Infected Cynomolgus Research Articles

Cytokine responses during acute simian Plasmodium cynomolgi and Plasmodium knowlesi infections.

Experimental infection of non-human primates with simian malaria parasites offers a controlled system to study malarial immunity. Plasmodium cynomolgi (P. vivax-like) and P. knowlesi (P. falciparum-like) infections in the rhesus monkey were used as a model to test the hypothesis that initial acute infection stimulates type 1/pro-inflammatory cytokine expression followed by a gradual type 2/anti-inflammatory response upon re-infection. This study analyzed cytokine gene expression (interleukin-12, interferon-gamma, tumor necrosis factor-alpha = type 1; interleukin-4, interleukin-10 = type 2) using a semi-quantitative reverse transcriptase-polymerase chain reaction in monkeys infected with each of the parasites (three per group). Clinicoparasitologic and serologic parameters were also monitored. Monkeys were re-infected to assess whether enhanced immunity could increase parasite clearance. The immune response to P. cynomolgi infection in rhesus monkeys seemed to be mediated by anti-parasite, pro-inflammatory responses during primary infection with a transition to protective type 2 responses after repeat infection. The immune responses to P. knowlesi infection were more varied. Anti-inflammatory responses were more prevalent during primary infection. Repeat infection stimulated a wide variety of responses; most included expression of tumor necrosis factor-alpha, a cytokine that has been associated with inflammatory and host-destructive effects (weight loss, fever, anemia). These observations further confirmed that the simian malaria/rhesus monkey model is well suited for studies on the regulation of immunity to acute Plasmodium infection.

Mosquitoes Mating on the Metro

Chen Xiao Ping from China asked some curious questions about such infections, including what complications occur, what dose induces infection without complications, how the immune response compares with that of P. vivax, what other infections would be caused by injection of monkey blood into people, and ‘How about the ethics of clinical trial using P. cynomolgi in human bodies?’ Ole Skovmand (ORSTOM, Montpellier, France) assumed the questions were academic, and pointed out that monkeys share many infectious diseases with people and that HIV in particular may have been of simian origin. Kevin Baird (Naval Medical Research Institute, Maryland, USA) said that an excellent history of P. cynomolgi infection of human beings can be found in the classic treatise ‘The Primate Malarias’ by G.R. Coatney et al., printed by the US Department of Health, Education and Welfare (now the Department of Health & Human Services), National Institutes of Health (1971). ‘It would be wonderful if Nih took the trouble and expense to reprint this book…P. cynomolgi can infect humans by mosquito bite [which] eliminates the risks…that would attend challenge with blood stages.’ Whether the experiment is ethical depends upon objectives and its safety, and how these are reviewed by an ethical board.

Causal Prophylactic and Radical Curative Activity of WR182393 (A Guanylhydrazone) against Plasmodium Cynomolgi in Macaca Mulatta

Primaquine is the only currently available drug effective against persistent tissue stages of relapsing malaria in humans. Causal prophylactic and radical curative properties of WR182393 (a guanylhydrazone) were investigated as part of an effort to evaluate alternatives to primaquine in the rhesus monkey (Macaca mulatta)/Plasmodium cynomolgi test model. The drug was suspended in dimethylsulfoxide for intramuscular (im) injection. A pilot study indicated causal prophylactic activity in a regimen of 40 mg base/kg/day im for three days beginning the day before intravenous challenge with 1 x 10(6) P. cynomolgi sporozoites. Regimens of 31, 10, 3.1, and 0 mg base/kg/day im for three days were then tested in groups of two monkeys given a similar challenge. The two animals given 31 mg base/kg/day remained parasite-free. Average time to parasitemia for the lower dosage groups was 38, 18, and 8 days respectively. Groups of two monkeys with sporozoite-induced P. cynomolgi infections were also treated for seven days with 31, 10, 3.1, and 0 mg base/kg/day im in combination with 10 mg base/kg/day of chloroquine orally. Both monkeys given 31 mg base/kg/day did not relapse. The average time to relapse following treatment was 48, 29, and 8 days, respectively, for the lower dosage groups. Compound WR182393 is the first non-8-aminoquinoline class of drug to exhibit both causal prophylactic and radical curative properties against a relapsing primate, vivax-like malaria.

Quinoline esters as potential antimalarial drugs: effect on relapses of Plasmodium cynomolgi infections in monkeys

Two compounds of the quinoline ester series, WR 197236 (6-butyl-4-hydroxy-3-methoxycarbonyl-7-β-phenoxyethoxyquinoline) and WR 194905 (4-acetoxy-6-decyloxy-7-isopropoxy-3-methoxycarbonyl-quinoline), exhibit anti-relapse activity against sporozoite-induced Plasmodium cynomolgi B infections in rhesus monkeys. Both the compounds have been found to be curative when given intramusculary in 7 daily doses of 15 mg/kg, and no relapses were observed during the observation period of 120 d.

Natural killer activity against human K562 tumour cells duringPlasmodium cynomolgimalarial infection of rhesus monkeys

This study assessed the natural killer (NK) cell activity profile during Plasmodium cynomolgi infection in rhesus monkeys. There was a significant decrease in the NK cell activity in the peripheral blood leukocytes of infected monkeys during the early, ascending phase of infection. However, as the parasite load decreased, NK cell activity returned to normal levels. This could be correlated with the peak increase in lymphocyte counts. This indicated that a decrease in NK cell activity observed at an earlier stage during an active P. vivax malarial infection was a temporary phenomenon.

Spectrum of the antimalarial activity of a new macrolide antibiotic midecamycin in mice and monkeys.

The antimalarial activity of a new macrolide antibiotic, midecamycin, has been evaluated against a sensitive strain of Plasmodium berghei, a chloroquine-resistant strain of P. yoelii nigeriensis and a simian parasite, P. cynomolgi B. The ED50 and ED90 values of this antibiotic administered in two divided daily doses were found to be 37.15 +/- 3.51 and 100.84 +/- 7.54 mg/kg, respectively, against P. berghei and 362.34 +/- 85.33 and 878.04 +/- 10.02 mg/kg, respectively, against P. yoelii nigeriensis. Doses above 45 mg/kg for 4 days significantly extended the mean survival time of treated mice infected with either of the two parasites. However, no appreciable blood schizontocidal (at 100 mg/kg X 7 days), anti-relapse (at 100 mg/kg X 7 days) or causal prophylactic activities (at 200 mg/kg X 3 days) were observed against P. cynomolgi infection in rhesus monkeys.

Compatibility of relapse patterns of Plasmodium cynomolgi infections in rhesus monkeys with continuous cyclical development and hypnozoite concepts of relapse.

This report encompasses the results of two studies on the relapse patterns of infections with the B strain of Plasmodium cynomolgi treated repetitively with chloroquine. One study of sizeable dimensions dealt primarily with relapses that occurred within 120 days of onset of patency in infections induced with inocula of 10(5) to 7 X 10(6) sporozoites. The second study, of more limited dimensions, dealt with relapses that occurred over a 689-day period after inoculation with 5 X 10(0) to 5 X 10(6) sporozoites. Both studies showed that with few exceptions relapses occurred at relatively regularly spaced intervals. The second study showed that frequency of relapse was related directly to the size of the sporozoite inoculum and inversely to the age of the infection; also that an inoculum larger than the minimum infective dose was required for relapse. Attempted correlation of these observations with the new and generally accepted hypnozoite concept of relapse uncovered two areas of serious incompatibility and numerous defects in the experimental base of this conceptualization. With limited provisos, the relapse patterns of infections with P. cynomolgi are fully compatible with the older cyclical development concept. The results of this study argue for caution in discarding this concept and for continuation of efforts to determine the genesis of the extended post-primary attack latent period that characterizes infections with the majority of strains of P. vivax.

Activities of the tetrahydrofuran derivative, BA-41,799, against Plasmodium cynomolgi infections in rhesus monkeys.

BA-41,799, a tetrahydrofuran derivative that at one time attracted considerable interest as an antimalarial agent because of a combination of structural novelty with activities against infections with Plasmodium berghei and Plasmodium berghei yoelii in mice, has been evaluated for its capacities to effect prophylaxis and radical cure in rhesus monkeys challenged or already infected with sporozoites of the drug-susceptible Ro strain or the pyrimethamine-resistant Ro/PM strain of Plasmodium cynomolgi, and for its capacity to effect suppressive cure of infections with trophozoites of these strains. At doses up to the maximum tolerated, BA-41,799 had only marginal activity against infections with the Ro strain and none against the Ro/PM strain. On the basis of past experiences, the above results suggest that BA-41,799 would have little to offer for prophylaxis, radical cure, or suppression of human infections with Plasmodium vivax.

Enhancement of a Simian Malarial Infection (Plasmodium Cynomolgi) in Mosquitoes Fed on Rhesus (Macaca Mulatta) Previously Infected with an Unrelated Malaria (Plasmodium Knowlesi) *

Abstract A Plasmodium knowlesi infection in rhesus terminated by curative drug therapy and followed by a P. cynomolgi infection greatly increases the gametocyte infectivity of the latter species. Mosquitoes feeding on these rhesus show a 3-fold increase in oocyst number and a high percentage of mosquitoes become positive for the P. cynomolgi infection. Over a 10-day feeding schedule, mosquitoes which fed on experimental rhesus with previous exposure to P. knowlesi produced a mean oocyst count of 43.1 as compared to an oocyst count of 14.1 for mosquitoes feeding on control animals, with no prior exposure to P. knowlesi. An average of 83.6% of mosquitoes fed on experimental rhesus developed oocysts, while 53.3% of mosquitoes fed on control rhesus became positive after the blood meal. Daily average P. cynomolgi gametocytemias were low and varied only slightly between control and experimental animals, as did average daily parasitemias of both groups of rhesus. The time interval between the two malarial infections did not appear to be critical, at least not within the period from 4–20 weeks used in the present experiments. Results of in vitro feeding of mosquitoes on P. cynomolgi-infected blood through a baudruche membrane confirmed and extended those obtained from mosquitoes fed directly on rhesus.

The Characteristics of Plasmodium cynomolgi Infections in Various Old World Primates *

Abstract This report summarizes the results of a comparative study of the major features of untreated infections with the B strain of Plasmodium cynomolgi in Macaca mulatta, M. irus (fascicularis), M. nemestrina, M. speciosa (arctoides), and Cercopithecus aethiops. The investigation included: delineation of the courses of trophozoite-induced and sporozoite-induced infections in these Old World primates; evaluation of their efficiencies in transmitting the above plasmodium through Anopheles freeborni; and assessment of host reactions to infection, with particular attention to impacts on erythroid elements of peripheral blood. In all important respects, the parasitic courses of infections in M. mulatta and C. aethiops (Kenyan origin) were identical, as were the reactions of these hosts to disease processes. M. mulatta was slightly more efficient than C. aethiops in transmitting P. cynomolgi through A. freeborni; however, this favored position may have been purchased by experimental design. The features of infections in M. irus, M. nemestrina, and M. speciosa differed significantly from those in M. mulatta. M. irus responded to challenge with trophozoites or sporozoites in a highly reproducible manner, but exhibited peak parasitemias and a long series of parasitic waves (recrudescences and/or relapses) of much lower intensities than were encountered in M. mulatta. M. nemestrina responded to such challenges in diverse manners. A few subjects exhibited parasitic courses almost identical with those encountered in M. irus. The majority exhibited extremely low level parasitemias of great persistence. These diverse parasitic courses were associated with specific physical features of this monkey. M. speciosa failed to support infections following inoculation with either trophozoites or sporozoites. Sporozoite challenges did lead to transient, extremely low level parasitemias, indicating that tissue stage schizogony had taken place. The unusual features of infections in M. nemestrina and M. speciosa could be of substantial interest to those concerned with factors which determine invasion of erythrocytes by plasmodia. Demonstration that untreated infections in M. mulatta and C. aethiops are essentially identical is of far more immediate importance. If responses of infections in these hosts to standard antimalarial drugs are also identical, the way is open to substituting C. aethiops for M. mulatta in studies on the biology and therapy of infections with P. cynomolgi, particularly in the search for radical curative drugs. Such substitution would meet a critical need at a time when access to feral M. mulatta is restricted.

Studies on the antimalarial effects of RC-12 and WR 14,997 on the development of Plasmodium cynomolgi in mosquitoes and Rhesus monkeys.

Abstract The antimalarial activity of RC-12 (1,2 dimethoxy-4-(bis-diethyl-aminoethyl)-amino-5-bromobenzene) and WR 14,997 (1-aminocyclopentane-carboxylic acid) against gametocytes and sporogony of Plasmodium cynomolgi was studied using Macaca mulatta monkeys and Anopheles maculatus mosquitoes. The effect of the drugs on the mosquito stages of the parasite was assessed both after treatment by gavage of infected monkeys and direct administration in sugar solutions to plasmodial-infected mosquitoes. Single- or multiple-dose treatments of RC-12 (25 mg/kg a day) were equally effective against gametocytes and sporogony of the parasite. Mosquito infection was interrupted within 8 to 24 hours following initial treatment. Feeding of RC-12 directly to infected mosquitoes resulted in no discernible effects on oocyst development and/or sporozoite formation in the mosquito. The salivary glands of drug-treated mosquitoes displayed marked morpho-pathological alterations as a result of drug ingestion. Repeated daily doses of WR 14,997 (60 mg/kg or 100 mg/kg) had no significant gametocytocidal, sporontocidal, or causal prophylactic activity against P. cynomolgi infections after being administered to the monkey host. In contrast, WR 14,997 exhibited a marked sporontocidal action against the parasite when the drug was administered with the mosquito diet. These results failed to support the assumption that there is a correlation in drug response between the sporogonic cycle of the malaria parasite in the invertebrate host and the tissue stages of the same parasite in the vertebrate host, when the drug was fed directly to the mosquito. However, there appears to be a direct relationship between the effect of the drug on the gametocytes and tissue stages when the drug is administered to the vertebrate host prior to mosquito feeding.

Gametocytocidal and sporontocidal effects of antimalarial drugs on malaria parasites: I. Effect of single and multiple doses of primaquine on Plasmodium cynomolgi

A study was undertaken to determine the gametocytocidal and sporontocidal activity of primaquine against blood-induced Plasmodium cynomolgi infections in seven rhesus monkeys ( Macaca mulatta). Infected animals were treated orally with single (1.95 mg/kg primaquine base) or multiple doses of primaquine (0.65 mg/kg/day × 5 primaquine base). The effect of the drug on the sporogonic stages of the parasite was observed in Anopheles maculatus mosquitoes fed at appropriate intervals before and after treatment began. Mosquitoes were also fed on control untreated monkeys on a parallel feeding schedule. The results indicated that primaquine given in the above doses exerted a marked sporontocidal activity within 4 hr after initial medication whereas its gametocytocidal effect first became obvious 2–3 days later. Single doses of primaquine were less effective as compared to multiple doses in the sense that full mosquito infectivity was restored as early as 3 days after single dosage treatment. Primaquine (as base) given in much smaller amounts (0.08 mg/kg/day × 5 or 0.24 mg/kg × 1) acted exclusively as a sporontocidal agent. The sporontocidal action of primaquine was very rapid. Its gametocytocidal effect was less apparent.

Clinical and physiological responses in sporozoite-induced B strain Plasmodium cynomolgi and Plasmodium vivax infections in normal volunteers

1. 1) Five inmate volunteers were experimentally infected by sporozoite inoculation with the B strain of P. cynomolgi. The course of their infection was contrasted with that of two volunteers infected with the Venezuelan strain of P. vivax. 2. 2) The group of patients infected with the B strain of P. cynomolgi demonstrated a prepatent period of 9–15 days, an incubation period of 10–17 days, with the duration of their febrile illness lasting 8–12 days. The maximum parasite density in this group was 1100 parasites/c.mm. 3. 3) The patients infected with P. vivax demonstrated a prepatent period of 14 days, with an incubation period of 15 days. The duration of their febrile illness was 19 days, with the maximum parasite density controlled to 16,770/c.mm. 4. 4) Both groups of patients exhibited tertian fever patterns, but with the fever rising higher and lasting longer in the P. vivax infected patients. Headache, abdominal pain, and hepatosplenomegaly were prominent in the B strain P. cynomolgi infections. Generalized malaise, anorexia, weight loss, and shaking chills were pronounced in the P. vivax infected volunteers. 5. 5) Significant laboratory findings in both groups of patients were anaemia, leucopenia, thrombocytopenia, an elevated erythrocyte sedimentation rate, and shortened survival time of labelled red blood cells. The group infected with P. vivax demonstrated a moderately severe anaemia with a depressed reticulocyte response in comparison to the group infected with the B strain of P. cynomolgi. 6. 6) Other positive findings were hypoalbuminaemia and hyperglobulinaemia in both infections and a fall in the excretion of 17-hydroxycorticosteroid excretion in three of the five volunteers infected with the B strain of P. cynomolgi.

Effect of milk diet on P. cynomolgi infections in monkeys.

Effect of milk diet on P. cynomolgi infections in monkeys.

Antimalarial activities of triazine metabolites of chlorguanide and dichlorguanide.

SummaryThe activities of the triazine metabolites of chlorguanide and dichlorguanide have been studied in P. cynomolgi infections in the rhesus monkey. The results show that the chlorguanide metabolite, CPT, has only one-half to one-fourth the activity of the parent drug, whereas the dichlorguanide metabolite, DCPT, has activity equal to that of chlorguanide. These findings are in marked contrast to reported results on P. gallinaceum infections in the chick, against which CPT and DCPT are respectively 10 and 100 times as effective as chlorguanide.