Pneumonia caused by host-adapted, multiple drug resistant bacterial pathogens is a major clinical problem, associated with both primary infections and complications of hospitalization. Much of the pathology associated with these pathogens is due to the host response that is elicited ; either excessive inflammation that causes respiratory failure or an immunosuppressive response that permits unimpeded bacterial replication, pulmonary damage and sepsis. Organisms such as MRSA, Pseudomonas aeruginosa and Klebsiella pneumoniae readily adapt to the milieu within the human airways, acquiring mutations that affect their metabolism, immunogenicity as well as their resistance to antimicrobial agents. The goal of our studies is to apply a comprehensive approach to fully characterize such host adapted pathogens, isolated from patients, by using whole gen ome sequencing, murine modeling of immunogenicity, and proteomics. This type of analysis can provide the data necessary to identify bacterial components associated with specific patterns of infection. Bacterial genes that are linked to immuno-pathogenicity can be identified in clinical isolates in real time, just as methicillin resistance genes are routinely screened in staphylococci. A better understanding of the host response that is elicited will be used to apply immunomodulatory therapy to complement the often ineffective antimicrobial agents used to treat pneumonia. In other branches of medicine, targeting the inflammasome, IL-1, T cell signaling and TNF cascades have become standards of care and new immune targets are under active development. A comprehensive understanding of both the properties of the infecting organism and the host response that is evoked can be used to develop a strategy of precision medicine for the treatment of bacterial pneumonia.

Public Health Relevance

The central premise of this project is that a comprehensive analysis of both the infecting organism and the host response that is activated, can be used to direct immunomodulatory therapy that will improve outcomes of severe bacterial pneumonia.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Unknown (R35)
Project #
5R35HL135800-02
Application #
9412191
Study Section
Special Emphasis Panel (ZHL1)
Program Officer
Caler, Elisabet V
Project Start
2017-01-11
Project End
2023-11-30
Budget Start
2017-12-01
Budget End
2018-11-30
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Pediatrics
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Prince, Alice; Wang, Hui; Kitur, Kipyegon et al. (2017) Humanized Mice Exhibit Increased Susceptibility to Staphylococcus aureus Pneumonia. J Infect Dis 215:1386-1395
Riquelme, Sebastián A; Hopkins, Benjamin D; Wolfe, Andrew L et al. (2017) Cystic Fibrosis Transmembrane Conductance Regulator Attaches Tumor Suppressor PTEN to the Membrane and Promotes Anti Pseudomonas aeruginosa Immunity. Immunity 47:1169-1181.e7
Ahn, Danielle; Prince, Alice (2017) Participation of Necroptosis in the Host Response to Acute Bacterial Pneumonia. J Innate Immun 9:262-270
Ahn, Danielle; Peñaloza, Hernán; Wang, Zheng et al. (2016) Acquired resistance to innate immune clearance promotes Klebsiella pneumoniae ST258 pulmonary infection. JCI Insight 1:e89704
Parker, Dane; Prince, Alice (2016) Immunoregulatory effects of necroptosis in bacterial infections. Cytokine 88:274-275