Article

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: 4.16). 02/2011; 79(5):1971-83. DOI: 10.1128/IAI.01269-10
Source: PubMed

ABSTRACT 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.

0 Bookmarks
 · 
87 Views
  • [Show abstract] [Hide abstract]
    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.
    International journal of medical microbiology: IJMM 05/2014; · 4.54 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: 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.
    Infection and immunity 02/2014; 82(2):640-9. · 4.16 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Lipooligosaccharide configurations were predicted in non-typeable Haemophilus influenzae isolates based on the presence of seven oligosaccharide-extension initiating genes (or alleles). Predicted configurations with 2-3 oligosaccharide extensions were more prevalent among middle ear than throat strains. In addition, strains with these configurations averaged higher levels of serum resistance than strains with other configurations.
    Journal of clinical microbiology 04/2014; · 4.23 Impact Factor

Preview

Download
0 Downloads
Available from