Ming H. Yuk, Ph.D.

Assistant Professor, Microbiology

Office Address:
University of Pennsylvania School of Medicine
201C Johnson Pavilion
3610 Hamilton Walk
Philadelphia, PA 19104-6076
215-573-6690; FAX 215-573-4184
mingy@mail.med.upenn.edu

RESEARCH SUMMARY

Modulation of host immune responses and cellular processes by bacterial type III secretion system

Regulation of biofilm formation in a specialized bacterial respiratory pathogen

We are using Bordetella bronchiseptica as a model system for studying bacterial-host interactions at the molecular level to help us understand how the bacteria manipulate host cellular processes to facilitate successful infection. B. bronchiseptica is a respiratory pathogen closely related to B. pertussis which causes whooping cough in humans. However, B. bronchiseptica naturally infects many laboratory animals, which allow us to study bacterial-host interactions in the context of natural infections.

B. bronchiseptica encodes a type III secretion system (found in many pathogenic Gram-negative bacteria) that has been shown to mediate long term bacterial colonization in infected hosts and decrease anti-bordetella antibody production. We have analyzed the interactions of wild type and type III secretion defective bacteria with dendritic cells (DCs), which are critical in establishing host innate and adaptive immune responses to infections. When compared to mice infected with a type III secretion mutant, respiratory dendritic cells migrate to the local lymph node more rapidly in wild type infected mice. In vitro, infected murine bone marrow derived DCs are rapidly matured and killed via a type III dependent mechanism. The maturation profile is aberrant from that which is usually seen in other bacterial infections. The type III secretion system activates DCs by increasing MHC2 and CD86 surface expression. Another virulence factor, the adenylate cyclase toxin, partially deactivates DCs by decreasing CD40 surface expression and IL-12 cytokine production. Therefore, the type III secretion system and adenylate cyclase toxin synergize to produce this aberrant DC response. We have also demonstrated that MAP kinases, key elements of cellular signal transduction pathways, are differentially modulated in different cell types by the type III secretion system. In a macrophage-like cell line type III secretion caused dowregulation of ERK and p38, whereas in a lung epithelial cell line ERK and p38 was activated. The results indicate that the functions of given MAP kinases are subject to the context of cell type specific perception of microbial stimuli. Our current studies focus on determining the interactions of Bordetella stimulated dendritic cells with T-cells to understand how the bacteria down regulate host immune responses, and also the molecular details of various signal transduction pathways that may be modulated by type III secreted proteins.

We have recently demonstrated that B. bronchiseptica can form biofilms. Biofilms are dynamic communities of bacterial cells that are attached onto solid substrates, and they play important roles in the life cycle of many bacterial species. We found that biofilm formation in B. bronchiseptica is regulated by the BvgAS two-component signal transduction system. Two known virulence factors, filamentous haemagglutinin and adenylate cyclase toxin, play critical roles in the regulation of biofilm formation in this species. We are currently determining the composition of the carbohydrate matrix that encase these biofilms and how the expression of this matrix is regulated. We are also examining the formation of Bordetella biofilms in the murine respiratory tract and determining its importance in colonization process.

RECENT PUBLICATIONS