A Novel Zinc Binding System, ZevAB, Is Critical for Survival of Nontypeable Haemophilus influenzae in a Murine Lung Infection Model

Rosadini, Charles V.; Gawronski, Jeffrey D.; Raimunda, Daniel; Argüello, José M.; Akerley, Brian J.

doi:10.1128/iai.05135-11

Cited by 36 publications

(46 citation statements)

References 73 publications

(101 reference statements)

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“…By informatics-based approaches, outer membrane protein P5 was identified as a candidate DsbAdependent protein with a potential role in this phenotype (34,35). In this report, we show that P5 in both Rd and an NTHi strain are required for full serum resistance.…”

Section: Discussionmentioning

confidence: 70%

“…Bioinformatic identification of putative DsbA substrates revealed a subset with potential roles in complement resistance (35); the outer membrane protein P5 was selected from this list as a candidate because it is ϳ50% identical to Escherichia coli outer membrane protein A (OmpA) (36), a factor previously shown to be important for complement resistance in E. coli (37)(38)(39). NTHi P5, a ␤-barrel protein with eight predicted transmembrane spans, four outer surface loops (40), and a predicted disulfide between C323 and C335, was shown to be required for virulence in a chinchilla ear infection model (41) and has also been implicated in adhesion of H. influenzae to various mucosal surface structures (42)(43)(44)(45)(46).…”

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confidence: 99%

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Outer Membrane Protein P5 Is Required for Resistance of Nontypeable Haemophilus influenzae to Both the Classical and Alternative Complement Pathways

2014

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The complement system is an important first line of defense against the human pathogen Haemophilus influenzae. To survive and propagate in vivo, H. influenzae has evolved mechanisms for subverting this host defense, most of which have been shown to involve outer surface structures, including lipooligosaccharide glycans and outer surface proteins. Bacterial defense against complement acts at multiple steps in the pathway by mechanisms that are not fully understood. Here we identify outer membrane protein P5 as an essential factor in serum resistance of both H. influenzae strain Rd and nontypeable H. influenzae (NTHi) clinical isolate NT127. P5 was essential for resistance of Rd and NT127 to complement in pooled human serum. Further investigation determined that P5 expression decreased cell surface binding of IgM, a potent activator of the classical pathway of complement, to both Rd and NT127. Additionally, P5 expression was required for NT127 to bind factor H (fH), an important inhibitor of alternative pathway (AP) activation. Collectively, the results obtained in this work highlight the ability of H. influenzae to utilize a single protein to perform multiple protective functions for evading host immunity.

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Section: Discussionmentioning

confidence: 70%

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confidence: 99%

Outer Membrane Protein P5 Is Required for Resistance of Nontypeable Haemophilus influenzae to Both the Classical and Alternative Complement Pathways

2014

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“…NTHi persistence on a mouse infection model has been previously assessed by intratracheal or intranasal inoculation of pathogenic strains and mutant derivatives, or of mutant derivatives of the nonpathogenic strain H. influenzae Rd KW20 (25,(54)(55)(56)(57). To assess the relative roles of LOS moieties in NTHi persistence and/or clearance within mice, we carried out intranasal infection of CD1 mice with NTHi 375 wild-type and mutant strains.…”

Section: Los Sugar Extension On Hep I Is Important To Nthi Infection mentioning

confidence: 99%

Relative Contributions of Lipooligosaccharide Inner and Outer Core Modifications to Nontypeable Haemophilus influenzae Pathogenesis

et al. 2013

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e Nontypeable Haemophilus influenzae (NTHi) is a frequent commensal of the human nasopharynx that causes opportunistic infection in immunocompromised individuals. Existing evidence associates lipooligosaccharide (LOS) with disease, but the specific and relative contributions of NTHi LOS modifications to virulence properties of the bacterium have not been comprehensively addressed. Using NTHi strain 375, an isolate for which the detailed LOS structure has been determined, we compared systematically a set of isogenic mutant strains expressing sequentially truncated LOS. The relative contributions of 2-keto-3-deoxyoctulosonic acid, the triheptose inner core, oligosaccharide extensions on heptoses I and III, phosphorylcholine, digalactose, and sialic acid to NTHi resistance to antimicrobial peptides (AMP), self-aggregation, biofilm formation, cultured human respiratory epithelial infection, and murine pulmonary infection were assessed. We show that opsX, lgtF, lpsA, lic1, and lic2A contribute to bacterial resistance to AMP; lic1 is related to NTHi self-aggregation; lgtF, lic1, and siaB are involved in biofilm growth; opsX and lgtF participate in epithelial infection; and opsX, lgtF, and lpsA contribute to lung infection. Depending on the phenotype, the involvement of these LOS modifications occurs at different extents, independently or having an additive effect in combination. We discuss the relative contribution of LOS epitopes to NTHi virulence and frame a range of pathogenic traits in the context of infection.

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“…Recently, a second zinc uptake system (ZevAB) was identified in nontypeable Haemophilus influenzae in addition to the ZnuABC system (28). In this case the Zev system was shown to be important for growth in the lungs (28). The important role of zinc in the onset of the host innate response would suggest that the battle for zinc availability between the pathogen and the host during the early stages of an infection will have implications in deciding the outcome of the pathogenhost interaction.…”

Section: Figmentioning

confidence: 99%

“…To our knowledge, the presence of two specific zinc uptake systems is rare in bacteria. Recently, a second zinc uptake system (ZevAB) was identified in nontypeable Haemophilus influenzae in addition to the ZnuABC system (28). In this case the Zev system was shown to be important for growth in the lungs (28).…”

Section: Figmentioning

confidence: 99%

Two Zinc Uptake Systems Contribute to the Full Virulence of Listeria monocytogenes during Growth In Vitro and In Vivo

et al. 2012

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We report here the identification and characterization of two zinc uptake systems, ZurAM and ZinABC, in the intracellular pathogen Listeria monocytogenes. Transcription of both operons was zinc responsive and regulated by the zinc-sensing repressor Zur. Deletion of either zurAM or zinA had no detectable effect on growth in defined media, but a double zurAM zinA mutant was unable to grow in the absence of zinc supplementation. Deletion of zinA had no detectable effect on intracellular growth in HeLa epithelial cells. In contrast, growth of the zurAM mutant was significantly impaired in these cells, indicating the importance of the ZurAM system during intracellular growth. Notably, the deletion of both zinA and zurAM severely attenuated intracellular growth, with the double mutant being defective in actin-based motility and unable to spread from cell to cell. Deletion of either zurAM or zinA had a significant effect on virulence in an oral mouse model, indicating that both zinc uptake systems are important in vivo and establishing the importance of zinc acquisition during infection by L. monocytogenes. The presence of two zinc uptake systems may offer a mechanism by which L. monocytogenes can respond to zinc deficiency within a variety of environments and during different stages of infection, with each system making distinct contributions under different stress conditions.

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A Novel Zinc Binding System, ZevAB, Is Critical for Survival of Nontypeable Haemophilus influenzae in a Murine Lung Infection Model

Cited by 36 publications

References 73 publications

Outer Membrane Protein P5 Is Required for Resistance of Nontypeable Haemophilus influenzae to Both the Classical and Alternative Complement Pathways

Outer Membrane Protein P5 Is Required for Resistance of Nontypeable Haemophilus influenzae to Both the Classical and Alternative Complement Pathways

Relative Contributions of Lipooligosaccharide Inner and Outer Core Modifications to Nontypeable Haemophilus influenzae Pathogenesis

Two Zinc Uptake Systems Contribute to the Full Virulence of Listeria monocytogenes during Growth In Vitro and In Vivo

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