of EAE in the cynomolgus macaque immunized with rhMOG/IFA. The residual amount of E. coli contaminants, as detected with mass spectrometry within rhMOG protein stocks, were found to significantly modulate the severity of clinical, radiological, and histologic hallmarks of EAE in macaques. Indeed, animals receiving the purest rhMOG showed milder disease severity, increased numbers of remissions, and reduced brain damage. Histologically, these animals presented a wider diversity of lesion types, including changes in normal-appearing white matter and prephagocytic lesions. Non-human primates EAE model with milder histologic lesions reflect more accurately ADD and permits to study of the pathogenesis of disease initiation and progression., (© 2021. The Author(s), under exclusive licence to United States and Canadian Academy of Pathology.)

Background: Non-human primate (NHP) could be an interesting model for osteoarthritis (OA) longitudinal studies but standard medical imaging protocols are not able to acquire sufficiently high-resolution images to depict the thinner cartilage (compared to human) in an in vivo context. The aim of this study was thus to develop and validate the acquisition protocols for knee joint examination of NHP using magnetic resonance imaging (MRI) at 1.5 T and X-ray micro-computed tomography arthrography (µCTA)., Methods: The first phase of the study focused on developing dedicated in vivo HR-MRI and µCTA protocols for simultaneous acquisitions of both knee joints on NHP. For MR, a dedicated two-channel receiver array coil and acquisition sequence were developed on a 1.5 T Siemens Sonata system and tuned to respect safety issues and reasonable examination time. For µCTA, an experimental setup was devised so as to fulfill similar requirements. The two imaging protocols were used during a longitudinal study so as to confirm that repeated injections of loxaglic acid (contrast agent used for µCTA) didn't induce any bias in cartilage assessment and to compare segmentation results from the two modalities. Lateral and medial cartilage tibial plateaus were assessed using a common image processing protocol leading to a 3D estimation of the cartilage thickness., Results: From HR-MRI and µCTA images, thickness distributions were extracted allowing for proper evaluation of knee cartilage thickness of the primates. Results obtained in vivo indicated that the µCTA protocol did not induce any bias in the measured cartilage parameters and moreover, segmentation results obtained from the two imaging modalities were consistent., Conclusions: MR and µCTA are valuable imaging tools for the morphological evaluation of cartilage in NHP models which in turn can be used for OA studies., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/qims-20-116). Dr. EC reports grants from European Commission - Eurostars co-funding, during the conduct of the study; other from Voxcan, from European Commission or French Research Ministry, personal fees from National Veterinary School of Lyon - VetAgro-Sup, outside the submitted work; and Voxcan is a CRO who sells preclinical studies in the domain of osteoarthritis to its clients. Drs. KTVK and OB report grants from Universite Lyon 1, during the conduct of the study. Drs. FT and HC report grants from European Commission - Eurostars co-funding, during the conduct of the study. Dr. LM reports grants from European Commission - Eurostars co-funding, during the conduct of the study; other from Voxcan, from European Commission or French Research Ministry, outside the submitted work. The other authors have no conflicts of interest to declare., (2021 Quantitative Imaging in Medicine and Surgery. All rights reserved.)

Atherosclerosis is a chronic systemic inflammatory disease, inducing cardiovascular and cerebrovascular acute events. A role of neuroinflammation is suspected, but not yet investigated in the gyrencephalic brain and the related activity at blood-brain interfaces is unknown. A non-human primate model of advanced atherosclerosis was first established using longitudinal blood samples, multimodal imaging and gene analysis in aged animals. Non-human primate carotid lesions were compared with human carotid endarterectomy samples. During the whole-body imaging session, imaging of neuroinflammation and choroid plexus function was performed. Advanced plaques were present in multiple sites, premature deaths occurred and downstream lesions (myocardial fibrosis, lacunar stroke) were present in this model. Vascular lesions were similar to in humans: high plaque activity on PET and MRI imaging and systemic inflammation (high plasma C-reactive protein levels: 42 ± 14 µg/ml). We also found the same gene association (metabolic, inflammatory and anti-inflammatory markers) as in patients with similar histological features. Metabolic imaging localized abnormal brain glucose metabolism in the frontal cortex. It corresponded to cortical neuro-inflammation (PET imaging) that correlated with C-reactive protein level. Multimodal imaging also revealed pronounced choroid plexus function impairment in aging atherosclerotic non-human primates. In conclusion, multimodal whole-body inflammation exploration at the vascular level and blood-brain interfaces identified high-risk aging atherosclerosis. These results open the way for systemic and central inflammation targeting in atherosclerosis in the new era of immunotherapy., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Stroke is a devastating disease. Endovascular mechanical thrombectomy is dramatically changing the management of acute ischemic stroke, raising new challenges regarding brain outcome and opening up new avenues for brain protection. In this context, relevant experiment models are required for testing new therapies and addressing important questions about infarct progression despite successful recanalization, reversibility of ischemic lesions, blood-brain barrier disruption and reperfusion damage. Here, we developed a minimally invasive non-human primate model of cerebral ischemia ( Macaca fascicularis ) based on an endovascular transient occlusion and recanalization of the middle cerebral artery (MCA). We evaluated per-occlusion and post-recanalization impairment on PET-MRI, in addition to acute and chronic neuro-functional assessment. Voxel-based analyses between per-occlusion PET-MRI and day-7 MRI showed two different patterns of lesion evolution: "symptomatic salvaged tissue" (SST) and "asymptomatic infarcted tissue" (AIT). Extended SST was present in all cases. AIT, remote from the area at risk, represented 45% of the final lesion. This model also expresses both worsening of fine motor skills and dysexecutive behavior over the chronic post-stroke period, a result in agreement with cortical-subcortical lesions. We thus fully characterized an original translational model of ischemia-reperfusion damage after stroke, with consistent ischemia time, and thrombus retrieval for effective recanalization.

Articular cartilage is built by chondrocytes which become less active with age. This declining function of the chondrocytes, together with the avascular nature of the cartilage, impedes the spontaneous healing of chondral injuries. These lesions can progress to more serious degenerative articular conditions as in the case of osteoarthritis. As no efficient cure for cartilage lesions exist yet, cartilage tissue engineering has emerged as a promising method aiming at repairing joint defects and restoring articular function. In the present work, we investigated if a new self-assembling peptide (referred as IEIK13), combined with articular chondrocytes treated with a chondrogenic cocktail (BMP-2, insulin and T3, designated BIT) could be efficient to restore full-thickness cartilage defects induced in the femoral condyles of a non-human primate model, the cynomolgus monkey. First, in vitro molecular studies indicated that IEIK13 was efficient to support production of cartilage by monkey articular chondrocytes treated with BIT. In vivo, cartilage implant integration was monitored non-invasively by contrast-enhanced micro-computed tomography, and then by post-mortem histological analysis and immunohistochemical staining of the condyles collected 3 months post-implantation. Our results revealed that the full-thickness cartilage injuries treated with either IEIK13 implants loaded with or devoid of chondrocytes showed similar cartilage-characteristic regeneration. This pilot study demonstrates that IEIK13 can be used as a valuable scaffold to support the in vitro activity of articular chondrocytes and the repair of articular cartilage defects, when implanted alone or with chondrocytes.

In an acute ischaemic stroke, understanding the dynamics of blood-brain barrier injury is of particular importance for the prevention of symptomatic haemorrhagic transformation. However, the available techniques assessing blood-brain barrier permeability are not quantitative and are little used in the context of acute reperfusion therapy. Nanoparticles cross the healthy or impaired blood-brain barrier through combined passive and active processes. Imaging and quantifying their transfer rate could better characterize blood-brain barrier damage and refine the delivery of neuroprotective agents. We previously developed an original endovascular stroke model of acute ischaemic stroke treated by mechanical thrombectomy followed by positron emission tomography-magnetic resonance imaging. Cerebral capillary permeability was quantified for two molecule sizes: small clinical gadolinium Gd-DOTA (<1 nm) and AGuIX ® nanoparticles (∼5 nm) used for brain theranostics. On dynamic contrast-enhanced magnetic resonance imaging, the baseline transfer constant K trans was 0.94 [0.48, 1.72] and 0.16 [0.08, 0.33] ×10 -3  min -1 , respectively, in the normal brain parenchyma, consistent with their respective sizes, and 1.90 [1.23, 3.95] and 2.86 [1.39, 4.52] ×10 -3  min -1 in choroid plexus, confirming higher permeability than brain parenchyma. At early reperfusion, K trans for both Gd-DOTA and AGuIX ® nanoparticles was significantly higher within the ischaemic area compared to the contralateral hemisphere; 2.23 [1.17, 4.13] and 0.82 [0.46, 1.87] ×10 -3  min -1 for Gd-DOTA and AGuIX ® nanoparticles, respectively. With AGuIX ® nanoparticles, K trans also increased within the ischaemic growth areas, suggesting added value for AGuIX ® . Finally, K trans was significantly lower in both the lesion and the choroid plexus in a drug-treated group (ciclosporin A, n  = 7) compared to placebo ( n  = 5). K trans quantification with AGuIX ® nanoparticles can monitor early blood-brain barrier damage and treatment effect in ischaemic stroke after reperfusion., (© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain.)

The properties of motor cortical local field potential (LFP) beta oscillations have been extensively studied. Their relationship to the local neuronal spiking activity was also addressed. Yet, whether there is an intrinsic relationship between the amplitude of beta oscillations and the firing rate of individual neurons remains controversial. Some studies suggest a mapping of spike rate onto beta amplitude, while others find no systematic relationship. To help resolve this controversy, we quantified in macaque motor cortex the correlation between beta amplitude and neuronal spike count during visuomotor behavior. First, in an analysis termed "task-related correlation", single-trial data obtained across all trial epochs were included. These correlations were significant in up to 32% of cases and often strong. However, a trial-shuffling control analysis recombining beta amplitudes and spike counts from different trials revealed these task-related correlations to reflect systematic, yet independent, modulations of the 2 signals with the task. Second, in an analysis termed "trial-by-trial correlation", only data from fixed trial epochs were included, and correlations were calculated across trials. Trial-by-trial correlations were weak and rarely significant. We conclude that there is no intrinsic relationship between the firing rate of individual neurons and LFP beta oscillation amplitude in macaque motor cortex., (© The Author(s) 2020. Published by Oxford University Press.)

Background: The brain bioavailability of novel small molecules developed to address central nervous system disease is classically documented through ex vivo or in vivo analyses conducted in rodent models. Data acquired in rodent models are, however, not easily transferrable to human as the pharmacokinetic and pharmacodynamics profiles of the species are quite different., Methods: Using drugs selected for their differential transport across the blood-brain barrier, we here demonstrate the feasibility of brain microdialysis in normal vigil macaque monkey by measuring brain extracellular fluid bioavailability of carbamazepine, digoxin, oxycodone, and quinidine., Results: All drugs, but digoxin, were found in dialysate samples. Drugs that are substrate of P-glycoprotein show a difference of bioavailability or brain pharmacokinetic parameters between rodents and primates., Conclusion: Data suggest that brain microdialysis in vigil macaque monkey, the species of choice for classic pharmacokinetic/pharmacodynamics studies could help predicting human brain bioavailability of a small molecule depending on the protein involved in the efflux transport from the brain., Competing Interests: None.

Periodontal furcation defects are usually addressed by the placement of a physical barrier which may limit the regenerative potential of periodontal wounds. This study morphometrically quantified the regenerative effect of brain-derived neurotrophic factor (BDNF) in furcation defects in a non-human primate model. Grade II furcation defects (with and without induced inflammation prior to surgery) were created on the first and second molars of eight non-human primates. Defects were treated with open flap debridement and subsequently filled with either: Group A; BDNF (500 µg mL -1 ) in high-molecular weight-hyaluronic acid (HMW-HA), Group B; BDNF (50 µg mL -1 ) in HMW-HA, Group C; HMW-HA acid only, Group D; unfilled defect, or Group E; BDNF (500 µg mL -1 ) in saline. Periodontal wound healing was observed every 2 weeks by computed-tomography. At 11 weeks all animals were sacrificed and maxillary and mandibular block biopsies were referred for nondecalcified histology. Linear measurements of new cementum (cellular and acellular) and periodontal ligament (PDL) formation were performed. Computerized-tomography reconstruction and software quantification demonstrated successful bone fill for all groups. However, histometric assessment demonstrated significantly higher level of total periodontal regeneration for the 500 µg mL -1 BDNF HMW-HA relative to all other groups. No significant differences in cementogenesis were observed among groups. Significantly higher acellular cementum formation was observed for sites where inflammation was not induced prior to surgical procedures. While all groups experienced similar bone fill and cementogenesis, the 500 µg mL -1 BDNF HMW-HA appeared to most effectively repair PDL (minimum increase of ∼22% relative to all groups; over 200% relative to unfilled defects). © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1611-1617, 2018., (© 2017 Wiley Periodicals, Inc.)

In this article, we report the safety evaluation of gadolinium-based nanoparticles in nonhuman primates (NHP) in the context of magnetic resonance imaging (MRI) studies in atherosclerosis bearing animals and healthy controls. In healthy NHP, the pharmacokinetics and toxicity profiles demonstrated the absence of dose, time, and sex-effects, as well as a suitable tolerance of intravenous administration of the nanoparticles. We investigated their imaging properties for arterial plaque imaging in a standard diet or a high cholesterol diet NHP, and compared their characteristics with clinically applied Gd-chelate. This preliminary investigation reports the efficient and safe imaging of atherosclerotic plaques., Competing Interests: F.L. and T.O. have to disclose the patent WO2011/135101. The patent protects the nanoparticles described in this publication: AGuIX®.

Brain bioavailability of drugs developed to address central nervous system diseases is classically documented through cerebrospinal fluid collected in normal animals, i.e., through an approximation as there are fundamental differences between cerebrospinal fluid and tissue contents. The fact that disease might affect brain availability of drugs is almost never considered at this stage although several conditions are associated with blood-brain barrier damage. Building upon our expertise in Parkinson's disease translational research, the present study addressed this gap comparing plasma and cerebrospinal fluid bioavailability of l-3,4-dihydroxyphenylalanine, carbamazepine, quinidine, lovastatin, and simvastatin, in healthy and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated macaques, the gold standard model of Parkinson's disease. The drugs were selected based upon their differential transport across the blood-brain barrier. Interestingly, brain bioavailability of quinidine was decreased while others were unaffected. Pharmacokinetics and pharmacodynamics experiments of drugs addressing Parkinson's disease might thus be performed in healthy animals unless the drugs are known to interact with the organic cation transporter., (© 2016 Wiley Periodicals, Inc.)

There is imperious need for efficient therapies against ubiquitous and life-threatening respiratory viruses, foremost among them being the human respiratory syncytial virus (hRSV). Several research groups who performed functional screens for broad-spectrum antivirals identified compounds targeting the de novo pyrimidine biosynthesis pathway. Despite their strong antiviral activity in vitro, whether such antimetabolites are effective in vivo remains highly controversial. Here, we evaluated two potent pyrimidine biosynthesis inhibitors developed in our laboratory, IPPA17-A04 and GAC50, in a model of mild hRSV-infection in cynomolgus macaques. In this model, hRSV replication is restricted to the epithelium of the upper respiratory tract, and is compatible with a topical treatment by intranasal sprays. The local administration of palivizumab, a neutralizing anti-hRSV antibody used in clinics, significantly reduced virus replication. In contrast, pyrimidine biosynthesis inhibitors did not show any inhibitory effect on hRSV growth when delivered topically as experimented in our model. Our results should help to better define the potential applications of this class of antimetabolites in the treatment of viral infections., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Staphylococcus aureus is well adapted to the human host. Evasion of the host phagocyte response is critical for successful infection. The staphylococcal bicomponent pore-forming toxins Panton-Valentine leukocidin LukSF-PV (PVL) and γ-hemolysin CB (HlgCB) target human phagocytes through interaction with the complement receptors C5aR1 and C5aR2. Currently, the apparent redundancy of both toxins cannot be adequately addressed in experimental models of infection because mice are resistant to PVL and HlgCB. The molecular basis for species specificity of the two toxins in animal models is not completely understood. We show that PVL and HlgCB feature distinct activity toward neutrophils of different mammalian species, where activity of PVL is found to be restricted to fewer species than that of HlgCB. Overexpression of various mammalian C5a receptors in HEK cells confirms that cytotoxicity toward neutrophils is driven by species-specific interactions of the toxins with C5aR1. By taking advantage of the species-specific engagement of the toxins with their receptors, we demonstrate that PVL and HlgCB differentially interact with human C5aR1 and C5aR2. In addition, binding studies illustrate that different parts of the receptor are involved in the initial binding of the toxin and the subsequent formation of lytic pores. These findings allow a better understanding of the molecular mechanism of pore formation. Finally, we show that the toxicity of PVL, but not of HlgCB, is neutralized by various C5aR1 antagonists. This study offers directions for the development of improved preclinical models for infection, as well as for the design of drugs antagonizing leukocidin toxicity., (Copyright © 2015 by The American Association of Immunologists, Inc.)

Iron homeostasis is essential for the integrity of brain monoaminergic functions and its deregulation might be involved in neurological movement disorders such as the restless legs syndrome (RLS). Although iron metabolism breakdown concomitantly appears with monoaminergic system dysfunction in iron-deficient rodents and in RLS patients, the direct consequences of peripheral iron deficiency in the central nervous system (CNS) of non-human primates have received little attention. Here, we evaluated the peripheral iron-depletion impact on brain monoamine levels in macaque monkeys. After documenting circadian variations of iron and iron-related proteins (hemoglobin, ferritin and transferrin) in both serum and cerebrospinal fluid (CSF) of normal macaques, repeated blood withdrawals (RBW) were used to reduce peripheral iron-related parameter levels. Decreased serum iron levels were paradoxically associated with increased CSF iron concentrations. Despite limited consequences on tissue monoamine contents (dopamine - DA, 3, 4-dihydroxyphenylacetic acid - DOPAC, homovanillic acid, L-3, 4-dihydroxyphenylalanine - L-DOPA, 5-8 hydroxytryptamine - 5-HT, 5-hydroxyindoleacetic acid - 5-HIAA and noradrenaline) measured with post-mortem chromatography, we found distinct and region-dependent relationships of these tissue concentrations with CSF iron and/or serum iron and/or blood hemoglobin. Additionally, striatal extracellular DA, DOPAC and 5-HIAA levels evaluated by in vivo microdialysis showed a substantial increase, suggesting an overall increase in both DA and 5-HT tones. Finally, a trending increase in general locomotor activity, measured by actimetry, was observed in the most serum iron-depleted macaques. Taken together, our data are compatible with an increase in nigrostriatal DAergic function in the event of iron deficiency and point to a specific alteration of the 5-HT/DA interaction in the CNS that is possibly involved in the etiology of RLS., (Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.)

There is no large-scale therapy available against human respiratory syncytial virus (hRSV), a major pathogen responsible for acute respiratory diseases. Macaques represent an interesting animal model to evaluate potential treatments because of their genetic, anatomical and immunological proximity with humans. However, the parameters that influence hRSV growth and control in this model are still poorly understood. We have documented in the following study the influence of age as well as repeated infections on the virological, clinical and immunological parameters of this animal model. Following intranasal inoculation, hRSV replicated in the upper respiratory tract for less than 15 days with no clinical signs regardless of age. Interestingly, we observed the induction of a local immune response at the nasal mucosa as assessed by expression profiles of inflammatory and IFN-stimulated genes. Animals also developed specific antibodies and were immune to reinfection. Thus, we showed that even in infant macaques, intranasal hRSV infection induced both local and systemic immune responses to efficiently control the virus., (© 2015 The Authors.)

Myocardial infarction is frequently developed in canine and porcine models but exceptionally in non-human primates. The aim of this study was to develop a minimally invasive myocardial ischemic/reperfusion model in the monkey intended to be combined with imaging techniques, in particular myocardial contrast echocardiography (MCE). A balloon-tipped catheter was advanced via the femoral artery into the left anterior descending artery (LAD) under fluoroscopic guidance in ten anaesthetized male rhesus monkeys (Macaca mulatta). The balloon was inflated to completely occlude the vessel. Coronary angiography (CA) was performed to control the reality of the LAD occlusion/reperfusion. The ischemia period was followed by 3-6 h of reperfusion. Myocardial perfusion was evaluated during ischemia and at reperfusion by MCE using a novel ultrasound contrast agent (BR38). Occlusion was successfully induced during 18-50 min in nine out of the ten evaluated monkeys. ST segment elevation indicated myocardial ischemia. MCE showed complete transmural arrest of myocardial blood flow during the ischemia period and no persistent microvascular perfusion defects during reperfusion. A minimally invasive closed-chest model was successfully developed for creating myocardial ischemia in the rhesus monkey (Macaca mulatta). This technique could have an important role in mimicking acute coronary syndrome under physiologically and ethically-acceptable conditions. MCE provides non-invasively information on myocardial perfusion status, information not available from CA.