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1.
PLoS Pathog ; 10(4): e1004079, 2014 Apr.
Article in English | MEDLINE | ID: mdl-24743880

ABSTRACT

In malaria-naïve individuals, Plasmodium falciparum infection results in high levels of parasite-infected red blood cells (iRBCs) that trigger systemic inflammation and fever. Conversely, individuals in endemic areas who are repeatedly infected are often asymptomatic and have low levels of iRBCs, even young children. We hypothesized that febrile malaria alters the immune system such that P. falciparum re-exposure results in reduced production of pro-inflammatory cytokines/chemokines and enhanced anti-parasite effector responses compared to responses induced before malaria. To test this hypothesis we used a systems biology approach to analyze PBMCs sampled from healthy children before the six-month malaria season and the same children seven days after treatment of their first febrile malaria episode of the ensuing season. PBMCs were stimulated with iRBC in vitro and various immune parameters were measured. Before the malaria season, children's immune cells responded to iRBCs by producing pro-inflammatory mediators such as IL-1ß, IL-6 and IL-8. Following malaria there was a marked shift in the response to iRBCs with the same children's immune cells producing lower levels of pro-inflammatory cytokines and higher levels of anti-inflammatory cytokines (IL-10, TGF-ß). In addition, molecules involved in phagocytosis and activation of adaptive immunity were upregulated after malaria as compared to before. This shift was accompanied by an increase in P. falciparum-specific CD4+Foxp3- T cells that co-produce IL-10, IFN-γ and TNF; however, after the subsequent six-month dry season, a period of markedly reduced malaria transmission, P. falciparum-inducible IL-10 production remained partially upregulated only in children with persistent asymptomatic infections. These findings suggest that in the face of P. falciparum re-exposure, children acquire exposure-dependent P. falciparum-specific immunoregulatory responses that dampen pathogenic inflammation while enhancing anti-parasite effector mechanisms. These data provide mechanistic insight into the observation that P. falciparum-infected children in endemic areas are often afebrile and tend to control parasite replication.


Subject(s)
Adaptive Immunity , CD4-Positive T-Lymphocytes/immunology , Cytokines/immunology , Malaria, Falciparum/immunology , Plasmodium falciparum/immunology , Adolescent , CD4-Positive T-Lymphocytes/metabolism , Child , Child, Preschool , Cytokines/blood , Female , Humans , Inflammation/blood , Inflammation/immunology , Inflammation/parasitology , Malaria, Falciparum/blood , Malaria, Falciparum/epidemiology , Male , Plasmodium falciparum/metabolism
2.
J Infect Dis ; 209(5): 789-98, 2014 Mar 01.
Article in English | MEDLINE | ID: mdl-24133188

ABSTRACT

BACKGROUND: Plasmodium falciparum reticulocyte-binding protein homologue 5 (PfRH5) is a blood-stage parasite protein essential for host erythrocyte invasion. PfRH5-specific antibodies raised in animals inhibit parasite growth in vitro, but the relevance of naturally acquired PfRH5-specific antibodies in humans is unclear. METHODS: We assessed pre-malaria season PfRH5-specific immunoglobulin G (IgG) levels in 357 Malian children and adults who were uninfected with Plasmodium. Subsequent P. falciparum infections were detected by polymerase chain reaction every 2 weeks and malaria episodes by weekly physical examination and self-referral for 7 months. The primary outcome was time between the first P. falciparum infection and the first febrile malaria episode. PfRH5-specific IgG was assayed for parasite growth-inhibitory activity. RESULTS: The presence of PfRH5-specific IgG at enrollment was associated with a longer time between the first blood-stage infection and the first malaria episode (PfRH5-seropositive median: 71 days, PfRH5-seronegative median: 18 days; P = .001). This association remained significant after adjustment for age and other factors associated with malaria risk/exposure (hazard ratio, .62; P = .02). Concentrated PfRH5-specific IgG purified from Malians inhibited P. falciparum growth in vitro. CONCLUSIONS: Naturally acquired PfRH5-specific IgG inhibits parasite growth in vitro and predicts protection from malaria. These findings strongly support efforts to develop PfRH5 as an urgently needed blood-stage malaria vaccine. CLINICAL TRIALS REGISTRATION: NCT01322581.


Subject(s)
Antibodies, Protozoan/immunology , Carrier Proteins/immunology , Malaria, Falciparum/immunology , Plasmodium falciparum/immunology , Adolescent , Adult , Child , Child, Preschool , Female , Humans , Immunoglobulin G/immunology , Infant , Malaria Vaccines/immunology , Malaria, Falciparum/parasitology , Malaria, Falciparum/transmission , Male , Placenta/immunology , Placenta/parasitology , Pregnancy , Reticulocytes/immunology , Reticulocytes/parasitology , Young Adult
3.
Clin Infect Dis ; 57(1): 40-7, 2013 Jul.
Article in English | MEDLINE | ID: mdl-23487390

ABSTRACT

BACKGROUND: In experimental models of human and mouse malaria, sterilizing liver stage immunity that blocks progression of Plasmodium infection to the symptomatic blood stage can be readily demonstrated. However, it remains unclear whether individuals in malaria-endemic areas acquire such immunity. METHODS: In Mali, 251 healthy children and adults aged 4-25 years who were free of blood-stage Plasmodium infection by polymerase chain reaction (PCR) were enrolled in a longitudinal study just prior to an intense 6-month malaria season. Subsequent clinical malaria episodes were detected by weekly active surveillance and self-referral. Asymptomatic P. falciparum infections were detected by blood-smear microscopy and PCR analysis of dried blood spots that had been collected every 2 weeks for 7 months. RESULTS: As expected, the risk of clinical malaria decreased with increasing age (log-rank test, P = .0038). However, analysis of PCR data showed no age-related differences in P. falciparum infection risk (log-rank test, P = .37). CONCLUSIONS: Despite years of exposure to intense P. falciparum transmission, there is no evidence of acquired, sterile immunity to P. falciparum infection in this population, even as clinical immunity to blood-stage malaria is clearly acquired. Understanding why repeated P. falciparum infections do not induce sterile protection may lead to insights for developing vaccines that target the liver stage in malaria-endemic populations.


Subject(s)
Adaptive Immunity , Malaria, Falciparum/epidemiology , Malaria, Falciparum/immunology , Plasmodium falciparum/immunology , Adult , Child , Cohort Studies , Humans , Longitudinal Studies , Malaria, Falciparum/prevention & control , Mali/epidemiology
4.
PLoS Pathog ; 6(5): e1000912, 2010 May 20.
Article in English | MEDLINE | ID: mdl-20502681

ABSTRACT

Immunity to Plasmodium falciparum (Pf) malaria is only acquired after years of repeated infections and wanes rapidly without ongoing parasite exposure. Antibodies are central to malaria immunity, yet little is known about the B-cell biology that underlies the inefficient acquisition of Pf-specific humoral immunity. This year-long prospective study in Mali of 185 individuals aged 2 to 25 years shows that Pf-specific memory B-cells and antibodies are acquired gradually in a stepwise fashion over years of repeated Pf exposure. Both Pf-specific memory B cells and antibody titers increased after acute malaria and then, after six months of decreased Pf exposure, contracted to a point slightly higher than pre-infection levels. This inefficient, stepwise expansion of both the Pf-specific memory B-cell and long-lived antibody compartments depends on Pf exposure rather than age, based on the comparator response to tetanus vaccination that was efficient and stable. These observations lend new insights into the cellular basis of the delayed acquisition of malaria immunity.


Subject(s)
B-Lymphocytes/immunology , B-Lymphocytes/parasitology , Immunologic Memory/immunology , Malaria, Falciparum/immunology , Plasmodium falciparum/immunology , Acute Disease , Adolescent , Adult , Antibodies, Protozoan/blood , Child , Child, Preschool , Female , Humans , Immunoglobulin G/blood , Immunophenotyping , Longitudinal Studies , Malaria, Falciparum/transmission , Male , Mali , Prospective Studies , Recurrence , Seasons , Young Adult
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