scholarly journals Anopheles gambiaeLackingAgTRIOInefficiently TransmitsPlasmodium bergheito Mice

2019 ◽  
Vol 87 (9) ◽  
Author(s):  
Yu-Min Chuang ◽  
Marianna Freudzon ◽  
Jing Yang ◽  
Yuemei Dong ◽  
George Dimopoulos ◽  
...  
Keyword(s):  
Plasmodium Berghei ◽  
Local Environment ◽  
Salivary Protein ◽  
Content Type ◽  
Relative Contribution ◽  
Expression Of Genes ◽  
Tnf Α ◽  
Sporozoite Infection

ABSTRACTAntibodies to AgTRIO, a mosquito salivary protein, partially reduce the initialPlasmodiumburden in mice. We therefore silencedAgTRIOin mosquitoes and determined the relative contribution of AgTRIO to the ability ofAnopheles gambiaeto transmitPlasmodium bergheito mice. RNA interference-mediated silencing ofAgTRIO inA. gambiaeresulted in a 60% reduction inAgTRIOexpression. The decrease inAgTRIOexpression did not alter the burden ofPlasmodiumsporozoites in mosquito salivary glands. When experimentally injected into mice, sporozoites fromAgTRIO-silenced mosquitoes colonized the liver less effectively than sporozoites from control mosquitoes. Silencing ofAgTRIOdid not decrease the infectivity of sporozoitesin vitroor influence the expression of genes associated withPlasmodiumcell adhesion or traversal activity. AgTRIO decreased the expression of proinflammation cytokines by splenocytesin vitro. Moreover,in vivo, AgTRIO decreased the expression ofTNF-αwhen coinjected with sporozoites into the skin and there was moreTNF-αexpression at the bite site ofAgTRIOknockdown mosquitoes than at the bite site of control mosquitoes. AgTRIO therefore influences the local environment in the vertebrate host, which facilitatesPlasmodiumsporozoite infection in mice.

scholarly journals Antimalarial Efficacy of Hydroxyethylapoquinine (SN-119) and Its Derivatives

2013 ◽  
Vol 58 (2) ◽  
pp. 820-827 ◽  
Author(s):  
Natalie G. Sanders ◽  
David J. Meyers ◽  
David J. Sullivan
Keyword(s):  
Plasmodium Berghei ◽  
Herg Channel ◽  
Preclinical Studies ◽  
Related Gene ◽  
Antimalarial Drug Resistance ◽  
Content Type ◽  
Channel Inhibition ◽  
Malaria Model

ABSTRACTQuinine and other cinchona-derived alkaloids, although recently supplanted by the artemisinins (ARTs), continue to be important for treatment of severe malaria. Quinine and quinidine have narrow therapeutic indices, and a safer quinine analog is desirable, particularly with the continued threat of antimalarial drug resistance. Hydroxyethylapoquinine (HEAQ), used at 8 g a day for dosing in humans in the 1930s and halving mortality from bacterial pneumonias, was shown to cure bird malaria in the 1940s and was also reported as treatment for human malaria cases. Here we describe synthesis of HEAQ and its novel stereoisomer hydroxyethylapoquinidine (HEAQD) along with two intermediates, hydroxyethylquinine (HEQ) and hydroxyethylquinidine (HEQD), and demonstrate comparable but elevated antimalarial 50% inhibitory concentrations (IC50) of 100 to 200 nM againstPlasmodium falciparumquinine-sensitive strain 3D7 (IC50, 56 nM). Only HEAQD demonstrated activity against quinine-tolerantP. falciparumstrains Dd2 and INDO with IC50s of 300 to 700 nM. HEQD had activity only against Dd2 with an IC50of 313 nM. In the lethal mouse malaria modelPlasmodium bergheiANKA, only HEQD had activity at 20 mg/kg of body weight comparable to that of the parent quinine or quinidine drugs measured by parasite inhibition and 30-day survival. In addition, HEQ, HEQD, and HEAQ (IC50≥ 90 μM) have little to no human ether-à-go-go-related gene (hERG) channel inhibition expressed in CHO cells compared to HEAQD, quinine, and quinidine (hERG IC50s of 27, 42, and 4 μM, respectively). HEQD more closely resembled quininein vitroandin vivoforPlasmodiuminhibition and demonstrated little hERG channel inhibition, suggesting that further optimization and preclinical studies are warranted for this molecule.

scholarly journals Mycobacterium avium Biofilm Attenuates Mononuclear Phagocyte Function by Triggering Hyperstimulation and Apoptosis during Early Infection

2013 ◽  
Vol 82 (1) ◽  
pp. 405-412 ◽  
Author(s):  
Sasha J. Rose ◽  
Luiz E. Bermudez
Keyword(s):  
Immune System ◽  
Mycobacterium Avium ◽  
Innate Immune System ◽  
Innate Immune ◽  
Mononuclear Phagocytes ◽  
Bacterial Killing ◽  
Content Type ◽  
Tnf Α

ABSTRACTMycobacterium aviumsubsp.hominissuisis an opportunistic human pathogen that has been shown to form biofilmin vitroandin vivo. Biofilm formationin vivoappears to be associated with infections in the respiratory tract of the host. The reasoning behind howM. aviumsubsp.hominissuisbiofilm is allowed to establish and persist without being cleared by the innate immune system is currently unknown. To identify the mechanism responsible for this, we developed anin vitromodel using THP-1 human mononuclear phagocytes cocultured with establishedM. aviumsubsp.hominissuisbiofilm and surveyed various aspects of the interaction, including phagocyte stimulation and response, bacterial killing, and apoptosis.M. aviumsubsp.hominissuisbiofilm triggered robust tumor necrosis factor alpha (TNF-α) release from THP-1 cells as well as superoxide and nitric oxide production. Surprisingly, the hyperstimulated phagocytes did not effectively eliminate the cells of the biofilm, even when prestimulated with gamma interferon (IFN-γ) or TNF-α or cocultured with natural killer cells (which have been shown to induce anti-M. aviumsubsp.hominissuisactivity when added to THP-1 cells infected with planktonicM. aviumsubsp.hominissuis). Time-lapse microscopy and the TUNEL (terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling) assay determined that contact with theM. aviumsubsp.hominissuisbiofilm led to early, widespread onset of apoptosis, which is not seen until much later in planktonicM. aviumsubsp.hominissuisinfection. Blocking TNF-α or TNF-R1 during interaction with the biofilm significantly reduced THP-1 apoptosis but did not lead to elimination ofM. aviumsubsp.hominissuis. Our data collectively indicate thatM. aviumsubsp.hominissuisbiofilm induces TNF-α-driven hyperstimulation and apoptosis of surveilling phagocytes, which prevents clearance of the biofilm by cells of the innate immune system and allows the biofilm-associated infection to persist.

scholarly journals Transcriptional Regulator LsrB of Sinorhizobium meliloti Positively Regulates the Expression of Genes Involved in Lipopolysaccharide Biosynthesis

2014 ◽  
Vol 80 (17) ◽  
pp. 5265-5273 ◽  
Author(s):  
Guirong Tang ◽  
Ying Wang ◽  
Li Luo
Keyword(s):  
Sinorhizobium Meliloti ◽  
Sodium Dodecyl ◽  
Host Cells ◽  
Content Type ◽  
Expression Of Genes ◽  
New Findings ◽  
Promoter Dna ◽  
Transcriptional Start Sites

ABSTRACTRhizobia induce nitrogen-fixing nodules on host legumes, which is important in agriculture and ecology. Lipopolysaccharide (LPS) produced by rhizobia is required for infection or bacteroid survival in host cells. Genes required for LPS biosynthesis have been identified in severalRhizobiumspecies. However, the regulation of their expression is not well understood. Here,Sinorhizobium melilotiLsrB, a member of the LysR family of transcriptional regulators, was found to be involved in LPS biosynthesis by positively regulating the expression of thelrp3-lpsCDEoperon. AnlsrBin-frame deletion mutant displayed growth deficiency, sensitivity to the detergent sodium dodecyl sulfate, and acidic pH compared to the parent strain. This mutant produced slightly less LPS due to lower expression of thelrp3operon. Analysis of the transcriptional start sites of thelrp3andlpsCDEgene suggested that they constitute one operon. The expression oflsrBwas positively autoregulated. The promoter region oflrp3was specifically precipitated by anti-LsrB antibodiesin vivo. The promoter DNA fragment containing TN11A motifs was bound by the purified LsrB proteinin vitro. These new findings suggest thatS. melilotiLsrB is associated with LPS biosynthesis, which is required for symbiotic nitrogen fixation on some ecotypes of alfalfa plants.

scholarly journals Immunomodulatory Metabolites Released by the Frog-Killing Fungus Batrachochytrium dendrobatidis

2015 ◽  
Vol 83 (12) ◽  
pp. 4565-4570 ◽  
Author(s):  
Louise A. Rollins-Smith ◽  
J. Scott Fites ◽  
Laura K. Reinert ◽  
Andrea R. Shiakolas ◽  
Thomas P. Umile ◽  
...  
Keyword(s):  
Batrachochytrium Dendrobatidis ◽  
Leukemia Cell ◽  
Local Environment ◽  
Amphibian Declines ◽  
Leukemia Cell Line ◽  
Content Type ◽  
Isolation And Characterization ◽  
Human T Cell

Batrachochytrium dendrobatidisis a fungal pathogen in the phylum Chytridiomycota that causes the skin disease chytridiomycosis. Chytridiomycosis is considered an emerging infectious disease linked to worldwide amphibian declines and extinctions. Although amphibians have well-developed immune defenses, clearance of this pathogen from the skin is often impaired. Previously, we showed that the adaptive immune system is involved in the control of the pathogen, butB. dendrobatidisreleases factors that inhibitin vitroandin vivolymphocyte responses and induce lymphocyte apoptosis. Little is known about the nature of the inhibitory factors released by this fungus. Here, we describe the isolation and characterization of three fungal metabolites produced byB. dendrobatidisbut not by the closely related nonpathogenic chytridHomolaphlyctis polyrhiza. These metabolites are methylthioadenosine (MTA), tryptophan, and an oxidized product of tryptophan, kynurenine (Kyn). Independently, both MTA and Kyn inhibit the survival and proliferation of amphibian lymphocytes and the Jurkat human T cell leukemia cell line. However, working together, they become effective at much lower concentrations. We hypothesize thatB. dendrobatidiscan adapt its metabolism to release products that alter the local environment in the skin to inhibit immunity and enhance the survival of the pathogen.

scholarly journals Annona muricata Linn and Khaya grandifoliola C.DC. Reduce Oxidative Stress In Vitro and Ameliorate Plasmodium berghei-Induced Parasitemia and Cytokines in BALB/c Mice

2021 ◽  
Vol 26 ◽  
pp. 2515690X2110366
Author(s):  
Hope Onohuean ◽  
Abdullateef I. Alagbonsi ◽  
Ibe M. Usman ◽  
Keneth Iceland Kasozi ◽  
Athanasios Alexiou ◽  
...  
Keyword(s):  
Plasmodium Berghei ◽  
Radical Scavenging ◽  
Experimental Period ◽  
Annona Muricata ◽  
Tnf Α ◽  
Anti Oxidant ◽  
Ethanol Extracts ◽  
Radical Scavenging Properties

Background. Annona muricata and Khaya grandifoliola are ethnomedicinally used for the treatment of malaria and have been experimentally shown to have an anti-plasmodial effect, but the mechanisms involved are not fully understood. This study investigated the effect of the ethanol extracts of their leaves on parasitemia, radical scavenging and cytokines in Plasmodium berghei ANKA-infected BALB/c mice. Methods. BALB/c mice were infected with P. berghei and treated with chloroquine, A. muricata or K. grandifoliola extract for 4 days. The percentage of parasitemia and the level of cytokine expression were determined after treatment. Trace element, phytochemical and nitric oxide (NO) scavenging activity, 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging properties assays were done to study the antioxidant effects of AN and KG in vitro. Results. P. berghei consistently increased parasitemia in BALB/c mice. The tested doses (100-, 200-, and 400 mg/kg) of A. muricata and K. grandifoliola attenuated the P. berghei-induced elevation of parasitemia and cytokines (TNF-α, IL-5, and IL-6) in vivo during the experimental period, though not as much as chloroquine. Moreover, both extracts scavenged the DPPH and NO radicals, though A. muricata had more anti-oxidant effect than K. grandifoliola in-vitro. Conclusion. The ethanol extracts of A. muricata and K. grandifoliola reduce parasitemia in P. berghei-treated mice BALB/c by scavenging free radicals and reducing cytokines, though the extracts were not as effective as chloroquine.

scholarly journals Novel 4-Aminoquinoline Analogs Highly Active against the Blood and Sexual Stages of PlasmodiumIn VivoandIn Vitro

2012 ◽  
Vol 56 (9) ◽  
pp. 4685-4692 ◽  
Author(s):  
Fabián E. Sáenz ◽  
Tina Mutka ◽  
Kenneth Udenze ◽  
Ayoade M. J. Oduola ◽  
Dennis E. Kyle
Keyword(s):  
Plasmodium Berghei ◽  
Multidrug Resistant ◽  
New Drugs ◽  
Content Type ◽  
Highly Active ◽  
Resistant Strains ◽  
Sexual Stages ◽  
The 1960S

ABSTRACTNew drugs to treat malaria must act rapidly and be highly potent against asexual blood stages, well tolerated, and affordable to residents of regions of endemicity. This was the case with chloroquine (CQ), a 4-aminoquinoline drug used for the prevention and treatment of malaria. However, since the 1960s,Plasmodium falciparumresistance to this drug has spread globally, and more recently, emerging resistance to CQ byPlasmodium vivaxthreatens the health of 70 to 320 million people annually. Despite the emergence of CQ resistance, synthetic quinoline derivatives remain validated leads for new drug discovery, especially if they are effective against CQ-resistant strains of malaria. In this study, we investigated the activities of two novel 4-aminoquinoline derivatives, TDR 58845,N1-(7-chloro-quinolin-4-yl)-2-methyl-propane-1,2-diamine, and TDR 58846,N1-(7-chloro-quinolin-4-yl)-2,N2,N2-trimethylpropane-1,2-diamine and found them to be active againstP. falciparumin vitroandPlasmodium bergheiin vivo. TheP. falciparumclones and isolates tested were susceptible to TDR 58845 and TDR 58846 (50% inhibitory concentrations [IC50s] ranging from 5.52 to 89.8 nM), including the CQ-resistant reference clone W2 and two multidrug-resistant parasites recently isolated from Thailand and Cambodia. Moreover, these 4-aminoquinolines were active against early and lateP. falciparumgametocyte stages and cured BALB/c mice infected withP. berghei. TDR 58845 and TDR 58846 at 40 mg/kg were sufficient to cure mice, and total doses of 480 mg/kg of body weight were well tolerated. Our findings suggest these novel 4-aminoquinolines should be considered for development as potent antimalarials that can be used in combination to treat multidrug-resistantP. falciparumandP. vivax.

scholarly journals Bacterial Subfamily of LuxR Regulators That Respond to Plant Compounds

2011 ◽  
Vol 77 (13) ◽  
pp. 4579-4588 ◽  
Author(s):  
Sujatha Subramoni ◽  
Juan F. Gonzalez ◽  
Aaron Johnson ◽  
Maria Péchy-Tarr ◽  
Laurène Rochat ◽  
...  
Keyword(s):  
Plant Pathogens ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Gene Promoter ◽  
Pythium Ultimum ◽  
Content Type ◽  
Expression Of Genes ◽  
Plant Compounds

ABSTRACTPseudomonas fluorescensare rhizobacteria known for their biocontrol properties. Several antimicrobial functions are crucial for this process, and the experiments described here investigate the modulation of their expression during the plant-bacterium interaction. The role of a LuxR family regulator in interkingdom signaling has been investigated using genome-scale transcriptome analysis, gene promoter studiesin vivoandin vitro, biocontrol assays, and response to plant compounds. PsoR, a LuxR solo or orphan regulator ofP. fluorescens, was identified. PsoR is solubilized and activates alux-box-containing promoter only in the presence of macerated plants, suggesting the presence of a plant molecule(s) that most likely binds to PsoR. Gene expression profiles revealed that genes involved in the inhibition of plant pathogens were affected by PsoR, including a chitinase gene, iron metabolism genes, and biosynthetic genes of antifungal compounds. 2,4-Diacetylphloroglucinol production is PsoR dependent bothin vitroandin vivo.psoRmutants were significantly reduced for their ability to protect wheat plants from root rot, and damping-off caused byPythium ultimuminfection. PsoR most likely senses a molecule(s) in the plant and modulates expression of genes that have a role in biocontrol. PsoR and related proteins form a subfamily of LuxR family regulators in plant-associated bacteria.

scholarly journals RNA Sequencing Reveals Differences between the Global Transcriptomes of Salmonella enterica Serovar Enteritidis Strains with High and Low Pathogenicities

2013 ◽  
Vol 80 (3) ◽  
pp. 896-906 ◽  
Author(s):  
Devendra H. Shah
Keyword(s):  
Rna Sequencing ◽  
Salmonella Enterica ◽  
Negative Binomial ◽  
Phenotypic Diversity ◽  
Functional Characterization ◽  
Salmonella Enterica Serovar Enteritidis ◽  
Content Type ◽  
Expression Of Genes

ABSTRACTSalmonella entericaserovar Enteritidis is one of the important causes of bacterial food-borne gastroenteritis worldwide. Field strains ofS. Enteritidis are relatively genetically homogeneous; however, they show extensive phenotypic diversity and differences in virulence potential. RNA sequencing (RNA-Seq) was used to characterize differences in the global transcriptome between several genetically similar but phenotypically diverse poultry-associated field strains ofS. Enteritidis grown in laboratory medium at avian body temperature (42°C). TheseS. Enteritidis strains were previously characterized as high-pathogenicity (HP;n= 3) and low-pathogenicity (LP;n= 3) strains based on bothin vitroandin vivovirulence assays. Using the negative binomial distribution-based statistical tools edgeR and DESeq, 252 genes were identified as differentially expressed in LP strains compared with their expression in the HP strains (P< 0.05). A majority of genes (235, or 93.2%) showed significantly reduced expression, whereas a few genes (17, or 6.8%) showed increased expression in all LP strains compared with HP strains. LP strains showed a unique transcriptional profile that is characterized by significantly reduced expression of several transcriptional regulators and reduced expression of genes involved in virulence (e.g.,Salmonellapathogenicity island 1 [SPI-1], SPI-5, and fimbrial and motility genes) and protection against osmotic, oxidative, and other stresses, such as iron-limiting conditions commonly encountered within the host. Several functionally uncharacterized genes also showed reduced expression. This study provides a first concise view of the global transcriptional differences between field strains ofS. Enteritidis with various levels of pathogenicity, providing the basis for future functional characterization of several genes with potential roles in virulence or stress regulation ofS. Enteritidis.

scholarly journals 4(1H)-Quinolones with Liver Stage Activity against Plasmodium berghei

2012 ◽  
Vol 57 (1) ◽  
pp. 417-424 ◽  
Author(s):  
Alexis N. LaCrue ◽  
Fabián E. Sáenz ◽  
R. Matthew Cross ◽  
Kenneth O. Udenze ◽  
Andrii Monastyrskyi ◽  
...  
Keyword(s):  
Plasmodium Berghei ◽  
Bioluminescent Imaging ◽  
Liver Stage ◽  
Content Type ◽  
Stage Parasite

ABSTRACTWith the exception of primaquine, tafenoquine, and atovaquone, there are very few antimalarials that target liver stage parasites. In this study, a transgenicPlasmodium bergheiparasite (1052Cl1;PbGFP-Luccon) that expresses luciferase was used to assess the anti-liver stage parasite activity of ICI 56,780, a 7-(2-phenoxyethoxy)-4(1H)-quinolone (PEQ), as well as two 3-phenyl-4(1H)-quinolones (P4Q), P4Q-146 and P4Q-158, by using bioluminescent imaging (BLI). Results showed that all of the compounds were active against liver stage parasites; however, ICI 56,780 and P4Q-158 were the most active, with low nanomolar activityin vitroand causal prophylactic activityin vivo. This potent activity makes these compounds ideal candidates for advancement as novel antimalarials.

scholarly journals Host-Pathogen Interaction and Signaling Molecule Secretion Are Modified in thedpp3Knockout Mutant of Candida lusitaniae

2013 ◽  
Vol 82 (1) ◽  
pp. 413-422 ◽  
Author(s):  
Ayman Sabra ◽  
Jean-Jacques Bessoule ◽  
Vessela Atanasova-Penichon ◽  
Thierry Noël ◽  
Karine Dementhon
Keyword(s):  
Interleukin 10 ◽  
Gene Inactivation ◽  
Physical Contact ◽  
Knockout Mutant ◽  
Necrosis Factor Alpha ◽  
Content Type ◽  
Tnf Α ◽  
Candida Lusitaniae

ABSTRACTCandida lusitaniaeis an emerging opportunistic yeast and an attractive model to discover new virulence factors inCandidaspecies by reverse genetics. Our goal was to create adpp3Δ knockout mutant and to characterize the effects of this gene inactivation on yeastin vitroandin vivointeraction with the host. The secretion of two signaling molecules inCandidaspecies, phenethyl alcohol (PEA) and tyrosol, but not of farnesol was surprisingly altered in thedpp3Δ knockout mutant. NO and reactive oxygen species (ROS) production as well as tumor necrosis factor alpha (TNF-α) and interleukin 10 (IL-10) secretion were also modified in macrophages infected with this mutant. Interestingly, we found that the wild-type (WT) strain induced an increase in IL-10 secretion by zymosan-activated macrophages without the need for physical contact, whereas thedpp3Δ knockout mutant lost this ability. We further showed a striking role of PEA and tyrosol in this modulation. Last, theDPP3gene was found to be an essential contributor to virulence in mice models, leading to an increase in TNF-α secretion and brain colonization. Although reinsertion of a WTDPP3copy in thedpp3Δ knockout mutant was not sufficient to restore the WT phenotypesin vitro, it allowed a restoration of those observedin vivo. These data support the hypothesis that some of the phenotypes observed followingDPP3gene inactivation may be directly dependent onDPP3, while others may be the indirect consequence of another genetic modification that systematically arises when theDPP3gene is inactivated.

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