Primates and the Ecology of their Infectious Diseases: How will Anthropogenic Change Affect Host‐Parasite Interactions?

The sudden appearance of diseases like SARS (severe acute respiratory syndrome 1 ), the devastating impacts of diseases like Ebola on both human and wildlife communities, 2 , 3 and the immense social and economic costs created by viruses like HIV 4 underscore our need to understand the ecology of infectious diseases. Given that monkeys and apes often share parasites with humans, understanding the ecology of infectious diseases in nonhuman primates is of paramount importance. This is well illustrated by the HIV viruses, the causative agents of human AIDS, which evolved recently from related viruses of chimpanzees (Pan troglodytes) and sooty mangabeys (Cercocebus atys 5 ), as well as by the outbreaks of Ebola virus, which trace their origins to zoonotic transmissions from local apes. 6 A consideration of how environmental change may promote contact between humans and nonhuman primates and thus increase the possibility of sharing infectious diseases detrimental to humans or nonhuman primates is now paramount in conservation and human health planning.     

Nonhuman primates and the acquired immunodeficiency syndrome: a union of necessity

Because of the close phylogenetic relationship, nonhuman primates are highly susceptible to human pathogens, including infection of chimpanzees by the human immunodeficiency virus (HIV), the causative agent of AIDS. This, and the existence of a highly related simian virus, SIV, which causes an AIDS-like disease in macaques, emphasizes the continued importance of using nonhuman primates as model systems for identifying and developing prophylaxis and therapy for infectious agents and, in particular, for fighting the pandemic AIDS.     

Nonhuman primate infections after organ transplantation

Nonhuman primates, primarily rhesus macaques (Macaca mulatta), cynomolgus macaques (Macaca fascicularis), and baboons (Papio spp.), have been used extensively in research models of solid organ transplantation, mainly because the nonhuman primate (NHP) immune system closely resembles that of the human. Nonhuman primates are also frequently the model of choice for preclinical testing of new immunosuppressive strategies. But the management of post-transplant nonhuman primates is complex, because it often involves multiple immunosuppressive agents, many of which are new and have unknown effects. Additionally, the resulting immunosuppression carries a risk of infectious complications, which are challenging to diagnose. Last, because of the natural tendency of animals to hide signs of weakness, infectious complications may not be obvious until the animal becomes severely ill. For these reasons the diagnosis of infectious complications is difficult among post-transplant NHPs. Because most nonhuman primate studies in organ transplantation are quite small, there are only a few published reports concerning infections after transplantation in nonhuman primates. Based on our survey of these reports, the incidence of infection in NHP transplant models is 14%. The majority of reports suggest that many of these infections are due to reactivation of viruses endemic to the primate species, such as cytomegalovirus (CMV), polyomavirus, and Epstein-Barr virus (EBV)-related infections. In this review, we address the epidemiology, pathogenesis, role of prophylaxis, clinical presentation, and treatment of infectious complications after solid organ transplantation in nonhuman primates.     

Specific pathogen-free macaques: definition, history, and current production

Specific pathogen-free (SPF) macaque colonies are now requested frequently as a resource for research. Such colonies were originally conceived as a means to cull diseased animals from research-dedicated colonies, with the goal of eliminating debilitating or fatal infectious agents from the colony to improve the reproductive capacity of captive research animals. The initial pathogen of concern was Mycobacterium tuberculosis (M.tb.), recognized for many years as a pathogen of nonhuman primates as well as a human health target. More recently attention has focused on four viral pathogens as the basis for an SPF colony: simian type D retrovirus (SRV), simian immunodeficiency virus (SIV), simian T cell lymphotropic/leukemia virus (STLV), and Cercopithecine herpesvirus 1 (CHV-1). New technologies, breeding, and maintenance schemes have emerged to develop and provide SPF primates for research. In this review we focus on the nonhuman primates (NHPs) most common to North American NHP research facilities, Asian macaques, and the most common current research application of these animals, modeling of human AIDS.     

Gastrointestinal parasites of endemic and endangered free-ranging purple-faced leaf monkey (Semnopithecus vetulus) in Sri Lanka: effect of host group size and habitat type

Primates - Similar infectious agents may be shared among human and nonhuman primates due to their close proximity. Gastrointestinal parasitism is one of the main diseases which can be transmitted...     

In vitro manipulation of nonhuman primate gametes for embryo production and embryo transfer.

Since nonhuman primates are closely related to humans and share many physical similarities, they are important for use in research areas such as human infectious diseases, reproduction, physiology, endocrinology, metabolism, neurology and longevity. To develop and maintain these animals, we must establish techniques for in vitro manipulation of spermatozoa and eggs. For a decade my research group has been conducting basic research to establish embryo manipulation techniques and to clarify the reproductive phenomena in nonhuman primates. This article summarizes the past research on in vitro manipulation of nonhuman primate gametes, from collection of reproductive cells and in vitro fertilization to the birth of offspring after embryo transfer, as well as the current status of these research areas. The studies summarized here will directly lead to the development of standard techniques for practical and comprehensive use in nonhuman primates.     

Nonhuman primate quarantine: its evolution and practice

Nonhuman primates (NHPs) are imported to the United States for use in research, domestic breeding, and propagation of endangered populations in zoological gardens. During the past 60 years, individuals responsible for NHP importation programs have observed morbidity and mortality typically associated with infectious disease outbreaks. These outbreaks have included infectious agents such as tuberculosis, Herpesvirus sp., simian hemorrhagic fever, and filovirus infections such as the Ebola and Marburg viruses. Some outbreaks have affected both animal and human populations. These epizootics are attributable to a variety of factors, including increased population density, exposure of na?ve populations to new infectious agents, and stress. The practice of quarantining animals arriving in the United States was first applied by individual research programs to improve animal health and ensure the quality of animals entering research programs. The development of government regulations for nonhuman primate quarantine accompanied the recognition that imported NHPs could pose a risk to public health. This article briefly reviews the history of US NHP importation and the factors behind the development of NHP quarantine regulations. The focus is on regulations concerned with infectious disease, public health, and the health of domestic primate colonies. These regulations have had the dual benefit of protecting public health as well as reducing animal morbidity and mortality during importation and quarantine. We review current practices and facilities for nonhuman primate quarantine and identify challenges for the future.     

Opportunistic infections in immunologically compromised nonhuman primates

Despite advances in the husbandry of nonhuman primates, natural and experimentally induced diseases continue to pose risks to animal health. These risks are particularly important when such disease results in immunodeficient states that provide an opportunity for the development of opportunistic infections. Because opportunistic agents may serve as significant confounders to research and hold potential for zoonotic transmission, knowledge of disease pathogenesis, surveillance, and risk reduction is particularly important to individuals who work closely with primates. Endogenous diseases of primates that result in blunted immune responses and thus allow for the development of opportunistic infection include simian type D retroviruses and measles. In addition, simian immunodeficiency virus is a frequently studied experimental cause of immunosuppression. This article focuses on clinical and pathological aspects of the most common opportunistic infections that occur in nonhuman primates maintained in research settings. The complete elimination of all infectious agents from primate colonies may be impossible and unwarranted, but microbial surveillance programs can help both to define the complement of agents present in a colony and to elucidate their potential impacts on colony health, zoonotic risk, and experimental research. We discuss risk reduction through the use of quarantine procedures, specific pathogen-free animals, and environmental controls.     

Biosafety in acquired immunodeficiency syndrome (AIDS) studies using nonhuman primates

The safety recommendations for studies on acquired immunodeficiency syndrome (AIDS) using nonhuman primates are based on knowledge about the epidemiology of the disease in humans, characteristics of the virus, and standard methods for handling nonhuman primates in the laboratory. Appropriate procedures avoid exposure to potentially infectious materials by skin puncture or to mucous membranes by using appropriate disinfecting agents, physical containment, protective clothing, and animal handling techniques.     

Use of primates in research: a global overview

We assessed the use of nonhuman primates and nonhuman primate biological material in research by reviewing studies published in 2001 in peer-reviewed journals. The number and species of primates used, the origin of the animals, the type of study, the area of research of the investigation, and the location at which the research was performed were tabulated. Additionally, factors related to the animals that may have affected the outcome of the experiments were recorded. A total of 2,937 articles involving 4,411 studies that employed nonhuman primates or nonhuman primate biological material were identified and analyzed. More than 41,000 animals were represented in the studies published in 2001. In the 14% of studies for which re-use could be determined, 69% involved animals that had been used in previous experiments. Published studies most commonly used nonhuman primates or nonhuman primate biological material from the species Chlorocebus aethiops (19%), Macaca mulatta (18%), M. fascicularis (9%), and Papio spp. (6%). Of these studies, 54% were classified as in vitro studies, 14% as noninvasive, 30% as chronic, and 1% were considered acute. Nonhuman primates were primarily used in research areas in which they appear to be the most appropriate models for humans. The most common areas of research were microbiology (including HIV/AIDS (26%)), neuroscience (19%), and biochemistry/chemistry (12%). Most (84%) of the primate research published in 2001 was conducted in North America, Europe, and Japan. The animals and conditions under which they were housed and used were rarely described. Although it is estimated that nonhuman primates account for an extremely small fraction of all animals used in research, their special status makes it important to report the many husbandry and environmental factors that influence the research results generated. This analysis has identified that editors rarely require authors to provide comprehensive information concerning the subjects (e.g., their origin), treatment conditions, and experimental procedures utilized in the studies they publish. The present analysis addresses the use of primates for research, including the effects of a shortage of suitable nonhuman primate subjects in many research areas.     

结核病动物模型研究进展

结核病是由结核分枝杆菌感染引起的传染病,是危害人类健康的主要传染病之一。动物模型已经成为研究人类传染病的标准化工具。虽然对于结核分枝杆菌而言并没有真正意义的动物资源,但由于不同种类的动物,对分枝杆菌的敏感性不一样,因此可以成为结核病研究的有利工具。结核病最常用的实验动物模型包括小鼠、兔和豚鼠。每种动物有其自身特点,但并不能完全模拟人类疾病。通过建立结核病的动物模型,可以大大增加我们对疾病的病因、毒力和发病机制的理解。除了这三种模型外,非人灵长类也常被用于结核病的研究。本文总结了这几种结核病模型的研究状况。     

A new device for the capture and transport of small nonhuman primates in scientific research

Conventional methods of capturing marmosets and other small nonhuman primates (NHPs) require prolonged physical contact between animals and their handlers. This causes NHPs to become stressed and exhausted and can put both animals and handlers at risk of injury or exposure to infectious diseases. The authors designed a self-contained device for the capture and transport of small NHPs. Food rewards encourage primates to enter the device independently, and handlers can then easily access the animals for routine veterinary or experimental procedures. Preliminary observations suggest that marmosets quickly become accustomed to the device and that the device causes less stress than capture by hand or by net.     

Guidelines for developing and managing an environmental enrichment program for nonhuman primates.

Before implementing an environmental enrichment program for nonhuman primates, several issues should be considered. The assignment of enrichment tasks can be made to caretakers, a dedicated "enrichment technician," volunteers, students or individuals with training in behavioral science. Determining the enrichment techniques to be used must take into account personnel time available; the species, age, sex, and individual histories of the nonhuman primates; and experimental protocols for which animals are being maintained. Identifying the most beneficial way to use the available personnel time must be tailored for each institution. To meet federal regulations, records must be kept of the environmental enhancements available to each nonhuman primate. Good record-keeping will allow appropriate evaluation of the program. This evaluation should involve the animals' responses to the enrichment opportunity, cost and durability of enrichment items, human and nonhuman safety considerations, and personnel required. The well-being of captive nonhuman primates will be most improved if well-informed decisions are made in developing and managing environmental enrichment programs.     

Advantages and limitations of nonhuman primates as animal models in genetic research on complex diseases

Abstract: The genetic similarity between humans and nonhuman primates makes nonhuman primates uniquely suited as models for genetic research on complex physiological and behavioral phenotypes. By comparison with human subjects, nonhuman primates, like other animal models, have several advantages for these types of studies: 1) constant environmental conditions can be maintained over long periods of time, greatly increasing the power to detect genetic effects; 2) different environmental conditions can be imposed sequentially on individuals to characterize genotype-environment interactions; 3) complex pedigrees that are much more powerful for genetic analysis than typically available human pedigrees can be generated; 4) genetic hypotheses can be tested prospectively by selective matings; and 5) essential invasive and terminal experiments can be conducted. Limitations of genetic research with nonhuman primates include cost and availability. However, the ability to manipulate both genetic and environmental factors in captive primate populations indicates the promise of genetic research with these important animal models for illuminating complex disease processes. The utility of nonhuman primates for biomedical research on human health problems is illustrated by examples concerning the use of baboons in studies of osteoporosis, alcohol metabolism, and lipoproteins.     

Assessing the mammary gland of nonhuman primates: effects of endogenous hormones and exogenous hormonal agents and growth factors

This review provides a summary of the normal biology, development, and morphology of the breast in nonhuman primates (macaques), and of the major published work addressing hormonally-induced changes in the breast of these animals. The mammary glands of macaques are anatomically, developmentally, and physiologically similar to the human breast, with similar expression of sex steroid receptors (estrogen receptors alpha and beta, progesterone receptor A and B, androgen receptors), estrogen dependent markers, and steroid metabolizing enzymes. Genetic similarity between human beings and macaques is high, varying from 95-99% depending on the sequence evaluated. Macaques develop hyperplastic and cancerous lesions of the breast spontaneously, which are similar in type and prevalence to those of human beings. They have a reproductive physiology typical of anthropoid primates, including a distinct menarche and menopause, and a 28-day menstrual cycle. These similarities give unique value to the macaque model for evaluation of the effectiveness and safety of hormonal agents. Such agents considered in this review include estrogens and progestogens, combined therapies such as oral contraceptives and post-menopausal hormone therapies, androgens, selective estrogen receptor modulators, phytoestrogens, prolactin, somatotropin, epidermal growth factor, and other novel agents with hormonal or growth factor-like activity. This review also includes a consideration of selected background changes and typical strategies and markers used for evaluation of experimentally-induced changes, including biopsy-based strategies designed to control for inter-individual variability and minimize numbers of animals used.     

非人灵长类的体外受精和胚胎移植

非人灵长类的体外受精和胚胎移植是了解人类生殖机制,如卵的成熟调控,受精卵的成熟与分化,胚胎着床,控制某些遗传疾病以及保护珍稀灵长类和提高实验灵长类质量的有效途径。本文从非人灵长类卵的获取(包括超数排卵,非激素刺激动物取卵),精子处理(精液采集,冻存和精子获能),体外受精和胚胎移植、胚胎的冻存等方面介绍了有关研究概况和发展动态。     

Evaluation of pneumonia virus of mice as a possible human pathogen

Pneumonia virus of mice (PVM), a relative of human respiratory syncytial virus (RSV), causes respiratory disease in mice. There is serologic evidence suggesting widespread exposure of humans to PVM. To investigate replication in primates, African green monkeys (AGM) and rhesus macaques (n = 4) were inoculated with PVM by the respiratory route. Virus was shed intermittently at low levels by a subset of animals, suggesting poor permissiveness. PVM efficiently replicated in cultured human cells and inhibited the type I interferon (IFN) response in these cells. This suggests that poor replication in nonhuman primates was not due to a general nonpermissiveness of primate cells or poor control of the IFN response. Seroprevalence in humans was examined by screening sera from 30 adults and 17 young children for PVM-neutralizing activity. Sera from a single child (6%) and 40% of adults had low neutralizing activity against PVM, which could be consistent with increasing incidence of exposure following early childhood. There was no cross-reaction of human or AGM sera between RSV and PVM and no cross-protection in the mouse model. In native Western blots, human sera reacted with RSV but not PVM proteins under conditions in which AGM immune sera reacted strongly. Serum reactivity was further evaluated by flow cytometry using unfixed Vero cells infected with PVM or RSV expressing green fluorescent protein (GFP) as a measure of viral gene expression. The reactivity of human sera against RSV-infected cells correlated with GFP expression, whereas reactivity against PVM-infected cells was low and uncorrelated with GFP expression. Thus, PVM specificity was not evident. Our results indicate that the PVM-neutralizing activity of human sera is not due to RSV- or PVM-specific antibodies but may be due to low-affinity, polyreactive natural antibodies of the IgG subclass. The absence of PVM-specific antibodies and restriction in nonhuman primates makes PVM unlikely to be a human pathogen.     

Alternatives to continuous social housing.

Although social housing is desirable for social species of nonhuman primates, circumstances arise whereby social housing is precluded (for example, certain kinds of infectious disease or toxicologic research, when the health of the animal(s) would be compromised by social housing, and animals which respond behaviorally in an inappropriate manner to social housing). Nonsocial alternatives that provide increased environmental complexity to the home cage should then be considered. Nonsocial "environmental enrichment" schemes can be designed to enhance the expression of an individually housed nonhuman primate's locomotive/postural, manipulative, and foraging behaviors. In this way, nonsocial, but species-typical, behaviors can be promoted in the single cage housing condition.     

Macaque models of human infectious disease

Macaques have served as models for more than 70 human infectious diseases of diverse etiologies, including a multitude of agents-bacteria, viruses, fungi, parasites, prions. The remarkable diversity of human infectious diseases that have been modeled in the macaque includes global, childhood, and tropical diseases as well as newly emergent, sexually transmitted, oncogenic, degenerative neurologic, potential bioterrorism, and miscellaneous other diseases. Historically, macaques played a major role in establishing the etiology of yellow fever, polio, and prion diseases. With rare exceptions (Chagas disease, bartonellosis), all of the infectious diseases in this review are of Old World origin. Perhaps most surprising is the large number of tropical (16), newly emergent (7), and bioterrorism diseases (9) that have been modeled in macaques. Many of these human diseases (e.g., AIDS, hepatitis E, bartonellosis) are a consequence of zoonotic infection. However, infectious agents of certain diseases, including measles and tuberculosis, can sometimes go both ways, and thus several human pathogens are threats to nonhuman primates including macaques. Through experimental studies in macaques, researchers have gained insight into pathogenic mechanisms and novel treatment and vaccine approaches for many human infectious diseases, most notably acquired immunodeficiency syndrome (AIDS), which is caused by infection with human immunodeficiency virus (HIV). Other infectious agents for which macaques have been a uniquely valuable resource for biomedical research, and particularly vaccinology, include influenza virus, paramyxoviruses, flaviviruses, arenaviruses, hepatitis E virus, papillomavirus, smallpox virus, Mycobacteria, Bacillus anthracis, Helicobacter pylori, Yersinia pestis, and Plasmodium species. This review summarizes the extensive past and present research on macaque models of human infectious disease.     

Bonding, biophilia, biosynergy, and the future of primates in the wild

Human and nonhuman primates bond with one another in countless ways, and the results are varied and vital to the individuals and species involved. The manifesto that is the basis for the collection of essays in which this commentary is included proposes that the "human/nonhuman bonds that arise in primatological research and practice deserve and demand study and research." An essential corollary of this proposal is that the primatologists themselves must be studied. The aim of this essay is to explore the influence of human/nonhuman primate bonding on conservation practice and on the future of primates in the wild. This commentary applies the author's professional experience as a conservation psychologist and his research on the impact of profound interspecies bonds on human worldviews, attitudes, and behavior. It examines two general categories of bonds: those driven by Biophilia (human fascination with life) and those influenced by Biosynergy (mutual enrichment of life). It is the author's premise that biosynergy promotes complex collaborative interspecies bonds that broaden the conservationist's desire to enhance synergy among all organisms in an ecosystem. Conversely, biophilia induces relatively simple unidirectional bonds between humans and other animals that deepen the conservationist's desire to understand and protect certain species. This contrast raises some crucial questions. Do biophilia-driven bonds between conservationists and their favorite primates blind them to the synergistic needs of all species and impair their ability to work for sustained preservation of threatened habitat? Does biosynergy-based human/nature bonding enhance focus on conservation as an ecological science and thus ignore species-specific factors crucial to assure survival of endangered primates? How can both types of bonds be optimally applied to the conservation of wildlife and wilderness?