IL-10 plays a crucial role for the protection of experimental cerebral malaria by co-infection with non-lethal malaria parasites

Niikura, Mamoru; Kamiya, Shigeru; Nakane, Akio; Kita, Kiyoshi; Kobayashi, Fuminori

doi:10.1016/j.ijpara.2009.08.009

Cited by 27 publications

(30 citation statements)

References 32 publications

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“…In contrast, pregnant mice showed higher levels of the anti-inflammatory cytokine IL-10 than did nonpregnant mice. A previous study showed that IL-10 is involved in suppression of immunopathology, such as liver injury (23,39) and experimental cerebral malaria (40,41). However, it was also shown that suppression of immunopathology is mediated by CD4 ϩ natural regulatory T cells but not IL-10 (42).…”

Section: Discussionmentioning

confidence: 99%

Development of Severe Pathology in Immunized Pregnant Mice Challenged with Lethal Malaria Parasites

et al. 2013

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b Pregnant women are highly susceptible to malaria infection because of their low immunity and are at increased risk of maternal illness or death, in addition to spontaneous abortion, stillbirth, premature delivery, and low birth weight. However, the detailed pathogenesis of maternal malaria remains unclear. In this study, we evaluated a mouse model that shows similar severe pathological features of pregnant women during Plasmodium falciparum infection and investigated the pathogenesis of maternal malaria. Pregnant mice immunized by infection with an attenuated parasite, Plasmodium berghei XAT, were more susceptible to virulent P. berghei NK65 challenge/infection than were nonpregnant mice and showed high levels of parasitemia and a poor pregnancy outcome associated with placental pathology, such as accumulation of parasitized red blood cells, in the late phase of pregnancy. Notably, the pregnant immune mice challenged/infected with P. berghei NK65 developed liver injury associated with microvesicular fatty infiltration in late pregnancy. The pathological features were similar to acute fatty liver of pregnancy. Higher levels of gamma interferon and nitric oxide (NO) were found in plasma from pregnant immune mice infected with P. berghei NK65 than in plasma from nonpregnant mice. These findings suggest that development of liver injury and placental pathology in pregnant immune mice challenged/infected with P. berghei NK65 is accompanied by enhanced production of proinflammatory cytokines. Malaria is the most devastating parasitic disease of humans in tropical and subtropical regions, resulting in an estimated 0.6 to 1 million deaths per year (1). The populations at greatest risk of developing severe pathology are children under the age of 5 years and pregnant women in areas where Plasmodium falciparum is endemic (2-4). Every year, approximately 50 million women living in areas where malaria is endemic become pregnant. An estimated 10,000 of these women and 200,000 of their fetuses or infants die annually as a result of malaria during pregnancy (1, 2). Malaria during pregnancy is a major public health problem in areas of endemicity, especially in Africa.People living in regions where malaria is endemic acquire protective immunity against malaria parasites and often show asymptomatic infection. However, women are highly susceptible to malaria infection because of their low immunity during pregnancy and are at increased risk of maternal illness or death (5, 6). Malaria during pregnancy, in addition to maternal illness or death, is implicated in the occurrence of spontaneous abortion, stillbirth, premature delivery, and low birth weight (6). Recently, it has been demonstrated that pregnant mice infected with lethal Plasmodium berghei parasites show a feature similar to placental pathology and subsequently poor pregnancy outcome (7,8).Cerebral malaria (CM) or respiratory distress syndrome has been reported to be an infrequent but relevant cause of maternal death in women living in an area of sub-Saharan Africa where m...

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Section: Discussionmentioning

confidence: 99%

Development of Severe Pathology in Immunized Pregnant Mice Challenged with Lethal Malaria Parasites

et al. 2013

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“…IL-10 suppresses a Th1 response and has been shown in multiple studies to play a major role in preventing ECM (28,33,34,75). To investigate whether STAg-induced protection against ECM requires IL-10, we infected IL-10 Ϫ/Ϫ mice with P. berghei ANKA and treated mice with STAg after 24 h. STAg treatment was just as effective in wild-type (wt) and IL-10 Ϫ/Ϫ mice, as evidenced by similar percent survivals (Fig.…”

Section: Stag Treatment Alone and Stag Treatment Of P Berghei-infecmentioning

confidence: 99%

“…IL-12 induces downstream cytokines that mediate the immune response during Plasmodium infection. IL-12 induces IL-10 production (80), and IL-10 plays a major role in preventing ECM (28,33,34,76). Due to the immunosuppressive nature of IL-10, the induction of IL-10 could have prevented the localization of T cells to the brain.…”

Section: Anka-infected Il-12␤rmentioning

confidence: 99%

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Toxoplasma gondii Upregulates Interleukin-12 To Prevent Plasmodium berghei-Induced Experimental Cerebral Malaria

et al. 2014

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A chronic infection with the parasite Toxoplasma gondii has previously been shown to protect mice against subsequent viral, bacterial, or protozoal infections. Here we have shown that a chronic T. gondii infection can prevent Plasmodium berghei ANKA-induced experimental cerebral malaria (ECM) in C57BL/6 mice. Treatment with soluble T. gondii antigens (STAg) reduced parasite sequestration and T cell infiltration in the brains of P. berghei-infected mice. Administration of STAg also preserved blood-brain barrier function, reduced ECM symptoms, and significantly decreased mortality. STAg treatment 24 h post-P. berghei infection led to a rapid increase in serum levels of interleukin 12 (IL-12) and gamma interferon (IFN-␥). By 5 days after P. berghei infection, STAg-treated mice had reduced IFN-␥ levels compared to those of mock-treated mice, suggesting that reductions in IFN-␥ at the time of ECM onset protected against lethality. Using IL-10-and IL-12␤R-deficient mice, we found that STAg-induced protection from ECM is IL-10 independent but IL-12 dependent. Treatment of P. berghei-infected mice with recombinant IL-12 significantly decreased parasitemia and mortality. These data suggest that IL-12, either induced by STAg or injected as a recombinant protein, mediates protection from ECM-associated pathology potentially through early induction of IFN-␥ and reduction in parasitemia. These results highlight the importance of early IL-12 induction in protection against ECM.

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“…For example, mouse models, which do suffer from some obvious limitations (62), can serve as powerful tools for genetic, molecular, and biochemical analyses of immune-mediated responses to pathogens (28,29). Moreover, the availability of "knockout" mouse strains lacking genes and proteins that are critical for certain immune responses can help us identify more accurately the role of these molecules in immune resistance to specific pathogens (32,41,48,51).…”

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confidence: 99%

Protein Kinase C θ Deficiency Increases Resistance of C57BL/6J Mice toPlasmodium bergheiInfection-Induced Cerebral Malaria

et al. 2010

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Protein kinase C (PKC) functions as a core component of the immunological synapse and serves as a key protein in the integrated T-cell antigen receptor (TCR)/CD28-induced signaling cascade leading to T-cell activation. However, the involvement of PKC in host-mediated immune responses to pathogens has not been thoroughly investigated. We tested the consequences of PKC ablation on the host response to infection by Plasmodium berghei ANKA (PbA). We found that both PKC ؉/؉ and PKC ؊/؊ C57BL/6J mice are susceptible to infection with PbA. However, despite a similar parasite burden, PKC ؉/؉ mice had an earlier onset of neurological signs, characteristics of experimental cerebral malaria (ECM), resulting in an earlier death. These mice suffered from an early and pronounced splenomegaly with a concomitant increase in the total number of CD4 ؉ splenic T cells. In contrast, a large proportion of PbA-infected PKC ؊/؊ mice overcame the acute phase characterized by neurological symptoms and survived longer than PKC ؉/؉ mice. The partial resistance of PKC ؊/؊ mice to ECM was associated with an impaired production of Th1-type cytokines, including gamma interferon and tumor necrosis factor alpha/lymphotoxin-␣, which are known to exacerbate symptoms leading to ECM. In addition, PbA infection-induced LFA-1 expression in CD8 ؉ T cells was suppressed in PKC-deficient T cells, suggesting a diminished ability to adhere to endothelial cells and sequester in brain microvasculature, which may explain the decrease in neurological symptoms. These data implicate PKC in CD4 ؉ Th1 ؉ and CD8 ؉ T-cell-mediated immune responses during PbA infection that contribute to the development of ECM.

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IL-10 plays a crucial role for the protection of experimental cerebral malaria by co-infection with non-lethal malaria parasites

Cited by 27 publications

References 32 publications

Development of Severe Pathology in Immunized Pregnant Mice Challenged with Lethal Malaria Parasites

Development of Severe Pathology in Immunized Pregnant Mice Challenged with Lethal Malaria Parasites

Toxoplasma gondii Upregulates Interleukin-12 To Prevent Plasmodium berghei-Induced Experimental Cerebral Malaria

Protein Kinase C θ Deficiency Increases Resistance of C57BL/6J Mice toPlasmodium bergheiInfection-Induced Cerebral Malaria

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