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Necrotizing meningoencephalitis and pneumonitis in a simian immunodeficiency virus-infected rhesus macaque due to Acanthamoeba.

Free-living amoebae of the genus Acanthamoeba can cause a fatal disease of the brain in humans called granulomatous amoebic encephalitis. We present a case of meningoencephalitis and pneumonitis in a simian immunodeficiency virus (SIV)-infected rhesus macaque caused by Acanthamoeba sp. The animal became ill 176 days after intravenous inoculation with SIVmac251 after a short history of weight loss and a sudden onset of hind limb paresis and abnormal head movements. Histopathologic examination of hematoxylin and eosin-stained tissues revealed multifocal to coalescing necrotizing neutrophilic meningoencephalitis and pneumonitis. Immunofluorescence and polymerase chain reaction were used to identify the genus of amoeba as Acanthamoeba. Immunohistochemistry of immune cell markers was used to characterize the animal's immune response to the opportunistic amoebic infection with features of both innate and adaptive cell-mediated immunity. Although not previously reported, the potential transmission to humans, either through environmental contamination or contact with an infected animal, makes this disease a threat to laboratory animal care staff and pathologists.

Acanthamoeba↗

[Kinetic study of various cytokine mRNA expressions in rhesus treated with haploidentical peripheral blood stem cell transplantation].

This study was aimed to analyze the mRNA expression of cytokines (TGF-beta, IL-2, IL-6, IL-10, IFN-gamma, TNF-alpha, FAS-L) in five rhesus treated with haploidentical peripheral blood stem cell transplantation after nonmyeloablative preparative regimens and to explore the role of these cytokines in the development and pathology of acute graft-versus-host-disease (aGVHD). Five rhesus monkeys received nonmyeloablative haploidentical peripheral blood stem cells transplantation. Semi-quantitative reversed transcription polymerase chain reaction (RT-PCR) was used to analyze the kinetics of cytokine mRNA expression in the transplantation and aGVHD. The results showed that five rhesus monkeys acquired hematopoietic reconstitution successfully. The graft was rejected in one monkey which survived without disease, the other four achieved mixed chimerism and full donor chimerism. Chimerism of low centigrade in one monkey achieved high centigrade at 35 days after donor stem cell infusion. Intestinal aGVHD grade III developed in one monkey. Cytokines of Th1 and Th2 changed after transplantation. In period of aGVHD, expression of TGF-beta decreased but all others increased in various levels. When donor chimerism decreased, the cytokines decreased accordingly. It is concluded that the decrease of TGF-beta mRNA may be an indicator to predict aGVHD, and can be used as a differential diagnostic indicator for intestinal GVHD.

Animals↗

Immune responses against sexual stages of Plasmodium vivax during human malarial infections in Sri Lanka.

During natural infections of P. vivax malaria a variety of immune responses to the infection affect infectivity of the parasites to mosquitoes. Sexual stage antigens present in the blood stage parasites induce antibodies which may either enhance or suppress the infectivity of the sexual parasites to mosquitoes. Subsequent infections of P. vivax do not, unless occurring within less than 4 months, boost this response indicating a very short immune memory for the relevant antigens. Blood infection also results in the release of cytokines and other non-antibody factors which together can mediate death of the blood stage sexual parasites. These factors are associated with paroxysm in non-immune individuals. In individuals from an endemic area with age-acquired anti-disease immunity clinical symptoms are mild and the parasite killing factors are not induced.

Animals↗

Simian varicella infection in the African green monkey (Cercopithecus aethiops).

A severe and highly fatal disease occurred in African green monkeys (Cercopithecus aethiops). The disease was marked by an extensive maculo-vesicular rash. In fatal cases, multifocal necrosis and hemorrhage were found characteristically in many organs and tissues. New cases of the disease occurred over a 39-day period. Nine of 49 exposed African green monkeys were affected and five of the nine died. Four cynomolgus (Macaca fascicularis) and 31 stumptailed monkeys (Macaca arctoides) which were exposed were not affected. Delta Herposvirus was isolated from affected African green monkeys. Stumptailed monkeys housed in association with the African green monkeys, as well as those housed elsewhere, had significant serum concentrations of neutralizing antibodies to this agent.

Animals↗

Life on the edge: gastrointestinal parasites from the forest edge and interior primate groups.

Humans are responsible for massive changes to primate habitats, and one unanticipated consequence of these alterations may be changes in host-parasite interactions. Edges are a ubiquitous aspect of human disturbance to forest landscapes. Here we examine how changes associated with the creation of edges in Kibale National Park, Uganda, alter the parasite community that is supported by two species of African colobines: the endangered red colobus (Piliocolobus tephrosceles) and the black-and-white colobus (Colobus guereza). An analysis of 822 fecal samples from edge and forest interior groups revealed no difference in the richness of parasite communities (i.e., the number of parasite species recovered from the host's fecal sample). However, for both species the proportion of individuals with multiple infections was greater in edge than forest interior groups. The prevalence of specific parasites also varied between edge and forest interior groups. Oesophagostomum sp., a potentially deleterious parasite, was 7.4 times more prevalent in red colobus on the edge than in those in the forest interior, and Entamoeba coli was four times more prevalent in red colobus on the edge than in animals from the forest interior. Environmental contamination with parasites (measured as parasite eggs/gm feces) by red colobus from the edge and forest interior differed in a similar fashion to prevalence for red colobus, but it did not differ for black-and-white colobus. For example, egg counts of Oesophagostomum sp. were 10 times higher in red colobus from the edge than in those from the interior. The less severe infections in the black-and-white colobus relative to the red colobus may reflect the fact that black-and-white colobus raid agricultural crops while red colobus do not. This nutritional gain may facilitate a more effective immune response to parasites by the black-and-white colobus. The fact that animals on the edge are likely not nutritionally stressed raises an intriguing question as to what facilitates the elevated infections in edge animals. We speculate that interactions with humans may be linked to the observed patterns of infections, and hence that understanding the ecology of infectious diseases in nonhuman primates is of paramount importance for conservation and potentially for human-health planning.

Animals↗

Central memory CD4 T cells are the predominant cell subset resistant to anergy in SIV disease resistant sooty mangabeys.

OBJECTIVE: HIV infection in humans and experimental SIV infection in rhesus macaques leads to the loss of recall antigen responses, immunological anergy in CD4 T cells and AIDS. In contrast, natural infection in sooty mangabeys with SIV does not lead to disease despite high viral loads accompanied by resistance of their CD4 T cells to undergo immunological anergy. The objective of the study was to further elucidate the mechanisms that contribute to anergy resistance in CD4 T cells from sooty mangabeys and identify whether the anergy resistance is a function of a specific subset or the entire cell population. MATERIALS AND METHODS: Susceptibility or resistance to anergy was analyzed in antigen specific and defined CD4 T cell subsets from peripheral blood of sooty mangabeys and rhesus macaques by using an in vitro anergy inducing protocol; expression of the anergy associated gene GRAIL was measured. RESULTS: Antigen specific CD4 T cells from SIV disease resistant sooty mangabey are relatively resistant to the development of anergy. This resistance is associated with a lack of an upregulation of GRAIL. Conversely, rhesus macaque CD4 T cells are sensitive to anergy induction associated with upregulation of GRAIL. Furthermore the anergy resistant phenotype of sooty mangabey CD4 T cells predominantly resides in central memory cells defined either as CD4+CD45RA-CD62L+ or CD4+CD28+CD95+CCR7+. CONCLUSIONS: The maintenance of recall responses in sooty mangabeys is associated with the resistance of central memory CD4 T cells to the induction of anergy which may represent an important mechanism underlying SIV disease resistance in this species.

Animals↗

The incidence of coccidioidomycosis among nonhuman primates housed outdoors at the California Primate Research Center.

Serum from 191 nonhuman primates housed outdoors from October 1977 to October 1978 at the California Primate Research Center was assayed for the presence of antibody specific for coccidioidin. One Macaca mulatta had coccidioidal antibody which was found to be associated with disseminated coccidioidomycosis. One Macaca radiata had complement-fixing antibody specific for coccidioidin and a pulmonary lesion. Additionally, two other animals had coccidioidal antibody but lacked clinical evidence of disease. The source of infection is suspected to be a severe dust storm originating in southern California.

Animals↗

Studies of heart disease and failure in aged female squirrel monkeys (Saimiri sp.).

Lesions consistent with heart failure were found in 23 of 88 adult squirrel monkeys that died between 1995 and 1999 at the Squirrel Monkey Breeding and Research Resource (SMBRR). This provided a rationale for a study surveying aged animals in the SMBRR for normal cardiac characteristics, using echocardiography (ECHO) and electro-cardiogram. In the pilot study, ECHO and electrocardiography were performed on 59 healthy female squirrel monkeys aged 10 years or older and 39 five-year-old monkeys. Parameters were heart rate, P-wave duration and amplitude, and PR, QRS, and QT intervals (electrocardiography), and ejection fraction. Two animals with cardiomyopathy were identified and received similar testing. Advanced-study animals had the same measurements, plus left ventricular internal diameter-systole (LVIDs) and -diastole (LVIDd), left atrial diameter-diastole (LADd) and aortic root diameter-diastole (AoRDd) by use of ECHO. Significant differences were found between groups in LADd, and P-wave and QRS interval durations. In a clinical context, these differences were not considered to be substantial. Normal aged female squirrel monkeys had significant increases in heart dimension and longer P- and QRS-wave durations than did monkeys of a five-year-old control group, although the increases were not considered clinically relevant. This study documents myocardial dynamics in healthy saimiri and those with cardiomyopathy.

Aging↗

Blood flow in maxilla and mandible of normal and atherosclerotic rhesus monkeys.

Atherosclerotic vascular disease affects many individuals, particularly in an elderly population. This study examined alterations in the vasculature and blood flow in the maxilla and mandible in rhesus monkeys fed an atherogenic (high fat) diet. No significant difference was found in blood flow between different regions of the bone (anterior mandible, posterior mandible and maxilla) in animals on either a normal or a high fat diet but overall blood flow in the monkeys on the atherogenic diet was significantly lower (p less than 0.001) than in the control group. Histologic examination of tissue from the animals fed an atherogenic diet revealed minimal changes within the intrabony vasculature and measurements of these vessels showed no significant difference in the percentage of tissue occupied by vessel lumina or in average wall thickness between the groups of animals. On the other hand, tissue from the tongue exhibited gross atherosclerotic vascular lesions and examination of the carotid arteries revealed not only intimal plaques but extensive calcification. It thus appears that the decreased flow measured in the maxilla and mandible may be related to the severely involved afferent vessels rather than to functional changes in the local vasculature.

Animals↗

Intracerebral infusion of TNF-alpha and IL-6 failed to activate latent SIV infection in the brains of macaques inoculated with macrophage-tropic neuroadapted SIVmac.

Lymphocyte-tropic (L-tropic) SIVmac predictably causes immunosuppression and AIDS in rhesus macaques. SIV encephalitis, on the other hand, is caused mainly by macrophage-tropic (M-tropic) SIVmac. We have previously described the derivation of M-tropic, neuroadapted SIVmac from molecularly cloned, L-tropic SIVmac239. In this report we show that inoculation of four macaques with neuroadapted virus resulted in L-tropic SIVmac-related diseases in all four but neurological disease in only two of the four animals. Because cocultivation of infected macrophages with CD4+ lymphocytes results in production of tumor necrosis factor alpha and interleukin-6, we asked whether infiltration of supernatant fluids containing these cytokines into the brains of macaques infected with neuroadapted virus would enhance the development of neurological disease. These procedures failed to promote productive virus replication in the brain. Thus, although different degrees of immunosuppression and AIDS could be induced predictably with L-tropic virus, induction of neurological disease was not predictable even when animals were inoculated with neuroadapted M-tropic virus and inflammatory cytokines were infiltrated into the brains of these animals.

Animals↗

Experimental kuru in the gibbon and sooty mangabey and Creutzfeldt-Jakob disease in the pigtailed macaque. With a summary of the host range of the subacute spongiform virus encephalopathies.

The experimental host range for the slow virus infections causing subacute spongiform virus encephalopathies is enlarged in primates to include the gibbon for kuru, the pigtailed macaque for Creutzfeldt-Jakob disease, and the sooty mangabey for both diseases. The report is based on neuropathological evidence of the diseases in animals with preclinical lesions. A table lists all the species to which the subacute spongiform virus encephalopathies have been transmitted.

Animals↗

Five spontaneous deaths associated with Clostridium difficile in a colony of cotton-top tamarins (Saguinus oedipus).

Clostridium difficile toxin was detected in the feces of five cotton-top tamarins (Saguinus oedipus) that died spontaneously over a period of 10 weeks. Deaths occurred subsequent to antibiotic therapy for infectious diarrhea associated with Campylobacter spp. Relevant clinical signs of disease prior to death included weight loss, watery diarrhea, hematochezia, weakness, and sudden collapse. On histologic examination of the colon at necropsy, pseudomembranous colitis was evident in two cases, a lesion consistent with C. difficile lesions in humans. This finding prompted submission of feces for C. difficile toxin analysis from these five cases. Four of the tamarins were from a single room, and the fifth was housed nearby. The proximity of the cases raises the possibility of environmental contamination by resistant C. difficile spores or fecal spread of the organism as reported in hospitals, day-care centers, and nurseries. The relative importance of C. difficile and its potential role as an unrecognized cause of enteric disease secondary to antibiotic therapy in nonhuman primates is discussed.

Animals↗

N-0923, a selective dopamine D2 receptor agonist, is efficacious in rat and monkey models of Parkinson's disease.

Certain aminotetralins are known to be potent dopamine D2 receptor agonists. N-0923, [-]2-(N-propyl-N-2-thienylethylamino)-5- hydroxytetralin HCl, recognizes the high and low affinity states of the D2 receptor in membranes from bovine caudate with a Klow of 79 nM. The selectivity ratio is D2/D1 = 15 and D2/alpha 2 = 1.4. N-0923 also inhibits dopamine uptake and prolactin secretion, and it is an antagonist at the alpha 2 receptor. N-0923 (3-300 nmol/kg, s.c.) induced dose-dependent contralateral turning behavior in rats with unilateral 6-hydroxydopamine lesions of the substantia nigra. The ED50 of 30 nmol/kg was effective for 1 h. The positive enantiomer (N-0924; 300 nmol/kg, s.c.) was without effect. A hemiparkinsonian syndrome was induced in four Macaca nemestrina monkeys by unilateral infusion of the neurotoxin MPTP into the right carotid artery. Video recordings of free-moving behavior revealed bradykinesia, disuse of the contralateral upper limb and turning in a direction ipsilateral to the lesion. N-0923 (3-300 nmol/kg, i.m.) induced contralateral turning behavior, exploratory activity, and contralateral limb usage. The ED50 for turning (30 nmol/kg) was effective for 0.5 h. The potency order for induction of contralateral rotations was (+)-PHNO > N-0923 > bromocriptine. N-0924 (300 nmol/kg, i.m.) was ineffective. We conclude that N-0923 may be useful as a therapeutic agent in the treatment of Parkinson's disease.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

Rhesus macaques inoculated with molecularly cloned simian immunodeficiency virus.

We have isolated a biologically active molecular clone of simian immunodeficiency virus (SIV), SIVmac 1A11, originally obtained from a rhesus macaque at the New England Regional Primate Research Center. Virus derived from cells transfected with this clone is cytopathic for rhesus peripheral blood mononuclear cells, replicates in cultures of rhesus macrophages, and infects rhesus macaques when inoculated intravenously. Six macaques inoculated with SIVmac 1A11 all became infected and produced antibodies to viral envelope glycoproteins that neutralized virus. Antibodies to viral core proteins were detected in only one animal. No clinical signs of disease were observed throughout 7 months postinoculation.

Animals↗

Acute non-A, non-B hepatitis. Prolonged presence of the infectious agent in blood.

Non-A, non-B hepatitis, previously transmitted to chimpanzees by inoculation of human serum, was serially transmitted through a second and third passage to additional chimpanzees using serum drawn during acute non-A, non-B hepatitis. Sera obtained at weeks 4 and 5 after inoculation from two different chimpanzees, and from one chimpanzee at week 13 after inoculation, were shown to cause elevation of serum aminotransferase levels and abnormal liver biopsies in recipient chimpanzees, with no serologic evidence of hepatitis A or B, cytomegalovirus, or Epstein-Barr virus infection. Serum obtained 3 wk after inoculation did not cause elevation of aminotransferase levels in the recipient chimpanzee, although a single abnormal biopsy was obtained. Thus, the non-A, non-B hepatitis agent was present in serum during acute disease near the time of the first aminotransferase elevation (week 4; perhaps also week 3), and persisted at least until 1 week after the peak aminotransferase level (week 13).

Alanine Transaminase↗

Novel Kaposi's sarcoma-associated herpesvirus homolog in baboons.

Kaposi's sarcoma (KS) and lymphoproliferative diseases induced by KS-associated herpesvirus (KSHV/human herpesvirus 8) cause substantial morbidity and mortality in human immunodeficiency virus-infected individuals. To understand KSHV biology it is useful to investigate closely related rhadinoviruses naturally occurring in nonhuman primates. Here we report evidence for a novel KSHV homolog in captive baboon species (Papio anubis and other). Using degenerate PCR we identified a novel rhadinovirus, PapRV2, that has substantial sequence identity to two essential KSHV genes, the viral polymerase and thymidylate synthase. A subset of animals exhibited detectable PapRV2 viral load in peripheral blood mononuclear cells. Extensive serological analysis of nearly 200 animals in the colony demonstrated that the majority carried cross-reacting antibodies that recognize KSHV or macaque rhadinovirus antigens. Seroreactivity increased with age, similar to the age-specific prevalence of KSHV in the human population. This establishes baboons as a novel resource to investigate rhadinovirus biology, which can be developed into an animal model system for KSHV-associated human diseases, vaccine development, and therapy evaluation.

Amino Acid Sequence↗