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      Zoonotic Malaria: Non- Laverania Plasmodium Biology and Invasion Mechanisms

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          Abstract

          Malaria, which is caused by Plasmodium parasites through Anopheles mosquito transmission, remains one of the most life-threatening diseases affecting hundreds of millions of people worldwide every year. Plasmodium vivax, which accounts for the majority of cases of recurring malaria caused by the Plasmodium (non- Laverania) subgenus, is an ancient and continuing zoonosis originating from monkey hosts probably outside Africa. The emergence of other zoonotic malarias ( P. knowlesi, P. cynomolgi, and P. simium) further highlights the seriousness of the disease. The severity of this epidemic disease is dependent on many factors, including the parasite characteristics, host-parasite interactions, and the pathology of the infection. Successful infection depends on the ability of the parasite to invade the host; however, little is known about the parasite invasion biology and mechanisms. The lack of this information adds to the challenges to malaria control and elimination, hence enhancing the potential for continuation of this zoonosis. Here, we review the literature describing the characteristics, distribution, and genome details of the parasites, as well as host specificity, host-parasite interactions, and parasite pathology. This information will provide the basis of a greater understanding of the epidemiology and pathogenesis of malaria to support future development of strategies for the control and prevention of this zoonotic infection.

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          Comparative genomics of the neglected human malaria parasite Plasmodium vivax.

          The human malaria parasite Plasmodium vivax is responsible for 25-40% of the approximately 515 million annual cases of malaria worldwide. Although seldom fatal, the parasite elicits severe and incapacitating clinical symptoms and often causes relapses months after a primary infection has cleared. Despite its importance as a major human pathogen, P. vivax is little studied because it cannot be propagated continuously in the laboratory except in non-human primates. We sequenced the genome of P. vivax to shed light on its distinctive biological features, and as a means to drive development of new drugs and vaccines. Here we describe the synteny and isochore structure of P. vivax chromosomes, and show that the parasite resembles other malaria parasites in gene content and metabolic potential, but possesses novel gene families and potential alternative invasion pathways not recognized previously. Completion of the P. vivax genome provides the scientific community with a valuable resource that can be used to advance investigation into this neglected species.
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            The genome of the simian and human malaria parasite Plasmodium knowlesi.

            Plasmodium knowlesi is an intracellular malaria parasite whose natural vertebrate host is Macaca fascicularis (the 'kra' monkey); however, it is now increasingly recognized as a significant cause of human malaria, particularly in southeast Asia. Plasmodium knowlesi was the first malaria parasite species in which antigenic variation was demonstrated, and it has a close phylogenetic relationship to Plasmodium vivax, the second most important species of human malaria parasite (reviewed in ref. 4). Despite their relatedness, there are important phenotypic differences between them, such as host blood cell preference, absence of a dormant liver stage or 'hypnozoite' in P. knowlesi, and length of the asexual cycle (reviewed in ref. 4). Here we present an analysis of the P. knowlesi (H strain, Pk1(A+) clone) nuclear genome sequence. This is the first monkey malaria parasite genome to be described, and it provides an opportunity for comparison with the recently completed P. vivax genome and other sequenced Plasmodium genomes. In contrast to other Plasmodium genomes, putative variant antigen families are dispersed throughout the genome and are associated with intrachromosomal telomere repeats. One of these families, the KIRs, contains sequences that collectively match over one-half of the host CD99 extracellular domain, which may represent an unusual form of molecular mimicry.
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              Clinical and laboratory features of human Plasmodium knowlesi infection.

              Plasmodium knowlesi is increasingly recognized as a cause of human malaria in Southeast Asia but there are no detailed prospective clinical studies of naturally acquired infections. In a systematic study of the presentation and course of patients with acute P. knowlesi infection, clinical and laboratory data were collected from previously untreated, nonpregnant adults admitted to the hospital with polymerase chain reaction-confirmed acute malaria at Kapit Hospital (Sarawak, Malaysia) from July 2006 through February 2008. Of 152 patients recruited, 107 (70%) had P. knowlesi infection, 24 (16%) had Plasmodium falciparum infection, and 21 (14%) had Plasmodium vivax. Patients with P. knowlesi infection presented with a nonspecific febrile illness, had a baseline median parasitemia value at hospital admission of 1387 parasites/microL (interquartile range, 6-222,570 parasites/microL), and all were thrombocytopenic at hospital admission or on the following day. Most (93.5%) of the patients with P. knowlesi infection had uncomplicated malaria that responded to chloroquine and primaquine treatment. Based on World Health Organization criteria for falciparum malaria, 7 patients with P. knowlesi infection (6.5%) had severe infections at hospital admission. The most frequent complication was respiratory distress, which was present at hospital admission in 4 patients and developed after admission in an additional 3 patients. P. knowlesi parasitemia at hospital admission was an independent determinant of respiratory distress, as were serum creatinine level, serum bilirubin, and platelet count at admission (p < .002 for each). Two patients with knowlesi malaria died, representing a case fatality rate of 1.8% (95% confidence interval, 0.2%-6.6%). Knowlesi malaria causes a wide spectrum of disease. Most cases are uncomplicated and respond promptly to treatment, but approximately 1 in 10 patients develop potentially fatal complications.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                Pathogens
                Pathogens
                pathogens
                Pathogens
                MDPI
                2076-0817
                13 July 2021
                July 2021
                : 10
                : 7
                : 889
                Affiliations
                [1 ]Immunology Translational Research Programme, Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, Immunology Programme, Life Sciences Institute, National University of Singapore, Singapore 117545, Singapore; e0385049@ 123456u.nus.edu (J.W.H.); e0204997@ 123456u.nus.edu (F.T.); elqh18@ 123456nus.edu.sg (E.Q.H.L.)
                [2 ]Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore 138648, Singapore; Shifana_Raja_Abdeen@ 123456immunol.a-star.edu.sg
                [3 ]West Africa Centre for Cell Biology of Infectious Pathogens (WACCBIP), University of Ghana, Legon, Accra, Ghana; yaniweh@ 123456ug.edu.gh
                Author notes
                [†]

                Co-first author, these authors contributed equally to this work.

                Author information
                https://orcid.org/0000-0002-8415-2727
                https://orcid.org/0000-0001-9658-7528
                Article
                pathogens-10-00889
                10.3390/pathogens10070889
                8308728
                c4a546f0-6a82-4e53-bd46-08e2d8a5c8af
                © 2021 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( https://creativecommons.org/licenses/by/4.0/).

                History
                : 02 June 2021
                : 09 July 2021
                Categories
                Review

                zoonotic malaria,host species,genome,pathology,invasion mechanism

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