Evaluation of pilus vaccines for prevention of experimental otitis media caused by nontypable Haemophilus influenzae

Karasic, Raymond B.; Beste, David J.; To, Sam C. M.; Doyle, William J.; WOOD, SARAH W.; Carter, Melinda J.; TANPOWPONG, KUNCHITTHAPE; Bluestone, Charles D.; Brinton, Charles C.

doi:10.1097/00006454-198901001-00022

Cited by 26 publications

(23 citation statements)

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“…Croucher reported that rlrA was negatively associated with age in children providing ecologic support to selection against pilus expression as antibodies directed against the pilus components are acquired following repeated pneumococcal colonization [14] Karasic demonstrated that pilus negative strains of nontypable Haemophilus influenzae were virulent in an EOM chinchilla model and, similar to our observations, that pilus-expressing strains were selected against when animals were immunized with pilus protein [15]. Clinically, Moschioni et al reported that 30% of middle ear isolates contained the Pl-1 pilus island, consistent with its distribution among isolates from other sources [16].…”

Section: Discussionsupporting

confidence: 82%

Variation of Pneumococcal Pilus-1 Expression Results in Vaccine Escape during Experimental Otitis Media [EOM]

Figueira

Moschioni²,

Angelis³

et al. 2014

PLoS ONE

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The pneumococcal Pilus-1 enhances attachment to epithelial cells in the respiratory tract and subsequent invasion. Pilus-1 expression is bi-stable and positively regulated by the RlrA transcriptional regulator. To delineate the role of pilus-1 in Experimental Otitis Media (EOM), we evaluated colonization and disease due to a Streptococcus pneumoniae (SP) wild type strain (Taiwan19F-14 wt) and its otherwise isogenic pilus-1 and pilus-2 deficient mutant (Taiwan19F-14 ΔPI-1/PI-2-) as well as potential for a chimeric protein (RrgB321) vaccine candidate for prevention of middle ear (ME) disease.MethodsChinchillas were challenged intranasally with either Taiwan19F-14 wt or Taiwan19F-14PI-1/PI-2 deficient mutant. ME status was assessed and direct cultures performed. New cohorts of animals were immunized with RrgB321 or alum. Intranasal challenge with Taiwan19F-14 wt [erythromycin susceptible E(S)] was performed. Subsequently, a second cohort of animals was immunized and challenged with either Taiwan19F-14 wt or a Pilus-1 over-expressing mutant [Taiwan19F-14+pMU1328_Pc-rlrA mutant; E resistant (R)] strain. Pilus-1 expression was analyzed in SP isolated from nasopharynx (NP) and ME fluids by flow cytometry.ResultsCulture positive EOM developed following challenge with either wild type SP (Taiwan19F-14) or its pilus-1 deficient mutant. Culture positive EOM developed following challenge with wild type in both RrgB321 immunized and control animals. Pilus-1 expression in ME fluids was significantly higher in controls compared to immunized chinchillas. In second cohort of immunized and control animals challenged with the over-expressing Pilus-1 mutant, delayed development of EOM in the immunized animals was observed. Pneumococci recovered from ME fluid of immunized animals were no longer E(R) signifying the loss of the pMU1328_Pc-rlrA plasmid.ConclusionPneumococcal pilus-1 was not essential for EOM. Regulation of Pilus-1 expression in ME fluids in the presence of anti RrgB321 antibody was essential for survival of S. pneumoniae. Pneumococci have evolved mechanisms of regulation of non-essential surface proteins to evade host defenses.

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Section: Discussionsupporting

confidence: 82%

Variation of Pneumococcal Pilus-1 Expression Results in Vaccine Escape during Experimental Otitis Media [EOM]

Figueira

Moschioni²,

Angelis³

et al. 2014

PLoS ONE

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“…Consistent with the fact that type b strains occupy a limited number of clonal clusters, most type b strains express pili that belong to a single serotype (the LKP4 group). As an example, in the chinchilla model of otitis media, Karasic et al found that immunization with puri¢ed pili protected animals from challenge with the homologous piliated strain, but failed to protect from challenge with a heterologous piliated strain [80]. Although the major structural subunits from di¡erent strains show substantial similarity in amino acid sequence, antiserum raised against a particular piliated strain is usually not broadly reactive, indicating that immunodominant epitopes in the mature pilus structure are likely conformational and strain-speci¢c in nature [77,79].…”

Section: Hemagglutinating Pilimentioning

confidence: 99%

Molecular determinants of the pathogenesis of disease due to non-typable Haemophilus influenzae

Rao¹

1999

FEMS Microbiology Reviews

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Non-typable Haemophilus influenzae is a common commensal organism in the human upper respiratory tract and an important cause of localized respiratory tract disease. The pathogenesis of disease begins with bacterial colonization of the nasopharynx, a process that involves establishment on the mucosal surface and evasion of local immune mechanisms. Under the proper circumstances, the organism spreads contiguously to the middle ear, the sinuses, or the lungs, and then stimulates a brisk inflammatory response, producing symptomatic infection. In this review, we summarize our present understanding of the molecular determinants of this sequence of events. Continued investigation of the molecular mechanism of non-typable H. influenzae pathogenicity should facilitate development of novel approaches to the treatment and prevention of H. influenzae disease.

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“…However, it is also involved in many acute and chronic infections such as otitis media, asthma and chronic obstructive pulmonary disease (COPD) (Karasic et al, 1989; Berkovitch et al, 2002; Revai et al, 2008; Essilfie et al, 2011, 2012; Moghaddam et al, 2011). The occurrence of these infections is linked to the ability of H. influenzae to persist in different niches in the human body, including the lung, nasopharynx, and the middle ear.…”

Section: Introductionmentioning

confidence: 99%

Metabolic versatility in Haemophilus influenzae: a metabolomic and genomic analysis

et al. 2014

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Haemophilus influenzae is a host adapted human pathogen known to contribute to a variety of acute and chronic diseases of the upper and lower respiratory tract as well as the middle ear. At the sites of infection as well as during growth as a commensal the environmental conditions encountered by H. influenzae will vary significantly, especially in terms of oxygen availability, however, the mechanisms by which the bacteria can adapt their metabolism to cope with such changes have not been studied in detail. Using targeted metabolomics the spectrum of metabolites produced during growth of H. influenzae on glucose in RPMI-based medium was found to change from acetate as the main product during aerobic growth to formate as the major product during anaerobic growth. This change in end-product is likely caused by a switch in the major route of pyruvate degradation. Neither lactate nor succinate or fumarate were major products of H. influenzae growth under any condition studied. Gene expression studies and enzyme activity data revealed that despite an identical genetic makeup and very similar metabolite production profiles, H. influenzae strain Rd appeared to favor glucose degradation via the pentose phosphate pathway, while strain 2019, a clinical isolate, showed higher expression of enzymes involved in glycolysis. Components of the respiratory chain were most highly expressed during microaerophilic and anaerobic growth in both strains, but again clear differences existed in the expression of genes associated e.g., with NADH oxidation, nitrate and nitrite reduction in the two strains studied. Together our results indicate that H. influenzae uses a specialized type of metabolism that could be termed “respiration assisted fermentation” where the respiratory chain likely serves to alleviate redox imbalances caused by incomplete glucose oxidation, and at the same time provides a means of converting a variety of compounds including nitrite and nitrate that arise as part of the host defence mechanisms.

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Evaluation of pilus vaccines for prevention of experimental otitis media caused by nontypable Haemophilus influenzae

Cited by 26 publications

References 0 publications

Variation of Pneumococcal Pilus-1 Expression Results in Vaccine Escape during Experimental Otitis Media [EOM]

Variation of Pneumococcal Pilus-1 Expression Results in Vaccine Escape during Experimental Otitis Media [EOM]

Molecular determinants of the pathogenesis of disease due to non-typable Haemophilus influenzae

Metabolic versatility in Haemophilus influenzae: a metabolomic and genomic analysis

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