Progress 10/01/20 to 09/30/21
Outputs
Target Audience:Scientific community and students Changes/Problems:There are no changes in addition to what was emphasized during the previous reporting period. What opportunities for training and professional development has the project provided?Principal Investigator: IPEC Faculty Development Institute: Building a Framework for Interprofessional Education for Collaborative Practice & Health Equity (2021) University of Florida: Diversity and Inclusion Workshop (2021) Annual NIAMRRE Conference Planning Committee (University of Nebraska - Lincoln) (2021) Southeastern/Florida Branch American Society for Microbiology Awards Committee (2021) Southeastern Branch of the American Society for Microbiology Policy Committee Member (2021) National Institute of Antimicrobial Resistance Research and Education, Chair of the Advisory Council (2021) National Institute of Antimicrobial Resistance Research and Education, Vice-Chair of the Advisory Council (2020) ? Students: Dr. Czyz serves on nine graduate student committees. He actively trains and mentors undergraduate and graduate students Michael Butcher was selected for the University Scholar Program to continue research on phages in the Czyz lab (2021-2022). Autumn Dove, a graduate student, received a first-place Graduate Outstanding Poster Talk at the FL/SEB ASM Virtual Join Meeting. March 26, 2021. Alyssa Walker, a graduate student, received a first-place Graduate Presentation at the North Central Florida Chapter of the Society for Neuroscience. Alyssa C Walker, Alfonso S. Vaziriyan-Sani, Emily T. Donahue, Rohan Bhargava, Autumn S. Dove, Keelnatham T. Shanmugam, Daniel M. Czy?. Colonization of the C. elegans gut with human enteric bacterial pathogens leads to proteostasis disruption that is rescued by butyrate. North Central Florida Society for Neuroscience Virtual Chapter Conference. Abstract/Poster. February 19, 2021. How have the results been disseminated to communities of interest?The results have been disseminated through scientific meetings, conferences, and publications. What do you plan to do during the next reporting period to accomplish the goals?During the next reporting period, we anticipate determining the mechanisms by which bacteria (and possibly their products) affect host protein folding homeostasis. Furthermore, we anticipate on determining the mechanisms of one of the inhibitorsof bacterial uptake that we are working on.
Impacts
What was accomplished under these goals?
The Czyz Laboratory finished a screen of 2,400 approved drugs for ones that target phagocytic cells and either enhance or inhibit the uptake of E. coli. We are currently working on determining the mechanisms by which the identified small-molecules modulator of bacterial uptake function. Additionally, we are currently deciphering the effect by which bacteria from the gut microbiome affect protein folding upon colonization of the C. elegans intestine. We finished screening all culturable isolates from the Human Microbiome Project and found bacteria that are beneficial (suppress toxic protein aggregation) and detrimental (enhance toxic protein aggregation). Characterizing the effect of gut residents on protein folding could potentially reveal new diagnoses, prophylactics, and therapeutic approaches against protein conformational diseases.
Publications
- Type:
Journal Articles
Status:
Accepted
Year Published:
2021
Citation:
Walker CA, Rohan Bhargava, Vaziriyan-Sani AS, Donahue ET, Bhargava R, Dove AS, Gebhardt MJ, Czyz DM. Colonization of the Caenorhabditis elegans gut with human enteric bacterial pathogens leads to proteostasis disruption that is rescued by butyrate. 2021. PLOS Pathogens.
- Type:
Journal Articles
Status:
Accepted
Year Published:
2021
Citation:
Vaziriyan-Sani AS, Handy RD, Walker AC, Pagolu CN, Enslow SM, Czy? DM. Automating Aggregate Quantification in Caenorhabditis elegans. J Vis Exp. 2021;(176):10.3791/62997. Published 2021 Oct 14. doi:10.3791/62997
- Type:
Conference Papers and Presentations
Status:
Accepted
Year Published:
2021
Citation:
Alyssa C Walker, Alfonso S. Vaziriyan-Sani, Emily T. Donahue, Rohan Bhargava, Autumn S. Dove, Keelnatham T. Shanmugam, Daniel M. Czy?. Colonization of the C. elegans gut with human enteric bacterial pathogens leads to proteostasis disruption that is rescued by butyrate. Midwest Stress Response and Molecular Chaperone Meeting. Abstract/Poster. January 16, 2021.
- Type:
Conference Papers and Presentations
Status:
Accepted
Year Published:
2021
Citation:
*Alyssa C Walker, Alfonso S. Vaziriyan-Sani, Emily T. Donahue, Rohan Bhargava, Autumn S. Dove, Keelnatham T. Shanmugam, Daniel M. Czy?. Colonization of the C. elegans gut with human enteric bacterial pathogens leads to proteostasis disruption that is rescued by butyrate. North Central Florida Society for Neuroscience Virtual Chapter Conference. Abstract/Poster Talk. February 19, 2021.
- Type:
Conference Papers and Presentations
Status:
Accepted
Year Published:
2021
Citation:
Alyssa C Walker, Alfonso S. Vaziriyan-Sani, Emily T. Donahue, Rohan Bhargava, Autumn S. Dove, Keelnatham T. Shanmugam, Daniel M. Czy?. Colonization of the C. elegans gut with human enteric bacterial pathogens leads to proteostasis disruption that is rescued by butyrate. Emerging Pathogen Institute Day. University of Florida, Gainesville, Florida. Abstract/Poster Talk. February 25, 2021.
- Type:
Conference Papers and Presentations
Status:
Accepted
Year Published:
2021
Citation:
Autumn S Dove, Rohan Bhargava, Alyssa C Walker, Maegawa GHB, Daniel M Czyz. Drug Repurposing Screen for Anti-infectives Identifies Quinacrine as an Intracellular Host-targeted Antibiotic. Emerging Pathogen Institute Day. University of Florida, Gainesville, Florida. Abstract/Poster Talk. February 25, 2021.
- Type:
Conference Papers and Presentations
Status:
Accepted
Year Published:
2021
Citation:
*Dove A, Walker AC, Maegawa GHB, Czyz DM. Drug repurposing screen for anti-infectives identifies quinacrine as an intracellular host-targeted antibiotic. Southeast Branch/Florida ASM Meeting. Abstract/Poster Talk. March 26, 2021. Virtual Meeting.
- Type:
Conference Papers and Presentations
Status:
Accepted
Year Published:
2021
Citation:
Alyssa C Walker, Rohan Bhargava, Alfonso S. Vaziriyan-Sani, Christine Pourciau, Emily T. Donahue, , Autumn S. Dove, Michael M. Gebhardt, Garrett Ellward, Tony Romeo, Daniel M. Czy?. Colonization of the C. elegans gut with human enteric bacterial pathogens leads to proteostasis disruption that is rescued by butyrate. World Microbe Forum. Abstract/Poster Talk. June 20-24, 2021.
- Type:
Conference Papers and Presentations
Status:
Accepted
Year Published:
2021
Citation:
*Dove A, Walker AC, Maegawa GHB, Czyz DM. Drug repurposing screen for anti-infectives identifies quinacrine as an intracellular host-targeted antibiotic. World Microbe Forum. Abstract/Poster Talk. June 20-24, 2021.
- Type:
Conference Papers and Presentations
Status:
Accepted
Year Published:
2021
Citation:
Daniel Czyz. Deciphering the effect of bacteria on protein conformational diseases. 2021 New Investigator in Alzheimers Disease Meeting. American Federation of Aging Research. Talk/Virtual. October 4, 2021.
|
Progress 10/01/19 to 09/30/20
Outputs
Target Audience:
Nothing Reported
Changes/Problems:One of the major changesto the project is the direction of aim two. Instead of studying horizontal gene transfer, I focused more on studying the effect of bacteria on protein folding homeostasis (II-2). What opportunities for training and professional development has the project provided?I have attended a semester-long CTSI Mentor Academy and multiple faculty development programs, including Developing Grant Portfolio. Additionally, I mentored and supervised four graduate students and ten undergraduate students. How have the results been disseminated to communities of interest?Both the PI, graduate and undergraduate students have been disseminating research findings through attending and presenting at meetings and conferences. What do you plan to do during the next reporting period to accomplish the goals?During the next reporting period, I plan to complete screening 2,400 drugs for modulators of bacterial uptake and begin employing the C. elegans model in the study of host-bacteria interaction.
Impacts
What was accomplished under these goals?
We began screening a library of 2,400 approved drugs for those that specifically target human phagocytic cells to modulate their activity to uptake bacteria. Such an immunomodulatory approach has the potential to enhance the uptake of common extracellular bacteria and inhibit cellular entry by common intracellular bacterial pathogens. We are currently continuing the screen. In addition, we established a C. elegans model to study the effect of bacteria on the protein folding environment. This project is also ongoing during this reporting period.
Publications
- Type:
Conference Papers and Presentations
Status:
Other
Year Published:
2020
Citation:
25th Annual Midwest Stress Response and Molecular Chaperone Meeting. Northwestern University, Evanston, IL. Butyrate Suppresses Bacteria-induced Protein Aggregation in C. elegans Models of Protein Conformational Diseases. January 18, 2020.
- Type:
Conference Papers and Presentations
Status:
Other
Year Published:
2020
Citation:
*Autumn S Dove, Rohan Bhargava, Alyssa C Walker, Maegawa GHB, Daniel M Czyz. A macrophage-based screen yields host-targeting modulators of bacterial uptake. National Institute of Antimicrobial Resistance Research and Education Knowledge Exchange Virtual Poster Session. Abstract/Talk/Poster. July 31, 2020.
- Type:
Conference Papers and Presentations
Status:
Other
Year Published:
2020
Citation:
*Rohan Bhargava, Mark G Gorelik, Alyssa C Walker, Tony Romeo, Daniel M Czyz. Identifying butyrogenic bacteria in the human microbiome. National Institute of Antimicrobial Resistance Research and Education Knowledge Exchange Virtual Poster Session. Abstract/Talk/Poster. July 30, 2020.
- Type:
Conference Papers and Presentations
Status:
Other
Year Published:
2020
Citation:
Walker A, Dove A, Donahue E, Vaziriyan-Sani A, Hoffman BJ, Dove A, Shanmugam KT, Czyz DM. Butyrate suppresses bacteria-induced protein aggregation in C. elegans models of protein conformational diseases. Southeast Branch ASM Meeting. Abstract/Poster/Talk. February 22, 2020. University of Alabama, Huntsville, Alabama
- Type:
Conference Papers and Presentations
Status:
Other
Year Published:
2020
Citation:
Dove A, Maegawa GHB, Czyz DM. Identification of host-targeting modulators of bacterial uptake using a novel assay for quantifying intracellular bacteria. Southeast Branch ASM Meeting. Abstract/Talk. February 21, 2020. University of Alabama, Huntsville, Alabama
- Type:
Conference Papers and Presentations
Status:
Other
Year Published:
2020
Citation:
Walker A, Dove A, Donahue E, Vaziriyan-Sani A, Hoffman BJ, Dove A, Czyz DM. Butyrate suppresses bacteria-induced protein aggregation in C. elegans models of protein conformational diseases. Emerging Pathogen Institute Day. Abstract/Poster. February 7, 2020. University of Florida, Gainesville, Florida
- Type:
Conference Papers and Presentations
Status:
Other
Year Published:
2020
Citation:
Dove A, Walker A, Maegawa GHB, Czyz DM. A macrophage-based screen yields host-targeting modulators. Emerging Pathogen Institute Day. Abstract/Poster. February 13, 2020. University of Florida, Gainesville, Florida
- Type:
Conference Papers and Presentations
Status:
Other
Year Published:
2020
Citation:
Walker A, Donahue E, Vaziriyan-Sani A, Dove A, Hoffman BJ, Shanmugam KT, Czyz DM. Butyrate Suppresses Bacteria-induced Protein Aggregation in C. elegans Models of Protein Conformational Diseases. Abstract/Poster/Talk. January 18, 2020. 25th Annual Midwest Stress Response and Molecular Chaperone Meeting. Northwestern University, Evanston, Illinois
|
Progress 10/02/18 to 09/30/19
Outputs
Target Audience:-The target audience of the proposed work are individualsaffected by bacterial infections and protein conformational diseases (i.e. Alzheimer's disease, Parkinson's disease, ALS, Huntington's disease, etc). -During the funding period, the PI also developed and taught a course on antimicrobial resistance to undergraduate and graduate students. Changes/Problems:We have changed part II of the project. Instead of studying horizontal gene transfer in the C. elegans gut, we began working on the effect of bacteria on their host.Recent discoveries demonstrate that bacteria contribute to the pathogenesis of protein conformational diseases. However, the identities of bacteria that influence protein folding in their host and the underlying mechanisms by which this influence is executed remain largely unknown. We began deciphering the role of pathogenic bacteria that reside in the human gut on host proteostasis using the C. elegans intestine. We found that opportunistic pathogens often associated with gastroenteritis--including members of the Enterobacteriaceae family and other species such as Listeria, Vibrio, Pseudomonas, and Acinetobacter--enhanced protein aggregation upon colonization of the intestine. Interestingly, these bacteria not only disrupt the protein folding environment in the host intestine, but also in neurons and muscle tissue. Furthermore, we observed that colonization of the C. elegans intestine with proteostasis disrupting bacteria enhanced protein aggregation in the F1 generation. Taken together, these data suggest that bacteria may release "signals" that affect distal tissues, including the gonad. Many commensal bacteria produce short-chain fatty acids; among these molecules, butyrate was recently shown to mitigate the severity of protein conformational diseases. We found that butyrate enhanced bacteria-mediated protein aggregation at low physiological concentrations but suppressed bacteria-induced aggregation at high therapeutic concentrations. To examine the effect of butyrate-producing bacteria on host proteostasis, we colonized the C. elegans intestine with bacteria engineered to overproduce butyrate. The resulting increase in endogenous butyrate enhanced proteostasis in the intestine and other tissues, as assessed by a decrease in protein aggregation in the host. Collectively, our results demonstrate that pathogenic enteric bacteria disrupt host proteostasis and enhance aggregation of metastable proteins. These findings suggest that dysbiosis between commensal butyrate-producing bacteria and pathogenic enteric species may have a detrimental effect on host proteostasis. What opportunities for training and professional development has the project provided?-The project helped to train ten undergraduate students (Heelesh Bapatla, Alfonso Vaziriyan-Sani, Shelby Harding, Lillianne Marcheggiani, Nelson Gonzalez, Emily Herring, Troy Benvenuto, Adrienne Hernandez, Emily Donahue, and Natalia Andraka). Six of these students havesince graduated and moved onto medical or professional schools. -Alyssa Walker joined the lab as an MS student and switched her degree program to PhD -Autumn Dove joined the lab as a PhD student and works full time on the host-directed antimicrobials project -Both Alyssa and Autumn presented their work at the 2019 UF Emerging Pathogen Institute Day and at departmental retreats. -Alfonso Vaziriyan-Sani was an undergraduate student volunteering in the lab. During the Summer of 2019, he received a Summer Internship to work full time. Alfonso has been in the lab for the past two years and he will continue to work on a Master's degree in the Czyz Lab. -Adrienne Hernandez and Troy Benvenuto, both undergraduate students, received an NSF/USDA S-STEM Summer Undergraduate Research Experience funding (2019). Since then, Troy has graduated and Adrienne continues to volunteer in the lab. All students were expected to participate in scientific research guided by their mentor graduate students and supervised by the Principal Investigator. How have the results been disseminated to communities of interest?-During the 2018-2019 reporting period, the project was still in its developmental stage. Therefore, there were not too many results to disseminate. Nonetheless, Alyssa Walker and Autumn Dove presented their work at a Departmental Retreat and at the UF Emerging Pathogen Institute Day. What do you plan to do during the next reporting period to accomplish the goals?-Both Alyssa Walker and Autumn Dove are finishing up their experiments for their first publications. The goal for 2019-2020 period is to complete phase I of each project and publish the results. Each student will begin mechanistic studies to understand the mechanisms of action of drugs that modulate bacterial uptake and the mechanisms involved in the bacteria-mediated modulation of protein homeostasis
Impacts
What was accomplished under these goals?
-We have developed a novel assay to assess intracellular bacteria -Using this new assay, we began screening 2,400 FDA-approved drugs for the ones that either enhance or suppress phagocytic immune cell-mediated uptake of bacteria -We developed C. elegans models of bacterial colonization that allow us to study host-bacterial interaction -We have demonstrated that pathogenic antibiotic-resistant enteric bacteria disrupt host protein homeostasis leading to toxic protein aggregation
Publications
- Type:
Conference Papers and Presentations
Status:
Published
Year Published:
2019
Citation:
Dove A, Walker A, Czyz DM. Host-targeted Approach Against MDR Gram-negative Bacteria. Emerging Pathogen Institute Day. Abstract/Poster. February 7, 2019. University of Florida, Gainesville, Florida
Walker A, Dove A, Hoffman BJ, Czyz DM. The effect of human gut microbiota on the organismal proteostasis. Emerging Pathogen Institute Day. Abstract/Poster. February 7, 2019. University of Florida, Gainesville, Florida
|
|