Humoral and Cellular Immunity to Plasmodium falciparum Merozoite Surface Protein 1 and Protection From Infection With Blood-Stage Parasites

Moormann, Ann M.; Sumba, Peter Odada; Chelimo, Kiprotich; Fang, Hua; Tisch, Daniel J.; Dent, Arlene E.; John, Chandy C.; Long, Carole A.; Vulule, John; Kazura, James W.

doi:10.1093/infdis/jit134

Cited by 32 publications

(36 citation statements)

References 48 publications

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“…Several studies carried out in low-, medium-, and high-transmission areas have measured the time required for Plasmodium parasites to reappear in the blood of individuals after parasitemia has been cleared with blood-stagespecific antimalarial compounds (14,15,21,30,(44)(45)(46)(47). Interestingly, these and other modeling studies have revealed a discrepancy between the estimated number of infective bites per human per time unit (i.e., the EIR) and the resulting force of infection (FOI; i.e., the rate of new blood-stage infections) (16,33).…”

Section: Induction Of Type I Ifn and Ifn-␥ By A First P Berghei Livementioning

confidence: 99%

Innate Immunity Induced by Plasmodium Liver Infection Inhibits Malaria Reinfections

et al. 2015

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bFollowing transmission through a mosquito bite to the mammalian host, Plasmodium parasites first invade and replicate inside hepatocytes before infecting erythrocytes and causing malaria. The mechanisms limiting Plasmodium reinfections in humans living in regions of malaria endemicity have mainly been explored by studying the resistance induced by the blood stage of infection. However, epidemiologic studies have suggested that in high-transmission areas, preerythrocytic stages also activate host resistance to reinfection. This, along with the recent discovery that liver infections trigger a specific and effective type I interferon (IFN) response, prompted us to hypothesize that this pre-erythrocyte-stage-induced resistance is linked to liver innate immunity. Here, we combined experimental approaches and mathematical modeling to recapitulate field studies and understand the molecular basis behind such resistance. We present a newly established mouse reinfection model and demonstrate that rodent malaria liver-stage infection inhibits reinfection. This protection relies on the activation of innate immunity and involves the type I IFN response and the antimicrobial cytokine gamma IFN (IFN-␥). Importantly, mathematical simulations indicate that the predictions based on our experimental murine reinfection model fit available epidemiological data. Overall, our study revealed that liver-stage-induced innate immunity may contribute to the preerythrocytic resistance observed in humans in regions of malaria hyperendemicity. Malaria accounts for over half a million deaths per year and is thus the most prevalent parasitic human disease worldwide (1). The disease is caused by an intracellular protozoan parasite of the genus Plasmodium that infects multiple hosts, such as Anopheles mosquitoes and humans and other mammalians (2). Infection begins with a bite of a female mosquito that injects a few Plasmodium sporozoites, which represent the mosquito-transmitted parasite form, into the skin of the mammalian host. After migrating through skin cells (3), sporozoites enter the bloodstream and are then rapidly and specifically retained in the liver sinusoids. Sporozoites then cross the sinusoidal barrier (4) and traverse several liver cells until individual parasites invade a final hepatocyte with the formation of a parasitophorous vacuole (5). Inside this vacuolar niche, sporozoites asymptomatically develop and replicate into thousands of erythrocyte-infective parasites, termed merozoites (6). Finally, merozoites are released into the bloodstream and rapidly infect erythrocytes, initiating the blood stage and the clinical phase of infection (7).Malaria reinfections are common, especially in regions of high malaria transmission. Plasmodium parasites present an extraordinarily high rate of polymorphism; consequently, the host can be reinfected by different parasites that repeatedly escape the immune response (8). Therefore, efficient immunity to reinfection in one individual is obtained only after many years of facing recurrent infe...

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Section: Induction Of Type I Ifn and Ifn-␥ By A First P Berghei Livementioning

confidence: 99%

Innate Immunity Induced by Plasmodium Liver Infection Inhibits Malaria Reinfections

et al. 2015

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“…These cytokines facilitate immune priming and can influence whether the immune response promotes the onset of immunity or assists immune escape. DC-generated IL-12 can drive T cell IFN-␥ secretion and promote cytotoxic capacity (15), as well as facilitate the development of clinical immunity to malaria (16)(17)(18)(19). TNF can promote the maturation and survival of DCs in vitro (20,21), but in circulating blood TNF is not sufficient for maturation of CD1c ϩ mDCs (9).…”

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confidence: 99%

Profoundly Reduced CD1c ⁺ Myeloid Dendritic Cell HLA-DR and CD86 Expression and Increased Tumor Necrosis Factor Production in Experimental Human Blood-Stage Malaria Infection

et al. 2016

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dDendritic cells (DCs) are sentinels of the immune system that uniquely prime naive cells and initiate adaptive immune responses. CD1c (BDCA-1) myeloid DCs (CD1c ؉ mDCs) highly express HLA-DR, have a broad Toll-like receptor (TLR) repertoire, and secrete immune modulatory cytokines. To better understand immune responses to malaria, CD1c؉ mDC maturation and cytokine production were examined in healthy volunteers before and after experimental intravenous Plasmodium falciparum infection with 150-or 1,800-parasite-infected red blood cells (pRBCs). After either dose, CD1c؉ mDCs significantly reduced HLA-DR expression in prepatent infections. Circulating CD1c ؉ mDCs did not upregulate HLA-DR after pRBC or TLR ligand stimulation and exhibited reduced CD86 expression. At peak parasitemia, CD1c؉ mDCs produced significantly more tumor necrosis factor (TNF), whereas interleukin-12 (IL-12) production was unchanged. Interestingly, only the 1,800-pRBC dose caused a reduction in the circulating CD1c؉ mDC count with evidence of apoptosis. The 1,800-pRBC dose produced no change in T cell IFN-␥ or IL-2 production at peak parasitemia or at 3 weeks posttreatment. Overall, CD1c؉ mDCs are compromised by P. falciparum exposure, with impaired HLA-DR and CD86 expression, and have an increased capacity for TNF but not IL-12 production. A first prepatent P. falciparum infection is sufficient to modulate CD1c ؉ mDC responsiveness, likely contributing to hampered effector T cell cytokine responses and assisting parasite immune evasion.

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“…Research suggests a protective effect both for antibodies (18)(19)(20)(21) and effector T cell cytokine responses (particularly gamma interferon [IFN-␥]) (21)(22)(23)(24). As the induction and maintenance of both effective B cell (antibody) and T cell (cytokine) responses require functional DC (25) and each may be modulated by Treg cells (26), we sought to examine these cells in both children and adults with patent asymptomatic P. falciparum or P. vivax infection and to compare their responses to those seen with acute uncomplicated P. falciparum or P. vivax malaria.…”

mentioning

confidence: 99%

Preserved Dendritic Cell HLA-DR Expression and Reduced Regulatory T Cell Activation in Asymptomatic Plasmodium falciparum and P. vivax Infection

et al. 2015

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Humoral and Cellular Immunity to Plasmodium falciparum Merozoite Surface Protein 1 and Protection From Infection With Blood-Stage Parasites

Abstract: Evaluating combined allele-specific cellular and humoral immunity elicited by malaria provides a more informative measure of protection relative to evaluation of either measure alone.

Cited by 32 publications

References 48 publications

Innate Immunity Induced by Plasmodium Liver Infection Inhibits Malaria Reinfections

Innate Immunity Induced by Plasmodium Liver Infection Inhibits Malaria Reinfections

Profoundly Reduced CD1c ⁺ Myeloid Dendritic Cell HLA-DR and CD86 Expression and Increased Tumor Necrosis Factor Production in Experimental Human Blood-Stage Malaria Infection

Preserved Dendritic Cell HLA-DR Expression and Reduced Regulatory T Cell Activation in Asymptomatic Plasmodium falciparum and P. vivax Infection

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Humoral and Cellular Immunity to Plasmodium falciparum Merozoite Surface Protein 1 and Protection From Infection With Blood-Stage Parasites

Abstract: Evaluating combined allele-specific cellular and humoral immunity elicited by malaria provides a more informative measure of protection relative to evaluation of either measure alone.

Cited by 32 publications

References 48 publications

Innate Immunity Induced by Plasmodium Liver Infection Inhibits Malaria Reinfections

Innate Immunity Induced by Plasmodium Liver Infection Inhibits Malaria Reinfections

Profoundly Reduced CD1c + Myeloid Dendritic Cell HLA-DR and CD86 Expression and Increased Tumor Necrosis Factor Production in Experimental Human Blood-Stage Malaria Infection

Preserved Dendritic Cell HLA-DR Expression and Reduced Regulatory T Cell Activation in Asymptomatic Plasmodium falciparum and P. vivax Infection

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Profoundly Reduced CD1c ⁺ Myeloid Dendritic Cell HLA-DR and CD86 Expression and Increased Tumor Necrosis Factor Production in Experimental Human Blood-Stage Malaria Infection