Recently, we discovered that a secreted chitinase of Legionella pneumophila, the agent of Legionnaires'disease, promotes the persistence of the bacterium in the lungs of experimentally infected mice. In vitro experiments then documented that the L. pneumophila chitinase (ChiA) promotes growth in lung epithelial cells but not in macrophages. Taken together, these data are the first demonstration of a chitinase, a type of enzyme that is traditionally viewed as only being relevant in chitin-containing environmental niches, acting like a virulence factor. Thus, we hypothesize that bacterial chitinases represent a new class of virulence factor. To explore this hypothesis, we will further investigate the role of chitinase in L. pneumophila intracellular infection of lung cells as well as test for the first time the importance of a chitinase in the virulence of a second intracellular pathogen, Listeria monocytogenes. More specifically, we will determine the intracellular location of and trafficking patterns influenced by ChiA and begin to ascertain the effects of ChiA on the lung inflammatory response. For the Listeria experiments, new chitinase mutants will be constructed and then, after confirmation of their loss of chitinase activity and their in vitro growth characteristics, tested in murine models of listeriosis. The proposed studies will i) increase our understanding of the pathogenesis of Lp, which is an important public health concern within the US and throughout the world, ii) examine for the first time the role of chitinase in the pathogenesis of L. monocytogenes, an organism that is also an important public health concern, iii) expand our appreciation of bacterial intracellular infection and the novel role that a chitinase can have in it, iv) have implications for numerous other environmental pathogens that also express chitinases, and iv) offer potential new targets for disease diagnosis, treatment, or prevention.

Public Health Relevance

We recently discovered that the secreted chitinase of Legionella pneumophila promotes bacterial persistence in the lungs of experimentally infected mice. From this novel finding, we hypothesize that microbial chitinases, which have traditionally been viewed as being relevant only in environmental niches, actually represent a new class of virulence factor and therefore are potential new targets for antimicrobial therapy. To explore this hypothesis, we will further investigate the role of chitinase in L. pneumophila intracellular infection of lung cells as well as test for the first time the importance of chitinases in the virulence of a second intracellular pathogen, Listeria monocytogenes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI076693-01A1
Application #
7594923
Study Section
Special Emphasis Panel (ZRG1-IDM-A (90))
Program Officer
Mills, Melody
Project Start
2009-01-01
Project End
2010-12-31
Budget Start
2009-01-01
Budget End
2009-12-31
Support Year
1
Fiscal Year
2009
Total Cost
$243,000
Indirect Cost
Name
Northwestern University at Chicago
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Chaudhuri, Swarnava; Gantner, Benjamin N; Ye, Richard D et al. (2013) The Listeria monocytogenes ChiA chitinase enhances virulence through suppression of host innate immunity. MBio 4:e00617-12
Pearce, Meghan M; Theodoropoulos, Nicole; Mandel, Mark J et al. (2012) Legionella cardiaca sp. nov., isolated from a case of native valve endocarditis in a human heart. Int J Syst Evol Microbiol 62:2946-54
Rouf, Ruella; Karaba, Sara M; Dao, Jenny et al. (2011) Stenotrophomonas maltophilia strains replicate and persist in the murine lung, but to significantly different degrees. Microbiology 157:2133-42
Pearce, Meghan M; Theodoropoulos, Nicole; Noskin, Gary A et al. (2011) Native valve endocarditis due to a novel strain of Legionella. J Clin Microbiol 49:3340-2
McCoy-Simandle, Kessler; Stewart, Catherine R; Dao, Jenny et al. (2011) Legionella pneumophila type II secretion dampens the cytokine response of infected macrophages and epithelia. Infect Immun 79:1984-97
Chaudhuri, Swarnava; Bruno, Joseph C; Alonzo 3rd, Francis et al. (2010) Contribution of chitinases to Listeria monocytogenes pathogenesis. Appl Environ Microbiol 76:7302-5
Söderberg, Maria A; Cianciotto, Nicholas P (2010) Mediators of lipid A modification, RNA degradation, and central intermediary metabolism facilitate the growth of Legionella pneumophila at low temperatures. Curr Microbiol 60:59-65
Cianciotto, Nicholas P (2009) Many substrates and functions of type II secretion: lessons learned from Legionella pneumophila. Future Microbiol 4:797-805