ArcA-Regulated Glycosyltransferase Lic2B Promotes Complement Evasion and Pathogenesis of Nontypeable Haemophilus influenzae

Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, 55 Lake Ave. N., S6-242, Worcester, MA 01655, USA.
Infection and immunity (Impact Factor: 3.73). 02/2011; 79(5):1971-83. DOI: 10.1128/IAI.01269-10
Source: PubMed


Signaling mechanisms used by Haemophilus influenzae to adapt to conditions it encounters during stages of infection and pathogenesis are not well understood. The ArcAB two-component
signal transduction system controls gene expression in response to respiratory conditions of growth and contributes to resistance
to bactericidal effects of serum and to bloodstream infection by H. influenzae. We show that ArcA of nontypeable H. influenzae (NTHI) activates expression of a glycosyltransferase gene, lic2B. Structural comparison of the lipooligosaccharide (LOS) of a lic2B mutant to that of the wild-type strain NT127 revealed that lic2B is required for addition of a galactose residue to the LOS outer core. The lic2B gene was crucial for optimal survival of NTHI in a mouse model of bacteremia and for evasion of serum complement. The results
demonstrate that ArcA, which controls cellular metabolism in response to environmental reduction and oxidation (redox) conditions,
also coordinately controls genes that are critical for immune evasion, providing evidence that NTHI integrates redox signals
to regulate specific countermeasures against host defense.

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    • "Recently, in encapsulated as well as non-typeable H. influenzae (NTHi) strains, changes in LOS structures were shown to be responsible for alterations in serum resistance (for overview see Hallström and Riesbeck, 2010). Interestingly, Wong et al. reported that ArcA regulates a LOS specific glycosyltransferase, encoded by lic2B, which affects serum resistance in one clinical NTHi isolate (Wong et al., 2011). A similar phenotype was also identified earlier, by testing survival of an Hib arcA mutant strain in human serum (De Souza-Hart et al., 2003). "
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    ABSTRACT: Haemophilus influenzae is a Gram-negative bacillus and a frequent commensal of the human nasopharynx. Earlier work demonstrated that in H. influenzae type b, L-lactate metabolism is associated with serum resistance and in vivo survival of the organism. To further gain insight into lactate utilization of the non-typeable (NTHi) isolate 2019 and laboratory prototype strain Rd KW20, deletion mutants of the L-lactate dehydrogenase (lctD) and permease (lctP) were generated and characterized. It is shown, that the apparent KM of L-lactate uptake is 20.1 μM as determined for strain Rd KW20. Comparison of the COPD isolate NTHi 2019-R with the corresponding lctP knockout strain for survival in human serum revealed no lactate dependent serum resistance. In contrast, we observed a 4-fold attenuation of the mutant strain in a murine model of nasopharyngeal colonization. Characterization of lctP transcriptional control shows that the lactate utilization system in H. influenzae is not an inductor inducible system. Rather negative feedback regulation was observed in the presence of L-lactate and this is dependent on the ArcAB regulatory system. Additionally, for 2019 it was found that lactate may have signalling function leading to increased cell growth in late log phase under conditions where no L-lactate is metabolized. This effect seems to be ArcA independent and was not observed in strain Rd KW20. We conclude that L-lactate is an important carbon-source and may act as host specific signal substrate which fine tunes the globally acting ArcAB regulon and may additionally affect a yet unknown signalling system and thus may contribute to enhanced in vivo survival.
    No preview · Article · May 2014 · International journal of medical microbiology: IJMM
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    • "Supporting a more general role for ArcA in the regulation of lic2B was the identification of a putative ArcA-binding site in the promoter region of lic2B from a type b strain. Loss of ArcA led to increased deposition of iC3b, a cleavage product of complement component factor C3b on the bacterial surface (Wong et al., 2011). As Lic2B is important for NTHi survival in a mouse model of bacteremia, as well as for serum survival during anaerobic growth, it was suggested that ArcA senses changes in host environments due to alteration of redox conditions and thus can coordinately regulate expression of genes that are critical for immune evasion. "
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    ABSTRACT: Haemophilus influenzae is a commensal of the human upper respiratory tract. H. influenzae can, however, move out of its commensal niche and cause multiple respiratory tract diseases. Such diseases include otitis media in young children, as well as exacerbations of chronic obstructive pulmonary disease (COPD), sinusitis, conjunctivitis, and bronchitis. During the course of colonization and infection, H. influenzae must withstand oxidative stress generated by multiple reactive oxygen species produced endogenously, by other co-pathogens and by host cells. H. influenzae has, therefore, evolved multiple mechanisms that protect the cell against oxygen-generated stresses. In this review, we will describe these systems relative to the well-described systems in Escherichia coli. Moreover, we will compare how H. influenzae combats the effect of oxidative stress as a necessary phenotype for its roles as both a successful commensal and pathogen.
    Full-text · Article · Mar 2012 · Frontiers in Cellular and Infection Microbiology
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    • "The biochemical properties of FNR in H. influenzae have not been studied, however its predicted amino acid sequence is 79% identical to that of E. coli and it regulates target genes containing a similar FNR binding motif in their promoter regions under low oxygen conditions consistent with a similar function (Stewart and Bledsoe, 2005; Harrington et al., 2009). Despite functional similarities of these regulators to those of E. coli, there are important differences in the sets of genes these two factors control in H. influenzae, and these differences have been linked to mechanisms of pathogenesis (Wong et al., 2007, 2011; Harrington et al., 2009). "
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    ABSTRACT: Haemophilus influenzae is a Gram-negative bacterium that has no identified natural niche outside of the human host. It primarily colonizes the nasopharyngeal mucosa in an asymptomatic mode, but has the ability to disseminate to other anatomical sites to cause otitis media, upper, and lower respiratory tract infections, septicemia, and meningitis. To persist in diverse environments the bacterium must exploit and utilize the nutrients and other resources available in these sites for optimal growth/survival. Recent evidence suggests that regulatory factors that direct such adaptations also control virulence determinants required to resist and evade immune clearance mechanisms. In this review, we describe the recent application of whole-genome approaches that together provide insight into distinct survival mechanisms of H. influenzae in the context of different sites of pathogenesis.
    Full-text · Article · Mar 2012 · Frontiers in Cellular and Infection Microbiology
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