Streptococcus pneumoniae is a common invasive mucosal pathogen. Local and systemic manifestations range from asymptomatic colonization, to sinusitis and otitis media, to community-acquired pneumonia, bacteremia, and meningitis, resulting in up to 40,0000 deaths/year in the US alone. The local host and bacterial factors that determine whether S. pneumoniae causes no disease, mucosal disease, or invasive disease are not well-characterized. We propose to characterize the mechanisms of control of pneumococcal infections operative at the initial steps in their pathogenesis from nasopharyngeal colonization to aspiration into upper respiratory mucosae and alveoli, prior to alveolar injury and invasion into tissue and blood. We have shown that IgA reactive with pneumococcal capsular polysaccharide (PPS) mediates killing by neutrophils by both complement-dependent and -independent conditions. IgA and IgG may both contribute to defense of the lower respiratory tract by initiating killing by macrophages and neutrophils and by inhibiting adherence to epithelial cells. We will characterize the molecular and biochemical features of PPS-specific Ig which determine their functional role, their effective interactions with local phagocytic cells, as well as the adaptive mechanisms of the organism which may subvert these protective mechanisms. Hypotheses: (1) Molecular and biochemical characteristics of capsule-specific IgA and IgG (e.g., mutation rates of immunoglobulin genes (VH), momeric, polymeric, and secretory structure of IgA, avidity, and pattern of IgA glycosylation) determine their functional efficiency to inhibit adherence and mediate killing by phagocytes. (2) Bacterial virulence factors (e.g., IgA1 protease, choline-binding protein A, and phase variation) subvert the ability of PPS-specific IgA to control S. pneumoniae. (3) The local host environment (e.g., complement, C-reactive protein) determines the phagocytes' ability of IgA and IgG to initiate killing of S. pneumoniae. The specific objectives of this proposal are designed to illuminate the unique features of the local host-pathogen interaction and defense against these extremely common and serious mucosal infections with S. pneumoniae in children and adults.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI048796-04
Application #
6699652
Study Section
Special Emphasis Panel (ZRG1-MBC-2 (01))
Program Officer
Klein, David L
Project Start
2001-03-01
Project End
2006-02-28
Budget Start
2004-03-01
Budget End
2005-02-28
Support Year
4
Fiscal Year
2004
Total Cost
$252,000
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
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Kunisaki, Ken M; Rice, Kathryn L; Janoff, Edward N et al. (2008) Exhaled nitric oxide, systemic inflammation, and the spirometric response to inhaled fluticasone propionate in severe chronic obstructive pulmonary disease: a prospective study. Ther Adv Respir Dis 2:55-64
Jackson, Lisa A; Janoff, Edward N (2008) Pneumococcal vaccination of elderly adults: new paradigms for protection. Clin Infect Dis 47:1328-38
Mantis, Nicholas J; Palaia, Jana; Hessell, Ann J et al. (2007) Inhibition of HIV-1 infectivity and epithelial cell transfer by human monoclonal IgG and IgA antibodies carrying the b12 V region. J Immunol 179:3144-52
Boulware, David R; Daley, Charles L; Merrifield, Cynthia et al. (2007) Rapid diagnosis of pneumococcal pneumonia among HIV-infected adults with urine antigen detection. J Infect 55:300-9
Nguyen, John T; Myers, Nicollette; Palaia, Jana et al. (2007) Humoral responses to oxidized low-density lipoprotein and related bacterial antigens after pneumococcal vaccine. Transl Res 150:172-9
Fasching, Claudine E; Grossman, Tracy; Corthesy, Blaise et al. (2007) Impact of the molecular form of immunoglobulin A on functional activity in defense against Streptococcus pneumoniae. Infect Immun 75:1801-10
Gordon, Stephen B; Janoff, Edward N; Sloper, Dan et al. (2005) HIV-1 infection is associated with altered innate pulmonary immunity. J Infect Dis 192:1412-6
Jarvis, Gary A; Janoff, Edward N; Cheng, Hui et al. (2005) Human T lymphotropic virus type II infection and humoral responses to pneumococcal polysaccharide and tetanus toxoid vaccines. J Infect Dis 191:1239-44
King, Samantha J; Hippe, Karen R; Gould, Jane M et al. (2004) Phase variable desialylation of host proteins that bind to Streptococcus pneumoniae in vivo and protect the airway. Mol Microbiol 54:159-71

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