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      IFNγ/IL-10 Co-producing Cells Dominate the CD4 Response to Malaria in Highly Exposed Children


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          Although evidence suggests that T cells are critical for immunity to malaria, reliable T cell correlates of exposure to and protection from malaria among children living in endemic areas are lacking. We used multiparameter flow cytometry to perform a detailed functional characterization of malaria-specific T cells in 78 four-year-old children enrolled in a longitudinal cohort study in Tororo, Uganda, a highly malaria-endemic region. More than 1800 episodes of malaria were observed in this cohort, with no cases of severe malaria. We quantified production of IFNγ, TNFα, and IL-10 (alone or in combination) by malaria-specific T cells, and analyzed the relationship of this response to past and future malaria incidence. CD4 + T cell responses were measurable in nearly all children, with the majority of children having CD4 + T cells producing both IFNγ and IL-10 in response to malaria-infected red blood cells. Frequencies of IFNγ/IL10 co-producing CD4 + T cells, which express the Th1 transcription factor T-bet, were significantly higher in children with ≥2 prior episodes/year compared to children with <2 episodes/year ( P<0.001) and inversely correlated with duration since malaria ( Rho = −0.39, P<0.001). Notably, frequencies of IFNγ/IL10 co-producing cells were not associated with protection from future malaria after controlling for prior malaria incidence. In contrast, children with <2 prior episodes/year were significantly more likely to exhibit antigen-specific production of TNFα without IL-10 ( P = 0.003). While TNFα-producing CD4 + T cells were not independently associated with future protection, the absence of cells producing this inflammatory cytokine was associated with the phenotype of asymptomatic infection. Together these data indicate that the functional phenotype of the malaria-specific T cell response is heavily influenced by malaria exposure intensity, with IFNγ/IL10 co-producing CD4 + T cells dominating this response among highly exposed children. These CD4 + T cells may play important modulatory roles in the development of antimalarial immunity.

          Author Summary

          Despite reports of decreasing malaria morbidity across many parts of Africa, the incidence of malaria among children continues to be very high in Uganda, even in the setting of insecticide-treated bednets and artemisinin-based combination therapy. Additional control measures, including a vaccine, are sorely needed in these settings, but progress has been limited by our lack of understanding of immunologic correlates of exposure and protection. T cell responses to malaria are thought to be important for protection in experimental models, but their role in protecting against naturally acquired infection is not clear. In this study, we performed detailed assessments of the malaria-specific T cell response among 4-year-old children living in Tororo, Uganda, an area of high malaria transmission. We found that recent malaria infection induces a malaria-specific immune response dominated by Th1 T cells co-producing IFNγ and IL-10, and that these cells are not associated with protection from future infection. IFNγ/IL-10 co-producing cells have been described in several parasitic infections and are hypothesized to be important in limiting CD4-mediated pathology, but they may also prevent the development of sterilizing immunity. These observations have important implications for understanding the pathophysiology of malaria in humans and for malaria vaccine development.

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          Most cited references70

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          Protection against a malaria challenge by sporozoite inoculation.

          An effective vaccine for malaria is urgently needed. Naturally acquired immunity to malaria develops slowly, and induction of protection in humans can be achieved artificially by the inoculation of radiation-attenuated sporozoites by means of more than 1000 infective mosquito bites. We exposed 15 healthy volunteers--with 10 assigned to a vaccine group and 5 assigned to a control group--to bites of mosquitoes once a month for 3 months while they were receiving a prophylactic regimen of chloroquine. The vaccine group was exposed to mosquitoes that were infected with Plasmodium falciparum, and the control group was exposed to mosquitoes that were not infected with the malaria parasite. One month after the discontinuation of chloroquine, protection was assessed by homologous challenge with five mosquitoes infected with P. falciparum. We assessed humoral and cellular responses before vaccination and before the challenge to investigate correlates of protection. All 10 subjects in the vaccine group were protected against a malaria challenge with the infected mosquitoes. In contrast, patent parasitemia (i.e., parasites found in the blood on microscopical examination) developed in all five control subjects. Adverse events were mainly reported by vaccinees after the first immunization and by control subjects after the challenge; no serious adverse events occurred. In this model, we identified the induction of parasite-specific pluripotent effector memory T cells producing interferon-gamma, tumor necrosis factor alpha, and interleukin-2 as a promising immunologic marker of protection. Protection against a homologous malaria challenge can be induced by the inoculation of intact sporozoites. (ClinicalTrials.gov number, NCT00442377.) 2009 Massachusetts Medical Society
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            Determinants of Viral Clearance and Persistence during Acute Hepatitis C Virus Infection

            The virological and immunological features of hepatitis C virus (HCV) infection were studied weekly for 6 months after accidental needlestick exposure in five health care workers, four of whom developed acute hepatitis that progressed to chronicity while one subject cleared the virus. In all subjects, viremia was first detectable within 1–2 weeks of inoculation, 1 month or more before the appearance of virus-specific T cells. The subject who cleared the virus experienced a prolonged episode of acute hepatitis that coincided with a CD38+ IFN-γ− CD8+ T cell response to HCV and a small reduction in viremia. Subsequently, a strong CD4+ T cell response emerged and the CD8+ T cells became CD38− and started producing IFN-γ in response to HCV, coinciding with a rapid 100,000-fold decrease in viremia that occurred without a corresponding surge of disease activity. Chronic infection developed in two subjects who failed to produce a significant T cell response and in two other subjects who initially mounted strong CD4+ T cell responses that ultimately waned. In all subjects, viremia was higher at the peak of acute hepatitis than it was when the disease began, and the disease improved during the viremia. These results provide the first insight into the host–virus relationship in humans during the incubation phase of acute HCV infection, and they provide the only insight to date into the virological and immunological characteristics of clinically asymptomatic acute HCV infection, the commonest manifestation of this disease. In addition, the results suggest that the vigor and quality of the antiviral T cell response determines the outcome of acute HCV infection, that the ability of HCV to outpace the T cell response may contribute to its tendency to persist; that the onset of hepatitis coincides with the onset of the CD8+T cell response, that disease pathogenesis and viral clearance are mediated by different CD8+ T cell populations that control HCV by both cytolytic and noncytolytic mechanisms, and that there are different pathways to viral persistence in asymptomatic and symptomatic acute HCV infection.
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              Malaria morbidity and pyrethroid resistance after the introduction of insecticide-treated bednets and artemisinin-based combination therapies: a longitudinal study.

              Substantial reductions in malaria have been reported in several African countries after distribution of insecticide-treated bednets and the use of artemisinin-based combination therapies (ACTs). Our aim was to assess the effect of these policies on malaria morbidity, mosquito populations, and asymptomatic infections in a west African rural population. We did a longitudinal study of inhabitants of Dielmo village, Senegal, between January, 2007, and December, 2010. We monitored the inhabitants for fever during this period and we treated malaria attacks with artesunate plus amodiaquine. In July, 2008, we offered longlasting insecticide (deltamethrin)-treated nets (LLINs) to all villagers. We did monthly night collections of mosquitoes during the whole study period, and we assessed asymptomatic carriage from cross-sectional surveys. Our statistical analyses were by negative binomial regression, logistic regression, and binomial or Fisher exact test. There were 464 clinical malaria attacks attributable to Plasmodium falciparum during 17,858 person-months of follow-up. The incidence density of malaria attacks averaged 5·45 (95% CI 4·90-6·05) per 100 person-months between January, 2007, and July, 2008, before the distribution of LLINs. Incidence density decreased to 0·41 (0·29-0·55) between August, 2008, and August, 2010, but increased back to 4·57 (3·54-5·82) between September and December, 2010--ie, 27-30 months after the distribution of LLINs. The rebound of malaria attacks were highest in adults and children aged 10 years or older: 45 (63%) of 71 malaria attacks recorded in 2010 compared with 126 (33%) of 384 in 2007 and 2008 (p<0·0001). 37% of Anopheles gambiae mosquitoes were resistant to deltamethrin in 2010, and the prevalence of the Leu1014Phe kdr resistance mutation increased from 8% in 2007 to 48% in 2010 (p=0·0009). Increasing pyrethroid resistance of A gambiae and increasing susceptibility of older children and adults, probably due to decreasing immunity, caused the rebound and age shift of malaria morbidity. Strategies to address the problem of insecticide resistance and to mitigate its effects must be urgently defined and implemented. Institut de Recherche pour le Développement and the Pasteur Institute of Dakar. Copyright © 2011 Elsevier Ltd. All rights reserved.

                Author and article information

                Role: Editor
                PLoS Pathog
                PLoS Pathog
                PLoS Pathogens
                Public Library of Science (San Francisco, USA )
                January 2014
                January 2014
                9 January 2014
                : 10
                : 1
                : e1003864
                [1 ]Department of Medicine, San Francisco General Hospital, University of California, San Francisco, San Francisco, California, United States of America
                [2 ]Infectious Diseases Research Collaboration, Kampala, Uganda
                [3 ]Center for Global Health, Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America
                [4 ]Department of Medicine, Makerere University College of Health Sciences, Kampala, Uganda
                [5 ]Department of Pediatrics, University of California, San Francisco, San Francisco, California, United States of America
                National Institute for Medical Research, United Kingdom
                Author notes

                The authors have declared that no competing interests exist.

                Conceived and designed the experiments: PJ BG GD MEF. Performed the experiments: PJ IEJ KB FN SW CE JB. Analyzed the data: PJ IEJ KB FN GD BG MEF. Contributed reagents/materials/analysis tools: AA MKM EA MRK JWT GD MEF. Wrote the paper: PJ IEJ KB FN AA SW CE MKM EA JB BG JWT MRK GD MEF.


                This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

                : 22 August 2013
                : 19 November 2013
                Page count
                Pages: 14
                This work was supported by the Centers for Disease Control and Prevention (Cooperative Agreement No U62P024421); NIH/NIAID R01AI093615 (MEF), UCSF Centers for AIDS Research (Supplement to MEF, P30AI027763), NIH/NIAID U19AI089674 (GD), NIH/NIAID K23 AI100949 (PJ), and Burroughs Wellcome Fund/American Society of Tropical Medicine and Hygiene (PJ). Additional support was provided by the National Center for Advancing Translational Sciences/NIH, through UCSF-CTSI Grant Number UL1 TR000004. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The findings and conclusions in this paper are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention or the NIH.
                Research Article
                Clinical Immunology
                Immune Cells
                T Cells
                Adaptive Immunity
                Immune Tolerance
                Immunity to Infections
                Immune Response
                Infectious Diseases
                Parasitic Diseases
                Plasmodium Falciparum

                Infectious disease & Microbiology
                Infectious disease & Microbiology


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