A small percentage of invasive H. influenzae disease is (and probably has been) due to nontypable (i.e. unencapsulated) strains. With increasing immunization of children with H. influenzae conjugate capsular vaccines, the relative proportion of invasive disease due to nontypable organisms has increased: in certain locales it is the majority, in others only its prevalence has increased. Because of the concern that such cases will continue to increase in prevalence (because of the selective pressure exerted by vaccination against type b strains), it is important to understand the mechanism(s) used by unencapsulated H. influenzae to invade and cause bacteremia (and bacteremia-associated diseases) in immunocompetent immunized children. Our preliminary data indicate that the virulence determinant is carried by a novel bacteriophage (HP2) and the bacterium to replicate in blood by evading the complement system. Complement is recognized to be important in host defense against invasive H. influenzae infections in humans. The gene responsible for virulence has been designated the Human Serum Resistance 1 (hsr1) gene, and has no homolog in the current databases. Lysogenic conversion of only certain nontypeable H. influenzae results in conversion to virulence suggesting that """"""""accessory"""""""" genes are necessary, for full expression of virulence. The proposed research seeks to define the additional gene(s) responsible for the unusual virulence properly, determine the prevalence of these virulence genes in a panel on invasive nontypeable H. influenzae, define the mechanisms by which HP2 mitigates complement activity, and identify the accessory genes needed for expression of this virulence trait using the avirulent laboratory strain H. influenzae Rd. KW20. Understanding this virulence mechanism, which is unusual for unencapsulated H. influenzae, will permit identification of new surface components, which are potential vaccinogens. Antigenic epitopes of the gene products operative in this mechanism can be used to produce a new H. influenzae conjugate vaccine active against invasive isolates.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI044002-05
Application #
6632171
Study Section
Special Emphasis Panel (ZRG1-BM-2 (02))
Program Officer
Klein, David L
Project Start
2000-04-01
Project End
2005-03-31
Budget Start
2003-04-01
Budget End
2004-03-31
Support Year
5
Fiscal Year
2003
Total Cost
$358,000
Indirect Cost
Name
Seattle Biomedical Research Institute
Department
Type
DUNS #
070967955
City
Seattle
State
WA
Country
United States
Zip Code
98109
Ren, Dabin; Nelson, Kevin L; Uchakin, Peter N et al. (2012) Characterization of extended co-culture of non-typeable Haemophilus influenzae with primary human respiratory tissues. Exp Biol Med (Maywood) 237:540-7
Nelson, Kevin Lee; Smith, Arnold Lee (2010) Determination of capsulation status in Haemophilus influenzae by multiplex polymerase chain reaction. Diagn Microbiol Infect Dis 66:235-40
Erwin, Alice L; Sandstedt, Sara A; Bonthuis, Paul J et al. (2008) Analysis of genetic relatedness of Haemophilus influenzae isolates by multilocus sequence typing. J Bacteriol 190:1473-83
Erwin, Alice L; Smith, Arnold L (2007) Nontypeable Haemophilus influenzae: understanding virulence and commensal behavior. Trends Microbiol 15:355-62
Ho, Derek K; Ram, Sanjay; Nelson, Kevin L et al. (2007) lgtC expression modulates resistance to C4b deposition on an invasive nontypeable Haemophilus influenzae. J Immunol 178:1002-12
Erwin, Alice L; Bonthuis, Paul J; Geelhood, Jennifer L et al. (2006) Heterogeneity in tandem octanucleotides within Haemophilus influenzae lipopolysaccharide biosynthetic gene losA affects serum resistance. Infect Immun 74:3408-14
Erwin, Alice L; Allen, Simon; Ho, Derek K et al. (2006) Role of lgtC in resistance of nontypeable Haemophilus influenzae strain R2866 to human serum. Infect Immun 74:6226-35
Bishop-Hurley, Sharon L; Schmidt, Francis J; Erwin, Alice L et al. (2005) Peptides selected for binding to a virulent strain of Haemophilus influenzae by phage display are bactericidal. Antimicrob Agents Chemother 49:2972-8
Green, Bruce A; Baranyi, Elizabeth; Reilly, Thomas J et al. (2005) Certain site-directed, nonenzymatically active mutants of the Haemophilus influenzae P4 lipoprotein are able to elicit bactericidal antibodies. Infect Immun 73:4454-7
Erwin, Alice L; Nelson, Kevin L; Mhlanga-Mutangadura, Tendai et al. (2005) Characterization of genetic and phenotypic diversity of invasive nontypeable Haemophilus influenzae. Infect Immun 73:5853-63

Showing the most recent 10 out of 25 publications