Attaching and Effacing Pathogens: The Effector ABC of Immune Subversion

Riebisch, Anna Katharina; Mühlen, Sabrina

doi:10.2217/fmb-2019-0274

Cited by 5 publications

(3 citation statements)

References 78 publications

(125 reference statements)

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“…For example, E. coli serotype O157:H7 and other Shiga toxin-producing E. coli (STEC) can cause hemorrhagic colitis and hemolytic uremic syndrome. 27,28 Along with enteropathogenic E. coli (EPEC), which causes infant diarrhea, these enterohemorrhagic strains (EHEC) utilize a type III secretion system to inject the virulence factor, translocated intimin receptor (Tir), into the host cell. We detected near universal reactivity to ten Tir peptides (three non-homologous sets), and less reactivity against alpha-hemolysin (HlyA) and hemolysin (Hly) ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Prevalence, persistence, and genetics of antibody responses to protein toxins and virulence factors

Angkeow

Monaco

Chen

et al. 2021

Preprint

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Microbial exposures are crucial environmental factors that impact healthspan by sculpting the immune system and microbiota. Antibody profiling via programmable Phage ImmunoPrecipitation Sequencing (PhIP-Seq) provides a high-throughput, cost-effective approach for multiplexed detection of exposure and response to thousands of microbial protein products. Here we designed and constructed a library of 95,601 56 amino acid peptide tiles spanning a subset of environmental proteins more likely to be associated with immune responses: those with "toxin" or "virulence factor" keyword annotations. PhIP-Seq was used to profile the circulating antibodies of ~1,000 individuals against this "ToxScan" library of 14,430 toxins and virulence factors from 1,312 genera of organisms. In addition to a detailed analysis of six commonly encountered human commensals and pathogens, we study the age-dependent stability of the ToxScan profile and use a genome-wide association study (GWAS) to find that the MHC-II locus modulates the selection of bacterial epitopes. We detect previously described anti-flagellin antibody responses in a Crohn's disease cohort and identify a novel association between anti-flagellin antibodies and juvenile dermatomyositis (JDM). PhIP-Seq with the ToxScan library provides a new window into exposure and immune responses to environmental protein toxins and virulence factors, which can be used to study human health and disease at cohort scale.

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Section: Resultsmentioning

confidence: 99%

Prevalence, persistence, and genetics of antibody responses to protein toxins and virulence factors

Angkeow

Monaco

Chen

et al. 2021

Preprint

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“…coli is a gram-negative bacterium frequently found as a commensal in the human gastrointestinal tract, but many virulent pathotypes cause diarrheal illness, urinary tract infections, and invasive infections such as bacteremia and neonatal meningitis. For example, E. coli serotype O157:H7 and other Shiga toxinproducing E. coli (STEC) can cause hemorrhagic colitis and hemolytic uremic syndrome (Riebisch and M€ uhlen, 2020;Tack et al, 2020). Along with enteropathogenic E. coli (EPEC), which causes infant diarrhea, these enterohemorrhagic (EHEC) strains utilize a type III secretion system to inject the virulence factor, Tir, into the host cell.…”

Section: S Pyogenes (Group a Streptococcusmentioning

confidence: 99%

Phage display of environmental protein toxins and virulence factors reveals the prevalence, persistence, and genetics of antibody responses

Angkeow¹,

Monaco²,

Chen³

et al. 2022

Immunity

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“…Other effector proteins mediate the loss of cell-cell junction integrity to invade lower tissues. Furthermore, several effector proteins are involved in the inhibition of innate immune signaling pathways, resulting in the inhibition of cytokine and chemokine release which, in turn, interferes with the recruitment of and clearance by immune cells (43, 44). The formation of the T3SS has also been associated with the formation of pores in and subsequent hemolysis of erythrocytes (8, 37).…”

Section: Discussionmentioning

confidence: 99%

Identification of translocation inhibitors targeting the type III secretion system of enteropathogenic Escherichia coli

Mühlen

Zapol’skii

Bilitewski

et al. 2021

Preprint

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Infections with enteropathogenic E. coli (EPEC) cause severe diarrhea in children. The non-invasive bacteria adhere to enterocytes of the small intestine and use a type III secretion system (T3SS) to inject effector proteins into host cells to modify and exploit cellular processes in favor of bacterial survival and replication. Several studies have shown that the T3SSs of bacterial pathogens are essential for virulence. Furthermore, the loss of T3SS-mediated effector translocation results in increased immune recognition and clearance of the bacteria. The T3SS is, therefore, considered a promising target for antivirulence strategies and novel therapeutics development. Here, we report the results of a high-throughput screening assay based on the translocation of the EPEC effector protein Tir. Using this assay, we screened more than 13,000 small molecular compounds of six different compound libraries and identified three substances which showed a significant dose-dependent effect on translocation without adverse effects on bacterial or eukaryotic cell viability. Additionally, these substances reduced bacterial binding to host cells, effector-dependent cell detachment and abolished A/E lesion formation without affecting the expression of components of the T3SS or associated effector proteins. Moreover, no effects of the inhibitors on bacterial motility or Shiga-toxin expression were observed. In summary, we have identified three new compounds that strongly inhibit T3SS-mediated translocation of effectors into mammalian cells, which could be valuable as lead substances for treating EPEC and EHEC infections.

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Attaching and Effacing Pathogens: The Effector ABC of Immune Subversion

Cited by 5 publications

References 78 publications

Prevalence, persistence, and genetics of antibody responses to protein toxins and virulence factors

Prevalence, persistence, and genetics of antibody responses to protein toxins and virulence factors

Phage display of environmental protein toxins and virulence factors reveals the prevalence, persistence, and genetics of antibody responses

Identification of translocation inhibitors targeting the type III secretion system of enteropathogenic Escherichia coli

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