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Article ; Online: Interactions of pathogenic

Sheikh, Alaullah / Fleckenstein, James M

2023 Volume 14, Page(s) 1120331

Abstract: ... The ... ...

Abstract	The pathogenic
MeSH term(s)	Escherichia coli/genetics ; Phenotype ; Virulence ; Virulence Factors
Chemical Substances	Virulence Factors
Language	English
Publishing date	2023-02-14
Publishing country	Switzerland
Document type	Journal Article ; Review ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, N.I.H., Extramural
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2023.1120331
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Article ; Online: Emerging Themes in the Molecular Pathogenesis of Enterotoxigenic Escherichia coli.

Fleckenstein, James M / Sheikh, Alaullah

The Journal of infectious diseases

2021 Volume 224, Issue 12 Suppl 2, Page(s) S813–S820

Abstract: Enterotoxigenic Escherichia coli (ETEC) are ubiquitous diarrheal pathogens that thrive in areas lacking basic human needs of clean water and sanitation. These genetically plastic organisms cause tremendous morbidity among disadvantaged young children, in ...

Abstract	Enterotoxigenic Escherichia coli (ETEC) are ubiquitous diarrheal pathogens that thrive in areas lacking basic human needs of clean water and sanitation. These genetically plastic organisms cause tremendous morbidity among disadvantaged young children, in the form of both acute diarrheal illness and sequelae of malnutrition and growth impairment. The recent discovery of additional plasmid-encoded virulence factors and elucidation of their critical role in the molecular pathogenesis of ETEC may inform new approaches to the development of broadly protective vaccines. Although the pathogens have been closely linked epidemiologically with nondiarrheal sequelae, these conditions remain very poorly understood. Similarly, while canonical effects of ETEC toxins on cellular signaling promoting diarrhea are clear, emerging data suggest that these toxins may also drive changes in intestinal architecture and associated sequelae. Elucidation of molecular events underlying these changes could inform optimal approaches to vaccines that prevent acute diarrhea and ETEC-associated sequelae.
MeSH term(s)	Bacterial Toxins ; Child ; Child, Preschool ; Diarrhea/prevention & control ; Enterotoxigenic Escherichia coli/genetics ; Enterotoxigenic Escherichia coli/immunology ; Enterotoxins ; Escherichia coli Infections/prevention & control ; Escherichia coli Proteins ; Escherichia coli Vaccines ; Humans ; Malnutrition ; Plasmids
Chemical Substances	Bacterial Toxins ; Enterotoxins ; Escherichia coli Proteins ; Escherichia coli Vaccines
Language	English
Publishing date	2021-07-14
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	3019-3
ISSN	1537-6613 ; 0022-1899
ISSN (online)	1537-6613
ISSN	0022-1899
DOI	10.1093/infdis/jiab359
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Article ; Online: Acute Bacterial Gastroenteritis.

Fleckenstein, James M / Matthew Kuhlmann, F / Sheikh, Alaullah

Gastroenterology clinics of North America

2021 Volume 50, Issue 2, Page(s) 283–304

Abstract: Acute bacterial gastroenteritis is among the most common infections worldwide, with millions of infections annually in the United States. Much of the illness is foodborne, occurring as both sporadic cases and large multistate outbreaks. Pathogen ... ...

Abstract	Acute bacterial gastroenteritis is among the most common infections worldwide, with millions of infections annually in the United States. Much of the illness is foodborne, occurring as both sporadic cases and large multistate outbreaks. Pathogen evolution through genetic exchange of virulence traits and antibiotic resistance determinants poses challenges for empiric therapy. Culture-independent diagnostic tests in clinical laboratories afford rapid diagnosis and expanded identification of pathogens. However, cultures remain important to generate sensitivity data and strain archiving for outbreak investigations. Most infections are self-limited, permitting judicious selection of antibiotic use in more severe forms of illness.
MeSH term(s)	Bacteria ; Disease Outbreaks ; Foodborne Diseases/diagnosis ; Foodborne Diseases/epidemiology ; Gastroenteritis/diagnosis ; Gastroenteritis/epidemiology ; Humans ; United States
Language	English
Publishing date	2021-04-23
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S. ; Review
ZDB-ID	92114-2
ISSN	1558-1942 ; 0889-8553
ISSN (online)	1558-1942
ISSN	0889-8553
DOI	10.1016/j.gtc.2021.02.002
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Article ; Online: Bacterial lipopolysaccharide inhibits colonic carrier-mediated uptake of thiamin pyrophosphate: roles for TLR4 receptor and NF-κB/P38/JNK signaling pathway.

Anthonymuthu, Selvaraj / Sabui, Subrata / Lee, Katherine / Sheikh, Alaullah / Fleckenstein, James M / Said, Hamid M

American journal of physiology. Cell physiology

2023 Volume 325, Issue 3, Page(s) C758–C769

Abstract: This study investigated the effect of the bacterial endotoxin lipopolysaccharide (LPS) on colonic uptake of thiamin pyrophosphate (TPP), the biologically active form of vitamin B1 that is generated by gut microbiota. We used three complementary models in ...

Abstract	This study investigated the effect of the bacterial endotoxin lipopolysaccharide (LPS) on colonic uptake of thiamin pyrophosphate (TPP), the biologically active form of vitamin B1 that is generated by gut microbiota. We used three complementary models in our study: in vitro (human-derived colonic epithelial NCM460), ex vivo (human differentiated colonoid monolayers), and in vivo (mouse colonic tissue). The results showed that exposure of NCM460 cells to LPS leads to a significant inhibition of carrier-mediated TPP uptake as well as in decreased expression of the colonic TPP transporter (cTPPT) protein, mRNA, and heterologous nuclear RNA (hnRNA) compared with untreated controls. Similarly, exposure of human differentiated colonoid monolayers and mice to LPS caused significant inhibition in colonic carrier-mediated TPP uptake and in cTPPT protein, mRNA, and hnRNA expression. The effect of LPS on colonic TPP uptake and cTTPT expression was also found to be associated with a significant reduction in activity of the
MeSH term(s)	Humans ; Mice ; Animals ; Thiamine Pyrophosphate/metabolism ; NF-kappa B/metabolism ; Toll-Like Receptor 4/genetics ; Toll-Like Receptor 4/metabolism ; Lipopolysaccharides/pharmacology ; Diphosphates ; MAP Kinase Signaling System ; RNA, Heterogeneous Nuclear/metabolism ; Cell Line ; Thiamine/metabolism ; RNA, Messenger/metabolism
Chemical Substances	Thiamine Pyrophosphate (Q57971654Y) ; NF-kappa B ; Toll-Like Receptor 4 ; Lipopolysaccharides ; Diphosphates ; RNA, Heterogeneous Nuclear ; Thiamine (X66NSO3N35) ; RNA, Messenger ; TLR4 protein, human
Language	English
Publishing date	2023-07-31
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	392098-7
ISSN	1522-1563 ; 0363-6143
ISSN (online)	1522-1563
ISSN	0363-6143
DOI	10.1152/ajpcell.00272.2023
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Article ; Online: Tumor necrosis factor α impedes colonic thiamin pyrophosphate and free thiamin uptake: involvement of JNK/ERK

Anthonymuthu, Selvaraj / Sabui, Subrata / Sheikh, Alaullah / Fleckenstein, James M / Said, Hamid M

American journal of physiology. Cell physiology

2022 Volume 323, Issue 6, Page(s) C1664–C1680

Abstract: The aim of this study was to examine the effect of TNFα (i.e., a predominant proinflammatory cytokine produced during chronic gut inflammation) on colonic uptake of thiamin pyrophosphate (TPP) and free thiamin, forms of vitamin B1 that are produced by ... ...

Abstract	The aim of this study was to examine the effect of TNFα (i.e., a predominant proinflammatory cytokine produced during chronic gut inflammation) on colonic uptake of thiamin pyrophosphate (TPP) and free thiamin, forms of vitamin B1 that are produced by the gut microbiota and are absorbed via distinct carrier-mediated systems. We utilized human-derived colonic epithelial CCD841 and NCM460 cells, human differentiated colonoid monolayers, and mouse intact colonic tissue preparations together with an array of cellular/molecular approaches in our investigation. The results showed that exposure of colonic epithelial cells to TNFα leads to a significant inhibition in TPP and free thiamin uptake. This inhibition was associated with:
MeSH term(s)	Humans ; Mice ; Animals ; Thiamine Pyrophosphate/metabolism ; Tumor Necrosis Factor-alpha/metabolism ; Acinar Cells/metabolism ; Thiamine/metabolism ; Thiamine/pharmacology ; Membrane Transport Proteins/genetics ; Membrane Transport Proteins/metabolism
Chemical Substances	Thiamine Pyrophosphate (Q57971654Y) ; Tumor Necrosis Factor-alpha ; diphosphoric acid (4E862E7GRQ) ; Thiamine (X66NSO3N35) ; SLC19A2 protein, human ; Membrane Transport Proteins ; SLC19A3 protein, human ; Slc19a2 protein, mouse
Language	English
Publishing date	2022-11-07
Publishing country	United States
Document type	Journal Article
ZDB-ID	392098-7
ISSN	1522-1563 ; 0363-6143
ISSN (online)	1522-1563
ISSN	0363-6143
DOI	10.1152/ajpcell.00458.2022
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Article ; Online: Designing vaccines to neutralize effective toxin delivery by enterotoxigenic Escherichia coli.

Fleckenstein, James M / Sheikh, Alaullah

Toxins

2014 Volume 6, Issue 6, Page(s) 1799–1812

Abstract: Enterotoxigenic Escherichia coli (ETEC) are a leading cause of diarrheal illness in developing countries. Despite the discovery of these pathogens as a cause of cholera-like diarrhea over 40 years ago, and decades of vaccine development effort, there ... ...

Abstract	Enterotoxigenic Escherichia coli (ETEC) are a leading cause of diarrheal illness in developing countries. Despite the discovery of these pathogens as a cause of cholera-like diarrhea over 40 years ago, and decades of vaccine development effort, there remains no broadly protective ETEC vaccine. The discovery of new virulence proteins and an improved appreciation of the complexity of the molecular events required for effective toxin delivery may provide additional avenues to pursue in development of an effective vaccine to prevent severe diarrhea caused by these important pathogens.
MeSH term(s)	Animals ; Antibodies, Neutralizing/therapeutic use ; Biological Transport ; Dysentery/immunology ; Dysentery/microbiology ; Dysentery/prevention & control ; Enterotoxigenic Escherichia coli/immunology ; Enterotoxigenic Escherichia coli/physiology ; Enterotoxins/antagonists & inhibitors ; Enterotoxins/metabolism ; Escherichia coli Infections/immunology ; Escherichia coli Infections/microbiology ; Escherichia coli Infections/prevention & control ; Escherichia coli Proteins/antagonists & inhibitors ; Escherichia coli Proteins/metabolism ; Escherichia coli Vaccines/therapeutic use ; Host-Pathogen Interactions ; Humans ; Virulence Factors/antagonists & inhibitors ; Virulence Factors/metabolism
Chemical Substances	Antibodies, Neutralizing ; Enterotoxins ; Escherichia coli Proteins ; Escherichia coli Vaccines ; Virulence Factors
Language	English
Publishing date	2014-06-10
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S. ; Review
ZDB-ID	2518395-3
ISSN	2072-6651 ; 2072-6651
ISSN (online)	2072-6651
ISSN	2072-6651
DOI	10.3390/toxins6061799
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Article ; Online: Novel antigens for enterotoxigenic Escherichia coli vaccines.

Fleckenstein, James / Sheikh, Alaullah / Qadri, Firdausi

Expert review of vaccines

2014 Volume 13, Issue 5, Page(s) 631–639

Abstract: Enterotoxigenic Escherichia coli (ETEC) are the most common bacterial pathogens causing diarrhea in developing countries where they lead to hundreds of thousands of deaths, mostly in children. These organisms are a leading cause of diarrheal illness in ... ...

Abstract	Enterotoxigenic Escherichia coli (ETEC) are the most common bacterial pathogens causing diarrhea in developing countries where they lead to hundreds of thousands of deaths, mostly in children. These organisms are a leading cause of diarrheal illness in travelers to endemic countries. ETEC pathogenesis, and consequently vaccine approaches, have largely focused on plasmid-encoded enterotoxins or fimbrial colonization factors. To date these approaches have not yielded a broadly protective vaccine. However, recent studies suggest that ETEC pathogenesis is more complex than previously appreciated and involves additional plasmid and chromosomally encoded virulence molecules that can be targeted in vaccines. Here, we review recent novel antigen discovery efforts, potential contribution of these proteins to the molecular pathogenesis of ETEC and protective immunity, and the potential implications for development of next generation vaccines for important pathogens. These proteins may help to improve the effectiveness of future vaccines by making them simpler and possibly broadly protective because of their conserved nature.
MeSH term(s)	Animals ; Antigens, Bacterial/immunology ; Enterotoxigenic Escherichia coli/drug effects ; Enterotoxigenic Escherichia coli/immunology ; Escherichia coli Infections/immunology ; Escherichia coli Infections/prevention & control ; Escherichia coli Vaccines/administration & dosage ; Escherichia coli Vaccines/immunology ; Humans
Chemical Substances	Antigens, Bacterial ; Escherichia coli Vaccines
Language	English
Publishing date	2014-04-04
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2181284-6
ISSN	1744-8395 ; 1476-0584
ISSN (online)	1744-8395
ISSN	1476-0584
DOI	10.1586/14760584.2014.905745
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Article ; Online: Enterotoxigenic Escherichia coli heat-labile toxin drives enteropathic changes in small intestinal epithelia.

Sheikh, Alaullah / Tumala, Brunda / Vickers, Tim J / Martin, John C / Rosa, Bruce A / Sabui, Subrata / Basu, Supratim / Simoes, Rita D / Mitreva, Makedonka / Storer, Chad / Tyksen, Erik / Head, Richard D / Beatty, Wandy / Said, Hamid M / Fleckenstein, James M

Nature communications

2022 Volume 13, Issue 1, Page(s) 6886

Abstract: Enterotoxigenic E. coli (ETEC) produce heat-labile (LT) and/or heat-stable (ST) enterotoxins, and commonly cause diarrhea in resource-poor regions. ETEC have been linked repeatedly to sequelae in children including enteropathy, malnutrition, and growth ... ...

Abstract	Enterotoxigenic E. coli (ETEC) produce heat-labile (LT) and/or heat-stable (ST) enterotoxins, and commonly cause diarrhea in resource-poor regions. ETEC have been linked repeatedly to sequelae in children including enteropathy, malnutrition, and growth impairment. Although cellular actions of ETEC enterotoxins leading to diarrhea are well-established, their contributions to sequelae remain unclear. LT increases cellular cAMP to activate protein kinase A (PKA) that phosphorylates ion channels driving intestinal export of salt and water resulting in diarrhea. As PKA also modulates transcription of many genes, we interrogated transcriptional profiles of LT-treated intestinal epithelia. Here we show that LT significantly alters intestinal epithelial gene expression directing biogenesis of the brush border, the major site for nutrient absorption, suppresses transcription factors HNF4 and SMAD4 critical to enterocyte differentiation, and profoundly disrupts microvillus architecture and essential nutrient transport. In addition, ETEC-challenged neonatal mice exhibit substantial brush border derangement that is prevented by maternal vaccination with LT. Finally, mice repeatedly challenged with toxigenic ETEC exhibit impaired growth recapitulating the multiplicative impact of recurring ETEC infections in children. These findings highlight impacts of ETEC enterotoxins beyond acute diarrheal illness and may inform approaches to prevent major sequelae of these common infections including malnutrition that impact millions of children.
MeSH term(s)	Mice ; Animals ; Enterotoxins/genetics ; Escherichia coli Proteins/genetics ; Escherichia coli Proteins/metabolism ; Enterotoxigenic Escherichia coli/genetics ; Enterotoxigenic Escherichia coli/metabolism ; Escherichia coli Infections/prevention & control ; Diarrhea ; Malnutrition
Chemical Substances	heat-labile enterotoxin, E coli (D9K3SN2LNY) ; Enterotoxins ; Escherichia coli Proteins
Language	English
Publishing date	2022-11-12
Publishing country	England
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, N.I.H., Extramural
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-022-34687-7
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Article ; Online: CEACAMs serve as toxin-stimulated receptors for enterotoxigenic

Sheikh, Alaullah / Tumala, Brunda / Vickers, Tim J / Alvarado, David / Ciorba, Matthew A / Bhuiyan, Taufiqur Rahman / Qadri, Firdausi / Singer, Bernhard B / Fleckenstein, James M

Proceedings of the National Academy of Sciences of the United States of America

2020 Volume 117, Issue 46, Page(s) 29055–29062

Abstract: ... The ... ...

Abstract	The enterotoxigenic
MeSH term(s)	Adhesins, Bacterial/metabolism ; Antigens, CD/genetics ; Antigens, CD/metabolism ; Bacterial Toxins/metabolism ; Caco-2 Cells ; Cell Adhesion Molecules/genetics ; Cell Adhesion Molecules/metabolism ; Diarrhea/microbiology ; Enterotoxigenic Escherichia coli/metabolism ; Epithelial Cells/metabolism ; Escherichia coli Infections/metabolism ; Escherichia coli Infections/microbiology ; GPI-Linked Proteins/genetics ; GPI-Linked Proteins/metabolism ; HeLa Cells ; Host-Pathogen Interactions ; Humans ; Intestinal Mucosa/metabolism ; Transcriptome
Chemical Substances	Adhesins, Bacterial ; Antigens, CD ; Bacterial Toxins ; CEACAM6 protein, human ; Cell Adhesion Molecules ; GPI-Linked Proteins
Language	English
Publishing date	2020-11-02
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.2012480117
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Article ; Online: Enterotoxigenic

Sheikh, Alaullah / Wangdi, Tamding / Vickers, Tim J / Aaron, Bailey / Palmer, Margot / Miller, Mark J / Kim, Seonyoung / Herring, Cassandra / Simoes, Rita / Crainic, Jennifer A / Gildersleeve, Jeffrey C / van der Post, Sjoerd / Hansson, Gunnar C / Fleckenstein, James M

Infection and immunity

2021 Volume 90, Issue 2, Page(s) e0057221

Abstract: Enterotoxigenic Escherichia coli (ETEC) isolates are genetically diverse pathological variants of E. coli defined by the production of heat-labile (LT) and/or heat-stable (ST) toxins. ETEC strains are estimated to cause hundreds of millions of cases of ... ...

Abstract	Enterotoxigenic Escherichia coli (ETEC) isolates are genetically diverse pathological variants of E. coli defined by the production of heat-labile (LT) and/or heat-stable (ST) toxins. ETEC strains are estimated to cause hundreds of millions of cases of diarrheal illness annually. However, it is not clear that all strains are equally equipped to cause disease, and asymptomatic colonization with ETEC is common in low- to middle-income regions lacking basic sanitation and clean water where ETEC are ubiquitous. Recent molecular epidemiology studies have revealed a significant association between strains that produce EatA, a secreted autotransporter protein, and the development of symptomatic infection. Here, we demonstrate that LT stimulates production of MUC2 mucin by goblet cells in human small intestine, enhancing the protective barrier between pathogens and enterocytes. In contrast, using explants of human small intestine as well as small intestinal enteroids, we show that EatA counters this host defense by engaging and degrading the MUC2 mucin barrier to promote bacterial access to target enterocytes and ultimately toxin delivery, suggesting that EatA plays a crucial role in the molecular pathogenesis of ETEC. These findings may inform novel approaches to prevention of acute diarrheal illness as well as the sequelae associated with ETEC and other pathogens that rely on EatA and similar proteases for efficient interaction with their human hosts.
MeSH term(s)	Bacterial Toxins/genetics ; Bacterial Toxins/metabolism ; Diarrhea ; Enterocytes ; Enterotoxigenic Escherichia coli/metabolism ; Enterotoxins/metabolism ; Escherichia coli Infections/microbiology ; Escherichia coli Proteins/genetics ; Escherichia coli Proteins/metabolism ; Humans ; Intestine, Small ; Mucin-2/genetics ; Mucin-2/metabolism ; Mucins/metabolism
Chemical Substances	Bacterial Toxins ; Enterotoxins ; Escherichia coli Proteins ; MUC2 protein, human ; Mucin-2 ; Mucins
Language	English
Publishing date	2021-11-22
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	218698-6
ISSN	1098-5522 ; 0019-9567
ISSN (online)	1098-5522
ISSN	0019-9567
DOI	10.1128/IAI.00572-21
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