Streptococcus pneumoniae (pneumococcus) is the most common cause of community-acquired pneumonia. Interactions of this pathogen with humans are complex, with pneumococcus causing a spectrum of disease ranging from asymptomatic colonization of upper airways to multi-organ infection and death. We propose to elucidate the hepatic acute phase response triggered by pneumococci in the lungs, and to examine whether pneumococcal subversion of this response is a critical virulence determinant during lung infection. The hepatic acute phase response is triggered by cytokines during pneumonia, with liver activation dependent on IL-6 (triggering STAT3) and on TNF and IL-1 (triggering NF-?B). We postulate that expression of these cytokines during pneumonia is driven by NF-?B RelA in resident lung myeloid cells, and these cytokines then activate both STAT3 and NF-?B in hepatocytes to mediate acute phase protein expression essential to preventing the spread of infection and inflammatory injury from the lungs to other organs and tissues. To test the central hypothesis that the hepatic acute phase response functions as a vascular shield to prevent dissemination of infection and injury from the infected lung, we propose to pursue the following specific aims: 1) Test the hypothesis that lung resident macrophages and dendritic cells initiate the hepatic acute phase response during pneumonia, using mice in which cytokine expression is inhibited by RelA mutation selectively in myeloid cells and in resident lung leukocytes. 2) Test the hypothesis that the hepatic acute phase response limits both dissemination of infection (bacteremia) and dissemination of injury (ARDS and multi-organ failure) during pneumonia, using mice in which the hepatic acute phase response is inhibited by combined targeting of both STAT3 and RelA selectively in hepatocytes. 3) Test the hypothesis that pneumococci subverting the hepatic acute phase response are more invasive in human patients and mouse models, using clinical isolates from human patients with asymptomatic carriage or bacteremic pneumonia in in vitro screens and in vivo models of infection. Innovations include the novel concepts to be tested, as well as the mice deficient in RelA and/or STAT3 in select cells and the in vitro screening assays of clinical isolates of pneumococcus. The proposed studies will have significance for filling knowledge gaps (elucidating the regulation and function of the acute phase response during pneumonia) and will guide further studies aiming to differentiate and treat particularly susceptible patients and especially virulent pneumococci.

Public Health Relevance

Streptococcus pneumoniae (pneumococcus) infection is the leading cause of pneumonia, and the spreading of pneumococcus from the lungs also causes bloodstream and brain infections which are life-threatening. The proposed studies will test whether and how activation of the liver prevents the spread of infection and disease from the lung to other organs. This new knowledge will guide further studies aiming to identify people who are especially susceptible and bacteria that are especially virulent, in order to better prevent and treat pneumococcal infections.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL079392-07
Application #
8250351
Study Section
Special Emphasis Panel (ZRG1-CVRS-J (02))
Program Officer
Eu, Jerry Pc
Project Start
2004-12-01
Project End
2016-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
7
Fiscal Year
2012
Total Cost
$410,194
Indirect Cost
$159,541
Name
Boston University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118
Kamata, Hirofumi; Yamamoto, Kazuko; Wasserman, Gregory A et al. (2016) Epithelial Cell-Derived Secreted and Transmembrane 1a Signals to Activated Neutrophils during Pneumococcal Pneumonia. Am J Respir Cell Mol Biol 55:407-18
Traber, Katrina E; Hilliard, Kristie L; Allen, Eri et al. (2015) Induction of STAT3-Dependent CXCL5 Expression and Neutrophil Recruitment by Oncostatin-M during Pneumonia. Am J Respir Cell Mol Biol 53:479-88
Quinton, Lee J; Mizgerd, Joseph P (2015) Dynamics of lung defense in pneumonia: resistance, resilience, and remodeling. Annu Rev Physiol 77:407-30
Hilliard, Kristie L; Allen, Eri; Traber, Katrina E et al. (2015) Activation of Hepatic STAT3 Maintains Pulmonary Defense during Endotoxemia. Infect Immun 83:4015-27
Hilliard, Kristie L; Allen, Eri; Traber, Katrina E et al. (2015) The Lung-Liver Axis: A Requirement for Maximal Innate Immunity and Hepatoprotection during Pneumonia. Am J Respir Cell Mol Biol 53:378-90
Ubags, Niki D; Vernooy, Juanita H; Burg, Elianne et al. (2014) The role of leptin in the development of pulmonary neutrophilia in infection and acute lung injury. Crit Care Med 42:e143-51
Hyatt, Lynnae D; Wasserman, Gregory A; Rah, Yoon J et al. (2014) Myeloid ZFP36L1 does not regulate inflammation or host defense in mouse models of acute bacterial infection. PLoS One 9:e109072
Mizgerd, Joseph P (2014) The infant nose. Introducing the respiratory tract to the world. Am J Respir Crit Care Med 190:1206-7
Yamamoto, Kazuko; Ahyi, Ayele-Nati N; Pepper-Cunningham, Zachary A et al. (2014) Roles of lung epithelium in neutrophil recruitment during pneumococcal pneumonia. Am J Respir Cell Mol Biol 50:253-62
Wilson, Andrew A; Kwok, Letty W; Porter, Emily L et al. (2013) Lentiviral delivery of RNAi for in vivo lineage-specific modulation of gene expression in mouse lung macrophages. Mol Ther 21:825-33

Showing the most recent 10 out of 32 publications