Plasmodium falciparum complicated malaria: Modulation and connectivity between exportome and variant surface antigen gene families

Subudhi, Amit Kumar; Boopathi, P.A.; Pandey, Isha; Kohli, R. S.; Karwa, Rohan; Middha, Sheetal; Acharya, Jyoti; Kochar, Sanjay Kumar; Kochar, Dhanpat Kumar; Das, Ashis

doi:10.1016/j.molbiopara.2015.05.005

Cited by 10 publications

(9 citation statements)

References 89 publications

(113 reference statements)

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“…Studies to understand the role of PfEMP1 in SM pathogenesis have been mainly focused on children in Africa (15,18,19) and information on adult severe patients still remains scarce (43). However, in areas of unstable transmission, SM occurs across age groups.…”

Section: Discussionmentioning

confidence: 99%

Severe adult malaria is associated with specific PfEMP1 adhesion types and high parasite biomass

Bernabeu

Danziger

Avril

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

127

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The interplay between cellular and molecular determinants that lead to severe malaria in adults is unexplored. Here, we analyzed parasite virulence factors in an infected adult population in India and investigated whether severe malaria isolates impair endothelial protein C receptor (EPCR), a protein involved in coagulation and endothelial barrier permeability. Severe malaria isolates overexpressed specific members of the Plasmodium falciparum var gene/ PfEMP1 (P. falciparum erythrocyte membrane protein 1) family that bind EPCR, including DC8 var genes that have previously been linked to severe pediatric malaria. Machine learning analysis revealed that DC6-and DC8-encoding var transcripts in combination with high parasite biomass were the strongest indicators of patient hospitalization and disease severity. We found that DC8 CIDRα1 domains from severe malaria isolates had substantial differences in EPCR binding affinity and blockade activity for its ligand activated protein C. Additionally, even a low level of inhibition exhibited by domains from two cerebral malaria isolates was sufficient to interfere with activated protein C-barrier protective activities in human brain endothelial cells. Our findings demonstrate an interplay between parasite biomass and specific PfEMP1 adhesion types in the development of adult severe malaria, and indicate that low impairment of EPCR function may contribute to parasite virulence. malaria | Plasmodium falciparum | var | PfEMP1 | EPCR

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Section: Discussionmentioning

confidence: 99%

Severe adult malaria is associated with specific PfEMP1 adhesion types and high parasite biomass

Bernabeu

Danziger

Avril

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

127

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“…Export of variant surface antigens (VSA) constitutes a crucial mechanism employed by the parasite to successfully evade the host immune system and establish a long‐lasting chronic infection (Gardner et al, ; Kaviratne, Khan, Jarra, & Preiser, ; Lowe, Mosobo, & Bull, ). Studies have also suggested that VSA play a critical role in parasite‐mediated pathology (Buffet et al, ; Dzikowski, Templeton, & Deitsch, ; Fernandez, Hommel, Chen, Hagblom, & Wahlgren, ; Rowe, Moulds, Newbold, & Miller, ; Subudhi et al ., ; Warimwe et al ., ). Three large exported multigene families have been identified in P. falciparum ( Gardner et al, ; Lavazec, Sanyal, & Templeton, ) .…”

Section: Introductionmentioning

confidence: 98%

Expression dynamics and physiologically relevant functional study of STEVOR in asexual stages ofPlasmodium falciparuminfection

Singh

Madnani

Lim

et al. 2017

Cellular Microbiology

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The extensive modification of Plasmodium falciparum-infected erythrocytes by variant surface antigens plays a major role in immune evasion and malaria-induced pathology. Here, using high-resolution microscopy, we visualize the spatio-temporal expression dynamics of STEVOR, an important variant surface antigens family, in a stage-dependent manner. We demonstrate that it is exported to the cell surface where protein molecules cluster and preferentially localize in proximity to knobs. Quantitative evidence from our force measurements and microfluidic assays reveal that STEVOR can effectively mediate the formation of stable, robust rosettes under static and physiologically relevant flow conditions. Our results extend previously published studies in P. falciparum and emphasize the role of STEVOR in rosetting, an important contributor to disease pathology.

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“…Comparison of parasite gene expression levels has been performed with a small number of adults with noncerebral severe malaria (predominantly subjects with renal impairment) versus those with uncomplicated malaria by using a custom microarray designed to identify a broader repertoire of genes from variant gene families of parasites ( 205 ). Given the small size of that study, it was surprising that 380 genes were identified as being differentially expressed, with a notable downregulation of genes associated with host cell entry in severe malaria as well as enrichment for metabolic processes and RNA splicing and the differential expression of a range of variant surface antigens ( 205 ). The generalizability of these findings remains to be determined.…”

Section: Transcriptomic Studies Of Malariamentioning

confidence: 99%

Transcriptomic Studies of Malaria: a Paradigm for Investigation of Systemic Host-Pathogen Interactions

Lee

Georgiadou

Otto

et al. 2018

Microbiol Mol Biol Rev

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SUMMARYTranscriptomics, the analysis of genome-wide RNA expression, is a common approach to investigate host and pathogen processes in infectious diseases. Technical and bioinformatic advances have permitted increasingly thorough analyses of the association of RNA expression with fundamental biology, immunity, pathogenesis, diagnosis, and prognosis. Transcriptomic approaches can now be used to realize a previously unattainable goal, the simultaneous study of RNA expression in host and pathogen, in order to better understand their interactions. This exciting prospect is not without challenges, especially as focus moves from interactions in vitro under tightly controlled conditions to tissue- and systems-level interactions in animal models and natural and experimental infections in humans. Here we review the contribution of transcriptomic studies to the understanding of malaria, a parasitic disease which has exerted a major influence on human evolution and continues to cause a huge global burden of disease. We consider malaria a paradigm for the transcriptomic assessment of systemic host-pathogen interactions in humans, because much of the direct host-pathogen interaction occurs within the blood, a readily sampled compartment of the body. We illustrate lessons learned from transcriptomic studies of malaria and how these lessons may guide studies of host-pathogen interactions in other infectious diseases. We propose that the potential of transcriptomic studies to improve the understanding of malaria as a disease remains partly untapped because of limitations in study design rather than as a consequence of technological constraints. Further advances will require the integration of transcriptomic data with analytical approaches from other scientific disciplines, including epidemiology and mathematical modeling.

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Plasmodium falciparum complicated malaria: Modulation and connectivity between exportome and variant surface antigen gene families

Cited by 10 publications

References 89 publications

Severe adult malaria is associated with specific PfEMP1 adhesion types and high parasite biomass

Severe adult malaria is associated with specific PfEMP1 adhesion types and high parasite biomass

Expression dynamics and physiologically relevant functional study of STEVOR in asexual stages ofPlasmodium falciparuminfection

Transcriptomic Studies of Malaria: a Paradigm for Investigation of Systemic Host-Pathogen Interactions

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