Lipoprotein e (P4) of Haemophilus influenzae: role in heme utilization and pathogenesis

Morton, Daniel J.; Smith, Ann; VanWagoner, Timothy M.; Seale, Thomas W.; Whitby, Paul W.; Stull, Terrence L.

doi:10.1016/j.micinf.2007.03.013

Cited by 22 publications

(21 citation statements)

References 27 publications

(48 reference statements)

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“…Type IV pili are important for nasopharyngeal colonization and in vivo growth of H. influenzae [30], [35]. Since pilA is important for early biofilm formation, mono- and co-culture biofilms were grown for 4h and 24h and relative gene expression was calculated.…”

Section: Resultsmentioning

confidence: 99%

Regulation of Virulence Gene Expression Resulting from Streptococcus pneumoniae and Nontypeable Haemophilus influenzae Interactions in Chronic Disease

et al. 2011

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Chronic rhinosinusitis (CRS) is a common inflammatory disease of the sinonasal cavity mediated, in part, by polymicrobial communities of bacteria. Recent molecular studies have confirmed the importance of Streptococcus pneumoniae and nontypeable Haemophilus influenzae (NTHi) in CRS. Here, we hypothesize that interaction between S. pneumoniae and NTHi mixed-species communities cause a change in bacterial virulence gene expression. We examined CRS as a model human disease to validate these polymicrobial interactions. Clinical strains of S. pneumoniae and NTHi were grown in mono- and co-culture in a standard biofilm assay. Reverse transcriptase real-time PCR (RTqPCR) was used to measure gene expression of key virulence factors. To validate these results, we investigated the presence of the bacterial RNA transcripts in excised human tissue from patients with CRS. Consequences of physical or chemical interactions between microbes were also investigated. Transcription of NTHi type IV pili was only expressed in co-culture in vitro, and expression could be detected ex vivo in diseased tissue. S. pneumoniae pyruvate oxidase was up-regulated in co-culture, while pneumolysin and pneumococcal adherence factor A were down-regulated. These results were confirmed in excised human CRS tissue. Gene expression was differentially regulated by physical contact and secreted factors. Overall, these data suggest that interactions between H. influenzae and S. pneumoniae involve physical and chemical mechanisms that influence virulence gene expression of mixed-species biofilm communities present in chronically diseased human tissue. These results extend previous studies of population-level virulence and provide novel insight into the importance of S. pneumoniae and NTHi in CRS.

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Section: Resultsmentioning

confidence: 99%

Regulation of Virulence Gene Expression Resulting from Streptococcus pneumoniae and Nontypeable Haemophilus influenzae Interactions in Chronic Disease

et al. 2011

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“…In H. influenzae , lipoprotein E is essential for hemin uptake and the utilization of Nicotinamide adenine dinucleotide [45], [88], [89]. As A. pleuropneumoniae biotype-1 is also dependent on exogenous sources of Nicotinamide adenine dinucleotide for growth [90], lipoprotein E could also be relevant for the pathogenesis of this bacterium.…”

Section: Discussionmentioning

confidence: 99%

Transcriptional Portrait of Actinobacillus pleuropneumoniae during Acute Disease - Potential Strategies for Survival and Persistence in the Host

et al. 2012

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BackgroundGene expression profiles of bacteria in their natural hosts can provide novel insight into the host-pathogen interactions and molecular determinants of bacterial infections. In the present study, the transcriptional profile of the porcine lung pathogen Actinobacillus pleuropneumoniae was monitored during the acute phase of infection in its natural host.Methodology/Principal FindingsBacterial expression profiles of A. pleuropneumoniae isolated from lung lesions of 25 infected pigs were compared in samples taken 6, 12, 24 and 48 hours post experimental challenge. Within 6 hours, focal, fibrino hemorrhagic lesions could be observed in the pig lungs, indicating that A. pleuropneumoniae had managed to establish itself successfully in the host. We identified 237 differentially regulated genes likely to encode functions required by the bacteria for colonization and survival in the host. This group was dominated by genes involved in various aspects of energy metabolism, especially anaerobic respiration and carbohydrate metabolism. Remodeling of the bacterial envelope and modifications of posttranslational processing of proteins also appeared to be of importance during early infection. The results suggested that A. pleuropneumoniae is using various strategies to increase its fitness, such as applying Na+ pumps as an alternative way of gaining energy. Furthermore, the transcriptional data provided potential clues as to how A. pleuropneumoniae is able to circumvent host immune factors and survive within the hostile environment of host macrophages. This persistence within macrophages may be related to urease activity, mobilization of various stress responses and active evasion of the host defenses by cell surface sialylation.Conclusions/SignificanceThe data presented here highlight the importance of metabolic adjustments to host conditions as virulence factors of infecting microorganisms and help to provide insight into the mechanisms behind the efficient colonization and persistence of A. pleuropneumoniae during acute disease.

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“…In this study, we demonstrated that dsbA is required for H. influenzae bacteremia caused by both unencapsulated strain Rd and a virulent encapsulated type b strain. Heme uptake is required for aerobic growth of H. influenzae, which cannot synthesize the porphyrin ring (24,70), and several heme utilization pathways have been implicated in bloodstream infection by H. influenzae (47,61). We demonstrate that the heme transport protein, HbpA, contains a DsbA-dependent disulfide bond.…”

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confidence: 84%

The Periplasmic Disulfide Oxidoreductase DsbA Contributes to Haemophilus influenzae Pathogenesis

2008

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Haemophilus influenzae is an obligate human pathogen that persistently colonizes the nasopharynx and causes disease when it invades the bloodstream, lungs, or middle ear. Proteins that mediate critical interactions with the host during invasive disease are likely to be secreted. Many secreted proteins require addition of disulfide bonds by the DsbA disulfide oxidoreductase for activity or stability. In this study, we evaluated the role in H. influenzae pathogenesis of DsbA, as well as HbpA, a substrate of DsbA. Mutants of H. influenzae Rd and type b strain Eagan having nonpolar deletions of dsbA were attenuated for bacteremia in animal models, and complemented strains exhibited virulence equivalent to that of the parental strains. Comparison of predicted secreted proteins in H. influenzae to known DsbA substrates in other species revealed several proteins that could contribute to the role of dsbA in virulence. One candidate, the heme transport protein, HbpA, was examined because of the importance of exogenous heme for aerobic growth of H. influenzae. The presence of a dsbA-dependent disulfide bond in HbpA was verified by an alkylation protection assay, and HbpA was less abundant in a dsbA mutant. The hbpA mutant exhibited reduced bacteremia in the mouse model, and complementation restored its in vivo phenotype to that of the parental strain. These results indicate that dsbA is required in vivo and that HbpA and additional DsbA-dependent factors are likely to participate in H. influenzae pathogenesis.Haemophilus influenzae efficiently colonizes the human nasopharyngeal mucosa in a primarily asymptomatic manner, and the carriage frequency is ϳ80% in healthy adults (48). However, it can disseminate to other anatomical sites and cause otitis media, upper and lower respiratory tract infections, septicemia, and meningitis in children (13,22,37,44,(48)(49)(50)63). The incidence of H. influenzae meningitis has dramatically declined in populations immunized with a vaccine against the type b capsular polysaccharide. The vaccine has not affected the incidence of infection with nontypeable H. influenzae (NTHi) strains, which lack the capsule. NTHi strains predominantly cause respiratory tract infections and otitis media but in rare cases can invade the bloodstream, leading to meningitis. This disease profile raises the possibility that genes promoting intravascular invasion could be present in NTHi strains (15,18,53,54). However, the molecular basis for the invasive properties of H. influenzae that promote transmission from the nasopharynx to the bloodstream or middle ear is not fully understood.Secreted bacterial proteins mediate critical aspects of pathogenesis, including attachment, nutrient utilization, and subversion of host defenses. Many secreted proteins of gram-negative bacteria acquire disulfide bonds in the periplasm that stabilize their mature, folded structures (9). Formation of such linkages has been most extensively studied in Escherichia coli, in which a series of disulfide oxidoreductases (Dsb) create and e...

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Lipoprotein e (P4) of Haemophilus influenzae: role in heme utilization and pathogenesis

Cited by 22 publications

References 27 publications

Regulation of Virulence Gene Expression Resulting from Streptococcus pneumoniae and Nontypeable Haemophilus influenzae Interactions in Chronic Disease

Regulation of Virulence Gene Expression Resulting from Streptococcus pneumoniae and Nontypeable Haemophilus influenzae Interactions in Chronic Disease

Transcriptional Portrait of Actinobacillus pleuropneumoniae during Acute Disease - Potential Strategies for Survival and Persistence in the Host

The Periplasmic Disulfide Oxidoreductase DsbA Contributes to Haemophilus influenzae Pathogenesis

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