Elimination of Schistosoma mansoni Adult Worms by Rhesus Macaques: Basis for a Therapeutic Vaccine?

Infection with blood-dwelling schistosome worms is a major cause of human disease in many tropical countries. Despite intensive efforts a vaccine has proved elusive, not least because the chronic nature of the infection provides few pointers for vaccine development. The rhesus macaque appears unique among animal models in that adult worms establish but are eventually lost. We investigated whether this was due to pathological or immunological causes by monitoring the fate of a schistosome infection, and were able to rule out escape of worms from the portal system as a result of egg-induced vascular shunts. A substantial worm population established in all animals but there was a wide variation in the numbers recovered at 18 weeks. We observed a strong inverse association between the rapidity and intensity of the IgG response and worm burden. Rather than an acute lethal attack, immune-mediated elimination of worms appeared to be a prolonged process directed against vital components of exposed surfaces, causing worms to starve to death. We suggest that if the mechanisms deployed by the rhesus macaque could be replicated in humans by administration of key recombinant antigens, they would form the basis for a vaccine with both prophylactic and therapeutic properties

Reference Intervals and Percentiles for Hematologic and Serum Biochemical Values in Captive Bred Rhesus (Macaca mulatta) and Cynomolgus Macaques (Macaca fascicularis)

Several physiological characteristics and housing conditions are known to affect hematologic and serum biochemical values in macaques. However, the studies that have been conducted either report values calculated based on a small number of animals, were designed specifically to document the effect of a particular condition on the normal range of hematologic and serum biochemical values, or used parametric assumptions to calculate hematologic and serum biochemical reference intervals. We conducted a retrospective longitudinal cohort study to estimate reference intervals for hematologic and serum biochemical values in clinically healthy macaques based on observed percentiles without parametric assumptions. Data were obtained as part of the Biomedical Primate Research Centre (Rijswijk, The Netherlands) health monitoring program between 2018 and 2021. In total, 4009 blood samples from 1475 macaques were analyzed with a maximum of one repeat per year per animal. Data were established by species, gender, age, weight-for-height indices, pregnancy, sedation protocol, and housing conditions. Most of the parameters profoundly affected just some hematologic and serum biochemical values. A significant glucose difference was observed between the ketamine and ketamine-medetomidine sedation protocols. The results emphasize the importance of establishing uniform experimental groups with validated animal husbandry and housing conditions to improve the reproducibility of the experiments

Tolerant and intolerant macaques show different levels of structural complexity in their vocal communication

International audienceWe tested the social complexity hypothesis which posits that animals living in complex social environments should use complex communication systems. We focused on two components of vocal complexity: diversity (number of categories of calls) and flexibility (degree of gradation between categories of calls). We compared the acoustic structure of vocal signals in groups of macaques belonging to four species with varying levels of uncertainty (i.e. complexity) in social tolerance (the higher the degree of tolerance, the higher the degree of uncertainty): two intolerant species, Japanese and rhesus macaques, and two tolerant species, Tonkean and crested macaques. We recorded the vocalizations emitted by adult females in affiliative, agonistic and neutral contexts. We analysed several acoustic variables: call duration, entropy, time and frequency energy quantiles. The results showed that tolerant macaques displayed higher levels of vocal diversity and flexibility than intolerant macaques in situations with a greater number of options and consequences, i.e. in agonistic and affiliative contexts. We found no significant differences between tolerant and intolerant macaques in the neutral context where individuals are not directly involved in social interaction. This shows that species experiencing more uncertain social interactions displayed greater vocal diversity and flexibility, which supports the social complexity hypothesis

Longitudinal positron emission tomography and postmortem analysis reveals widespread neuroinflammation in SARS-CoV-2 infected rhesus macaques

BACKGROUND: Coronavirus disease 2019 (COVID-19) patients initially develop respiratory symptoms, but they may also suffer from neurological symptoms. People with long-lasting effects after acute infections with severe respiratory syndrome coronavirus 2 (SARS-CoV-2), i.e., post-COVID syndrome or long COVID, may experience a variety of neurological manifestations. Although we do not fully understand how SARS-CoV-2 affects the brain, neuroinflammation likely plays a role. METHODS: To investigate neuroinflammatory processes longitudinally after SARS-CoV-2 infection, four experimentally SARS-CoV-2 infected rhesus macaques were monitored for 7 weeks with 18-kDa translocator protein (TSPO) positron emission tomography (PET) using [18F]DPA714, together with computed tomography (CT). The baseline scan was compared to weekly PET-CTs obtained post-infection (pi). Brain tissue was collected following euthanasia (50 days pi) to correlate the PET signal with TSPO expression, and glial and endothelial cell markers. Expression of these markers was compared to brain tissue from uninfected animals of comparable age, allowing the examination of the contribution of these cells to the neuroinflammatory response following SARS-CoV-2 infection. RESULTS: TSPO PET revealed an increased tracer uptake throughout the brain of all infected animals already from the first scan obtained post-infection (day 2), which increased to approximately twofold until day 30 pi. Postmortem immunohistochemical analysis of the hippocampus and pons showed TSPO expression in cells expressing ionized calcium-binding adaptor molecule 1 (IBA1), glial fibrillary acidic protein (GFAP), and collagen IV. In the hippocampus of SARS-CoV-2 infected animals the TSPO+ area and number of TSPO+ cells were significantly increased compared to control animals. This increase was not cell type specific, since both the number of IBA1+TSPO+ and GFAP+TSPO+ cells was increased, as well as the TSPO+ area within collagen IV+ blood vessels. CONCLUSIONS: This study manifests [18F]DPA714 as a powerful radiotracer to visualize SARS-CoV-2 induced neuroinflammation. The increased uptake of [18F]DPA714 over time implies an active neuroinflammatory response following SARS-CoV-2 infection. This inflammatory signal coincides with an increased number of TSPO expressing cells, including glial and endothelial cells, suggesting neuroinflammation and vascular dysregulation. These results demonstrate the long-term neuroinflammatory response following a mild SARS-CoV-2 infection, which potentially precedes long-lasting neurological symptoms

Medical imaging of pulmonary disease in SARS-CoV-2-exposed non-human primates

Chest X-ray (CXR), computed tomography (CT), and positron emission tomography-computed tomography (PET-CT) are noninvasive imaging techniques widely used in human and veterinary pulmonary research and medicine. These techniques have recently been applied in studies of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-exposed non-human primates (NHPs) to complement virological assessments with meaningful translational readouts of lung disease. Our review of the literature indicates that medical imaging of SARS-CoV-2-exposed NHPs enables high-resolution qualitative and quantitative characterization of disease otherwise clinically invisible and potentially provides user-independent and unbiased evaluation of medical countermeasures (MCMs). However, we also found high variability in image acquisition and analysis protocols among studies. These findings uncover an urgent need to improve standardization and ensure direct comparability across studies

Correction:How the COVID-19 pandemic highlights the necessity of animal research (vol 30, pg R1014, 2020)

(Current Biology 30, R1014–R1018; September 21, 2020) As a result of an author oversight in the originally published version of this article, a number of errors were introduced in the author list and affiliations. First, the middle initials were omitted from the names of several authors. Second, the surname of Dr. van Dam was mistakenly written as “Dam.” Third, the first name of author Bernhard Englitz was misspelled as “Bernard” and the surname of author B.J.A. Pollux was misspelled as “Pullox.” Finally, Dr. Keijer's first name was abbreviated rather than written in full. These errors, as well as various errors in the author affiliations, have now been corrected online

A Comparative Study of Chest CT With Lung Ultrasound After SARS-CoV-2 Infection in the Assessment of Pulmonary Lesions in Rhesus Monkeys (Macaca Mulatta)

Lung ultrasound (LUS) is a fast and non-invasive modality for the diagnosis of several diseases. In humans, LUS is nowadays of additional value for bedside screening of hospitalized SARS-CoV-2 infected patients. However, the diagnostic value of LUS in SARS-CoV-2 infected rhesus monkeys, with mild-to-moderate disease, is unknown. The aim of this observational study was to explore correlations of the LUS appearance of abnormalities with COVID-19-related lesions detected on computed tomography (CT). There were 28 adult female rhesus monkeys infected with SARS-CoV-2 included in this study. Chest CT and LUS were obtained pre-infection and 2-, 7-, and 14-days post infection. Twenty-five animals were sub-genomic PCR positive in their nose/throat swab for at least 1 day. CT images were scored based on the degree of involvement for lung lobe. LUS was scored based on the aeration and abnormalities for each part of the lungs, blinded to CT findings. Most common lesions observed on CT were ground glass opacities (GGOs) and crazy paving patterns. With LUS, confluent or multiple B-lines with or without pleural abnormalities were observed which is corresponding with GGOs on CT. The agreement between the two modalities was similar over the examination days. Pleural line abnormalities were clearly observed with LUS, but could be easily missed on CT. Nevertheless, due to the air interface LUS was not able to examine the complete volume of the lung. The sensitivity of LUS was high though the diagnostic efficacy for mild-to-moderate disease, as seen in macaques, was relatively low. This leaves CT the imaging modality of choice for diagnosis, monitoring, and longitudinal assessment of a SARS-CoV-2 infection in macaques

Preclinical Marmoset Model for Targeting Chronic Inflammation as a Strategy to Prevent Alzheimer’s Disease

Due to the aging population, modern society is facing an increasing prevalence of neurological diseases such as Alzheimer′s disease (AD). AD is an age‐related chronic neurodegenerative disorder for which no satisfying therapy exists. Understanding the mechanisms underlying the onset of AD is necessary to find targets for protective treatment. There is growing awareness of the essential role of the immune system in the early AD pathology. Amyloidopathy, the main feature of early‐stage AD, has a deregulating effect on the immune function. This is reciprocal as the immune system also affects amyloidopathy. It seems that the inflammatory reaction shows a heterogeneous pattern depending on the stage of the disease and the variation between individuals, making not only the target but also the timing of treatment important. The lack of relevant translational animal models that faithfully reproduce clinical and pathogenic features of AD is a major cause of the delay in developing new disease‐modifying therapies and their optimal timing of administration. This review describes the communication between amyloidopathy and inflammation and the possibility of using nonhuman primates as a relevant animal model for preclinical AD research

Retrospective Evaluation of a Minor Dietary Change in Non-Diabetic Group-Housed Long-Tailed Macaques (Macaca fascicularis)

Macaques in captivity are prone to becoming overweight and obese, which may cause several health problems. A diet that mimics the natural diet of macaques may prevent these problems and improve animal welfare. Adjusting captive diets towards a more natural composition may include increasing fiber content and lowering the glycemic index, i.e., reducing the impact on blood glucose levels. Such a dietary change was implemented in our long-tailed macaque (Macaca fascicularis) breeding colony. The basic diet of monkey chow pellets remained the same, while the supplementary provisioning of bread was replaced by grains and vegetables. This study is a retrospective evaluation, based on electronic health records, that investigated whether this minor dietary change had a beneficial effect on relative adiposity and overweight-related health parameters in 44 non-diabetic, group-housed, female long-tailed macaques. Relative adiposity was measured with a weight-for-height index and blood samples were collected during yearly health checks. Glycemic response and lipid metabolism were evaluated using several biochemical parameters. Relative adiposity and overweight status did not differ after dietary change. Yet, relatively heavy individuals generally lost body weight, while relatively lean individuals gained body weight, leading to a more balanced body weight dynamic. Dietary change did not affect HbA1c and triglyceride levels, while fructosamine and cholesterol levels were significantly reduced. Thus, the minor dietary change had no significant effect on overweight status, but some biochemical parameters related to the risk of diabetes and cardiovascular disease were positively affected. This study emphasizes the importance of evaluating husbandry changes and that critically reviewing husbandry practices can provide valuable insights to improve animal health and welfare

Retrospective Evaluation of a Minor Dietary Change in Non-Diabetic Group-Housed Long-Tailed Macaques (Macaca fascicularis)

Macaques in captivity are prone to becoming overweight and obese, which may cause several health problems. A diet that mimics the natural diet of macaques may prevent these problems and improve animal welfare. Adjusting captive diets towards a more natural composition may include increasing fiber content and lowering the glycemic index, i.e., reducing the impact on blood glucose levels. Such a dietary change was implemented in our long-tailed macaque (Macaca fascicularis) breeding colony. The basic diet of monkey chow pellets remained the same, while the supplementary provisioning of bread was replaced by grains and vegetables. This study is a retrospective evaluation, based on electronic health records, that investigated whether this minor dietary change had a beneficial effect on relative adiposity and overweight-related health parameters in 44 non-diabetic, group-housed, female long-tailed macaques. Relative adiposity was measured with a weight-for-height index and blood samples were collected during yearly health checks. Glycemic response and lipid metabolism were evaluated using several biochemical parameters. Relative adiposity and overweight status did not differ after dietary change. Yet, relatively heavy individuals generally lost body weight, while relatively lean individuals gained body weight, leading to a more balanced body weight dynamic. Dietary change did not affect HbA1c and triglyceride levels, while fructosamine and cholesterol levels were significantly reduced. Thus, the minor dietary change had no significant effect on overweight status, but some biochemical parameters related to the risk of diabetes and cardiovascular disease were positively affected. This study emphasizes the importance of evaluating husbandry changes and that critically reviewing husbandry practices can provide valuable insights to improve animal health and welfare