Serum cytokine profiles in experimental human malaria. Relationship to protection and disease course after challenge.

Harpaz, Rafael; Edelman, Robert; Wasserman, Steven S.; Levine, Fred; Davis, Jean E.; Sztein, Marcelo B.

doi:10.1172/jci115889

Cited by 81 publications

(48 citation statements)

References 65 publications

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“…7 These observations agree with previous conclusions based on pathologic studies of humans and murine models that implicate an overproduction of proinflammatory and TH-1 cytokines as an important factor in the immunopathogenesis of cerebral malaria. 7,[13][14][15][16][17][18]22 Results of this study indicate differences in local cytokine response in various regions of the brain after plasmodial infection. The proinflammatory cytokines (IL-1␤ and TNF-␣) and TH-1 cytokine (IFN-␥) had the highest levels of mRNA expression in the cerebellum during late P. coatneyi infection in rhesus monkeys.…”

Section: Discussionmentioning

confidence: 99%

Expression of proinflammatory cytokines in four regions of the brain in Macaque mulatta (rhesus) monkeys infected with Plasmodium coatneyi.

Tongren

Yang²,

Collins³

et al. 2000

The American Journal of Tropical Medicine and Hygiene

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Abstract. We have characterized brain cytokine expression profiles in the Plasmodium coatneyi/rhesus (Macaque mulatta) malaria model. Eight rhesus monkeys were included in the study; four were infected with P. coatneyi, and four were used as uninfected controls. All inoculated animals became infected. Eleven days after parasite inoculation, the rhesus monkeys were killed and tissue samples from 4 regions of the brain (cortex and white matter of the cerebrum, cerebellum, and midbrain) were collected for quantitation of mRNA expression of cytokines, adhesion molecules, and inducible nitric oxide synthetase (iNOS) by reverse transcriptase-polymerase chain reaction (RT-PCR). The expression levels of tumor necrosis actor-alpha (TNF-␣), gamma interferon (IFN-␥), interleukin-1-beta (IL-1␤), intercellular adhesion molecule-1 (ICAM-1) and inducible nitric oxide synethetase (iNOS) were highest in the cerebellum of infected animals, correlating well with pathologic observations of sequestration of parasitized erythrocytes in this region of the brain. Infected animals also had higher TNF-␣ expression levels in the cortex and IL-1␤ expression levels in the cortex, white matter, and midbrain. Thus, the expression of pro-inflammatory and T helper-1 (TH-1) cytokines, adhesion molecules, and iNOS appears to predominate in the cerebellum of infected rhesus monkeys.

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Section: Discussionmentioning

confidence: 99%

Expression of proinflammatory cytokines in four regions of the brain in Macaque mulatta (rhesus) monkeys infected with Plasmodium coatneyi.

Tongren

Yang²,

Collins³

et al. 2000

The American Journal of Tropical Medicine and Hygiene

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“…Human studies have also reported a putatively protective role of IL-6 during malarial infection. For example, an early increase in IL-6 was recorded in volunteers vaccinated with irradiated sporozoites and later challenged with Plasmodium falciparum (52). These volunteers were fully protected from malarial infection.…”

Section: Figmentioning

confidence: 99%

Protective Effect of Chronic Schistosomiasis in Baboons Coinfected with Schistosoma mansoni and Plasmodium knowlesi

et al. 2016

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c Malaria and schistosomiasis coinfections are common, and chronic schistosomiasis has been implicated in affecting the severity of acute malaria. However, whether it enhances or attenuates malaria has been controversial due the lack of appropriately controlled human studies and relevant animal models. To examine this interaction, we conducted a randomized controlled study using the baboon (Papio anubis) to analyze the effect of chronic schistosomiasis on severe malaria. Two groups of baboons (n ‫؍‬ 8 each) and a schistosomiasis control group (n ‫؍‬ 3) were infected with 500 Schistosoma mansoni cercariae. At 14 and 15 weeks postinfection, one group was given praziquantel to treat schistosomiasis infection. Four weeks later, the two groups plus a new malaria control group (n ‫؍‬ 8) were intravenously inoculated with 10 5 Plasmodium knowlesi parasites and monitored daily for development of severe malaria. A total of 81% of baboons exposed to chronic S. mansoni infection with or without praziquantel treatment survived malaria, compared to only 25% of animals infected with P. knowlesi only (P ‫؍‬ 0.01). Schistosome-infected animals also had significantly lower parasite burdens (P ‫؍‬ 0.004) than the baboons in the P. knowlesi-only group and were protected from severe anemia. Coinfection was associated with increased spontaneous production of interleukin-6 (IL-6), suggesting an enhanced innate immune response, whereas animals infected with P. knowlesi alone failed to develop mitogen-driven tumor necrosis factor alpha and IL-10, indicating the inability to generate adequate protective and balancing immunoregulatory responses. These results indicate that chronic S. mansoni attenuates the severity of P. knowlesi coinfection in baboons by mechanisms that may enhance innate immunity to malaria. P olyparasitism is common in low-resource countries, especially in sub-Saharan Africa. Coinfections may alter disease outcomes and affect both drug and vaccine efficacies (1, 2). The majority of studies on coinfections have focused on interactions between malaria and chronic helminth infections. Interest in studying malaria and schistosomiasis, in particular, comes from the major overlap of the two diseases in areas where they are endemic and the fact that these infections account for a large proportion of global morbidity and mortality (3, 4). Because of the chronicity of schistosome infection, most studies have focused on its impact on susceptibility to clinical malaria.Studies on malaria and schistosomiasis coinfections in human and animal models have generated contradicting results. Although some animal studies have shown that chronic schistosomiasis protects against severe malaria (5), others have reported that a concurrent schistosome infection enhances the severity of malaria (6-10). Many factors may account for these differences, including mouse strain, duration and intensity of the helminth infection, Plasmodium strain or species, inoculum size, or route of malaria infection (skin or blood stage) (11). An important limitat...

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“…Furthermore, it is becoming clear that innate responses can differ between individuals (25,36) with potential clinical implications. To date, only two-rather small-studies have exploited the unique opportunity offered by experimental infection of malaria-naive volunteers (during the evaluation of antimalarial vaccines) to study the very early stages of the immune response to malaria (37,38), and it has been difficult to draw any generalizable conclusions from them. Here, we present a detailed longitudinal analysis of 11 different cytokine responses in 18 experimentally infected individuals, using a highly sensitive, bead-based multiplex assay, and we compare these responses with peripheral parasite densities, as measured by quantitative real-time PCR (39).…”

Section: R Esearch On the Immunology Of Malaria Infection Has Beenmentioning

confidence: 99%

Innate Immune Responses to Human Malaria: Heterogeneous Cytokine Responses to Blood-Stage Plasmodium falciparum Correlate with Parasitological and Clinical Outcomes

Walther

Woodruff

Edele

et al. 2006

The Journal of Immunology

142

118

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Taking advantage of a sporozoite challenge model established to evaluate the efficacy of new malaria vaccine candidates, we have explored the kinetics of systemic cytokine responses during the prepatent period of Plasmodium falciparum infection in 18 unvaccinated, previously malaria-naive subjects, using a highly sensitive, bead-based multiplex assay, and relate these data to peripheral parasite densities as measured by quantitative real-time PCR. These data are complemented with the analysis of cytokine production measured in vitro from whole blood or PBMC, stimulated with P. falciparum-infected RBC. We found considerable qualitative and quantitative interindividual variability in the innate responses, with subjects falling into three groups according to the strength of their inflammatory response. One group secreted moderate levels of IFN-γ and IL-10, but no detectable IL-12p70. A second group produced detectable levels of circulating IL-12p70 and developed very high levels of IFN-γ and IL-10. The third group failed to up-regulate any significant proinflammatory responses, but showed the highest levels of TGF-β. Proinflammatory responses were associated with more rapid control of parasite growth but only at the cost of developing clinical symptoms, suggesting that the initial innate response may have far-reaching consequences on disease outcome. Furthermore, the in vitro observations on cytokine kinetics presented here, suggest that intact schizont-stage infected RBC can trigger innate responses before rupture of the infected RBC.

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Serum cytokine profiles in experimental human malaria. Relationship to protection and disease course after challenge.

Cited by 81 publications

References 65 publications

Expression of proinflammatory cytokines in four regions of the brain in Macaque mulatta (rhesus) monkeys infected with Plasmodium coatneyi.

Expression of proinflammatory cytokines in four regions of the brain in Macaque mulatta (rhesus) monkeys infected with Plasmodium coatneyi.

Protective Effect of Chronic Schistosomiasis in Baboons Coinfected with Schistosoma mansoni and Plasmodium knowlesi

Innate Immune Responses to Human Malaria: Heterogeneous Cytokine Responses to Blood-Stage Plasmodium falciparum Correlate with Parasitological and Clinical Outcomes

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