Role of
            <i>lgtC</i>
            in Resistance of Nontypeable
            <i>Haemophilus influenzae</i>
            Strain R2866 to Human Serum

Erwin, Alice L.; Allen, Simon; Ho, Derek K.; Bonthuis, Paul J.; Jarisch, Justin; Nelson, Kevin L.; Tsao, David L.; Unrath, William C.; Watson, Michael; Gibson, Bradford W.; Apicella, Michael A.; Smith, Arnold L.

doi:10.1128/iai.01699-06

Cited by 12 publications

(21 citation statements)

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“…Serum resistance of an encapsulated strain is imparted largely by the presence of the polysaccharide capsule (Moxon & Kroll, 1988), as evidenced by the serum resistance of a bexA 2 and phenotypically unencapsulated strain Eagan with an IC 50 value of 1.20 % (K. L. Nelson and A. L. Smith, unpublished data). In an invasive unencapsulated strain, such as R2866 (INT-1), serum resistance results from phase-variable expression of the lgtC-mediated aGal1-4bGal epitope, which mimics the p K blood group, with the resulting phase variant not being recognized as foreign (Weiser & Pan, 1998;Erwin et al, 2006a). The lic2B and lic2C LOS biosynthetic genes flanked by the infA and ksgA genes are associated with a serum-resistance phenotype in a serotype b strain (High et al, 1996;Hood et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Adhesin genes and serum resistance in Haemophilus influenzae type f isolates

Watson

Nelson

Nguyen

et al. 2013

Journal of Medical Microbiology

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The incidence of invasive infections due to Haemophilus influenzae has decreased significantly in developed countries with high rates of vaccination against H. influenzae serotype b (Hib). This vaccine provides no protection against H. influenzae serotype f (Hif), typically associated with invasive infections in adults with chronic disease and/or immunodeficiency, and rarely in otherwise healthy adults and children. The specific properties of Hif associated with virulence remain largely uncharacterized. A panel of 26 Hif strains consisting of both invasive disease-associated and mucosal surface non-invasive disease-associated isolates was surveyed by DNA fingerprinting, biotyping and PCR detection of hmw1, hmw2, hsf, the hif fimbrial locus and the lipooligosaccharide (LOS) biosynthetic island, and assessment of b-lactamase expression and determination of resistance to the bactericidal activity of normal adult human serum. Repetitive sequence-based PCR fingerprinting differentiated the 26 strains into three clusters, with the majority of isolates (22/26, 84.6 %) clustered into a single indistinguishable group. Most isolates (24/26, 92.3 %) were of biotype I and two isolates produced b-lactamase with detection of a conjugative plasmid, and the isolates displayed a range of resistances to the bactericidal activity of human serum. All 26 isolates carried the adhesin hsf, 21 carried a partial hif fimbrial operon and 4 had the adhesin genes hmw1/2. A LOS biosynthetic island was detected in 20 isolates consisting of the genes lic2BC. It was concluded that Hif has many recognized virulence properties and comprises a relatively homogeneous group independent of the anatomical source from which it was isolated. INTRODUCTIONHaemophilus influenzae, a human-restricted Gram-negative coccobacillus, is a commensal of the upper respiratory mucosa and a pathogen commonly causing airway mucosal disease and occasional invasive disease. Since Margaret Pittman's original description of capsular serotypes among H. influenzae isolates in 1931 (Pittman, 1931), H. influenzae serotype b (Hib) had been the most clinically significant strain causing invasive disease (e.g. meningitis, epiglottitis, septicaemia and osteomyelitis) in previously well infants and children (Aubrey & Tang, 2003). Since the early 1990s, routine administration of the Hib conjugate vaccines (which induce protective levels of anti-capsular antibody) has virtually eliminated Hib disease among infants and young children in developed countries (Agrawal & Murphy, 2011;Ladhani, 2012). However, the vaccine provides no protection from infection due to nonb serotypes, including H. influenzae serotype f (Hif), which remains a rare but significant cause of invasive infection. Given the reduction in Hib carriage among Hib conjugate vaccine recipients, concern exists as to whether invasive disease due to Hif or other non-b encapsulated strains will become more prevalent due to serotype replacement Abbreviations: BLNAR, b-lactamase-negative ampicillin-resistant; CSF, cerebrospinal ...

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Section: Discussionmentioning

confidence: 99%

Adhesin genes and serum resistance in Haemophilus influenzae type f isolates

Watson

Nelson

Nguyen

et al. 2013

Journal of Medical Microbiology

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“…1A) [18]. In pathogenic Gram-negative bacteria such as Neisseria and Haemophilus, LgtC is required for the biosynthesis of the terminal digalactoside epitope -D-Galp-(1,4)--DGalp in the lipooligosaccharide (LOS) structures of the outer core of the cell envelope [19]. LgtC expression has been associated with high-level serum resistance in nontypeable Haemophilus influenzae (NTHi) [19], and inhibition of LgtC and related GTs that are involved in LOS biosynthesis has been suggested as a strategy for antimicrobial drug discovery [18].…”

Section: Introductionmentioning

confidence: 99%

“…In pathogenic Gram-negative bacteria such as Neisseria and Haemophilus, LgtC is required for the biosynthesis of the terminal digalactoside epitope -D-Galp-(1,4)--DGalp in the lipooligosaccharide (LOS) structures of the outer core of the cell envelope [19]. LgtC expression has been associated with high-level serum resistance in nontypeable Haemophilus influenzae (NTHi) [19], and inhibition of LgtC and related GTs that are involved in LOS biosynthesis has been suggested as a strategy for antimicrobial drug discovery [18]. LgtC is an excellent starting point for such an approach not only because of its role in bacterial virulence, but also because of its structural and mechanistic communalities with other bacterial GTs [18], which have made it a widely used model system for mechanistic and structural studies in this enzyme family.…”

Section: Introductionmentioning

confidence: 99%

Covalent inhibitors of LgtC: A blueprint for the discovery of non-substrate-like inhibitors for bacterial glycosyltransferases

Smith

Vivoli

et al. 2017

Bioorganic & Medicinal Chemistry

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. Covalent inhibitors of LgtC: a blueprint for the discovery of non-substrate-like inhibitors for bacterial glycosyltransferases. Bioorganic and Medicinal Chemistry, 25(12), 3182-3194. https://doi.org/10.1016/j.bmc.2017.04.006Citing this paper Please note that where the full-text provided on King's Research Portal is the Author Accepted Manuscript or Post-Print version this may differ from the final Published version. If citing, it is advised that you check and use the publisher's definitive version for pagination, volume/issue, and date of publication details. And where the final published version is provided on the Research Portal, if citing you are again advised to check the publisher's website for any subsequent corrections. General rightsCopyright and moral rights for the publications made accessible in the Research Portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognize and abide by the legal requirements associated with these rights.•Users may download and print one copy of any publication from the Research Portal for the purpose of private study or research.•You may not further distribute the material or use it for any profit-making activity or commercial gain •You may freely distribute the URL identifying the publication in the Research Portal Take down policyIf you believe that this document breaches copyright please contact librarypure@kcl.ac.uk providing details, and we will remove access to the work immediately and investigate your claim. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.-1 - data reveals that non-catalytic cysteines are a common motif in the active site of many bacterial glycosyltransferases. Our results can therefore serve as a blueprint for the rational design of non-substrate-like, covalent inhibitors against a broad range of other bacterial glycosyltransferases.-3 -

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“…These LOS oligosaccharides include structures that are antigenically similar to host cell-surface glycolipids and may also contain the host membrane constituents sialic acid (NeuAc) and phosphorylcholine (PCho) (41). LOS confers resistance to host killing (8,9,37) and is also the primary target of the Toll-like receptor 4 pathway that mediates protection against H. influenzae in the airways (47). It has been established that NTHi strains that express NeuAc-LOS forms comprise a greater proportion of biofilm communities than of planktonic cultures, and that mutations eliminating these forms decrease biofilm formation and bacterial persistence in animal models of OM (4,12,18,43).…”

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Phosphorylcholine Decreases Early Inflammation and Promotes the Establishment of Stable Biofilm Communities of Nontypeable Haemophilus influenzae Strain 86-028NP in a Chinchilla Model of Otitis Media

et al. 2007

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Haemophilus influenzae is a gram-negative pleiomorphic bacterium that is a common commensal/mutualist within the human airways (30). Encapsulated H. influenzae strains are overt pathogens causing invasive disease (3) and have largely been contained by a vaccine effective against the predominant capsular serotype b strains (32). In contrast, the so-called nontypeable H. influenzae (NTHi) strains lacking capsular polysaccharides remain predominant in asymptomatic carriage and localized airway infections (14, 29). These infections are mostly opportunistic in nature and include bronchiopneumonia, sinusitis, and otitis media (OM). OM is among the most common pediatric infections, causing an estimated ϳ$5 billion in costs of treatment and parents' missed work days per year (20). OM infections include chronic OM that is difficult to resolve with antibiotic therapy, and it has long been postulated that chronic OM involves the formation of bacterial biofilm communities (5, 35). In support of that hypothesis, biofilms have been visualized in tympanostomy drain tubes removed from patients with OM and on middle ear tissue from experimentally infected chinchillas (7,18,33). More recent evidence shows that NTHi and other bacterial agents are present within biofilms on tissue specimens obtained from patients with chronic and recurrent OM (13).The H. influenzae surface is covered with lipooligosaccharide (LOS) endotoxins that lack a repeating O side chain. Instead, the H. influenzae LOS features a diverse collection of LOS glycoforms that differ in the length, content, and nature of the chemical linkages found in the oligosaccharide portion. These LOS oligosaccharides include structures that are antigenically similar to host cell-surface glycolipids and may also contain the host membrane constituents sialic acid (NeuAc) and phosphorylcholine (PCho) (41). LOS confers resistance to host killing (8,9,37) and is also the primary target of the Toll-like receptor 4 pathway that mediates protection against H. influenzae in the airways (47). It has been established that NTHi strains that express NeuAc-LOS forms comprise a greater proportion of biofilm communities than of planktonic cultures, and that mutations eliminating these forms decrease biofilm formation and bacterial persistence in animal models of OM (4,12,18,43). More recently, we showed that LOS purified from biofilms has decreased potency as an inflammatory agonist, which correlated with an increase in PCho ϩ LOS forms that were present within biofilms (55). In this study, we compared the virulence

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Role of lgtC in Resistance of Nontypeable Haemophilus influenzae Strain R2866 to Human Serum

Cited by 12 publications

References 0 publications

Adhesin genes and serum resistance in Haemophilus influenzae type f isolates

Adhesin genes and serum resistance in Haemophilus influenzae type f isolates

Covalent inhibitors of LgtC: A blueprint for the discovery of non-substrate-like inhibitors for bacterial glycosyltransferases

Phosphorylcholine Decreases Early Inflammation and Promotes the Establishment of Stable Biofilm Communities of Nontypeable Haemophilus influenzae Strain 86-028NP in a Chinchilla Model of Otitis Media

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