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      Immune Escape Strategies of Malaria Parasites

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          Abstract

          Malaria is one of the most life-threatening infectious diseases worldwide. Immunity to malaria is slow and short-lived despite the repeated parasite exposure in endemic areas. Malaria parasites have evolved refined machinery to evade the immune system based on a range of genetic changes that include allelic variation, biomolecular exposure of proteins, and intracellular replication. All of these features increase the probability of survival in both mosquitoes and the vertebrate host. Plasmodium species escape from the first immunological trap in its invertebrate vector host, the Anopheles mosquitoes. The parasites have to pass through various immunological barriers within the mosquito such as anti-microbial molecules and the mosquito microbiota in order to achieve successful transmission to the vertebrate host. Within these hosts, Plasmodium species employ various immune evasion strategies during different life cycle stages. Parasite persistence against the vertebrate immune response depends on the balance among virulence factors, pathology, metabolic cost of the host immune response, and the parasites ability to evade the immune response. In this review we discuss the strategies that Plasmodium parasites use to avoid the vertebrate host immune system and how they promote successful infection and transmission.

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          Most cited references63

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          Adhesion of Plasmodium falciparum-infected erythrocytes to human cells: molecular mechanisms and therapeutic implications

          Severe malaria has a high mortality rate (15–20%) despite treatment with effective antimalarial drugs. Adjunctive therapies for severe malaria that target the underlying disease process are therefore urgently required. Adhesion of erythrocytes infected with Plasmodium falciparum to human cells has a key role in the pathogenesis of life-threatening malaria and could be targeted with antiadhesion therapy. Parasite adhesion interactions include binding to endothelial cells (cytoadherence), rosetting with uninfected erythrocytes and platelet-mediated clumping of infected erythrocytes. Recent research has started to define the molecular mechanisms of parasite adhesion, and antiadhesion therapies are being explored. However, many fundamental questions regarding the role of parasite adhesion in severe malaria remain unanswered. There is strong evidence that rosetting contributes to severe malaria in sub-Saharan Africa; however, the identity of other parasite adhesion phenotypes that are implicated in disease pathogenesis remains unclear. In addition, the possibility of geographic variation in adhesion phenotypes causing severe malaria, linked to differences in malaria transmission levels and host immunity, has been neglected. Further research is needed to realise the untapped potential of antiadhesion adjunctive therapies, which could revolutionise the treatment of severe malaria and reduce the high mortality rate of the disease.
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            Manipulation of host hepatocytes by the malaria parasite for delivery into liver sinusoids.

            The merozoite stage of the malaria parasite that infects erythrocytes and causes the symptoms of the disease is initially formed inside host hepatocytes. However, the mechanism by which hepatic merozoites reach blood vessels (sinusoids) in the liver and escape the host immune system before invading erythrocytes remains unknown. Here, we show that parasites induce the death and the detachment of their host hepatocytes, followed by the budding of parasite-filled vesicles (merosomes) into the sinusoid lumen. Parasites simultaneously inhibit the exposure of phosphatidylserine on the outer leaflet of host plasma membranes, which act as "eat me" signals to phagocytes. Thus, the hepatocyte-derived merosomes appear to ensure both the migration of parasites into the bloodstream and their protection from host immunity.
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              Human Antibodies Fix Complement to Inhibit Plasmodium falciparum Invasion of Erythrocytes and Are Associated with Protection against Malaria

              Summary Antibodies play major roles in immunity to malaria; however, a limited understanding of mechanisms mediating protection is a major barrier to vaccine development. We have demonstrated that acquired human anti-malarial antibodies promote complement deposition on the merozoite to mediate inhibition of erythrocyte invasion through C1q fixation and activation of the classical complement pathway. Antibody-mediated complement-dependent (Ab-C′) inhibition was the predominant invasion-inhibitory activity of human antibodies; most antibodies were non-inhibitory without complement. Inhibitory activity was mediated predominately via C1q fixation, and merozoite surface proteins 1 and 2 were identified as major targets. Complement fixation by antibodies was very strongly associated with protection from both clinical malaria and high-density parasitemia in a prospective longitudinal study of children. Ab-C′ inhibitory activity could be induced by human immunization with a candidate merozoite surface-protein vaccine. Our findings demonstrate that human anti-malarial antibodies have evolved to function by fixing complement for potent invasion-inhibitory activity and protective immunity.
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                Author and article information

                Contributors
                Journal
                Front Microbiol
                Front Microbiol
                Front. Microbiol.
                Frontiers in Microbiology
                Frontiers Media S.A.
                1664-302X
                17 October 2016
                2016
                : 7
                : 1617
                Affiliations
                [1] 1Departamento de Microbiologia Geral, Universidade Federal do Rio de Janeiro Rio de Janeiro, Brazil
                [2] 2Division of Parasitology, Council of Scientific and Industrial Research-Central Drug Research Institute Lucknow, Uttar Pradesh, India
                [3] 3Academy of Scientific and Innovative Research Anusandhan Bhawan, New Delhi, India
                [4] 4Division of Parasitology, Department of Microbiology, New York University School of Medicine New York, NY, USA
                [5] 5Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro Rio de Janeiro, Brazil
                Author notes

                Edited by: Magdalena Plebanski, Monash University, Australia

                Reviewed by: Urszula Krzych, Walter Reed Army Institute of Research, USA; Miguel Prudêncio, Instituto de Medicina Molecular, Portugal

                *Correspondence: Alexandre Morrot morrot@ 123456micro.ufrj.br

                This article was submitted to Microbial Immunology, a section of the journal Frontiers in Microbiology

                Article
                10.3389/fmicb.2016.01617
                5066453
                27799922
                018f3987-95b9-43ab-9e49-e61174c0d015
                Copyright © 2016 Gomes, Bhardwaj, Rivera-Correa, Freire-De-Lima and Morrot.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 29 June 2016
                : 28 September 2016
                Page count
                Figures: 0, Tables: 0, Equations: 0, References: 73, Pages: 7, Words: 6461
                Funding
                Funded by: Conselho Nacional de Desenvolvimento Científico e Tecnológico 10.13039/501100003593
                Funded by: Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro 10.13039/501100004586
                Categories
                Microbiology
                Mini Review

                Microbiology & Virology
                plamosdium,evasion strategies,liver stage,blood stage,malaria,microbiology,immulogy

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