The modA10 phasevarion of nontypeable Haemophilus influenzae R2866 regulates multiple virulence-associated traits

VanWagoner, Timothy M., Atack, John M., Nelson,Kevin L., Smith, Hannah K., Fox, Kate L., Jennings,Michael P., Stull, Terrence L. and Smith, Arnold L. (2016) The modA10 phasevarion of nontypeable Haemophilus influenzae R2866 regulates multiple virulence-associated traits. Microbial Pathogenesis, 92 60-67. doi:10.1016/j.micpath.2015.12.006

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Author VanWagoner, Timothy M.
Atack, John M.
Nelson,Kevin L.
Smith, Hannah K.
Fox, Kate L.
Jennings,Michael P.
Stull, Terrence L.
Smith, Arnold L.
Title The modA10 phasevarion of nontypeable Haemophilus influenzae R2866 regulates multiple virulence-associated traits
Formatted title
The modA10 phasevarion of nontypeable Haemophilus influenzae R2866 regulates multiple virulence-associated traits
Journal name Microbial Pathogenesis   Check publisher's open access policy
ISSN 1096-1208
0882-4010
Publication date 2016-03-01
Year available 2015
Sub-type Article (original research)
DOI 10.1016/j.micpath.2015.12.006
Open Access Status File (Author Post-print)
Volume 92
Start page 60
End page 67
Total pages 8
Place of publication London, United Kingdom
Publisher Academic Press
Language eng
Subject 2404 Microbiology
2725 Infectious Diseases
Abstract Non-typeable Haemophilus influenzae (NTHi) is a human restricted commensal and pathogen that elicits inflammation by adhering to and invading airway epithelia cells: transcytosis across these cells can result in systemic infection. NTHi strain R2866 was isolated from the blood of a normal 30-month old infant with meningitis, and is unusual for NTHi in that it is able to cause systemic infection. Strain R2866 is able to replicate in normal human serum due to expression of lgtC which mimics human blood group p(k). R2866 contains a phase-variable DNA methyltransferase, modA10 which switches ON and OFF randomly and reversibly due to polymerase slippage over a long tetrameric repeat tract located in its open reading frame. Random gain or loss of repeats during replication can results in expressed (ON), or not expressed (OFF) states, the latter due to a frameshift or transcriptional termination at a premature stop codon. We sought to determine if the unusual virulence of R2866 was modified by modA10 phase-variation. A modA10 knockout mutant was found to have increased adherence to, and invasion of, human ear and airway monolayers in culture, and increased invasion and transcytosis of polarized human bronchial epithelial cells. Intriguingly, the rate of bacteremia was lower in the infant rat model of infection than a wild-type R2866 strain, but the fatality rate was greater. Transcriptional analysis comparing the modA10 knockout to the R2866 wild-type parent strain showed increased expression of genes in the modA10 knockout whose products mediate cellular adherence. We conclude that loss of ModA10 function in strain R2866 enhances colonization and invasion by increasing expression of genes that allow for increased adherence, which can contribute to the increased virulence of this strain.
Formatted abstract
Non-typeable Haemophilus influenzae (NTHi) is a human restricted commensal and pathogen that elicits inflammation by adhering to and invading airway epithelia cells: transcytosis across these cells can result in systemic infection. NTHi strain R2866 was isolated from the blood of a normal 30-month old infant with meningitis, and is unusual for NTHi in that it is able to cause systemic infection. Strain R2866 is able to replicate in normal human serum due to expression of lgtC which mimics human blood group pk. R2866 contains a phase-variable DNA methyltransferase, modA10 which switches ON and OFF randomly and reversibly due to polymerase slippage over a long tetrameric repeat tract located in its open reading frame. Random gain or loss of repeats during replication can results in expressed (ON), or not expressed (OFF) states, the latter due to a frameshift or transcriptional termination at a premature stop codon. We sought to determine if the unusual virulence of R2866 was modified by modA10 phase-variation. A modA10 knockout mutant was found to have increased adherence to, and invasion of, human ear and airway monolayers in culture, and increased invasion and transcytosis of polarized human bronchial epithelial cells. Intriguingly, the rate of bacteremia was lower in the infant rat model of infection than a wild-type R2866 strain, but the fatality rate was greater. Transcriptional analysis comparing the modA10 knockout to the R2866 wild-type parent strain showed increased expression of genes in the modA10 knockout whose products mediate cellular adherence. We conclude that loss of ModA10 function in strain R2866 enhances colonization and invasion by increasing expression of genes that allow for increased adherence, which can contribute to the increased virulence of this strain.
Keyword DNA methylase
Haemophilus influenzae
Pathogenesis
Phase variation
Virulence
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID 46512
Institutional Status UQ
Additional Notes Published online 21 December 2015

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2016 Collection
School of Chemistry and Molecular Biosciences
 
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