Direct ex vivo gene expression profiling of malaria patients reveals common virulence gene expression in first-time infected patients and severe cases

AbstractSequestration of Plasmodium falciparum-infected erythrocytes to host endothelium through the parasite-derived PfEMP1 adhesion proteins is central to the development of malaria pathogenesis. PfEMP1 proteins have diversified and expanded to encompass many sequence variants conferring the same array of human endothelial receptor binding phenotypes. Here, we analyzed RNA-seq profiles of parasites isolated from 32 P. falciparum infected travelers returning to Germany. Patients were categorized into either malaria naïve (n=15) or pre-exposed (n=17), and into severe (n=8) or non-severe (n=24) cases. Expression analysis of PfEMP1-encoding var genes showed that severe malaria was associated with PfEMP1 containing the endothelial protein C receptor (EPCR)-binding CIDRα1 domain, whereas CD36-binding PfEMP1 was linked to non-severe malaria outcomes. In addition, gene expression-guided determination of parasite age suggested that circulating parasites from non-severe malaria patients were older than parasites from severe malaria patients. First-time infected patients were also more likely to develop severe symptoms and tended to be infected for a longer period, which thus appeared to select for parasites with more efficient sequestration and therefore more pathogenic PfEMP1 variants.

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Common virulence gene expression in adult first-time infected malaria patients and severe cases

eLife ◽

10.7554/elife.69040 ◽

2021 ◽

Vol 10 ◽

Author(s):

Jan Stephan Wichers ◽

Gerry Tonkin-Hill ◽

Thorsten Thye ◽

Ralf Krumkamp ◽

Benno Kreuels ◽

...

Keyword(s):

Severe Malaria ◽

De Novo ◽

Differential Expression Analysis ◽

Virulence Gene ◽

Host Responses ◽

Rna Seq ◽

Endothelial Protein C Receptor ◽

Virulence Gene Expression ◽

Infected Adult ◽

First Time

Sequestration of Plasmodium falciparum-infected erythrocytes to host endothelium through the parasite-derived PfEMP1 adhesion proteins is central to the development of malaria pathogenesis. PfEMP1 proteins have diversified and expanded to encompass many sequence variants conferring each parasite a similar array of human endothelial receptor binding phenotypes. Here, we analyzed RNA-seq profiles of parasites isolated from 32 P. falciparum infected adult travelers returning to Germany. Patients were categorized into either malaria naïve (n=15) or pre-exposed (n=17), and into severe (n=8) or non-severe (n=24) cases. For differential expression analysis of PfEMP1-encoding var gene transcripts were de novo assembled from RNA-seq data and, in parallel, var expressed sequence tags were analyzed and used to predict the encoded domain composition of the transcripts. Both approaches showed in concordance that severe malaria was associated with PfEMP1 containing the endothelial protein C receptor (EPCR)-binding CIDRα1 domain, whereas CD36-binding PfEMP1 was linked to non-severe malaria outcomes. First-time infected adults were more likely to develop severe symptoms and tended to be infected for a longer period. Thus, parasites with more pathogenic PfEMP1 variants are more common in patients with a naïve immune status and/or adverse inflammatory host responses to first infections favors growth of EPCR-binding parasites.

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Comparison ofSalmonella entericaSerovars Typhi and Typhimurium Reveals Typhoidal Serovar-Specific Responses to Bile

Infection and Immunity ◽

10.1128/iai.00490-17 ◽

2017 ◽

Vol 86 (3) ◽

Cited By ~ 10

Author(s):

Rebecca Johnson ◽

Matt Ravenhall ◽

Derek Pickard ◽

Gordon Dougan ◽

Alexander Byrne ◽

...

Keyword(s):

Gene Expression ◽

Virulence Gene ◽

Specific Response ◽

Acid Uptake ◽

Expression Data ◽

Rna Seq ◽

Western Blots ◽

Content Type ◽

Virulence Gene Expression ◽

Uptake And Metabolism

ABSTRACTSalmonella entericaserovars Typhi and Typhimurium cause typhoid fever and gastroenteritis, respectively. A unique feature of typhoid infection is asymptomatic carriage within the gallbladder, which is linked withS. Typhi transmission. Despite this,S. Typhi responses to bile have been poorly studied. Transcriptome sequencing (RNA-Seq) ofS. Typhi Ty2 and a clinicalS. Typhi isolate belonging to the globally dominant H58 lineage (strain 129-0238), as well asS. Typhimurium 14028, revealed that 249, 389, and 453 genes, respectively, were differentially expressed in the presence of 3% bile compared to control cultures lacking bile.fadgenes, theactP-acsoperon, and putative sialic acid uptake and metabolism genes (t1787 to t1790) were upregulated in all strains following bile exposure, which may represent adaptation to the small intestine environment. Genes within theSalmonellapathogenicity island 1 (SPI-1), those encoding a type IIII secretion system (T3SS), and motility genes were significantly upregulated in bothS. Typhi strains in bile but downregulated inS. Typhimurium. Western blots of the SPI-1 proteins SipC, SipD, SopB, and SopE validated the gene expression data. Consistent with this, bile significantly increasedS. Typhi HeLa cell invasion, whileS. Typhimurium invasion was significantly repressed. Protein stability assays demonstrated that inS. Typhi the half-life of HilD, the dominant regulator of SPI-1, is three times longer in the presence of bile; this increase in stability was independent of the acetyltransferase Pat. Overall, we found thatS. Typhi exhibits a specific response to bile, especially with regard to virulence gene expression, which could impact pathogenesis and transmission.

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In vivo and ex vivo regulation of bacterial virulence gene expression

Current Opinion in Microbiology ◽

10.1016/s1369-5274(98)80138-0 ◽

1998 ◽

Vol 1 (1) ◽

pp. 17-26 ◽

Cited By ~ 41

Author(s):

Peggy A Cotter ◽

Jeff F Miller

Keyword(s):

Gene Expression ◽

Ex Vivo ◽

Virulence Gene ◽

Bacterial Virulence ◽

Virulence Gene Expression

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Vibrio harveyi virulence gene expression in vitro and in vivo during infection in black tiger shrimp Penaeus monodon

Diseases of Aquatic Organisms ◽

10.3354/dao03475 ◽

2020 ◽

Vol 139 ◽

pp. 153-160

Author(s):

S Peeralil ◽

TC Joseph ◽

V Murugadas ◽

PG Akhilnath ◽

VN Sreejith ◽

...

Keyword(s):

Gene Expression ◽

Virulence Genes ◽

Vibrio Harveyi ◽

Penaeus Monodon ◽

Challenge Test ◽

Virulence Gene ◽

Economic Losses ◽

Virulence Gene Expression

Luminescent Vibrio harveyi is common in sea and estuarine waters. It produces several virulence factors and negatively affects larval penaeid shrimp in hatcheries, resulting in severe economic losses to shrimp aquaculture. Although V. harveyi is an important pathogen of shrimp, its pathogenicity mechanisms have yet to be completely elucidated. In the present study, isolates of V. harveyi were isolated and characterized from diseased Penaeus monodon postlarvae from hatcheries in Kerala, India, from September to December 2016. All 23 tested isolates were positive for lipase, phospholipase, caseinase, gelatinase and chitinase activity, and 3 of the isolates (MFB32, MFB71 and MFB68) showed potential for significant biofilm formation. Based on the presence of virulence genes, the isolates of V. harveyi were grouped into 6 genotypes, predominated by vhpA+ flaB+ ser+ vhh1- luxR+ vopD- vcrD+ vscN-. One isolate from each genotype was randomly selected for in vivo virulence experiments, and the LD50 ranged from 1.7 ± 0.5 × 103 to 4.1 ± 0.1 × 105 CFU ml-1. The expression of genes during the infection in postlarvae was high in 2 of the isolates (MFB12 and MFB32), consistent with the result of the challenge test. However, in MFB19, even though all genes tested were present, their expression level was very low and likely contributed to its lack of virulence. Because of the significant variation in gene expression, the presence of virulence genes alone cannot be used as a marker for pathogenicity of V. harveyi.

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Faculty Opinions recommendation of Inducible control of virulence gene expression in Listeria monocytogenes: temporal requirement of listeriolysin O during intracellular infection.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1009891.138457 ◽

2002 ◽

Author(s):

Colin Hill

Keyword(s):

Gene Expression ◽

Listeria Monocytogenes ◽

Virulence Gene ◽

Listeriolysin O ◽

Virulence Gene Expression ◽

Intracellular Infection

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Faculty Opinions recommendation of The integration host factor (IHF) integrates stationary-phase and virulence gene expression in Salmonella enterica serovar Typhimurium.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1030734.367872 ◽

2006 ◽

Author(s):

Stephen Busby

Keyword(s):

Gene Expression ◽

Stationary Phase ◽

Salmonella Enterica ◽

Salmonella Enterica Serovar Typhimurium ◽

Virulence Gene ◽

Integration Host Factor ◽

Host Factor ◽

Virulence Gene Expression ◽

Serovar Typhimurium

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Faculty Opinions recommendation of Small molecule control of virulence gene expression in Francisella tularensis.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1168406.630587 ◽

2009 ◽

Author(s):

Vincenzo Scarlato

Keyword(s):

Gene Expression ◽

Francisella Tularensis ◽

Small Molecule ◽

Virulence Gene ◽

Virulence Gene Expression

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Plant nitrate supply regulates Erwinia amylovora virulence gene expression in Arabidopsis

Molecular Plant Pathology ◽

10.1111/mpp.13114 ◽

2021 ◽

Author(s):

Mahsa Farjad ◽

Gilles Clément ◽

Alban Launay ◽

Roua Jeridi ◽

Sylvie Jolivet ◽

...

Keyword(s):

Gene Expression ◽

Erwinia Amylovora ◽

Virulence Gene ◽

Virulence Gene Expression ◽

Nitrate Supply

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Nutritional Regulation of the Sae Two-Component System by CodY inStaphylococcus aureus

Journal of Bacteriology ◽

10.1128/jb.00012-18 ◽

2018 ◽

Vol 200 (8) ◽

Cited By ~ 14

Author(s):

Kevin D. Mlynek ◽

William E. Sause ◽

Derek E. Moormeier ◽

Marat R. Sadykov ◽

Kurt R. Hill ◽

...

Keyword(s):

Gene Expression ◽

Virulence Factors ◽

Virulence Gene ◽

Nutrient Depletion ◽

Global Regulator ◽

Two Component System ◽

Component System ◽

Content Type ◽

Virulence Gene Expression ◽

Two Component

ABSTRACTStaphylococcus aureussubverts innate defenses during infection in part by killing host immune cells to exacerbate disease. This human pathogen intercepts host cues and activates a transcriptional response via theS. aureusexoprotein expression (SaeR/SaeS [SaeR/S]) two-component system to secrete virulence factors critical for pathogenesis. We recently showed that the transcriptional repressor CodY adjusts nuclease (nuc) gene expression via SaeR/S, but the mechanism remained unknown. Here, we identified two CodY binding motifs upstream of thesaeP1 promoter, which suggested direct regulation by this global regulator. We show that CodY shares a binding site with the positive activator SaeR and that alleviating direct CodY repression at this site is sufficient to abrogate stochastic expression, suggesting that CodY repressessaeexpression by blocking SaeR binding. Epistasis experiments support a model that CodY also controlssaeindirectly through Agr and Rot-mediated repression of thesaeP1 promoter. We also demonstrate that CodY repression ofsaerestrains production of secreted cytotoxins that kill human neutrophils. We conclude that CodY plays a previously unrecognized role in controlling virulence gene expression via SaeR/S and suggest a mechanism by which CodY acts as a master regulator of pathogenesis by tying nutrient availability to virulence gene expression.IMPORTANCEBacterial mechanisms that mediate the switch from a commensal to pathogenic lifestyle are among the biggest unanswered questions in infectious disease research. Since the expression of most virulence genes is often correlated with nutrient depletion, this implies that virulence is a response to the lack of nourishment in host tissues and that pathogens likeS. aureusproduce virulence factors in order to gain access to nutrients in the host. Here, we show that specific nutrient depletion signals appear to be funneled to the SaeR/S system through the global regulator CodY. Our findings reveal a strategy by whichS. aureusdelays the production of immune evasion and immune-cell-killing proteins until key nutrients are depleted.

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