Developing a nontypeable Haemophilus influenzae (NTHi) vaccine

Poolman, J. T.; Bakaletz, Lauren O.; Cripps, Allan W.; Denoël, Philippe; Forsgren, Arne; Kyd, Jennelle M.; Lobet, Yves

doi:10.1016/s0264-410x(00)00288-7

Cited by 104 publications

(80 citation statements)

References 46 publications

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“…P1 (35-50 kDa) P2 (40 kDa), P4 (28 kDa), P5 (27)(28)(29)(30)(31)(32)(33)(34)(35), and protein D (42 kDa) are all OMPs of H. influenzae that has approximately the corresponding size to the ligands found in the Far Western blot and may be suggested as possible FH-binding ligands (62). P2 is the most abundant protein in the outer membrane, it is highly immunogenic, and the variability allows the bacteria to evade protective Abs (63). P2 and P5 have adhesive capacity, and protein D has been shown to be involved in the infection process; therefore, all these proteins are important virulence factors of H. influenzae (64).…”

Section: Discussionmentioning

confidence: 99%

Haemophilus influenzae Interacts with the Human Complement Inhibitor Factor H

Hallström

Zipfel

Blom

et al. 2008

The Journal of Immunology

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Pathogenic microbes acquire human complement inhibitors to circumvent the innate immune system. In this study, we identify two novel host-pathogen interactions, factor H (FH) and factor H-like protein 1 (FHL-1), the inhibitors of the alternative pathway that binds to Hib. A collection of clinical Haemophilus influenzae isolates was tested and the majority of encapsulated and unencapsulated bound FH. The isolate Hib 541 with a particularly high FH-binding was selected for detailed analysis. An increased survival in normal human serum was observed with Hib 541 as compared with the low FH-binding Hib 568. Interestingly, two binding domains were identified within FH; one binding site common to both FH and FHL-1 was located in the N-terminal short consensus repeat domains 6–7, whereas the other, specific for FH, was located in the C-terminal short consensus repeat domains 18–20. Importantly, both FH and FHL-1, when bound to the surface of Hib 541, retained cofactor activity as determined by analysis of C3b degradation. Two H. influenzae outer membrane proteins of ∼32 and 40 kDa were detected with radiolabeled FH in Far Western blot. Taken together, in addition to interactions with the classical, lectin, and terminal pathways, H. influenzae interferes with the alternative complement activation pathway by binding FH and FHL-1, and thereby reducing the complement-mediated bactericidal activity resulting in an increased survival. In contrast to incubation with active complement, H. influenzae had a reduced survival in FH-depleted human serum, thus demonstrating that FH mediates a protective role at the bacterial surface.

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Section: Discussionmentioning

confidence: 99%

Haemophilus influenzae Interacts with the Human Complement Inhibitor Factor H

Hallström

Zipfel

Blom

et al. 2008

The Journal of Immunology

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“…This is a widely accepted model of noninvasive disease caused by H. influenzae (1,24,56). An isogenic mutant strain from which the set of three hgp genes had been deleted exhibited a significant reduction in virulence compared to its wild-type progenitor.…”

Section: Discussionmentioning

confidence: 99%

“…At any given time, the majority of healthy adults and children over 5 years of age harbor this microorganism as a commensal in the nasopharynx (17,64). H. influenzae is a frequent cause of noninvasive disease, including respiratory infections (48,64) and otitis media (4,56,64). Infection by H. influenzae also produces invasive disease, including epiglottitis, pneumonia, bacteremia, meningitis (54,64), and occasionally endophthalmitis, leading to blindness (2).…”

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confidence: 99%

“…Of the six biochemically and antigenically distinct capsular types (a to f), serotype b strains accounted for the vast majority of bacteremia and meningitis cases prior to the introduction of vaccines based on the type b capsule (54). While such vaccines have nearly eradicated meningitis caused by type b strains in the developed world (54,67), they lack effectiveness against other capsular types (3, 58) and against nontypeable strains (47,56). The identification of outer membrane proteins with indispensable functions in vivo could provide new potential targets for development of a vaccine with a broader range of efficacy against H. influenzae infections.…”

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confidence: 99%

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Complex Role of Hemoglobin and Hemoglobin-Haptoglobin Binding Proteins in Haemophilus influenzae Virulence in the Infant Rat Model of Invasive Infection

Seale¹,

Morton²,

Whitby³

et al. 2006

Infect Immun

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Haemophilus influenzae requires an exogenous heme source for aerobic growth in vitro. Hemoglobin or hemoglobin-haptoglobin satisfies this requirement. Heme acquisition from hemoglobin-haptoglobin is mediated by proteins encoded by hgp genes. Both Hgps and additional proteins, including those encoded by the hxu operon, provide independent pathways for hemoglobin utilization. Recently we showed that deletion of the set of three hgp genes from a nontypeable strain (86-028NP) of H. influenzae attenuated virulence in the chinchilla otitis media model of noninvasive disease. The present study was undertaken to investigate the role of the hgp genes in virulence of the wild-type serotype b clinical isolate HI689 in the infant rat model of hematogenous meningitis, an established model of invasive disease requiring aerobic growth. Bacteremia of high titer and long duration (>14 days) and histopathologically confirmed meningitis occurred in >95% of infant rats challenged at 5 days of age with strain HI689. While mutations disrupting either the Hgp-or Hxu-mediated pathway of heme acquisition had no effect on virulence in infant rats, an isogenic mutant deficient for both pathways was unable to sustain bacteremia or produce meningitis. In contrast, mutations disrupting either pathway decreased the limited ability of H. influenzae to initiate and sustain bacteremia in weanling rats. Biochemical and growth studies also indicated that infant rat plasma contains multiple heme sources that change with age. Taken together, these data indicate that both the hgp genes and the hxuC gene are virulence determinants in the rat model of human invasive disease.

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“…The encapsulated H. influenzae serotype b (Hib) usually causes invasive infections, such as meningitis and septicemia (2), whereas the much more common nonencapsulated, or nontypeable, H. influenzae (NTHi) is a major cause of otitis media, sinusitis, and pneumonia (8). General vaccination against Hib has reduced the incidence of Hib infection to a near minimum (10), while attempts to construct a vaccine against the costly NTHi infections have as yet been unsuccessful due to a high genetic heterogeneity among NTHi strains (20). An extensively studied virulence factor and potential vaccine candidate in H. influenzae is protein D, a 42-kDa conserved lipoprotein expressed on the bacterial surface (1,13,21,24).…”

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confidence: 99%

Differencesin Genetic and Transcriptional Organization of theglpTQOperons betweenHaemophilus influenzaeType b andNontypeableStrains

Song

Janson

2003

J Bacteriol

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The glpTQ operon of Haemophilus influenzae type b (Hib) and nontypeable H. influenzae (NTHi) strains is highly conserved, except for a 1.4-kb glpTQ intergenic region that was found in most Hib strains. The presence of this intergenic region results in divergent glpTQ transcriptional profiles for Hib and NTHi where Hib strains appear to have evolved an alternative promoter for glpQ expression. Based on the intergenic region's low G؉C content, we speculate that this DNA fragment was acquired by lateral transfer.Haemophilus influenzae is a common pathogen, especially among children, but the clinical manifestations are largely type specific. The encapsulated H. influenzae serotype b (Hib) usually causes invasive infections, such as meningitis and septicemia (2), whereas the much more common nonencapsulated, or nontypeable, H. influenzae (NTHi) is a major cause of otitis media, sinusitis, and pneumonia (8). General vaccination against Hib has reduced the incidence of Hib infection to a near minimum (10), while attempts to construct a vaccine against the costly NTHi infections have as yet been unsuccessful due to a high genetic heterogeneity among NTHi strains (20). An extensively studied virulence factor and potential vaccine candidate in H. influenzae is protein D, a 42-kDa conserved lipoprotein expressed on the bacterial surface (1,13,21,24). An isogenic protein D-negative mutant has been shown to be less effective than its wild-type parental strain in its ability to (i) cause experimental otitis media in rats (14), (ii) cause damage to ciliated human respiratory epithelium (15), and (iii) promote internalization into human monocytic cells (17). The mechanism behind the virulence properties of protein D is unknown but may involve choline decoration of H. influenzae lipooligosaccharides (LOS), since protein D expression allows H. influenzae to obtain choline from cocultured host cells and subsequently incorporate this molecule into its LOS (6).The ability of protein D to promote the incorporation of choline into LOS comes from its glycerophosphodiester phosphodiesterase activity, catalyzing the hydrolysis of glycerophosphodiesters into glycerol-3-phosphate (G3P) and an alcohol (14, 18). The gene encoding protein D (hpd) is homologous to glpQ of Escherichia coli (16) and other bacteria. The glpQ gene belongs to the glp regulon that is involved in the utilization of glycerol and of G3P and its precursors as energy sources and to supply precursors for phospholipid biosynthesis. In E. coli and Bacillus subtilis (19), glpQ is transcribed together with glpT, which is located upstream of glpQ and encodes a G3P permease that acts as a G3P-inorganic phosphate antiporter (5). The E. coli glpTQ operon is induced by G3P and repressed by the catabolic repressor glucose as well as a glp-specific repressor protein, GlpR (28). Available restriction fragment length polymorphism (RFLP) data and DNA sequences of the glpTQ region of H. influenzae suggest that its organization differs between strains (7,13,24,25). RFLP analysis based on...

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Developing a nontypeable Haemophilus influenzae (NTHi) vaccine

Cited by 104 publications

References 46 publications

Haemophilus influenzae Interacts with the Human Complement Inhibitor Factor H

Haemophilus influenzae Interacts with the Human Complement Inhibitor Factor H

Complex Role of Hemoglobin and Hemoglobin-Haptoglobin Binding Proteins in Haemophilus influenzae Virulence in the Infant Rat Model of Invasive Infection

Differencesin Genetic and Transcriptional Organization of theglpTQOperons betweenHaemophilus influenzaeType b andNontypeableStrains

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