Interferon-gamma--central mediator of protective immune responses against the pre-erythrocytic and blood stage of malaria.

Contains fulltext : 87979.pdf (publisher's version ) (Open Access)Immune responses against Plasmodium parasites, the causative organisms of malaria, are traditionally dichotomized into pre-erythrocytic and blood-stage components. Whereas the central role of cellular responses in pre-erythrocytic immunity is well established, protection against blood-stage parasites has generally been ascribed to humoral responses. A number of recent studies, however, have highlighted the existence of cellular immunity against blood-stage parasites, in particular, the prominence of IFN-gamma production. Here, we have undertaken to chart the contribution of this prototypical cellular cytokine to immunity against pre-erythrocytic and blood-stage parasites. We summarize the various antiparasitic effector functions that IFN-gamma serves to induce, review an array of data about its protective effects, and scrutinize evidence for any deleterious, immunopathological outcome in malaria patients. We discuss the activation and contribution of different cellular sources of IFN-gamma production during malaria infection and its regulation in relation to exposure. We conclude that IFN-gamma forms a central mediator of protective immune responses against pre-erythrocytic and blood-stage malaria parasites and identify a number of implications for rational malaria vaccine development.1 december 201

Pro-inflammatory cytokine responses against Plasmodium falciparum: Induction, dynamics and protective role of interferon-gamma in malaria

Contains fulltext : 87187.pdf (publisher's version ) (Open Access)Radboud Universiteit Nijmegen, 17 juni 2011Promotores : Sauerwein, R.W., Netea, M.G. Co-promotores : Hermans, P.W.M., Figdor, C.G., Troye-Blomberg, M.240 p

Correlates of malaria vaccine efficacy

Introduction: An effective vaccine against malaria forms a global health priority. Both naturally acquired immunity and sterile protection induced by irradiated sporozoite immunization were described decades ago. Still no vaccine exists that sufficiently protects children in endemic areas. Identifying immunological correlates of vaccine efficacy can inform rational vaccine design and potentially accelerate clinical development.Areas covered: We discuss recent research on immunological correlates of malaria vaccine efficacy, including: insights from state-of-the-art omics platforms and systems vaccinology analyses; functional anti-parasitic assays; pre-immunization predictors of vaccine efficacy; and comparison of correlates of vaccine efficacy against controlled human malaria infections (CHMI) and against naturally acquired infections.Expert Opinion: Effective vaccination may be achievable without necessarily understanding immunological correlates, but the relatively disappointing efficacy of malaria vaccine candidates in target populations is concerning. Hypothesis-generating omics and systems vaccinology analyses, alongside assessment of pre-immunization correlates, have the potential to bring about paradigm-shifts in malaria vaccinology. Functional assays may represent in vivo effector mechanisms, but have scarcely been formally assessed as correlates. Crucially, evidence is still meager that correlates of vaccine efficacy against CHMI correspond with those against naturally acquired infections in target populations. Finally, the diversity of immunological assays and efficacy endpoints across malaria vaccine trials remains a major confounder

[Development of vaccines against malaria; progress with contributions from the Netherlands]

Five years ago, the very first malaria vaccine, RTS,S/AS01, received a positive evaluation by the European Medicines Agency. Although this vaccine does not achieve the WHO's target of 75% protection, it does set the standard for all new vaccine candidates. In this article, we describe the progress made in the development of several second-generation malaria vaccines, an area where Dutch research has made major contributions. These include vaccines with live, attenuated Plasmodium falciparumsporozoites and transmission-blocking vaccines. Thanks in part to Dutch contributions, the development of vaccines against malaria has recently made significant progress on the way to the finish line: a vaccine that provides protection to the most vulnerable population - young children in Africa

Optimizing RTS,S Vaccination Strategies: Give It Your Best Parting Shot

Contains fulltext : 229462.pdf (Publisher’s version ) (Closed access

Fast and fierce versus slow and smooth: Heterogeneity in immune responses to Plasmodium in the controlled human malaria infection model

Contains fulltext : 218865.pdf (Publisher’s version ) (Open Access)Controlled human malaria infection (CHMI) is an established model in clinical malaria research. Upon exposure to Plasmodium falciparum parasites, malaria-naive volunteers differ in dynamics and composition of their immune profiles and subsequent capacity to generate protective immunity. CHMI volunteers are either inflammatory responders who have prominent cellular IFN-gamma production primarily driven by adaptive T cells, or tempered responders who skew toward antibody-mediated humoral immunity. When exposed to consecutive CHMIs under antimalarial chemoprophylaxis, individuals who can control parasitemia after a single immunization (fast responders) are more likely to be protected against a subsequent challenge infection. Fast responders tend to be inflammatory responders who can rapidly induce long-lived IFN-gamma(+) T cell responses. Slow responders or even non-responders can also be protected, but via a more diverse range of responses that take a longer time to reach full protective efficacy, in part due to their tempered phenotype. The latter group can be identified at baseline before CHMI by higher expression of inhibitory ligands CTLA-4 and TIM-3 on CD4(+) T cells. Delineating heterogeneity in human immune responses to P. falciparum will facilitate rational design and strategy towards effective malaria vaccines

Short report: Severe Plasmodium falciparum malaria in Cameroon: associated with the glutathione S-transferase M1 null genotype.

Contains fulltext : 49315.pdf (publisher's version ) (Open Access)Glutathione S-transferases (GST) are a family of enzymes involved in phase-II detoxification of endogenous and xenobiotic compounds. Polymorphisms in GST genes have been associated with susceptibility to different diseases. In this study we determined the frequencies of polymorphisms in GSTM1, GSTT1, and GSTP1 in DNA of 138 children from Cameroon, presenting with uncomplicated malaria (N = 19), malaria with minor complications (N = 81), or severe malaria (N = 38). Analyses of GSTM1 and GSTT1 were performed using PCR-multiplex procedure, while GSTP1 was done by PCR-RFLP. Subjects presenting with malaria with complications were found more often of the GSTM1-null genotype (58-64%) as compared with those with uncomplicated malaria (32%), a difference that was statistically significant. We conclude that the GSTM1-null genotype is associated with malaria with complications

Plasmodium falciparum infection causes proinflammatory priming of human TLR responses.

Contains fulltext : 52709.pdf (publisher's version ) (Closed access)TLRs are a major group of pattern recognition receptors that are crucial in initiating innate immune responses and are capable of recognizing Plasmodium ligands. We have investigated TLR responses during acute experimental P. falciparum (P.f.) infection in 15 malaria-naive volunteers. TLR-4 responses in whole blood ex vivo stimulations were characterized by significantly (p < 0.01) up-regulated proinflammatory cytokine production during infection compared with baseline, whereas TLR-2/TLR-1 responses demonstrated increases in both proinflammatory and anti-inflammatory cytokine production. Responses through other TLRs were less obviously modified by malaria infection. The degree to which proinflammatory TLR responses were boosted early in infection was partially prognostic of clinical inflammatory parameters during the subsequent clinical course. Although simultaneous costimulation of human PBMC with P.f. lysate and specific TLR stimuli in vitro did not induce synergistic effects on cytokine synthesis, PBMC started to respond to subsequent TLR-4 and TLR-2 stimulation with significantly (p < 0.05) increased TNF-alpha and reduced IL-10 production following increasing periods of preincubation with P.f. Ag. In contrast, preincubation with preparations derived from other parasitic, bacterial, and fungal pathogens strongly suppressed subsequent TLR responses. Taken together, P.f. primes human TLR responses toward a more proinflammatory cytokine profile both in vitro and in vivo, a characteristic exceptional among microorganisms

Ocular syphilis acquired through oral sex in two HIV-infected patients.

Two cases of ocular syphilis are described in HIV-infected individuals after unprotected oral sex. The primary syphilitic lesion remained unnoticed and lues was therefore only diagnosed after visual symptoms developed

Responses to malarial antigens are altered in helminth-infected children.

Contains fulltext : 81667.pdf (publisher's version ) (Closed access)Malaria and helminth infections often coincide in the same tropical regions. Studies of the consequences of helminth and malaria coinfection in humans have been few and are mainly epidemiological, with little information on cellular immune responses. In this study, we investigated the antimalarial immune responses of Ghanaian children living in a rural area with a high prevalence of both helminth infection and Plasmodium falciparum infection. Whole blood specimens were cultured with P. falciparum-infected red blood cells (iRBCs), and pro- and anti-inflammatory cytokines and immune regulatory molecules were measured. In response to iRBCs, levels of interleukin (IL)-10, but not tumor necrosis factor-alpha,were higher in samples from helminth-infected children than in those from uninfected children, as was expression of the regulatory molecules suppressor of cytokine signaling (SOCS)-3, Foxp3, and programmed death (PD)-1. Furthermore, a significant correlation was found between SOCS-3 gene expression and IL-10 production. These results indicate that the presence of helminth infection modulates the immune response to malarial parasites, making it more anti-inflammatory