Abstract
BackgroundNontypeable Haemophilus influenzae (NTHi) is a significant human pathogen responsible for respiratory tract infections and the most common cause of recurrent otitis media. Type II toxin-antitoxin (TA) systems are genetic elements that code for a stable protein toxin and a labile antitoxin that are thought to be involved in metabolic regulation of bacteria by enabling a switch to a dormant state under stress conditions. The contribution to infection persistence of the NTHi TA loci vapBC-1 and vapXD was examined in this study.ResultsDeletions in vapBC-1, vapXD and vapBC-1 vapXD significantly decreased the survival of NTHi co-cultured with primary human respiratory tissue at the air-liquid interface and in the chinchilla model of otitis media. The TA deletions did not affect the growth dynamics of the mutants in rich media, their ultra-structural morphology, or display appreciable synergy during NTHi infections. The toxin and antitoxin proteins of both pairs heterodimerized in vivo. Consistent with our previous findings regarding the VapC-1 toxin, the NTHi VapD toxin also displayed ribonuclease activity.ConclusionsWe conclude that the vapBC-1 and vapXD TA loci enhance NTHi survival and virulence during infection in vitro and in vivo using a mechanism of mRNA cleavage, and that these conserved TA pairs represent new targets for the prophylaxis and therapy of otitis media and other NTHi-caused mucosal diseases.
Highlights
Nontypeable Haemophilus influenzae (NTHi) is a significant human pathogen responsible for respiratory tract infections and the most common cause of recurrent otitis media
Interactions of the Vap proteins in vivo To detect the ability of VapB-1 and VapC-1 to form heterodimers in vivo, β-galactosidase activity assays were carried out using an E. coli-based LexA protein-protein interaction reporter system as previously described [31]
With no protein fused to the LexA DNA binding domain (DBD) of either plasmid pSR658 or pSR659 in strain SU202, the repressor cannot form a dimer, and the expression of the lacZ reporter gene is constitutive
Summary
Nontypeable Haemophilus influenzae (NTHi) is a significant human pathogen responsible for respiratory tract infections and the most common cause of recurrent otitis media. Nontypeable Haemophilus influenzae (NTHi) is a Gramnegative organism that is both a common commensal of the upper respiratory tract as well as a significant cause of respiratory tract infections in humans. There is controversy whether the reported biofilm is an outcome of infectious interactions between the host and NTHi or a programmed phenotype of NTHi virulence [13]. These observations have advanced our understanding, much of the pathogenesis of NTHi-induced otitis media, especially recurrent otitis media, is largely unknown
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