Na+ Influx Induced by New Antimalarials Causes Rapid Alterations in the Cholesterol Content and Morphology of Plasmodium falciparum.

Abstract:

:Among the several new antimalarials discovered over the past decade are at least three clinical candidate drugs, each with a distinct chemical structure, that disrupt Na+ homeostasis resulting in a rapid increase in intracellular Na+ concentration ([Na+]i) within the erythrocytic stages of Plasmodium falciparum. At present, events triggered by Na+ influx that result in parasite demise are not well-understood. Here we report effects of two such drugs, a pyrazoleamide and a spiroindolone, on intraerythrocytic P. falciparum. Within minutes following the exposure to these drugs, the trophozoite stage parasite, which normally contains little cholesterol, was made permeant by cholesterol-dependent detergents, suggesting it acquired a substantial amount of the lipid. Consistently, the merozoite surface protein 1 and 2 (MSP1 and MSP2), glycosylphosphotidylinositol (GPI)-anchored proteins normally uniformly distributed in the parasite plasma membrane, coalesced into clusters. These alterations were not observed following drug treatment of P. falciparum parasites adapted to grow in a low [Na+] growth medium. Both cholesterol acquisition and MSP1 coalescence were reversible upon the removal of the drugs, implicating an active process of cholesterol exclusion from trophozoites that we hypothesize is inhibited by high [Na+]i. Electron microscopy of drug-treated trophozoites revealed substantial morphological changes normally seen at the later schizont stage including the appearance of partial inner membrane complexes, dense organelles that resemble "rhoptries" and apparent nuclear division. Together these results suggest that [Na+]i disruptor drugs by altering levels of cholesterol in the parasite, dysregulate trophozoite to schizont development and cause parasite demise.

journal_name

PLoS Pathog

journal_title

PLoS pathogens

authors

Das S,Bhatanagar S,Morrisey JM,Daly TM,Burns JM Jr,Coppens I,Vaidya AB

doi

10.1371/journal.ppat.1005647

subject

Has Abstract

pub_date

2016-05-26 00:00:00

pages

e1005647

issue

5

eissn

1553-7366

issn

1553-7374

pii

PPATHOGENS-D-16-00050

journal_volume

12

pub_type

杂志文章
  • Peli1 signaling blockade attenuates congenital zika syndrome.

    abstract::Zika virus (ZIKV) infects pregnant women and causes devastating congenital zika syndrome (CZS). How the virus is vertically transmitted to the fetus and induces neuronal loss remains unclear. We previously reported that Pellino (Peli)1, an E3 ubiquitin ligase, promotes p38MAPK activation in microglia and induction of ...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1008538

    authors: Luo H,Li G,Wang B,Tian B,Gao J,Zou J,Shi S,Zhu S,Peng BH,Adam A,Martinez A,Hein K,Winkelmann ER,Mahmoud Y,Zhou X,Shan C,Rossi S,Weaver S,Barrett ADT,Sun SC,Zhang W,Shi PY,Wu P,Wang T

    更新日期:2020-06-16 00:00:00

  • Long noncoding RNA MARL regulates antiviral responses through suppression miR-122-dependent MAVS downregulation in lower vertebrates.

    abstract::Increasing evidence suggests important roles for long noncoding RNAs (lncRNAs) as new gene modulators involved in various biological processes. However, the function roles of lncRNAs in lower vertebrates are still unknown. Here, we firstly identify a lncRNA, named MAVS antiviral-related lncRNA (MARL), as a key regulat...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1008670

    authors: Chu Q,Xu T,Zheng W,Chang R,Zhang L

    更新日期:2020-07-17 00:00:00

  • Novel escape mutants suggest an extensive TRIM5α binding site spanning the entire outer surface of the murine leukemia virus capsid protein.

    abstract::After entry into target cells, retroviruses encounter the host restriction factors such as Fv1 and TRIM5α. While it is clear that these factors target retrovirus capsid proteins (CA), recognition remains poorly defined in the absence of structural information. To better understand the binding interaction between TRIM5...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1002011

    authors: Ohkura S,Goldstone DC,Yap MW,Holden-Dye K,Taylor IA,Stoye JP

    更新日期:2011-03-01 00:00:00

  • The novel interaction between Neisseria gonorrhoeae TdfJ and human S100A7 allows gonococci to subvert host zinc restriction.

    abstract::Neisseria gonorrhoeae causes the sexually-transmitted infection gonorrhea, a global disease that is difficult to treat and for which there is no vaccine. This pathogen employs an arsenal of conserved outer membrane proteins called TonB-dependent transporters (TdTs) that allow the gonococcus to overcome nutritional imm...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1007937

    authors: Maurakis S,Keller K,Maxwell CN,Pereira K,Chazin WJ,Criss AK,Cornelissen CN

    更新日期:2019-08-01 00:00:00

  • Autophagy protein Atg3 is essential for maintaining mitochondrial integrity and for normal intracellular development of Toxoplasma gondii tachyzoites.

    abstract::Autophagy is a cellular process that is highly conserved among eukaryotes and permits the degradation of cellular material. Autophagy is involved in multiple survival-promoting processes. It not only facilitates the maintenance of cell homeostasis by degrading long-lived proteins and damaged organelles, but it also pl...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1002416

    authors: Besteiro S,Brooks CF,Striepen B,Dubremetz JF

    更新日期:2011-12-01 00:00:00

  • Infection-adapted emergency hematopoiesis promotes visceral leishmaniasis.

    abstract::Cells of the immune system are derived from hematopoietic stem cells (HSCs) residing in the bone marrow. HSCs become activated in response to stress, such as acute infections, which adapt the bone marrow output to the needs of the immune response. However, the impact of infection-adapted HSC activation and differentia...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1006422

    authors: Abidin BM,Hammami A,Stäger S,Heinonen KM

    更新日期:2017-08-07 00:00:00

  • Yersinia pseudotuberculosis YopH targets SKAP2-dependent and independent signaling pathways to block neutrophil antimicrobial mechanisms during infection.

    abstract::Yersinia suppress neutrophil responses by using a type 3 secretion system (T3SS) to inject 6-7 Yersinia effector proteins (Yops) effectors into their cytoplasm. YopH is a tyrosine phosphatase that causes dephosphorylation of the adaptor protein SKAP2, among other targets in neutrophils. SKAP2 functions in reactive oxy...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1008576

    authors: Shaban L,Nguyen GT,Mecsas-Faxon BD,Swanson KD,Tan S,Mecsas J

    更新日期:2020-05-11 00:00:00

  • Retention and loss of RNA interference pathways in trypanosomatid protozoans.

    abstract::RNA interference (RNAi) pathways are widespread in metaozoans but the genes required show variable occurrence or activity in eukaryotic microbes, including many pathogens. While some Leishmania lack RNAi activity and Argonaute or Dicer genes, we show that Leishmania braziliensis and other species within the Leishmania...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1001161

    authors: Lye LF,Owens K,Shi H,Murta SM,Vieira AC,Turco SJ,Tschudi C,Ullu E,Beverley SM

    更新日期:2010-10-28 00:00:00

  • Transcriptome-Wide Cleavage Site Mapping on Cellular mRNAs Reveals Features Underlying Sequence-Specific Cleavage by the Viral Ribonuclease SOX.

    abstract::Many viruses express factors that reduce host gene expression through widespread degradation of cellular mRNA. An example of this class of proteins is the mRNA-targeting endoribonuclease SOX from the gamma-herpesvirus Kaposi's sarcoma-associated herpesvirus (KSHV). Previous studies indicated that cleavage of messenger...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1005305

    authors: Gaglia MM,Rycroft CH,Glaunsinger BA

    更新日期:2015-12-08 00:00:00

  • Host prion protein expression levels impact prion tropism for the spleen.

    abstract::Prions are pathogens formed from abnormal conformers (PrPSc) of the host-encoded cellular prion protein (PrPC). PrPSc conformation to disease phenotype relationships extensively vary among prion strains. In particular, prions exhibit a strain-dependent tropism for lymphoid tissues. Prions can be composed of several su...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1008283

    authors: Béringue V,Tixador P,Andréoletti O,Reine F,Castille J,Laï TL,Le Dur A,Laisné A,Herzog L,Passet B,Rezaei H,Vilotte JL,Laude H

    更新日期:2020-07-23 00:00:00

  • The Salmonella type III effector SspH2 specifically exploits the NLR co-chaperone activity of SGT1 to subvert immunity.

    abstract::To further its pathogenesis, S. Typhimurium delivers effector proteins into host cells, including the novel E3 ubiquitin ligase (NEL) effector SspH2. Using model systems in a cross-kingdom approach we gained further insight into the molecular function of this effector. Here, we show that SspH2 modulates innate immunit...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1003518

    authors: Bhavsar AP,Brown NF,Stoepel J,Wiermer M,Martin DD,Hsu KJ,Imami K,Ross CJ,Hayden MR,Foster LJ,Li X,Hieter P,Finlay BB

    更新日期:2013-01-01 00:00:00

  • A type VII secretion system of Streptococcus gallolyticus subsp. gallolyticus contributes to gut colonization and the development of colon tumors.

    abstract::Streptococcus gallolyticus subspecies gallolyticus (Sgg) has a strong clinical association with colorectal cancer (CRC) and actively promotes the development of colon tumors. However, the molecular determinants involved in Sgg pathogenicity in the gut are unknown. Bacterial type VII secretion systems (T7SS) mediate pa...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1009182

    authors: Taylor JC,Gao X,Xu J,Holder M,Petrosino J,Kumar R,Liu W,Höök M,Mackenzie C,Hillhouse A,Brashear W,Nunez MP,Xu Y

    更新日期:2021-01-06 00:00:00

  • Plasma membrane profiling defines an expanded class of cell surface proteins selectively targeted for degradation by HCMV US2 in cooperation with UL141.

    abstract::Human cytomegalovirus (HCMV) US2, US3, US6 and US11 act in concert to prevent immune recognition of virally infected cells by CD8+ T-lymphocytes through downregulation of MHC class I molecules (MHC-I). Here we show that US2 function goes far beyond MHC-I degradation. A systematic proteomic study using Plasma Membrane ...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1004811

    authors: Hsu JL,van den Boomen DJ,Tomasec P,Weekes MP,Antrobus R,Stanton RJ,Ruckova E,Sugrue D,Wilkie GS,Davison AJ,Wilkinson GW,Lehner PJ

    更新日期:2015-04-14 00:00:00

  • Kinetics of myeloid dendritic cell trafficking and activation: impact on progressive, nonprogressive and controlled SIV infections.

    abstract::We assessed the role of myeloid dendritic cells (mDCs) in the outcome of SIV infection by comparing and contrasting their frequency, mobilization, phenotype, cytokine production and apoptosis in pathogenic (pigtailed macaques, PTMs), nonpathogenic (African green monkeys, AGMs) and controlled (rhesus macaques, RMs) SIV...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1003600

    authors: Wijewardana V,Kristoff J,Xu C,Ma D,Haret-Richter G,Stock JL,Policicchio BB,Mobley AD,Nusbaum R,Aamer H,Trichel A,Ribeiro RM,Apetrei C,Pandrea I

    更新日期:2013-01-01 00:00:00

  • NS2 protein of hepatitis C virus interacts with structural and non-structural proteins towards virus assembly.

    abstract::Growing experimental evidence indicates that, in addition to the physical virion components, the non-structural proteins of hepatitis C virus (HCV) are intimately involved in orchestrating morphogenesis. Since it is dispensable for HCV RNA replication, the non-structural viral protein NS2 is suggested to play a centra...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1001278

    authors: Popescu CI,Callens N,Trinel D,Roingeard P,Moradpour D,Descamps V,Duverlie G,Penin F,Héliot L,Rouillé Y,Dubuisson J

    更新日期:2011-02-10 00:00:00

  • Cooperation between Epstein-Barr virus immune evasion proteins spreads protection from CD8+ T cell recognition across all three phases of the lytic cycle.

    abstract::CD8+ T cell responses to Epstein-Barr virus (EBV) lytic cycle expressed antigens display a hierarchy of immunodominance, in which responses to epitopes of immediate-early (IE) and some early (E) antigens are more frequently observed than responses to epitopes of late (L) expressed antigens. It has been proposed that t...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1004322

    authors: Quinn LL,Zuo J,Abbott RJ,Shannon-Lowe C,Tierney RJ,Hislop AD,Rowe M

    更新日期:2014-08-21 00:00:00

  • De novo synthesis of VP16 coordinates the exit from HSV latency in vivo.

    abstract::The mechanism controlling the exit from herpes simplex virus latency (HSV) is of central importance to recurrent disease and transmission of infection, yet interactions between host and viral functions that govern this process remain unclear. The cascade of HSV gene transcription is initiated by the multifunctional vi...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1000352

    authors: Thompson RL,Preston CM,Sawtell NM

    更新日期:2009-03-01 00:00:00

  • Revealing the sequence and resulting cellular morphology of receptor-ligand interactions during Plasmodium falciparum invasion of erythrocytes.

    abstract::During blood stage Plasmodium falciparum infection, merozoites invade uninfected erythrocytes via a complex, multistep process involving a series of distinct receptor-ligand binding events. Understanding each element in this process increases the potential to block the parasite's life cycle via drugs or vaccines. To i...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1004670

    authors: Weiss GE,Gilson PR,Taechalertpaisarn T,Tham WH,de Jong NW,Harvey KL,Fowkes FJ,Barlow PN,Rayner JC,Wright GJ,Cowman AF,Crabb BS

    更新日期:2015-02-27 00:00:00

  • Exclusive dependence of IL-10Rα signalling on intestinal microbiota homeostasis and control of whipworm infection.

    abstract::The whipworm Trichuris trichiura is a soil-transmitted helminth that dwells in the epithelium of the caecum and proximal colon of their hosts causing the human disease, trichuriasis. Trichuriasis is characterized by colitis attributed to the inflammatory response elicited by the parasite while tunnelling through intes...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1007265

    authors: Duque-Correa MA,Karp NA,McCarthy C,Forman S,Goulding D,Sankaranarayanan G,Jenkins TP,Reid AJ,Cambridge EL,Ballesteros Reviriego C,Sanger Mouse Genetics Project.,3i consortium.,Müller W,Cantacessi C,Dougan G,Grencis RK,Ber

    更新日期:2019-01-14 00:00:00

  • The RNA Binding Specificity of Human APOBEC3 Proteins Resembles That of HIV-1 Nucleocapsid.

    abstract::The APOBEC3 (A3) cytidine deaminases are antiretroviral proteins, whose targets include human immunodeficiency virus type-1 (HIV-1). Their incorporation into viral particles is critical for antiviral activity and is driven by interactions with the RNA molecules that are packaged into virions. However, it is unclear wh...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1005833

    authors: York A,Kutluay SB,Errando M,Bieniasz PD

    更新日期:2016-08-19 00:00:00

  • Multiple roles of PP2A binding motif in hepatitis B virus core linker and PP2A in regulating core phosphorylation state and viral replication.

    abstract::Hepatitis B virus (HBV) capsid or core protein (HBc) contains an N-terminal domain (NTD) and a C-terminal domain (CTD) connected by a short linker peptide. HBc plays a critical role in virtually every step of viral replication, which is further modulated by dynamic phosphorylation and dephosphorylation of its CTD. Whi...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1009230

    authors: Xi J,Luckenbaugh L,Hu J

    更新日期:2021-01-25 00:00:00

  • Red-light is an environmental effector for mutualism between begomovirus and its vector whitefly.

    abstract::Environments such as light condition influence the spread of infectious diseases by affecting insect vector behavior. However, whether and how light affects the host defense which further affects insect preference and performance, remains unclear, nor has been demonstrated how pathogens co-adapt light condition to fac...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1008770

    authors: Zhao P,Zhang X,Gong Y,Wang D,Xu D,Wang N,Sun Y,Gao L,Liu SS,Deng XW,Kliebenstein DJ,Zhou X,Fang RX,Ye J

    更新日期:2021-01-11 00:00:00

  • Viral and cellular proteins containing FGDF motifs bind G3BP to block stress granule formation.

    abstract::The Ras-GAP SH3 domain-binding proteins (G3BP) are essential regulators of the formation of stress granules (SG), cytosolic aggregates of proteins and RNA that are induced upon cellular stress, such as virus infection. Many viruses, including Semliki Forest virus (SFV), block SG induction by targeting G3BP. In this wo...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1004659

    authors: Panas MD,Schulte T,Thaa B,Sandalova T,Kedersha N,Achour A,McInerney GM

    更新日期:2015-02-06 00:00:00

  • Seasonal pulses of Marburg virus circulation in juvenile Rousettus aegyptiacus bats coincide with periods of increased risk of human infection.

    abstract::Marburg virus (family Filoviridae) causes sporadic outbreaks of severe hemorrhagic disease in sub-Saharan Africa. Bats have been implicated as likely natural reservoir hosts based most recently on an investigation of cases among miners infected in 2007 at the Kitaka mine, Uganda, which contained a large population of ...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1002877

    authors: Amman BR,Carroll SA,Reed ZD,Sealy TK,Balinandi S,Swanepoel R,Kemp A,Erickson BR,Comer JA,Campbell S,Cannon DL,Khristova ML,Atimnedi P,Paddock CD,Crockett RJ,Flietstra TD,Warfield KL,Unfer R,Katongole-Mbidde E,Downin

    更新日期:2012-01-01 00:00:00

  • Retromer regulates HIV-1 envelope glycoprotein trafficking and incorporation into virions.

    abstract::The envelope glycoprotein (Env) of the Human Immunodeficiency Virus Type-1 (HIV-1) is a critical determinant of viral infectivity, tropism and is the main target for humoral immunity; however, little is known about the cellular machinery that directs Env trafficking and its incorporation into nascent virions. Here we ...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1004518

    authors: Groppelli E,Len AC,Granger LA,Jolly C

    更新日期:2014-11-13 00:00:00

  • Host cytosolic RNA sensing pathway promotes T Lymphocyte-mediated mycobacterial killing in macrophages.

    abstract::Mycobacterial infection leads to activation of the RIG-I/MAVS/TBK1 RNA sensing pathway in macrophages but the consequences of this activation remains poorly defined. In this study, we determined that activation of this RNA sensing pathway stimulates ICAM-1 expression in M.avium-infected macrophage through the inhibiti...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1008569

    authors: Cheng Y,Kiene NJ,Tatarian A,Eix EF,Schorey JS

    更新日期:2020-05-28 00:00:00

  • Broadening of neutralization activity to directly block a dominant antibody-driven SARS-coronavirus evolution pathway.

    abstract::Phylogenetic analyses have provided strong evidence that amino acid changes in spike (S) protein of animal and human SARS coronaviruses (SARS-CoVs) during and between two zoonotic transfers (2002/03 and 2003/04) are the result of positive selection. While several studies support that some amino acid changes between an...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1000197

    authors: Sui J,Aird DR,Tamin A,Murakami A,Yan M,Yammanuru A,Jing H,Kan B,Liu X,Zhu Q,Yuan QA,Adams GP,Bellini WJ,Xu J,Anderson LJ,Marasco WA

    更新日期:2008-11-01 00:00:00

  • Bacterial flagella: twist and stick, or dodge across the kingdoms.

    abstract::The flagellum organelle is an intricate multiprotein assembly best known for its rotational propulsion of bacteria. However, recent studies have expanded our knowledge of other functions in pathogenic contexts, particularly adherence and immune modulation, e.g., for Salmonella enterica, Campylobacter jejuni, Pseudomon...

    journal_title:PLoS pathogens

    pub_type: 杂志文章,评审

    doi:10.1371/journal.ppat.1004483

    authors: Rossez Y,Wolfson EB,Holmes A,Gally DL,Holden NJ

    更新日期:2015-01-15 00:00:00

  • Modulation of the Host Lipid Landscape to Promote RNA Virus Replication: The Picornavirus Encephalomyocarditis Virus Converges on the Pathway Used by Hepatitis C Virus.

    abstract::Cardioviruses, including encephalomyocarditis virus (EMCV) and the human Saffold virus, are small non-enveloped viruses belonging to the Picornaviridae, a large family of positive-sense RNA [(+)RNA] viruses. All (+)RNA viruses remodel intracellular membranes into unique structures for viral genome replication. Accumul...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1005185

    authors: Dorobantu CM,Albulescu L,Harak C,Feng Q,van Kampen M,Strating JR,Gorbalenya AE,Lohmann V,van der Schaar HM,van Kuppeveld FJ

    更新日期:2015-09-25 00:00:00

  • A calmodulin-like protein suppresses RNA silencing and promotes geminivirus infection by degrading SGS3 via the autophagy pathway in Nicotiana benthamiana.

    abstract::A recently characterized calmodulin-like protein is an endogenous RNA silencing suppressor that suppresses sense-RNA induced post-transcriptional gene silencing (S-PTGS) and enhances virus infection, but the mechanism underlying calmodulin-like protein-mediated S-PTGS suppression is obscure. Here, we show that a calmo...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1006213

    authors: Li F,Zhao N,Li Z,Xu X,Wang Y,Yang X,Liu SS,Wang A,Zhou X

    更新日期:2017-02-17 00:00:00