Pseudomonas aeruginosa is an opportunistic human pathogen capable of causing both acute infections, such as ventilator-associated pneumonia, as well as chronic colonization and infection of the respiratory tract. Acute infections with P. aeruginosa usually progress rapidly, both in human patients and in corresponding mammalian infection models;thus, it is not surprising that innate immune responses play a significant role in controlling this pathogen. Many P. aeruginosa molecules trigger host innate immune responses. In turn, multiple host pathways are capable of responding during infection by this pathogen. This complexity can be reduced by studying the responses of specific cell populations to P. aeruginosa in vitro;the challenge then lies in understanding whether and how these responses contribute to pathogenesis in an intact host. In this application we focus on bacterial molecules that influence how P. aeruginosa is recognized by the innate immune system, on the signaling pathways that are triggered by these molecules, and on the modification of these signals by bacterial effectors. By carrying out these experiments we will significantly increase our understanding of how host-pathogen interactions shape the immune response to P. aeruginosa in the lung. Such information is a first step to developing successful immunomodulatory strategies for the treatment of acute or chronic P. aeruginosa infections.

Public Health Relevance

The ability to respond rapidly to infecting bacteria protects most individuals from developing pneumonia due to Pseudomonas aeruginosa. In this application we investigate the immune pathways that are responsible for recognizing bacteria to generate this protective response. We then ask how bacterial toxins can interrupt this rapid immune response.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI081825-02
Application #
8111661
Study Section
Host Interactions with Bacterial Pathogens Study Section (HIBP)
Program Officer
Taylor, Christopher E,
Project Start
2010-08-01
Project End
2014-07-31
Budget Start
2011-08-01
Budget End
2012-07-31
Support Year
2
Fiscal Year
2011
Total Cost
$425,860
Indirect Cost
Name
Yale University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Lin, Christina K; Kazmierczak, Barbara I (2017) Inflammation: A Double-Edged Sword in the Response to Pseudomonas aeruginosa Infection. J Innate Immun 9:250-261
Rauch, Isabella; Tenthorey, Jeannette L; Nichols, Randilea D et al. (2016) NAIP proteins are required for cytosolic detection of specific bacterial ligands in vivo. J Exp Med 213:657-65
Kazmierczak, Barbara I; Schniederberend, Maren; Jain, Ruchi (2015) Cross-regulation of Pseudomonas motility systems: the intimate relationship between flagella, pili and virulence. Curr Opin Microbiol 28:78-82
Jhingran, Anupam; Kasahara, Shinji; Shepardson, Kelly M et al. (2015) Compartment-specific and sequential role of MyD88 and CARD9 in chemokine induction and innate defense during respiratory fungal infection. PLoS Pathog 11:e1004589
Jain, Ruchi; Kazmierczak, Barbara I (2014) A conservative amino acid mutation in the master regulator FleQ renders Pseudomonas aeruginosa aflagellate. PLoS One 9:e97439
Romberg, Neil; Al Moussawi, Khatoun; Nelson-Williams, Carol et al. (2014) Mutation of NLRC4 causes a syndrome of enterocolitis and autoinflammation. Nat Genet 46:1135-1139
Al Moussawi, Khatoun; Kazmierczak, Barbara I (2014) Distinct contributions of interleukin-1? (IL-1?) and IL-1? to innate immune recognition of Pseudomonas aeruginosa in the lung. Infect Immun 82:4204-11
Czechowska, Kamila; McKeithen-Mead, Saria; Al Moussawi, Khatoun et al. (2014) Cheating by type 3 secretion system-negative Pseudomonas aeruginosa during pulmonary infection. Proc Natl Acad Sci U S A 111:7801-6
Ledizet, Michel; Murray, Thomas S; Puttagunta, Sailaja et al. (2012) The ability of virulence factor expression by Pseudomonas aeruginosa to predict clinical disease in hospitalized patients. PLoS One 7:e49578
Lavoie, Elise G; Wangdi, Tamding; Kazmierczak, Barbara I (2011) Innate immune responses to Pseudomonas aeruginosa infection. Microbes Infect 13:1133-45

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