Professor and Research Cluster Coordinator
Department: Biochemistry and Microbiology; Pediatrics
Research Cluster: Infectious and Immunological Diseases
Office: BBSC 336-S | Laboratories: BBSC 315 and 331
Phone: (304) 696-7356 | Fax: (304) 696-7207
My research focuses on two areas: lung infections in Cystic Fibrosis and the role of segmented filamentous bacteria (SFB) in the gut immunity.
CYSTIC FIBROSIS BIOFILMS
The major cause of morbidity and mortality in patients with Cystic Fibrosis is chronic lung infections with the bacterial pathogen, Pseudomonas aeruginosa. During the course of infection, this bacterium overproduces a capsular polysaccharide called alginate. The overproduction of alginate is a marker for chronic infections and responsible for the disease progression. The goal of our research is to prevent the development of chronic infections by controlling the molecular mechanisms that govern alginate regulation. Alginate is negatively regulated by the transmembrane protein MucA. There are two molecular mechanisms by which P. aeruginosa regulates the production of alginate. The first is through the activation of the intramembrane proteases, and the second is through mutations in mucA. Previously we found that induction of a small envelope protein can activate the alginate biosynthetic pathway in the strains with a wild type mucA (Refs. 2 and 10). Additionally, we determined that increasing the activities of a specific protease, alginate overproduction can also be stably induced in strains with only a cytoplasmic portion of MucA (Refs. 3 and 9). These strains provide model systems for a pathway-based screen for potential biofilm inhibitors. Our ultimate goal is to develop therapeutics that target biofilm formation for clinical trials.
MODELING LUNG INFECTIONS
To investigate how the host defenses react to lung colonization by P. aeruginosa, we used a whole-body exposure system which nebulizes bacterial suspension in micron-size droplets (Ref. 12). Using this model, we previously screened 11 inbred mouse strains for the susceptibility to lung infection by P. aeruginosa PAO1. Mouse strain DBA/2 is hypersensitive to colonization and develops acute pneumonia as characterized by the alveolar exudate and edema formation coupled with specific induction of IL-17, monocyte chemotactic protein (MCP)-1 and vascular endothelial growth factor (VEGF) in the lung tissues (Ref. 11). Analysis of the antibacterial function of bone marrow derived naïve macrophages between the sensitive DBA/2 and the resistant C57BL/6 mice revealed that the macrophages of DBA/2 can perform phagocytosis, but the ingestion does not lead to the elimination of P. aeruginosa PAO1 (Figure 1). The goal of this project is to better understand the etiology of lung infections for the development of novel therapeutics.
Figure 1. DBA/2 naive macrophages have reduced bactericidal activity compared to C57BL/6. Epifluorescent images of naïve macrophages produced by bone marrow progenitor cells after a 20 min exposure to GFP-labeled P. aeruginosa PAO1. C57BL/6 macrophages are able to control P. aeruginosa growth significantly better (* = p<0.05, ANOVA, Student’s t test, Holm’s method) than DBA/2 macrophages for up to five hours of exposure. The control represents medium inoculated with bacteria in the absence of macrophages. Data plotted is the mean of three experiment.
SEGMENTED FILAMENTOUS BACTERIA (SFB)
Gut microbiota, a bacterial community made up of 500-1,000 different species, are important to human health. Within microbiota, there is a morphologically-distinct, symbiotic member known as segmented filamentous bacteria (SFB). SFB is an anaerobic, spore-forming Gram-positive bacterium that plays a vital role in the development of the immune system in mice. More specifically, SFB has been shown to attach to the apical epithelium of the small intestine to induce the interleukin-17-producing T helper (TH17) cells. TH17 cells are important for protection against intestinal pathogens, as well as maintaining gut homeostasis. However, little is known about the role of SFB in humans. Recently, we found that SFB colonization occurs early in human life, followed by an age-associated decrease in overall abundance (Ref. 6). We observed that the majority of 7 to 12 mo.-old Chinese infants carry SFB. However, SFB was not detected in older children (>3 years old). The presence of SFB in American children has never been investigated. We are currently conducting a survey to examine the prevalence of SFB in healthy American children, and determine if a correlation exists between SFB and various pediatric gastrointestinal tract (GI) diseases.
- Methods of detecting and controlling mucoid Pseudomonas biofilm production. Yu HD, Qiu D. US Patent 8,399,649, Issued in 2013.
- Methods for producing bacterial alginates. Yu HD, Damron FH, Qiu D. US Patent application No. 12/432,474, Priority date: April 29, 2008.
- Culture medium and methods for producing alginate from stable mucoid strains of Pseudomonas aeruginosa. Yu HD, Niles RM, Wang X, Dillon KD. US Patent application No. 13/348,897, Priority date: Jan. 14, 2011.
- Overexpression of CupB5 activates alginate overproduction in Pseudomonas aeruginosa by a novel AlgW-dependent mechanism.de Regt AK,Yin Y,Withers TR, Wang X, Baker TA, Sauer RT, Yu HD. Mol Microbiol. 2014 Jun 10. doi: 10.1111/mmi.12665. [Epub ahead of print]. PMID: 24913916
- Expression of mucoid induction factor MucE is dependent upon the alternate sigma factor AlgU in Pseudomonas aeruginosa. Yin Y, Damron FH, Withers TR, Pritchett CL, Wang X, Schurr MJ, Yu HD. BMC Microbiol 2013 Oct 18;13(1):232. PMID: 24138584
- Evidence for sigma factor competition in the regulation of alginate production by Pseudomonas aeruginosa. Yin Y, Withers TR, Wang X, Yu HD. PLoS One. 2013 Aug 22;8(8):e72329. PMID:23991093
- Truncation of type-IV pilin induces mucoidy in Pseudomonas aeruginosa strain PAO579. Withers TR, Damron FH, Yin Y, Yu HD. Microbiologyopen. 2013 Jun;2(3):459-70. PMID: 23533140
- Effect of intracellular expression of antimicrobial peptide LL-37 on the growth of Escherichia coli strain TOP10 under aerobic and anaerobic conditions. Liu W, Dong SL, Xu F, Wang XQ, Withers TR, Yu HD, Wang X. Antimicrob Agents Chemother. 2013 Oct;57(10):4707-16. PMID: 23856776
- Comparative analysis of the distribution of segmented filamentous bacteria in humans, mice and chickens. Yin Y, Wang Y, Zhu L, Liu W, Liao N, Jiang M, Zhu B, Yu HD, Xiang C, Wang X. ISME J. 2013 Mar;7(3):615-21. PMID: 23151642
- Vanadate and triclosan synergistically induce alginate production by Pseudomonas aeruginosa strain PAO1.Damron FH, Davis MR Jr, Withers TR, Ernst RK, Goldberg JB, Yu G, Yu HD. Mol Microbiol. 2011 Jul;81(2):554-70. PMID: 21631603
- The Pseudomonas aeruginosa sensor kinase KinB negatively controls alginate production through AlgW-dependent MucA proteolysis. Damron FH, Qiu D, Yu HD. J Bacteriol. 2009 Apr;191(7):2285-95. PMID: 19168621
- ClpXP proteases positively regulate alginate overexpression and mucoid conversion in Pseudomonas aeruginosa. Qiu D, Eisinger VM, Head NE, Pier GB, Yu HD. Microbiology. 2008 Jul;154:2119-30. PMID: 18599839
- Regulated proteolysis controls mucoid conversion in Pseudomonas aeruginosa. Qiu D, Eisinger VM, Rowen DW, Yu HD. Proc Natl Acad Sci U S A. 2007 May 8;104(19):8107-12. PMID: 17470813
- Defect in early lung defence against Pseudomonas aeruginosa in DBA/2 mice is associated with acute inflammatory lung injury and reduced bactericidal activity in naive macrophages. Wilson KR, Napper JM, Denvir J, Sollars VE, Yu HD. Microbiology. 2007 Apr;153:968-79. PMID: 17379707
- Persistent infections and immunity in cystic fibrosis. Yu H, Head NE Front Biosci. 2002 Feb 1;7:d442-57. Review. PMID: 11815305
Click here for a complete list of Dr. Yu’s publications
Jordan G. Sheppard, Senior (Biology Major), Marshall University
T. Ryan Withers, Ph.D. Staff Scientist (Progenesis Technologies, LLC)
Hongwei D. Yu, PI