Fragmentation of hyaluronan by host hyaluronidases are thought to elicit a danger signal that alert the host to the presence of potential harm. However, if such a signal is linked to enhanced killing of bacteria, it is counterintuitive why mos pathogens continue to express the enzyme. Here we show that hyaluronidase expressed by the pathogen Group B Streptococcus, unlike those express by eukaryotes and nonpathogenic Streptomyces, are anti-inflammatory and modulate inflammation by degrading hyaluronan down to sizes that not only fail to stimulate TLR activation, but which could inhibit Toll-like receptor signaling. This leads to the suppression of inflammation and enhanced survival of the pathogen during infection. Based on our findings, we hypothesize that pathogens have evolved hyaluronidases that are functionally different from hyaluronidases from environmental non-pathogens. To address the hypothesis, we will study the in vitro and in vivo immunomodulatory and virulence properties of hyaluronidases elaborated by several pathogens (GBS, S. pneumoniae, and S. aureus), non-pathogen (Streptomyces coelicolor), and opportunistic pathogens (Peptostreptococcus prevotii, E. faecalis). We will determine the size of their hyaluronan degradation products and the effect of these products on TLR2, TLR4, and Myd88 signaling. Our study aims to unravel a novel cross-species evolution-based immune evasion mechanism.

Public Health Relevance

Bacterial hyaluronidases have traditionally been thought to facilitate dissemination of pathogens through deep tissues. Here we propose that bacterial hyaluronidases also play an active role in immune evasion by modifying the size of hyaluronan degradation products.

Agency
National Institute of Health (NIH)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI103839-02
Application #
8661700
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
GU, Xin-Xing
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Cedars-Sinai Medical Center
Department
Type
DUNS #
City
Los Angeles
State
CA
Country
United States
Zip Code
90048