6 results on '"Hreha, Teri N."'
Search Results
2. Sex effects in pyelonephritis.
- Author
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Albracht, Clayton D., Hreha, Teri N., and Hunstad, David A.
- Subjects
AGE distribution ,SEX hormones ,IMMUNITY ,PYELONEPHRITIS ,SEX distribution ,URETHRA ,URINARY tract infections ,VESICO-ureteral reflux ,DISEASE risk factors - Abstract
Urinary tract infections (UTIs) are generally considered a disease of women. However, UTIs affect females throughout the lifespan, and certain male populations (including infants and elderly men) are also susceptible. Epidemiologically, pyelonephritis is more common in women but carries increased morbidity when it does occur in men. Among children, high-grade vesicoureteral reflux is a primary risk factor for upper-tract UTI in both sexes. However, among young infants with UTI, girls are outnumbered by boys; risk factors include posterior urethral valves and lack of circumcision. Recent advances in mouse models of UTI reveal sex differences in innate responses to UTI, which vary somewhat depending on the system used. Moreover, male mice and androgenized female mice suffer worse outcomes in experimental pyelonephritis; evidence suggests that androgen exposure may suppress innate control of infection in the urinary tract, but additional androgen effects, as well as non-hormonal sex effects, may yet be specified. Among other intriguing directions, recent experiments raise the hypothesis that the postnatal testosterone surge that occurs in male infants may represent an additional factor driving the higher incidence of UTI in males under 6 months of age. Ongoing work in contemporary models will further illuminate sex- and sex-hormone-specific effects on UTI pathogenesis and immune responses. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
3. The three NADH dehydrogenases of Pseudomonas aeruginosa: Their roles in energy metabolism and links to virulence.
- Author
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Hreha, Teri N., Foreman, Sara, Duran-Pinedo, Ana, Morris, Andrew R., Diaz-Rodriguez, Patricia, Jones, J. Andrew, Ferrara, Kristina, Bourges, Anais, Rodriguez, Lauren, Koffas, Mattheos A. G., Hahn, Mariah, Hauser, Alan R., and Barquera, Blanca
- Subjects
PSEUDOMONAS aeruginosa ,ENERGY metabolism ,DEHYDROGENASES ,NADH dehydrogenase ,ION transport (Biology) ,COFACTORS (Biochemistry) ,CONSERVATION of energy - Abstract
Pseudomonas aeruginosa is a ubiquitous opportunistic pathogen which relies on a highly adaptable metabolism to achieve broad pathogenesis. In one example of this flexibility, to catalyze the NADH:quinone oxidoreductase step of the respiratory chain, P. aeruginosa has three different enzymes: NUO, NQR and NDH2, all of which carry out the same redox function but have different energy conservation and ion transport properties. In order to better understand the roles of these enzymes, we constructed two series of mutants: (i) three single deletion mutants, each of which lacks one NADH dehydrogenase and (ii) three double deletion mutants, each of which retains only one of the three enzymes. All of the mutants grew approximately as well as wild type, when tested in rich and minimal medium and in a range of pH and [Na
+ ] conditions, except that the strain with only NUO (ΔnqrFΔndh) has an extended lag phase. During exponential phase, the NADH dehydrogenases contribute to total wild-type activity in the following order: NQR > NDH2 > NUO. Some mutants, including the strain without NQR (ΔnqrF) had increased biofilm formation, pyocyanin production, and killed more efficiently in both macrophage and mouse infection models. Consistent with this, ΔnqrF showed increased transcription of genes involved in pyocyanin production. [ABSTRACT FROM AUTHOR]- Published
- 2021
- Full Text
- View/download PDF
4. A host receptor enables type 1 pilus-mediated pathogenesis of Escherichia coli pyelonephritis.
- Author
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McLellan, Lisa K., McAllaster, Michael R., Kim, Arthur S., Tóthová, Ľubomíra, Olson, Patrick D., Pinkner, Jerome S., Daugherty, Allyssa L., Hreha, Teri N., Janetka, James W., Fremont, Daved H., Hultgren, Scott J., Virgin, Herbert W., and Hunstad, David A.
- Subjects
PYELONEPHRITIS ,ESCHERICHIA coli ,LECTINS ,URINARY tract infections ,BLADDER ,CRISPRS ,BACTERIAL cell surfaces ,BACTERIAL diseases - Abstract
Type 1 pili have long been considered the major virulence factor enabling colonization of the urinary bladder by uropathogenic Escherichia coli (UPEC). The molecular pathogenesis of pyelonephritis is less well characterized, due to previous limitations in preclinical modeling of kidney infection. Here, we demonstrate in a recently developed mouse model that beyond bladder infection, type 1 pili also are critical for establishment of ascending pyelonephritis. Bacterial mutants lacking the type 1 pilus adhesin (FimH) were unable to establish kidney infection in male C3H/HeN mice. We developed an in vitro model of FimH-dependent UPEC binding to renal collecting duct cells, and performed a CRISPR screen in these cells, identifying desmoglein-2 as a primary renal epithelial receptor for FimH. The mannosylated extracellular domain of human DSG2 bound directly to the lectin domain of FimH in vitro, and introduction of a mutation in the FimH mannose-binding pocket abolished binding to DSG2. In infected C3H/HeN mice, type 1-piliated UPEC and Dsg2 were co-localized within collecting ducts, and administration of mannoside FIM1033, a potent small-molecule inhibitor of FimH, significantly attenuated bacterial loads in pyelonephritis. Our results broaden the biological importance of FimH, specify the first renal FimH receptor, and indicate that FimH-targeted therapeutics will also have application in pyelonephritis. Author summary: Urinary tract infections (UTIs) are among the most common bacterial infections in humans. While much has been discovered about how E. coli cause bladder infections, less is known about the host-pathogen interactions that underlie kidney infection (pyelonephritis). We employed recently developed mouse models to show that bacterial surface fibers called type 1 pili, which bear the adhesive protein FimH and are known to mediate E. coli binding to bladder epithelium, are also required for ascending kidney infection. We developed a cell-culture model of bacterial binding to renal collecting duct, then performed a screen using the gene-editing tool CRISPR to identify the first known FimH receptor in the kidney. This epithelial cell-surface protein, desmoglein-2, was shown to directly bind FimH, and we localized this binding to specific extracellular domains of DSG2. Further, we showed that mannosides, small-molecule FimH inhibitors currently in development to treat bladder infection, are also effective in experimental kidney infection. Our study reveals a novel host-pathogen interaction during pyelonephritis and demonstrates how this interaction may be therapeutically targeted. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
5. Androgen-Influenced Polarization of Activin A-Producing Macrophages Accompanies Post-pyelonephritic Renal Scarring.
- Author
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Hreha, Teri N., Collins, Christina A., Daugherty, Allyssa L., Griffith, Jessie M., Hruska, Keith A., and Hunstad, David A.
- Subjects
ACTIVIN ,URINARY tract infections ,SCARS ,CHRONIC kidney failure ,MACROPHAGES ,PYELONEPHRITIS ,ANIMAL models in research - Abstract
Ascending bacterial pyelonephritis, a form of urinary tract infection (UTI) that can result in hospitalization, sepsis, and other complications, occurs in ~250,000 US patients annually; uropathogenic Escherichia coli (UPEC) cause a large majority of these infections. Although UTIs are primarily a disease of women, acute pyelonephritis in males is associated with increased mortality and morbidity, including renal scarring, and end-stage renal disease. Preclinical models of UTI have only recently allowed investigation of sex and sex-hormone effects on pathogenesis. We previously demonstrated that renal scarring after experimental UPEC pyelonephritis is augmented by androgen exposure; testosterone exposure increases both the severity of pyelonephritis and the degree of renal scarring in both male and female mice. Activin A is an important driver of scarring in non-infectious renal injury, as well as a mediator of macrophage polarization. In this work, we investigated how androgen exposure influences immune cell recruitment to the UPEC-infected kidney and how cell-specific activin A production affects post-pyelonephritic scar formation. Compared with vehicle-treated females, androgenized mice exhibited reduced bacterial clearance from the kidney, despite robust myeloid cell recruitment that continued to increase as infection progressed. Infected kidneys from androgenized mice harbored more alternatively activated (M2) macrophages than vehicle-treated mice, reflecting an earlier shift from a pro-inflammatory (M1) phenotype. Androgen exposure also led to a sharp increase in activin A-producing myeloid cells in the infected kidney, as well as decreased levels of follistatin (which normally antagonizes activin action). As a result, infection in androgenized mice featured prolonged polarization of macrophages toward a pro-fibrotic M2a phenotype, accompanied by an increase in M2a-associated cytokines. These data indicate that androgen enhancement of UTI severity and resulting scar formation is related to augmented local activin A production and corresponding promotion of M2a macrophage polarization. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
6. TGFβ1 orchestrates renal fibrosis following Escherichia coli pyelonephritis.
- Author
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Hreha, Teri N., Collins, Christina A., Daugherty, Allyssa L., Twentyman, Joy, Paluri, Nitin, and Hunstad, David A.
- Subjects
RENAL fibrosis ,URINARY tract infections ,ESCHERICHIA coli ,MESENCHYMAL stem cells ,CHRONIC kidney failure - Abstract
Renal scarring after pyelonephritis is linked to long‐term health risks for hypertension and chronic kidney disease. Androgen exposure increases susceptibility to, and severity of, uropathogenic Escherichia coli (UPEC) pyelonephritis and resultant scarring in both male and female mice, while anti‐androgen therapy is protective against severe urinary tract infection (UTI) in these models. This work employed androgenized female C57BL/6 mice to elucidate the molecular mechanisms of post‐infectious renal fibrosis and to determine how these pathways are altered by the presence of androgens. We found that elevated circulating testosterone levels primed the kidney for fibrosis by increasing local production of TGFβ1 before the initiation of UTI, altering the ratio of transcription factors Smad2 and Smad3 and increasing the presence of mesenchymal stem cell (MSC)‐like cells and Gli1 + activated myofibroblasts, the cells primarily responsible for deposition of scar components. Increased production of TGFβ1 and aberrations in Smad2:Smad3 were maintained throughout the course of infection in the presence of androgen, correlating with renal scarring that was not observed in non‐androgenized female mice. Pharmacologic inhibition of TGFβ1 signaling blunted myofibroblast activation. We conclude that renal fibrosis after pyelonephritis is exacerbated by the presence of androgens and involves activation of the TGFβ1 signaling cascade, leading to increases in cortical populations of MSC‐like cells and the Gli1 + activated myofibroblasts that are responsible for scarring. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
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