Dendritic cells, pro‐inflammatory responses, and antigen presentation in a rodent malaria infection

Langhorne, Jean; Albano, Frank R.; Hensmann, Meike; Sanni, Latifu A.; Cadman, Emma T.; Voisine, Cécile; Sponaas, Anne‐Marit

doi:10.1111/j.0105-2896.2004.00182.x

Cited by 93 publications

(86 citation statements)

References 122 publications

(218 reference statements)

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“…Plasmodium-specific CD4 T cells not only are important as a source of IFN-γ but also are essential for helping activate both CD8 T cells and B cells, which enhance the host anti-Plasmodium response (53). Although anti-Plasmodium antibody titers and CD8 T-cell populations were not affected by the presence of PMIF during a primary infection, it is not known whether PMIF also alters the ability of CD4 T cells to provide help in activating these adaptive immune cell populations.…”

Section: Discussionmentioning

confidence: 99%

APlasmodium-encoded cytokine suppresses T-cell immunity during malaria

Sun¹,

Holowka²,

Song³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

116

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The inability to acquire protective immunity against Plasmodia is the chief obstacle to malaria control, and inadequate T-cell responses may facilitate persistent blood-stage infection. Malaria is characterized by a highly inflammatory cytokine milieu, and the lack of effective protection against infection suggests that memory T cells are not adequately formed or maintained. Using a genetically targeted strain of Plasmodium berghei, we observed that the Plasmodium ortholog of macrophage migration inhibitory factor enhanced inflammatory cytokine production and also induced antigen-experienced CD4 T cells to develop into short-lived effector cells rather than memory precursor cells. The short-lived effector CD4 T cells were more susceptible to Bcl-2–associated apoptosis, resulting in decreased CD4 T-cell recall responses against challenge infections. These findings indicate that Plasmodia actively interfere with the development of immunological memory and may account for the evolutionary conservation of parasite macrophage migration inhibitory factor orthologs.

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Section: Discussionmentioning

confidence: 99%

APlasmodium-encoded cytokine suppresses T-cell immunity during malaria

Sun¹,

Holowka²,

Song³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

116

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“…4C, Lower). Nucleic acid-sensing TLRs (e.g., TLR9, TLR7) are highly expressed on dendritic cells (DCs) and were shown to be activated by Plasmodium products that play a relevant role in malaria pathogenesis (18,30,31). We thus sought to identify the effect of E6446 on cytokines produced by myeloid CD11c + MHCII + DCs using a flow cytometry (FACS) assay for intracellular cytokine staining.…”

Section: E6446 Prevents Hyperresponsiveness Of Tlrs and Lps-induced Smentioning

confidence: 99%

Therapeutical targeting of nucleic acid-sensing Toll-like receptors prevents experimental cerebral malaria

Franklin

Ishizaka

Lamphier

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

106

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Excessive release of proinflammatory cytokines by innate immune cells is an important component of the pathogenic basis of malaria. Proinflammatory cytokines are a direct output of Toll-like receptor (TLR) activation during microbial infection. Thus, interference with TLR function is likely to render a better clinical outcome by preventing their aberrant activation and the excessive release of inflammatory mediators. Herein, we describe the protective effect and mechanism of action of E6446, a synthetic antagonist of nucleic acid-sensing TLRs, on experimental cerebral malaria (ECM) induced by Plasmodium berghei ANKA. We show that in vitro, low doses of E6446 specifically inhibited the activation of human and mouse TLR9. Tenfold higher concentrations of this compound also inhibited the human TLR8 response to single-stranded RNA. In vivo, therapy with E6446 diminished the activation of TLR9 and prevented the exacerbated cytokine response observed during acute Plasmodium infection. Furthermore, severe signs of ECM, such as limb paralysis, brain vascular leak, and death, were all prevented by oral treatment with E6446. Hence, we provide evidence that supports the involvement of nucleic acid-sensing TLRs in malaria pathogenesis and that interference with the activation of these receptors is a promising strategy to prevent deleterious inflammatory responses that mediate pathogenesis and severity of malaria.immunotherapy | innate immunity | nucleic acid recognition | inflammation

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“…Given the overwhelming evidence for a crucial role for IFN-␥ in controlling acute murine malaria infections (23,25,54), we considered the possibility that failure to produce IFN-␥ in the initial few days of lethal P. yoelii infection might explain the very rapid parasite growth. In apparent support of this possibility, and consistent with patterns of NK activation, an early burst of IFN-␥ was observed in the plasma of PyNL-infected (but not PyL-infected) mice on day 1 p.i.…”

Section: P Yoelii-induced T-cell Hyporesponsiveness Is Both Cd11bmentioning

confidence: 99%

“…Proinflammatory cytokines are essential for the control of intraerythrocytic Plasmodium infections in humans and in experimental animals (23,25,54). Antigen-presenting cells (APCs) produce interleukin 12 (IL-12), IL-15, IL-18, and tumor necrosis factor alpha (TNF-␣) (17,26,31,32,37,38,40,44,45,48), which can rapidly activate cells of the innate immune system to produce gamma interferon (IFN-␥) (31,32,44,64).…”

mentioning

confidence: 99%

Macrophage-Mediated but Gamma Interferon-Independent Innate Immune Responses Control the Primary Wave ofPlasmodium yoeliiParasitemia

et al. 2007

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In most models of blood-stage malaria infection, proinflammatory immune responses are required for control of infection and elimination of parasites. We hypothesized therefore that the fulminant infections caused in mice by the lethal strain of Plasmodium yoelii (17XL) might be due to failure to activate a sufficient inflammatory response. Here we have compared the adaptive CD4 ؉ T-cell and innate immune response to P. yoelii 17XL with that induced by the self-resolving, nonlethal strain of P. yoelii, 17X(NL). During the first 7 to 9 days of infection, splenic effector CD4 ؉ T-cell responses were similar in mice with lethal and nonlethal infections with similar levels of activation in vivo and equivalent proliferation in vitro following mitogenic stimulation. Nonspecific T-cell hyporesponsiveness was observed at similar levels during both infections and was due, in part, to suppression mediated by CD11b ؉ cells. Importantly, however, RAG ؊/؊ mice were able to control the initial growth phase of nonlethal P. yoelii infection as effectively as wild-type mice, indicating that T cells and/or B cells play little, if any, role in control of the primary peak of parasitemia. Somewhat unexpectedly, we could find no clear role for either NK cells or gamma interferon (IFN-␥) in controlling primary P. yoelii infection. In contrast, depletion of monocytes/macrophages exacerbated parasite growth and anemia during both lethal and nonlethal acute P. yoelii infections, indicating that there is an IFN-␥-, NK cell-, and T-cell-independent pathway for induction of effector macrophages during acute malaria infection.

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Dendritic cells, pro‐inflammatory responses, and antigen presentation in a rodent malaria infection

Cited by 93 publications

References 122 publications

APlasmodium-encoded cytokine suppresses T-cell immunity during malaria

APlasmodium-encoded cytokine suppresses T-cell immunity during malaria

Therapeutical targeting of nucleic acid-sensing Toll-like receptors prevents experimental cerebral malaria

Macrophage-Mediated but Gamma Interferon-Independent Innate Immune Responses Control the Primary Wave ofPlasmodium yoeliiParasitemia

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