• View in gallery
    Figure 1.

    Sagittal and transverse FDG-PET images in a monkey at the level of the spleen before and after P. coatneyi infection. Arrow indicates position of the spleen. I, Sagittal image in J-31 before infection. II, Transverse image in J-31 before infection. III, Sagittal image in infected monkey J-31 with high parasitemia. IV, Transverse image in infected monkey J-31 with high parasitemia. Markedly increased FDG uptake was recognized in this monkey after infection.

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    Figure 2.

    H&E-stained sections of spleen of uninfected monkey J-30 (left column: A, C, E) and J-31 infected with P. coatneyi (right column: B, D, F). A and B, The remarkable increase in size of germinal centers contributed significantly to the increase in white pulp in infected monkey tissue. (original magnification ×40, bar = 100 μm). C and D, There was massive congestion of PRBCs, uninfected erythrocytes, and numerous malarial pigments were massively congested in the venous sinuses and splenic cords (original magnification ×100, bar = 100 μm). E and F, Macrophages containing malarial pigment were frequently recognized in the red pulp at high magnification (arrows) (original magnification ×400, bar = 10 μm).

  • View in gallery
    Figure 3.

    Immunohistochemically-stained sections of spleen of uninfected monkey J-30 (left column: A, C, E) and J-31 infected with P. coatneyi (right column: B, D, F). A and B, White pulp stained with anti-HLA-DP, DQ, DR antibody (g, germinal center; c, corona; mz, marginal zone; r, red pulp) (original magnification ×100, bar = 100 μm). C and D, Immunofluorescence staining of white pulp using anti-monkey IgG antibody (original magnification ×100, bar = 100 μm). E and F, Macrophages in red pulp stained with anti-CD68 antibody (arrows = malarial pigment) (original magnification ×400, bar = 10 μm).

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    Figure 4.

    Size of macrophages immunopositive for CD68 in splenic tissues from uninfected monkey J-30, P. coatneyi–infected monkey J-32 with low parasitemia and infected monkey J-33 with high parasitemia. (mean ± SD). *Parasitemia at autopsy.

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ENHANCEMENT OF SPLENIC GLUCOSE METABOLISM DURING ACUTE MALARIAL INFECTION: CORRELATION OF FINDINGS OF FDG-PET IMAGING WITH PATHOLOGICAL CHANGES IN A PRIMATE MODEL OF SEVERE HUMAN MALARIA

SATORU KAWAIDepartment of Tropical Medicine and Parasitology, Dokkyo University School of Medicine, Mibu, Tochigi, Japan; Department of Parasitology, Gunma University Graduate School of Medicine, Maebashi, Japan; Department of Diagnostic Radiology and Nuclear Medicine, Gunma University Graduate School of Medicine, Maebashi, Japan; Nishidai Clinic Diagnostic Imaging Center, Takashimadaira, Tokyo, Japan; Department of Radiology, Yokohama City University School of Medicine, Yokohama, Japan; Gunma University Graduate School of Health Sciences, Maebashi, Japan

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EIJI IKEDADepartment of Tropical Medicine and Parasitology, Dokkyo University School of Medicine, Mibu, Tochigi, Japan; Department of Parasitology, Gunma University Graduate School of Medicine, Maebashi, Japan; Department of Diagnostic Radiology and Nuclear Medicine, Gunma University Graduate School of Medicine, Maebashi, Japan; Nishidai Clinic Diagnostic Imaging Center, Takashimadaira, Tokyo, Japan; Department of Radiology, Yokohama City University School of Medicine, Yokohama, Japan; Gunma University Graduate School of Health Sciences, Maebashi, Japan

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MUNEHIRO SUGIYAMADepartment of Tropical Medicine and Parasitology, Dokkyo University School of Medicine, Mibu, Tochigi, Japan; Department of Parasitology, Gunma University Graduate School of Medicine, Maebashi, Japan; Department of Diagnostic Radiology and Nuclear Medicine, Gunma University Graduate School of Medicine, Maebashi, Japan; Nishidai Clinic Diagnostic Imaging Center, Takashimadaira, Tokyo, Japan; Department of Radiology, Yokohama City University School of Medicine, Yokohama, Japan; Gunma University Graduate School of Health Sciences, Maebashi, Japan

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JUN MATSUMOTODepartment of Tropical Medicine and Parasitology, Dokkyo University School of Medicine, Mibu, Tochigi, Japan; Department of Parasitology, Gunma University Graduate School of Medicine, Maebashi, Japan; Department of Diagnostic Radiology and Nuclear Medicine, Gunma University Graduate School of Medicine, Maebashi, Japan; Nishidai Clinic Diagnostic Imaging Center, Takashimadaira, Tokyo, Japan; Department of Radiology, Yokohama City University School of Medicine, Yokohama, Japan; Gunma University Graduate School of Health Sciences, Maebashi, Japan

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TETSUYA HIGUCHIDepartment of Tropical Medicine and Parasitology, Dokkyo University School of Medicine, Mibu, Tochigi, Japan; Department of Parasitology, Gunma University Graduate School of Medicine, Maebashi, Japan; Department of Diagnostic Radiology and Nuclear Medicine, Gunma University Graduate School of Medicine, Maebashi, Japan; Nishidai Clinic Diagnostic Imaging Center, Takashimadaira, Tokyo, Japan; Department of Radiology, Yokohama City University School of Medicine, Yokohama, Japan; Gunma University Graduate School of Health Sciences, Maebashi, Japan

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HONG ZHANGDepartment of Tropical Medicine and Parasitology, Dokkyo University School of Medicine, Mibu, Tochigi, Japan; Department of Parasitology, Gunma University Graduate School of Medicine, Maebashi, Japan; Department of Diagnostic Radiology and Nuclear Medicine, Gunma University Graduate School of Medicine, Maebashi, Japan; Nishidai Clinic Diagnostic Imaging Center, Takashimadaira, Tokyo, Japan; Department of Radiology, Yokohama City University School of Medicine, Yokohama, Japan; Gunma University Graduate School of Health Sciences, Maebashi, Japan

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NASIM KHANDepartment of Tropical Medicine and Parasitology, Dokkyo University School of Medicine, Mibu, Tochigi, Japan; Department of Parasitology, Gunma University Graduate School of Medicine, Maebashi, Japan; Department of Diagnostic Radiology and Nuclear Medicine, Gunma University Graduate School of Medicine, Maebashi, Japan; Nishidai Clinic Diagnostic Imaging Center, Takashimadaira, Tokyo, Japan; Department of Radiology, Yokohama City University School of Medicine, Yokohama, Japan; Gunma University Graduate School of Health Sciences, Maebashi, Japan

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KATSUMI TOMIYOSHIDepartment of Tropical Medicine and Parasitology, Dokkyo University School of Medicine, Mibu, Tochigi, Japan; Department of Parasitology, Gunma University Graduate School of Medicine, Maebashi, Japan; Department of Diagnostic Radiology and Nuclear Medicine, Gunma University Graduate School of Medicine, Maebashi, Japan; Nishidai Clinic Diagnostic Imaging Center, Takashimadaira, Tokyo, Japan; Department of Radiology, Yokohama City University School of Medicine, Yokohama, Japan; Gunma University Graduate School of Health Sciences, Maebashi, Japan

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TOMIO INOUEDepartment of Tropical Medicine and Parasitology, Dokkyo University School of Medicine, Mibu, Tochigi, Japan; Department of Parasitology, Gunma University Graduate School of Medicine, Maebashi, Japan; Department of Diagnostic Radiology and Nuclear Medicine, Gunma University Graduate School of Medicine, Maebashi, Japan; Nishidai Clinic Diagnostic Imaging Center, Takashimadaira, Tokyo, Japan; Department of Radiology, Yokohama City University School of Medicine, Yokohama, Japan; Gunma University Graduate School of Health Sciences, Maebashi, Japan

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HARUYASU YAMAGUCHIDepartment of Tropical Medicine and Parasitology, Dokkyo University School of Medicine, Mibu, Tochigi, Japan; Department of Parasitology, Gunma University Graduate School of Medicine, Maebashi, Japan; Department of Diagnostic Radiology and Nuclear Medicine, Gunma University Graduate School of Medicine, Maebashi, Japan; Nishidai Clinic Diagnostic Imaging Center, Takashimadaira, Tokyo, Japan; Department of Radiology, Yokohama City University School of Medicine, Yokohama, Japan; Gunma University Graduate School of Health Sciences, Maebashi, Japan

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KEN KATAKURADepartment of Tropical Medicine and Parasitology, Dokkyo University School of Medicine, Mibu, Tochigi, Japan; Department of Parasitology, Gunma University Graduate School of Medicine, Maebashi, Japan; Department of Diagnostic Radiology and Nuclear Medicine, Gunma University Graduate School of Medicine, Maebashi, Japan; Nishidai Clinic Diagnostic Imaging Center, Takashimadaira, Tokyo, Japan; Department of Radiology, Yokohama City University School of Medicine, Yokohama, Japan; Gunma University Graduate School of Health Sciences, Maebashi, Japan

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KEIGO ENDODepartment of Tropical Medicine and Parasitology, Dokkyo University School of Medicine, Mibu, Tochigi, Japan; Department of Parasitology, Gunma University Graduate School of Medicine, Maebashi, Japan; Department of Diagnostic Radiology and Nuclear Medicine, Gunma University Graduate School of Medicine, Maebashi, Japan; Nishidai Clinic Diagnostic Imaging Center, Takashimadaira, Tokyo, Japan; Department of Radiology, Yokohama City University School of Medicine, Yokohama, Japan; Gunma University Graduate School of Health Sciences, Maebashi, Japan

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HAJIME MATSUDADepartment of Tropical Medicine and Parasitology, Dokkyo University School of Medicine, Mibu, Tochigi, Japan; Department of Parasitology, Gunma University Graduate School of Medicine, Maebashi, Japan; Department of Diagnostic Radiology and Nuclear Medicine, Gunma University Graduate School of Medicine, Maebashi, Japan; Nishidai Clinic Diagnostic Imaging Center, Takashimadaira, Tokyo, Japan; Department of Radiology, Yokohama City University School of Medicine, Yokohama, Japan; Gunma University Graduate School of Health Sciences, Maebashi, Japan

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MAMORU SUZUKIDepartment of Tropical Medicine and Parasitology, Dokkyo University School of Medicine, Mibu, Tochigi, Japan; Department of Parasitology, Gunma University Graduate School of Medicine, Maebashi, Japan; Department of Diagnostic Radiology and Nuclear Medicine, Gunma University Graduate School of Medicine, Maebashi, Japan; Nishidai Clinic Diagnostic Imaging Center, Takashimadaira, Tokyo, Japan; Department of Radiology, Yokohama City University School of Medicine, Yokohama, Japan; Gunma University Graduate School of Health Sciences, Maebashi, Japan

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In the current study, to elucidate the clinical features of severe malaria, we performed whole-body positron emission tomography (PET) with 18F-fluorodeoxyglucose (FDG) of Plasmodium coatneyi–infected acute-phase Japanese macaques. The infected monkeys clearly exhibited increase in splenic FDG uptake indicating marked enhancement of glucose metabolism. The standardized uptake values (SUVs) of the spleen in the infected monkeys were significantly higher than those in the uninfected monkey. At autopsy, splenomegaly was clearly present in all infected monkeys, and histopathologic findings included hyperplasia of lymphoid follicles in white pulp, a large number of activated macrophage, and congestion of parasitized red blood cells (PRBCs) and malaria pigments in red pulp. We suggest that increase in splenic glucose uptake may thus be closely related to activation of splenic clearance system against blood-stage malarial parasites.

INTRODUCTION

Malaria is still a major cause of death and severe illness in most of the world, with 300 to 500 million new infections per year resulting in approximately 2.0 to 3.0 million deaths.1 The major clinical features of malaria are paroxysms of high fever, hemolytic anemia, and splenomegaly. In addition, falciparum malaria often causes serious or fatal complications such as cerebral malaria, hypoglycemia, renal failure, hepatic dysfunction, and adult respiratory distress syndrome.2 Several clinical indicators are associated with increased risk of fatal outcome of falciparum malaria, but the actual causes of death and mechanisms contributing to it are not well-established.

The clinical utility of positron emission tomography (PET) is well documented, and high-resolution imaging of 18F-fluorodeoxyglucose (FDG) has been used for many years to study glucose utilization in neoplasms and major organs such as the brain, heart and spleen.36 The mechanism of cellular uptake of FDG in tumor cells has been described in detail.3 Briefly, like glucose, FDG passes through the cellular membrane and is phosphorylated by glucose 6-hexokinase. Phosphorylated glucose enters the glycolytic pathway for energy production. Phosphorylated FDG, however, is not further metabolized and remains trapped in the cell. FDG thus accumulates within cells in proportion to the cellular rate of glycolysis.

It has also been demonstrated that elevated accumulation of FDG is associated with inflammatory and infectious diseases.710 Sugawara and others evaluated the feasibility of use of FDG-PET in patients with a variety of infections and concluded that FDG-PET appears to be a promising modality for rapid imaging of active human infections.10 In these previous studies using PET, however, little attention was directed to the use of FDG-PET for parasitic diseases including malaria.7

We have been studying the pathophysiological mechanisms of severe malaria using a nonhuman primate model of severe human malaria with cerebral involvement.1114 Our previous studies demonstrated that the Japanese macaque (Macaca fuscata) is highly susceptible to Plasmodium coatneyi infection and that pathologic findings in infected monkeys are similar to those observed in human falciparum malaria. The P. coatneyi–infected Japanese macaque thus appears to be a useful model for pathologic and pathophysiological studies of severe falciparum malaria.

To elucidate the clinical features of severe malaria, we performed whole-body PET scanning with FDG of P. coatneyi–infected Japanese macaques.14 We present here direct evidence concerning splenic glucose uptake by FDG-PET scanning in P. coatneyi–infected acute-phase Japanese macaques and demonstrate the relationship of such uptake to histopathological changes observed in splenic tissue.

MATERIALS AND METHODS

Experimental animals.

Four monkeys, J-30 (female), J-32 (male), J-31 (female), and J-33 (female), which were 3-year-old Japanese macaques weighing approximately 3.5 kg each, were examined (Table 1). Of the macaques, J-30 was used as an uninfected control and the other three macaques (J-31, J-32, and J-33) for the infected group. All monkeys were bred and grown in animal facilities in Japan. The investigators adhere to the Guidelines for the Use of Experimental Animals authorized by the Japanese Association for Laboratory Animal Science. The infected monkeys were intravenously inoculated with about 1 × 109 frozen P. coatneyi–infected erythrocytes (CDC strain). After inoculation, daily clinical follow-up of the monkeys was performed over the course of infection.

Hematological examinations.

For hematological examinations, venous blood samples were obtained every 3 or 4 days after infection. From the sixth day after infection, Giemsa-stained thin blood films were prepared daily from peripheral blood obtained by earprick, and development of parasites in the infected monkeys was monitored by microscopic observation. At the time of FDG administration, blood glucose levels in all cases were determined from venous blood using blood glucose reader (Medisafe GR-101, TERUMO Inc., Tokyo, Japan) according to the manufacturer’s instruction.

FDG production and PET scanning.

FDG was produced in the cyclotron facility at Gunma University Hospital using a modified method based on that of Hamacher and others.15 PET images were obtained with a whole-body PET scanner (SET2400W; Shimadzu Co., Kyoto, Japan) with 59.5- and 20.0-cm transverse fields of view, which produced 63 image planes with a 3.125-mm interval between images. Transverse resolution at the center of the field of view was 4.2 and 5.0 mm full width at half maximum.

PET scanning schedule.

PET scans of J-31 and J-32 were performed twice, before and after infection. J-30 and J-33 were scanned once, without infection and only after infection, respectively (Table 1). PET scans after infection were obtained on Day 13 (J-31 and J-33) or Day 12 (J-32). All animals were fasted for at least 12 hours before PET scan studies. For administration for FDG, all animals were initially anesthetized with intramascular injection of ketamine-HCl (15 mg/kg) and maintained with inhalation of 1.0–2.0% isoflurane in air (4 L/min). After intravenous injection of 148 MBq or 74 MBq FDG through the left cephalic vein, static PET images were obtained in supine position at 70–100 minutes after the injection. Acquisition times for emission scanning and transmission scanning were 10 and 4 minutes, respectively.

PET image analysis.

Attenuation-correlated images with FDG were reconstructed to 128 × 128 matrices with pixel dimensions of 4.0 mm in plane and 3.125 mm axially. Using attenuation-correlated images, injected doses of FDG, body weights, and cross-calibration factors between PET and dose calibrator, functional images of standardized uptake values (SUVs) were produced. SUV was defined as follows:

SUV=radioactive concentration in tissue (MBq/g)/(injected dose [MBq]/monkey body weight [g])

We manually placed one round region of interest (ROI) on the area corresponding to the center of the spleen on the SUV image of each animal. Mean SUV value of the ROI was considered a quantitative index of tissue uptake of FDG.

Histopathological examination.

All animals were exsanguinated under anesthesia with intramuscular injection of ketamine-HCl (15 mg/kg) after PET examination. They were autopsied and major organs include spleen were weighed and processed for histopathological observation.

Tissues were fixed in PLP (periodate-lysine-paraformaldehyde) solution (0.01M NaIO4–0.075 M lysine–2% paraformaldehyde) overnight. All tissues had been embedded in paraffin. Specimens from two infected monkeys (J-31 and J-32) and the uninfected control monkey J-30 were additionally embedded in optimum cold temperature medium (OCT; Miles Laboratories, Elkhart, IN) and were snap-frozen in a mixture of dry-ice-methylbutane (−75°C) and then stored at −80°C until they were processed.

Paraffin sections were examined with hematoxylin and eosin stain. For immunohistochemistry, paraffin sections were reacted with the following monoclonal antibodies and then with ABC elite kit (Vector Laboratories, Burlingame, CA). Immunoreaction was visualized with diaminobenzidine. We used a human HLA-DP, DQ, DR antibody (CR3/43, 1:30; DakoCytomation Inc., Kyoto, Japan) after preventing endogeneous peroxidase activity, by 0.3% H2O2 in 99% methanol at room temperature for 20 minutes and enhancement with autoclaving in pure water at 110° for 10 minutes. HLA-DP, DQ, DR is a MHC class II antigen on antigen-presenting cells, macrophages, and B cells and is a marker of activation of those cells.16 We also used a human CD68 antibody (KP1,1:50; DakoCytomation Inc.), a monocyte/macrophage marker, after blocking endogeneous peroxidase activity with H5IO6-PBS (1%) at room temperature for 20 minutes and enhancement with trypsin-PBS (0.03%) at 37°C for 6 minutes. The cross reaction of the antibody against monkey cells have been exhibited in previous works.17

The percentage area of white pulp per field (3.23 mm2) and the size of CD68-positive macrophages were calculated using Simple PCI (Compix, Inc., Cranberry Township, PA). For measurement of the percentage area of white pulp, 10 fields were randomly selected from each H&E-stained section and saved in our computer files. We manually enclosed each area by lines on the screen and determined the percentage area of white pulp and germinal center per field. For measurement of macrophage size, we randomly selected 50 CD68-positive cells in the red pulp of sections of J-30, J-32, and J-33. We manually enclosed the CD68-positive areas that surrounded nuclei by lines on the screen and measured their sizes without the nuclei. The splenic tissue of J-31 was not available for immunohistochemical study.

Cryostat sections (thickness, 4 μm) of frozen spleens obtained from J-30 (uninfected control monkey), J-31, and J-32 (infected monkeys) were washed in phosphate-buffered saline (PBS) and incubated in 2% bovine serum albumin (Sigma no. A4503-50G)/PBS for 10 minutes at room temperature. They were stained with fluorescein isothiocyanate–conjugated goat anti-monkey immunoglobulin G (IgG) antiserum (Cappel, Auror, OH) as a marker of activated B lymphocytes and plasma cells in splenic tissues. The antibody was used at dilutions between 1:200 and 1:500 in PBS containing 1% bovine serum albumin and incubated with the sections overnight at 4°C. The sections were then washed with PBS and 0.2% Tween 20/PBS, and they were mounted with Glycergel mounting medium (DakoCytomation Inc.).

Statistical analysis.

Statistical significance in hematological data was analyzed by using the Student’s two-tailed t distribution test. Difference in SUVs before and after infection were evaluated using the nonparametric Mann-Whitney U test. Comparisons among the sizes of macrophages were performed by one-way ANOVA with the Sheffe-type multiple comparison method. Probability values < 0.05 were considered significant.

RESULTS

Parasitemia and clinical course.

Parasites were first detected in the peripheral blood of infected Japanese macaques 7–8 days after infection; parasite densities then increased sharply a day or two prior to autopsy. Parasitemias of J-31, J-32, and J-33 were 17.9%, 1.6%, and 37.0%, respectively, on FDG-PET scans (Table 1). J-31 and J-33 initially tolerated malarial infection without behavioral change. Subsequent clinical signs of J-31 and J-33 ranged from partial anorexia to severe manifestations, such as complete anorexia, restlessness, and depression, correlated with the rapid increase in parasitemia, whereas J-32, which had a low level of parasitemia, exhibited no severe manifestations other than mild anorexia.

Hematological findings.

Hematological data for the experimental monkeys at first and second PET scans are shown in Table 1. At the first PET scan, hematocrit (HCT), hemoglobin concentration (HBG), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and mean corpuscular hemoglobin concentration (MCH) levels were 40.0 ± 3.2%, 12.2 ± 0.8 g/dL, 85.5 ± 3.4 fL, 26.2 ± 1.2 pg, and 30.6 ± 0.3% (mean ± SD), respectively. HCT (25.0 ± 3.0%) and HBG (7.5 ± 0.7 g/dL) at the second PET scan were significantly decreased in all infected monkeys (P < 0.05), but MCV, MCH, and MCHC did not differ significantly from the first PET scan (P > 0.05).

The mean blood glucose level at first PET scan was 104.3 ± 20.9 mg/dL. At the second PET scan, blood glucose level was significantly lower in all infected monkeys (67.3 ± 8.3 mg/dL, P < 0.05), but no correlation was found between peripheral parasite count and blood glucose level in the infected monkeys.

FDG uptake (SUV).

Whole-body FDG-PET scanning in the uninfected control monkey revealed no remarkable activation of FDG uptake in any organ (Figure 1, I and II). On the other hand, the infected monkeys clearly exhibited increase in splenic FDG uptake, indicating marked enhancement of glucose metabolism (Figure 1, III, arrow). The increase in FDG uptake in infected monkeys was diffuse throughout the entire spleen, and focal activation was noted in no particular region of the organ (Figure 1, IV, arrow).

Table 1 summarizes the SUV levels of spleen in the four macaques including the uninfected control monkey J-30. The mean level of SUV in uninfected monkeys was 1.6 ± 0.7, whereas the infected monkeys had significantly higher mean SUV levels (5.1 ± 0.6, P < 0.05).

Histopathological findings.

At autopsy, splenomegaly was clearly present in all infected monkeys. The spleen of the infected monkeys was significantly heavier than that of the uninfected control monkey (P < 0.05, Table 1). Dark red color and fragile parenchyma were observed on the cut surface of the spleen in the infected monkeys.

On light-microscopic examination of H&E-stained sections, the organization of white pulp in the infected monkeys was more clear than that in the uninfected control monkey (Figures 2A and 2B). Appearance of and remarkable increase in size of germinal centers were observed in infected monkey spleen. The percentage of white pulp in splenic tissue from the infected monkeys was significantly higher than that in the uninfected control tissue, and the percentage of area occupied by germinal centers in white pulp was also increased and contributed to the increasing white pulp (P < 0.05, Table 1).

In the infected monkeys J-31 and J-33 with high parasitemia, there was massive congestion of parasitized red blood cells (PRBCs), which contained early-to-middle trophozoites, uninfected erythrocytes, and numerous malarial pigments in the venous sinuses and splenic cords of red pulp (Figures 2C and 2D). In addition, macrophages containing malarial pigment were frequently recognized in the red pulp at high magnification (Figures 2E and 2F, arrow). On the other hand, infected monkey J-32 with low parasitemia exhibited scattered pigment in the red pulp (data not shown).

On HLA-DP, DQ, DR immunostaining of white pulp, in the uninfected control tissue, positive reaction was predominantly found in the coronas around germinal centers, and weakly positive reaction was recognized throughout entire germinal center (Figure 3A). In the infected monkeys, however, strongly HLA-DP, DQ, DR positive reaction was recognized throughout the entire germinal center, and a large number of positive cells were scattered over the corona and the marginal zone (Figure 3B).

In an attempt to examine the activity of B lymphocytes in white pulp, immunostaining with anti-IgG antibody was used. In the uninfected control tissue, distinct IgG-positive cells were observed as a prominent ring around the germinal center, which continued along the marginal zone (Figure 3C), whereas strongly IgG-positive reaction was recognized over the entire germinal center in infected monkey tissues (Figure 3D).

On CD68 immunostaining, the splenic macrophages in the infected monkeys were found to be larger than those in the uninfected control tissue (Figures 3E and 3F). The mean sizes with standard deviations of CD68-positive area of each macrophage excluding the nucleus are shown in Figure 4. The mean sizes of CD68-positive area in uninfected control monkey J-30, infected monkey J-32 with low parasitemia, and those with high parasitemia (J-33) were 34.0 ± 17.4 μm2, 60.4 ± 31.9 μm2, and 78.4 ± 26.1 μm2, respectively (Figure 4). Differences among the three groups were significant (P < 0.05).

DISCUSSION

The current study revealed distinct elevation of FDG uptake in the spleen of P. coatneyi–infected acute-phase Japanese macaques. High FDG accumulation in the spleen has been recognized in patients with malignant lymphoma and sarcoidosis18,19 but has not been reported in infectious diseases including malaria. Our study is the first to report marked increase in splenic glucose uptake due to serious malarial infection.

In malarial infection, the spleen plays a critical role in clearance of PRBCs and immunity against blood-stage parasites.20 It is the major site of elimination of PRBCs via erythro-phagocytosis, elaboration of protective immune mechanisms, and hypersensitivity reaction manifesting as splenic enlargement. In the current study, we found characteristic features of malaria in the spleen of infected monkeys. Splenomegaly was clearly detected in all infected monkeys, and histopathologic findings included hyperplasia of lymphoid follicles in white pulp, a large number of activated macrophages, and congestion of PRBCs and malaria pigments in red pulp. Similar histopathological changes in spleen have been observed in patients with acute falciparum malaria and in laboratory experiments using rodent models.21,22 Furthermore, in the current study, P. coatneyi–infected monkeys exhibited increase in splenic FDG uptake indicating marked enhancement of glucose metabolism. Increase in splenic glucose uptake may thus be closely related to activation of splenic clearance systems against blood-stage malarial parasites.

As is well-known, the germinal centers in splenic white pulp are sites of active production of B lymphocytes during antigenic stimulation.23 Proliferation of B lymphocytes in the germinal centers is associated with phenotypic changes and differentiation into plasma cells and memory B lymphocytes. In addition, dendritic cells and macrophages are present in germinal centers, where they present antigens to T lymphocytes.16 Histopathological examination of spleen in the current study revealed enlargement of the germinal centers in infected monkey tissue, which could be discriminated by immunostaining with anti-IgG antibody as well as by specific staining for MHC class II molecules. Although we did not specify the cell type that was positive, it is apparent that the majority of cells in germinal centers were activated B lymphocytes following proliferation, as activated B lymphocytes exhibit positive reaction for both MHC class II molecules and IgG. Scharko and others have studied FDG distribution in activated lymphoid tissues of rhesus macaques after simian immunodeficiency virus infection and showed higher uptake in B cells compared with those in CD4+ and CD8+ T cells.24 Similar observations are found in recent studies on accumulation of FDG in inflammatory tissue.25,26 Therefore, we suggest that one of possible reasons for the increase in splenic FDG uptake of P. coatneyi–infected monkeys may reflect the activation of B lymphocytes in the white pulp.

Kawabe and others observed high FDG uptake by the tonsils and follicular hyperplasia with proliferation of lymphocytes in the germinal centers in chronic tonsillitis and concluded that increased glucose metabolism in active inflammation involving lymphocyte proliferation was a cause of high FDG uptake by tonsils.8 Kato and others also described massive lymphocytic infiltration and lymph follicles at sites of high FDG accumulation in the pancreas.27 The mechanism of cellular FDG uptake in active inflammation involving lymphocyte proliferation is currently not fully understood but is probably related to the fact that lymphocytes use glucose as an energy source during their metabolic activity. We infer from these studies that levels of splenic glucose utilization during acute malaria appear to be affected by lymphocyte proliferation and activation in lymphoid follicles.

A characteristic feature of malaria is the development of splenomegaly associated with splenic macrophage hyperplasia. In a previous study on the mechanism of splenic macrophage hyperplasia, the number of splenic macrophages in P. berghei–infected mice dramatically increased within 4 days after infection.28 On the basis of this study, Wyler and Gallin found that most of the increase in splenic macrophages during acute phase do not appear to derive from local proliferation and suggested that splenic macrophages presumably increase as a result of “trapping” of blood monocytes.28 In the current study, we found a large number of activated macrophages in the enlarged spleen of infected monkeys. In addition, we observed marked increase in splenic FDG uptake, which was diffuse throughout the entire spleen. These findings suggest that both high density and functional activity of splenic macrophages may contribute to high FDG accumulation.

Some studies have investigated FDG uptake and distribution in inflammatory tissue that was induced experimentally in animal models. For instance, Yamada and others demonstrated that subcutaneous injection of turpentine oil could produce inflammation in rats, and high FDG uptake in the inflammatory site was observed.29 In this paper, moreover, they pointed out that grain counting on micro-autoradiography showed a high density was found in neutrophils and macrophages. Ogawa and others reported that macrophages are mainly responsible for the accumulation of FDG in atherosclerotic lesions in experimental animals,30 as atherosclerotic plaque is rich in macrophages and there is a strong correlation between accumulation of FDG and density of macrophages. These findings are direct evidence about increase of activated cellular FDG uptake by inflammatory cells such as macrophage. Therefore, hyperplasia and activation of splenic macrophages in malaria appears to be a cause of high FDG accumulation, and it is thought that splenic macrophages use glucose as an energy source for chemotaxis and phagocytosis.

Another possible reason for the increase in splenic FDG uptake is glucose consumption by the malarial parasite itself. It is known that host glucose is the main energy source for asexual stages of P. falciparum and that the more mature form of the parasite consumes up to 70 to 80 times the amount of glucose required by uninfected erythrocytes in vitro.31,32 Interestingly, in the current study, blood glucose level was significantly lower at second PET scan, whereas splenic FDG level was markedly increased in all infected monkeys. Histologic examination of infected tissue revealed massive congestion by numerous PRBCs in the red pulp. These findings suggest that the increased accumulation of FDG in the spleen of the infected monkeys may have been due to PRBC congestion itself. The parasites appear to consume enormous amounts of glucose as an energy source for development or survival after being trapped in the spleen. The mechanisms of survival of PRBCs in the spleen are not yet clearly understood but might depend upon local alterations of splenic conditions such as pH, glucose concentration, and oxygen partial pressure that influence disruption of PRBCs.33

Our findings demonstrated drastic changes in the tissue of the spleen due to acute P. coatneyi infection, including hyperplasia of splenic lymphoid follicles and macrophages indicating activation of these cells in response to antigenic stimulation. However, several investigators have reported that both activation and suppression of the splenic immune system are observed in primate malaria, rodent malaria, and patients with human malaria.3437 For instance, Kakinuma and others reported that splenic lymphoid follicles from macaques infected with P. knowlesi were small and indistinct, indicating immunosuppresive reaction,34 whereas Abildgaad and others reported that they were large and hyperplastic.35 In addition, Maegraith stated that hyperplasia of lymphocytes was evident in the splenic white pulp during the recovery period and after treatment of human patient with malaria.36 It seems likely that the changes in the splenic immune system are associated with dynamic alterations exhibited by hyperplastic or atrophic cell reactions during different phases of disease. In the current study, we obtained direct evidence for the correlation between glucose uptake and pathologic characteristics of the spleen in the acute phase of malaria. It is possible that level of glucose uptake in the spleen varies depending on disease status during the course of infection. Thus, further studies are needed to characterize the relationships between splenic FDG uptake and disease status of malaria, such as the chronic phase and recovery phase after treatment.

Several authors have demonstrated that many events take place in the spleen during malaria, including changes in histologic, immunologic, and physiologic characteristics.20,21,37,38 Although some techniques have been proposed for noninvasive evaluation of splenic alterations, it is difficult to accurately evaluate physiologic conditions during the course of malaria infection.39,40 PET is one example of such a technique and has the potential to yield the physiologic information necessary not only for diagnosis of cancers or site of inflammation based on altered tissue metabolism but also for monitoring of the effects of treatment on tissue metabolism.7 We recently detected reduction of cerebral metabolism in P. coatneyi–infected Japanese macaques on whole-body FDG-PET.16 Furthermore, in the current study, we determined correlations of splenic glucose uptake and histopathological changes in the same primate model. These findings will improve understanding of physiologic alterations of the host in serious malarial infection. We believe that whole-body FDG-PET may be useful for evaluating and monitoring pathophysiological processes involved in severe malaria.

In conclusion, our findings revealed distinct elevation of FDG uptake in the spleen during the acute phase in a primate model of severe human malaria. We suggest that this increase in FDG uptake in the spleen may be related to both activation of host splenic clearance systems and glucose consumption by congested malarial parasites themselves. Further studies will be needed to determine whether this increase in splenic glucose uptake plays a role in defensive reactions to malarial infection and has any clinical benefit.

Table 1

Hematological and splenic data in the experimental animals

Before infection (first scan)
Animal no. J-30 J-31 J-32 J-33 After infection (second scan)
Age (year)/sex 3/F 3/M 3/F 3/F Mean ± SD J-31 J-32 J-33 Mean ± SD
F, female; M, male; HCT, hematocrit; HGB, hemoglobin; MCV, mean corpuscular volume; fL, femtoliters; MCH, mean corpuscular hemoglobin; HCHC, mean corpuscular hemoglobin concentration; blood glucose, blood glucose level; SUV, standard uptake value; ND, no data.
* P < 0.05, Student’s t test.
HCT (%) 40.3 36.6 38.0 44.9 40.0 ± 3.2 20.7 26.7 27.5 25.0 ± 3.0*
HGB (g/dL) 12.2 11.4 11.7 13.6 12.2 ± 0.8 6.5 8.0 8.0 7.5 ± 0.7*
MCV (fL) 88.2 89.3 80.9 83.5 85.5 ± 3.4 90.8 80.7 87.6 86.4 ± 4.2
MCH (pg) 26.7 27.8 24.9 25.3 26.2 ± 1.2 28.5 24.2 25.5 26.0 ± 1.8
MCHC (%) 30.3 31.1 30.8 30.3 30.6 ± 0.3 31.4 30.0 29.1 30.2 ± 1.0
Blood glucose (mg/dL) 85 108 87 137 104.3 ± 20.9 79 63 60 67.3 ± 8.3*
Parasitemia (%) 17.9 1.6 37.0
SUV in spleen 1.8 0.7 2.3 ND 1.6 ± 0.7 5.1 5.9 4.4 5.1 ± 0.6*
Spleen weight at autopsy (g) 5.5 17.3 11.9 13.2 14.1 ± 2.3
Mean percentage of white pulp (%) 28 41* 42* 39* 40.7 ± 1.2
Figure 1.
Figure 1.

Sagittal and transverse FDG-PET images in a monkey at the level of the spleen before and after P. coatneyi infection. Arrow indicates position of the spleen. I, Sagittal image in J-31 before infection. II, Transverse image in J-31 before infection. III, Sagittal image in infected monkey J-31 with high parasitemia. IV, Transverse image in infected monkey J-31 with high parasitemia. Markedly increased FDG uptake was recognized in this monkey after infection.

Citation: The American Journal of Tropical Medicine and Hygiene Am J Trop Med Hyg 74, 3; 10.4269/ajtmh.2006.74.353

Figure 2.
Figure 2.

H&E-stained sections of spleen of uninfected monkey J-30 (left column: A, C, E) and J-31 infected with P. coatneyi (right column: B, D, F). A and B, The remarkable increase in size of germinal centers contributed significantly to the increase in white pulp in infected monkey tissue. (original magnification ×40, bar = 100 μm). C and D, There was massive congestion of PRBCs, uninfected erythrocytes, and numerous malarial pigments were massively congested in the venous sinuses and splenic cords (original magnification ×100, bar = 100 μm). E and F, Macrophages containing malarial pigment were frequently recognized in the red pulp at high magnification (arrows) (original magnification ×400, bar = 10 μm).

Citation: The American Journal of Tropical Medicine and Hygiene Am J Trop Med Hyg 74, 3; 10.4269/ajtmh.2006.74.353

Figure 3.
Figure 3.

Immunohistochemically-stained sections of spleen of uninfected monkey J-30 (left column: A, C, E) and J-31 infected with P. coatneyi (right column: B, D, F). A and B, White pulp stained with anti-HLA-DP, DQ, DR antibody (g, germinal center; c, corona; mz, marginal zone; r, red pulp) (original magnification ×100, bar = 100 μm). C and D, Immunofluorescence staining of white pulp using anti-monkey IgG antibody (original magnification ×100, bar = 100 μm). E and F, Macrophages in red pulp stained with anti-CD68 antibody (arrows = malarial pigment) (original magnification ×400, bar = 10 μm).

Citation: The American Journal of Tropical Medicine and Hygiene Am J Trop Med Hyg 74, 3; 10.4269/ajtmh.2006.74.353

Figure 4.
Figure 4.

Size of macrophages immunopositive for CD68 in splenic tissues from uninfected monkey J-30, P. coatneyi–infected monkey J-32 with low parasitemia and infected monkey J-33 with high parasitemia. (mean ± SD). *Parasitemia at autopsy.

Citation: The American Journal of Tropical Medicine and Hygiene Am J Trop Med Hyg 74, 3; 10.4269/ajtmh.2006.74.353

*

Address correspondence to Satoru Kawai, Departments of Tropical Medicine and Parasitology, Dokkyo University School of Medicine, Mibu, Tochigi 321-0293, Japan. E-mail: skawai@dokkyomed.ac.jp

Author’s addresses: Satoru Kawai, Jun Matsumoto, and Hajime Matsuda, Departments of Tropical Medicine and Parasitology, Dokkyo University School of Medicine, Mibu, Tochigi 321-0293, Japan, Fax: 81-282-86-6431, E-mails: skawai@dokkyomed.ac.jp, junmatsu222@hotmail.com, and hmatsuda@dokkyomed.ac.jp. Eiji Ikeda, Munehiro Sugiyama, Ken Katakura, and Mamoru Suzuki, Departments of Parasitology, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi 371-8511, Japan, Fax: 81-27-220-8025, E-mails: ikedaeiji@happytown.ne.jp, musugijp@yahoo.co.jp, kenkata@med.gunma-u.ac.jp, and suzuki@med.gunma-u.ac.jp. Tetsuya Higuchi, Hong Zhang, Nasim Khan, and Keigo Endo, Departments of Diagnostic Radiology and Nuclear Medicine, Gunma University School of Medicine, 3-39-22 Showa-machi, Maebashi 371-8511, Japan, Fax: 81-27-220-8025, E-mails: tetsuyah@showa.gunma-u.ac.jp, zhang@med.gunma-u.ac.jp, nasim@med.gunma-u.ac.jp, and endo@pop.med.gunma-u.ac.jp. Katsumi Tomiyoshi, Nishidai Clinic Diagnostic Imaging Center, 1-83-8 Takashimadaira, Tokyo 175-0082, Japan, Fax: 81-282-86-6431, E-mail: tomiyoshi@ncdic.org. Tomio In-oue, Department of Radiology, Yokohama City University School of Medicine, 3-9 Fukuura, Yokohama, Kanagawa 236-0004, Japan, Fax: 81-282-86-6431, E-mail: tomioi@med.yokohama-cu.ac.jp. Haruyasu Yamaguchi, Department of Physical Therapy, Gunma University Graduate School of Health Sciences, 3-39-22 Showa-machi, Maebashi 371-8511, Japan, Fax: 81-27-220-8999, E-mail: yamaguti@health.gunma-u.ac.jp.

Acknowledgments: The authors thank Professor Fumio Goto and Dr. Hideaki Obata for their instruction on anesthesia, Dr. Akihiro Ichikawa, Ms. Erika Misaki, Mr. Nao Taguchi, and Ms. Kyoko Ohta for their help in the experiments, and Dr. Masamichi Aikawa, Dr. Kenjiro Matsuno, Dr. Noboru Oriuchi, and Dr. Hiroshi Kageyama for their valuable advice.

Financial support: This work was supported by grants from the Grant-in-Aid for Scientific Research (A) (11307004) and (C) (12670239) from the Ministry of Education, Science, Sports and Culture, Japan, and a grant for Research on Emerging and Re-emerging Infectious Diseases (H12-Shinkou-17).

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Author Notes

Reprint requests: Satoru Kawai, Departments of Tropical Medicine and Parasitology, Dokkyo University School of Medicine, Mibu, Tochigi 321-0293, Japan, Fax: +81-282-86-6431, E-mail: skawai@dokkyomed.ac.jp.
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