Disease Category
Enteric Diseases
Infectious Diseases
Synonyms
Escherichia coli

Hyperhydration in Children With Shiga Toxin-Producing E. Coli Infection

The objective of this study is to determine if early high volume intravenous fluid administration (hyperhydration) may be effective in mitigating or preventing complications of shiga toxin-producing E. coli (STEC) infection in children and adolescents when compared with traditional approaches (conservative fluid management).

How E. coli Get the Power to Cause Urinary Tract Infections

Ji-Liang Gao, Ph.D.

Section or Unit Name
Molecular Signaling Section
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NIH Main Campus, Bethesda, MD
This Researcher/Clinician’s Person Page
Ji-Liang Gao, Ph.D.
Parent Lab/Program
Laboratory of Molecular Immunology
Program Description

We are interested in the factors that mediate immune cell migration. Chemoattractant receptors, including chemokine receptors and classic pattern recognition receptors such as N-formyl peptide receptors, are a subset of G protein-coupled receptors responsible for mediating cell migration. Our research began with the genetic cloning and identification of these receptors, progressing to the characterization of their biological roles in animal models through the creation of knockout mice.

Recently, our focus turned to the chemokine receptor CXCR4-related human genetic disease WHIM syndrome and found that chemokine receptor CXCR4 haploinsufficiency enhances hematopoietic stem cell engraftment. Currently, our efforts are directed towards gene-editing technology to cure WHIM syndrome by silencing the disease allele of CXCR4.

Selected Publications

Gao JL, Owusu-Ansah A, Yang A, Yim E, McDermott DH, Jacobs P, Majumdar S, Choi U, Sweeney CL, Malech HL, Murphy PM.CRISPR/Cas9-mediated Cxcr4 disease allele inactivation for gene therapy in a mouse model of WHIM syndrome. Blood. 2023 Jul 6;142(1):23-32.

McDermott DH, Gao JL, Liu Q, Siwicki M, Martens C, Jacobs P, Velez D, Yim E, Bryke CR, Hsu N, Dai Z, Marquesen MM, Stregevsky E, Kwatemaa N, Theobald N, Long Priel DA, Pittaluga S, Raffeld MA, Calvo KR, Maric I, Desmond R, Holmes KL, Kuhns DB, Balabanian K, Bachelerie F, Porcella SF, Malech HL, Murphy PM. Chromothriptic cure of WHIM syndrome. Cell. 2015 Feb 12;160(4):686-699.

Gao JL, Weaver JD, Tuo J, Wang LQ, Siwicki M, Despres D, Lizak M, Schneider EH, Kovacs W, Maminishkis A, Chen K, Yoshimura T, Ming Wang J, Chao Chan C, Murphy PM. Leukocyte chemotactic receptor Fpr1 protects against aging-related posterior subcapsular cataract formation. FASEB J. 2021 Feb;35(2):e21315.

Gao JL, Schneider EH, Dimitrov EL, Haun F, Pham TM, Mohammed AH, Usdin TB, Murphy PM. Reduced fear memory and anxiety-like behavior in mice lacking formylpeptide receptor 1. Behav Genet. 2011 Sep;41(5):724-33.

Gao JL, Wynn TA, Chang Y, Lee EJ, Broxmeyer HE, Cooper S, Tiffany HL, Westphal H, Kwon-Chung J, Murphy PM. Impaired host defense, hematopoiesis, granulomatous inflammation and type 1-type 2 cytokine balance in mice lacking CC chemokine receptor 1 J Exp Med. 1997 Jun 2;185(11):1959-68.

Gao JL, Kuhns DB, Tiffany HL, McDermott D, Li X, Francke U, Murphy PM. Structure and functional expression of the human macrophage inflammatory protein 1 alpha/RANTES receptor. J Exp Med. 1993 May 1;177(5):1421-7.

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Major Areas of Research
  • Immune cell trafficking
  • Gene therapy of WHIM syndrome through gene editing

Resistant E. coli Rises Despite Drop in Ciprofloxacin Use

Link Type
Funded-research
Media Type
Article
Publish or Event Date
Link URL
https://newsroom.uw.edu/news/resistant-e-coli-rises-despite-drop-ciprofloxacin-use
Research Institution
University of Washington School of Medicine
Short Title
Resistant E. coli Rises Despite Drop in Ciprofloxacin Use
Content Coordinator
Claudia Wair

Diagnostics Development Services

NIAID’s Diagnostics Development Services program offers reagents, platform testing, and planning and design support to accelerate product development of in vitro diagnostics (IVD) for infectious diseases, from research feasibility through clinical validation.

Study Links Gut Microbiome Dysbiosis with Recurrent Urinary Tract Infections

NIAID Now |

Recurrent urinary tract infections (rUTI) affect people all around the world and contribute greatly to morbidity, especially for females. In the United States, over one million women seek medical care for rUTIs each year, which are most commonly caused by uropathogenic Escherichia coli (E. coli) and treated with antibiotics.  While history of a prior UTI is a significant risk factor, other drivers of rUTI remain unknown.  The impact of the microbiome on health and disease is being appreciated in other organ systems.  Therefore, this study explored the microbiome connection between the gut and the bladder, or the gut-bladder axis, by characterizing the direct and indirect influences of gut microbiota on the bladder, including the effects of antibiotics to the infection and microbiome.  

This longitudinal clinical study was conducted over the course of a year and enrolled women with a history of rUTI (3 or more UTIs in the past 12 months) and women with no history of UTIs for comparison. Blood, urine, and fecal samples were collected from all study participants for analysis. Fecal samples were taken monthly, and additional samples were collected during and post any UTI. Data collected were analyzed with multi-omics techniques to determine diversity of gut microbiota, biomarkers of immune states, and presence of E. coli strains. 

The results of the study showed noteworthy differences between women with rUTIs and their healthy counterparts that may inform future treatment options. Women with history of rUTI had less diversity in their gut microbiota and markers of low-level inflammation. Results also showed that women with history of rUTI have different immunological biomarkers compared to women in the healthy cohort, suggesting their immune systems could respond differently to treatment. The transmission of E.coli from gut to bladder was similar in both cohorts, but symptoms only occurred for the women with history of rUTI. However, it was found that the UTI-causing E.coli strains colonized the gut and remained even after antibiotic treatment, potentially explaining reoccurrence of UTIs only in some participants. Furthermore, repeated use of antibiotics may exacerbate gut-bladder imbalance.  

The currently used antibiotics and regimens used to treat UTIs and rUTIs may be propagating recurring infections. Antibiotic use reduced gut microbiome diversity and failed to permanently clear uropathogenic E.coli infection, potentially impacting gut-bladder health in women with rUTIs. More specific targeted use of antibiotics, like small molecule therapeutics, may help to improve infections while minimizing disruption to other gut microbiota. Further research is needed to better understand treatment options that also assist in restoring a healthy microbiome.  

Reference: Worby CJ, et al. Longitudinal multi-omics analyses link gut microbiome dysbiosis with recurrent urinary tract infections in women. Nat Microbiol. 2022 May;7(5):630-639. doi: 10.1038/s41564-022-01107-x. Epub 2022 May 2. PMID: 35505248 

Contact Information

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niaidnews@niaid.nih.gov

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Sinu P. John, Ph.D.

Section or Unit Name
Signaling Systems Section
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Section/Unit: Location
NIH Main Campus, Bethesda, MD
This Researcher/Clinician’s Person Page
Sinu P. John, Ph.D.
Parent Lab/Program
Laboratory of Immune System Biology
Program Description

Our research focuses primarily on identification of cell intrinsic factors (protein coding and non-coding genes) associated with regulation of macrophage signaling. We use high throughput genome-wide techniques such as RNAi screening, CRISPR screening, RNA-seq, ATAC-seq, etc. to identify and characterize the genes and gene-regulatory mechanisms that modulate the immune response in macrophage cells. In addition, we study the role of various external factors (environmental pollutants, drugs, diet, etc.) that modulate the immune response in macrophages with an emphasis to develop therapeutic candidates for the treatment of infectious and immune diseases. We use both bacterial and several emerging viral models such as HIV, Influenza, SARS-CoV-2, etc. to study the impact of immune regulation by various intrinsic and external factors.

Selected Publications

John SP, Singh A, Sun J, Pierre MJ, Alsalih L, Lipsey C, Traore Z, Balcom-Luker S, Bradfield CJ, Song J, Markowitz TE, Smelkinson M, Ferrer M, Fraser IDC. Small-molecule screening identifies Syk kinase inhibition and rutaecarpine as modulators of macrophage training and SARS-CoV-2 infection. Cell Rep. 2022 Oct 4;41(1):111441.

John SP, Sun J, Carlson RJ, Cao B, Bradfield CJ, Song J, Smelkinson M, Fraser IDC. IFIT1 Exerts Opposing Regulatory Effects on the Inflammatory and Interferon Gene Programs in LPS-Activated Human Macrophages. Cell Rep. 2018 Oct 2;25(1):95-106.e6.

John SP, Chin CR, Perreira JM, Feeley EM, Aker AM, Savidis G, Smith SE, Elia AE, Everitt AR, Vora M, Pertel T, Elledge SJ, Kellam P, Brass AL. The CD225 domain of IFITM3 is required for both IFITM protein association and inhibition of influenza A virus and dengue virus replication. J Virol. 2013 Jul;87(14):7837-52.

Zhu J, Gaiha GD, John SP, Pertel T, Chin CR, Gao G, Qu H, Walker BD, Elledge SJ, Brass AL. Reactivation of latent HIV-1 by inhibition of BRD4. Cell Rep. 2012 Oct 25;2(4):807-16.

Everitt AR, Clare S, Pertel T, John SP, Wash RS, Smith SE, Chin CR, Feeley EM, Sims JS, Adams DJ, Wise HM, Kane L, Goulding D, Digard P, Anttila V, Baillie JK, Walsh TS, Hume DA, Palotie A, Xue Y, Colonna V, Tyler-Smith C, Dunning J, Gordon SB; GenISIS Investigators; MOSAIC Investigators; Smyth RL, Openshaw PJ, Dougan G, Brass AL, Kellam P. IFITM3 restricts the morbidity and mortality associated with influenza. Nature. 2012 Mar 25;484(7395):519-23.

Brass AL, Huang IC, Benita Y, John SP, Krishnan MN, Feeley EM, Ryan BJ, Weyer JL, van der Weyden L, Fikrig E, Adams DJ, Xavier RJ, Farzan M, Elledge SJ. The IFITM proteins mediate cellular resistance to influenza A H1N1 virus, West Nile virus, and dengue virus. Cell. 2009 Dec 24;139(7):1243-54.

Visit PubMed for a complete publication listing.

Major Areas of Research
  • Genes and epigenetic states modulating macrophage signaling and function
  • Identification and characterization of trained immunity stimuli
  • Applications of trained immunity in infectious and immune disease

Restricting Antibiotics for Livestock Could Limit Spread of Antibiotic-Resistant Infections in People

Link Type
Funded-research
Media Type
Article
Publish or Event Date
Link URL
https://deohs.washington.edu/news/restricting-antibiotics-livestock-could-limit-spread-antibiotic-resistant-infections-people
Research Institution
UW Department of Environmental & Occupational Health Sciences
Short Title
Restricting Antibiotics for Livestock Could Limit Spread of Antibiotic-Resistant Infections in People
Content Coordinator
Claudia Wair
Content Manager
Catey Laube Macdonald

E. coli Uses Serine to Abide Acidity

Some Hospitalized Patients’ Infections May Develop from Their Own Bacteria

Link Type
Funded-research
Media Type
Article
Publish or Event Date
Link URL
https://medicine.wustl.edu/news/some-patients-hospital-acquired-infections-may-develop-from-their-own-bacteria/
Research Institution
Washington University School of Medicine in St. Louis
Short Title
Some Hospitalized Patients’ Infections May Develop from Their Own Bacteria
Content Coordinator
Claudia Wair
Content Manager
Catey Laube Macdonald
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