CD40 Is Required for Protective Immunity against Liver Stage <i>Plasmodium</i> Infection

Murray, Scott O.; Mohar, Isaac; Miller, Jessica L.; Brempelis, Katherine J.; Vaughan, Ashley M.; Kappe, Stefan H. I.

doi:10.4049/jimmunol.1401724

Cited by 17 publications

(20 citation statements)

References 84 publications

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“…At day 11–15 p . i ., CD40-CD40L ligation, activation of NFκB in APCs, and recruitment of CD8+ T-cells, as reported previously [ 34 ], were likely to play a role in host survival. It would be interesting to investigate how the spike of day 2 IFN-I affects the adaptive immune response, including the effects of higher CD40 level on T-cell activation and isotype switching.…”

Section: Discussionsupporting

confidence: 72%

“…In malaria infection, CD40 was reported to be necessary for the maturation of liver DCs and for the accumulation of CD8 + T cells in the liver in response to the invading P . yoelii sporozoites [ 34 ]. Mice without CD40 were not able to withstand infectious challenge after immunization with a P .…”

Section: Discussionmentioning

confidence: 99%

“…CD40 is required for the maturation of liver dendritic cells, accumulation of CD8 + T cells in the liver, and effective APC licensing during P . yoelii sporozoite infection [ 34 ]. Activation and ligation of CD40 and CD40L are also associated with many neurologic and autoimmune diseases that are characterized by elevated levels of IFN-I [ 28 , 29 , 36 , 37 ].…”

Section: Introductionmentioning

confidence: 99%

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Increased CD40 Expression Enhances Early STING-Mediated Type I Interferon Response and Host Survival in a Rodent Malaria Model

Yao

Lin

et al. 2016

PLoS Pathog

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Both type I interferon (IFN-I) and CD40 play a significant role in various infectious diseases, including malaria and autoimmune disorders. CD40 is mostly known to function in adaptive immunity, but previous observations of elevated CD40 levels early after malaria infection of mice led us to investigate its roles in innate IFN-I responses and disease control. Using a Plasmodium yoelii nigeriensis N67 and C57BL/6 mouse model, we showed that infected CD40-/- mice had reduced STING and serum IFN-β levels day-2 post infection, higher day-4 parasitemia, and earlier deaths. CD40 could greatly enhance STING-stimulated luciferase signals driven by the IFN-β promoter in vitro, which was mediated by increased STING protein levels. The ability of CD40 to influence STING expression was confirmed in CD40-/- mice after malaria infection. Substitutions at CD40 TRAF binding domains significantly decreased the IFN-β signals and STING protein level, which was likely mediated by changes in STING ubiquitination and degradation. Increased levels of CD40, STING, and ISRE driven luciferase signal in RAW Lucia were observed after phagocytosis of N67-infected red blood cells (iRBCs), stimulation with parasite DNA/RNA, or with selected TLR ligands [LPS, poly(I:C), and Pam3CSK4]. The results suggest stimulation of CD40 expression by parasite materials through TLR signaling pathways, which was further confirmed in bone marrow derived dendritic cells/macrophages (BMDCs/BMDMs) and splenic DCs from CD40-/-, TLR3-/- TLR4-/-, TRIF-/-, and MyD88-/- mice after iRBC stimulation or parasite infection. Our data connect several signaling pathways consisting of phagocytosis of iRBCs, recognition of parasite DNA/RNA (possibly GPI) by TLRs, elevated levels of CD40 and STING proteins, increased IFN-I production, and longer host survival time. This study reveals previously unrecognized CD40 function in innate IFN-I responses and protective pathways in infections with malaria strains that induce a strong IFN-I response, which may provide important information for better understanding and management of malaria.

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Section: Discussionsupporting

confidence: 72%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Increased CD40 Expression Enhances Early STING-Mediated Type I Interferon Response and Host Survival in a Rodent Malaria Model

Yao

Lin

et al. 2016

PLoS Pathog

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“…through several distinct roles in T cell activation and T cell interaction with other immune cells. In a mouse model of immunity to liver stage plasmodial infection, CD40 had been shown to be critical for the full maturation of liver dendritic cells, accumulation of CD8(+) T cells in the liver, and protective immunity [19].…”

Section: Discussionmentioning

confidence: 99%

DNA Gene Expression to Study Immunologic Mechanisms for the Long-Term Cure of Malaria in Babies and Children in South-Western Nigeria

Thornthwaite¹,

Olufemi²,

Ademola³

et al. 2019

ABC

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Malaria infection has been a very serious public health problem in Nigeria and most parts of Africa. Development of antimalarial treatments capable of providing a permanent cure for malaria has been a herculean task for drug researchers. A trial of a novel, proprietary blend formulation (Triantimal TM) in gel caps for children (n = 112) and water-soluble, 18.51 nm diameter, Nu-traNanoSphere TM encapsulated Triantimal TM drops for babies (19.9 Months ± 8.7 SD, n = 15) was conducted in Osogbo, Nigeria. The enrolled subjects were screened for malaria, treated with Triantimal TM for 16 consecutive days and sera collected on days 0, 5, 10, 16, 30, 60, and 730. Also, 31 of the children donated buffy coat samples for the gene expression studies when sera were collected. The children showed 90.2% parasite-free at 60 days and 85.1% at 730 days. The babies revealed 93.3% parasite-free at 60 days. These data show for the first time a real possibility for a cure of malaria in Nigeria. The one-time, low dose, extended treatment and synergism of the natural components minimize the ability of the parasites to develop resistance, while boosting the immune system. Indeed, the DNA amplification data showed that all aspects of the humoral, innate, and innate defensin immunity are involved in the long-term immunity against P. falciparum in which may be termed a type of "in vivo immunization".

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“…A more detailed study showed that the two major splenic DCs subsets (CD8 α + CD11b − and CD8 α − CD11b + ) induced IFN γ producing CD8 + T cells specific for the circumsporozoite protein, the major sporozoite surface protein [ 72 ]. In addition, the CD8 + T cell protective response against a genetically modified P. yoelii strain was shown to be dependent on effective DC maturation obtained through CD40 signaling [ 73 ]. The fact that DCs are able to induce CD8 + T cell responses against antigens expressed in the preerythrocytic stage seems undisputable.…”

Section: Role Of Dendritic Cells During Plasmodium mentioning

confidence: 99%

Dendritic Cells and Their Multiple Roles during Malaria Infection

Amorim

Chagas

Sulczewski

et al. 2016

Journal of Immunology Research

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Dendritic cells (DCs) play a central role in the initiation of adaptive immune responses, efficiently presenting antigens to T cells. This ability relies on the presence of numerous surface and intracellular receptors capable of sensing microbial components as well as inflammation and on a very efficient machinery for antigen presentation. In this way, DCs sense the presence of a myriad of pathogens, including Plasmodium spp., the causative agent of malaria. Despite many efforts to control this infection, malaria is still responsible for high rates of morbidity and mortality. Different groups have shown that DCs act during Plasmodium infection, and data suggest that the phenotypically distinct DCs subsets are key factors in the regulation of immunity during infection. In this review, we will discuss the importance of DCs for the induction of immunity against the different stages of Plasmodium, the outcomes of DCs activation, and also what is currently known about Plasmodium components that trigger such activation.

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CD40 Is Required for Protective Immunity against Liver Stage Plasmodium Infection

Cited by 17 publications

References 84 publications

Increased CD40 Expression Enhances Early STING-Mediated Type I Interferon Response and Host Survival in a Rodent Malaria Model

Increased CD40 Expression Enhances Early STING-Mediated Type I Interferon Response and Host Survival in a Rodent Malaria Model

DNA Gene Expression to Study Immunologic Mechanisms for the Long-Term Cure of Malaria in Babies and Children in South-Western Nigeria

Dendritic Cells and Their Multiple Roles during Malaria Infection

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