Plasmodium coatneyi in rhesus macaques replicates the multisystemic dysfunction of severe malaria in humans.

Severe malaria, a leading cause of mortality among children and nonimmune adults, is a multisystemic disorder characterized by complex clinical syndromes that are mechanistically poorly understood. The interplay of various parasite and host factors is critical in the pathophysiology of severe malaria. However, knowledge regarding the pathophysiological mechanisms and pathways leading to the multisystemic disorders of severe malaria in humans is limited. Here, we systematically investigate infections with Plasmodium coatneyi, a simian malaria parasite that closely mimics the biological characteristics of P. falciparum, and develop baseline data and protocols for studying erythrocyte turnover and severe malaria in greater depth. We show that rhesus macaques (Macaca mulatta) experimentally infected with P. coatneyi develop anemia, coagulopathy, and renal and metabolic dysfunction. The clinical course of acute infections required suppressive antimalaria chemotherapy, fluid support, and whole-blood transfusion, mimicking the standard of care for the management of severe malaria cases in humans. Subsequent infections in the same animals progressed with a mild illness in comparison, suggesting that immunity played a role in reducing the severity of the disease. Our results demonstrate that P. coatneyi infection in rhesus macaques can serve as a highly relevant model to investigate the physiological pathways and molecular mechanisms of malaria pathogenesis in naïve and immune individuals. Together with high-throughput postgenomic technologies, such investigations hold promise for the identification of new clinical interventions and adjunctive therapies.

Chronic, constant-rate, gastric drug infusion in nontethered rhesus macaques (Macaca mulatta).

As part of a study of antipsychotic drug treatment in monkeys, we developed a technique to provide chronic, constant-rate, gastric drug infusion in nontethered rhesus macaques. This method allowed us to mimic the osmotic release oral delivery system currently used in humans for continuous enteral drug delivery. Rhesus macaques (n = 5) underwent gastric catheter placement by laparotomy. After the catheters were secured to the stomach, the remaining catheter length was exited through the lateral abdomen, tunneled subcutaneously along the back, and connected to a 2-mL osmotic pump enclosed in a subcutaneous pocket. Osmotic pumps were changed every 2 to 4 wk for 1 y and remained patent for the duration of the study. Four complications (including cutting of the catheter, incisional dehiscence at the pump site, and loss of 1 catheter into the abdominal cavity requiring catheter replacement) occurred among the 80 pump changes performed during the year-long study. At necropsy, histopathologic examination of the catheter implant sites revealed mild changes consistent with a foreign-body reaction. Our results indicate that the gastric catheter and osmotic pump system was well tolerated in rhesus macaques for as long as 12 mo after placement and suggest that this system will be an attractive option for use in studies that require chronic, constant-rate, gastric drug infusion in nontethered monkeys.

Towards a transgenic model of Huntington's disease in a non-human primate.

Non-human primates are valuable for modelling human disorders and for developing therapeutic strategies; however, little work has been reported in establishing transgenic non-human primate models of human diseases. Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder characterized by motor impairment, cognitive deterioration and psychiatric disturbances followed by death within 10-15 years of the onset of the symptoms. HD is caused by the expansion of cytosine-adenine-guanine (CAG, translated into glutamine) trinucleotide repeats in the first exon of the human huntingtin (HTT) gene. Mutant HTT with expanded polyglutamine (polyQ) is widely expressed in the brain and peripheral tissues, but causes selective neurodegeneration that is most prominent in the striatum and cortex of the brain. Although rodent models of HD have been developed, these models do not satisfactorily parallel the brain changes and behavioural features observed in HD patients. Because of the close physiological, neurological and genetic similarities between humans and higher primates, monkeys can serve as very useful models for understanding human physiology and diseases. Here we report our progress in developing a transgenic model of HD in a rhesus macaque that expresses polyglutamine-expanded HTT. Hallmark features of HD, including nuclear inclusions and neuropil aggregates, were observed in the brains of the HD transgenic monkeys. Additionally, the transgenic monkeys showed important clinical features of HD, including dystonia and chorea. A transgenic HD monkey model may open the way to understanding the underlying biology of HD better, and to the development of potential therapies. Moreover, our data suggest that it will be feasible to generate valuable non-human primate models of HD and possibly other human genetic diseases.

Evaluation and comparative analysis of a technique for laparoscopic ovariectomy in rhesus macaques (Macaca mulatta).

Surgical ovariectomy is commonly performed to support studies involving the rhesus macaque (Macaca mulatta). Traditionally, these procedures have been performed via laparotomy. We developed a laparoscopic approach to reduce surgical pain, decrease convalescence times, and reduce the total number of animals necessary to obtain valuable scientific data in studies requiring repeated intra-abdominal access in conjunction with ovariectomy. We used our new technique to perform laparoscopic ovariectomy on 8 adult female rhesus macaques; 2 additional animals underwent ovariectomy via laparotomy; data for these prospective groups were compared with retrospective data from conventionally ovariectomized macaques. The surgical time (ST; mean +/- standard error) for the laparoscopic procedures was 68 +/- 3 min, with a return-to-group time (RTG) of 8 +/- 1 d. In comparison, ST for the retrospective group was 54 +/- 3 min, with a mean RTG of 33 +/- 5 d (range, 15 to 60 d). ST differed significantly between groups. ST for the laparoscopic procedure was longer (mean difference, 14 min; 95% confidence interval, 6 to 21 min), but laparotomized animals consistently had higher RTG (6 d for the prospective group [n = 2] and 25 d for the retrospective group [n = 9]). All study animals had estradiol levels of less than 5.6 pg/ml at 6 mo after surgery. We therefore conclude that laparoscopic ovariectomy of rhesus macaques is a safe and effective technique that may reduce postoperative recovery times.