The ModA2 Phasevarion of nontypeable Haemophilus influenzae Regulates Resistance to Oxidative Stress and Killing by Human Neutrophils

• Published in: Scientific reports Vol. 7; no. 1; pp. 3161 - 11
• Main Authors: Brockman, Kenneth L., Branstool, M. Taylor, Atack, John M., Robledo-Avila, Frank, Partida-Sanchez, Santiago, Jennings, Michael P., Bakaletz, Lauren O.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 09-06-2017; Nature Publishing Group; Nature Portfolio
• Subjects: 45/70; 631/208/325/2482; 631/250/255/1318; 631/326/421; 631/337/176/1988; Child; Chromosomes, Bacterial; DNA (Cytosine-5-)-Methyltransferases - genetics; DNA (Cytosine-5-)-Methyltransferases - metabolism; DNA methyltransferase; Gene Expression Regulation, Bacterial; Haemophilus Infections - immunology; Haemophilus Infections - metabolism; Haemophilus Infections - microbiology; Haemophilus influenzae; Haemophilus influenzae - enzymology; Haemophilus influenzae - genetics; Host-Pathogen Interactions - genetics; Host-Pathogen Interactions - immunology; Humanities and Social Sciences; Humans; Leukocytes (neutrophilic); Microbial Viability; Microenvironments; multidisciplinary; Nasopharynx; Nasopharynx - immunology; Nasopharynx - microbiology; Neutrophils - immunology; Neutrophils - microbiology; Oxidative Stress; Pathogens; Phagocytosis; Primary Cell Culture; Reactive Oxygen Species - immunology; Reactive Oxygen Species - metabolism; Respiratory tract; Respiratory tract diseases; Science; Science (multidisciplinary); Subpopulations
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-017-03552-9

Nontypeable
Haemophilus influenzae
(NTHI) is the causative agent of multiple respiratory tract infections. Several human pathogens, including NTHI, possess a novel genetic system, termed the phasevarion, which mediates a rapid and reversible change in the expression of many genes throughout the chromosome. This occurs by phase variation of a single gene (
modA
) that encodes a DNA methyltransferase and results in two phenotypically distinct subpopulations, ON and OFF. NTHI encounters many pressures within the various microenvironments of its human host as the disease course evolves from one of asymptomatic nasopharyngeal carriage to overt disease. These include oxidative stresses, which are present throughout the respiratory tract. To persist in the human nasopharynx and as a pathogen throughout the airways, NTHI must be able to mitigate toxic levels of oxidative stress. Here we show that expression of ModA2,
modA2
ON status, resulted in increased sensitivity to oxidative stress. Furthermore, the
modA2
ON status resulted in decreased resistance to neutrophil-mediated killing, which resulted in selection for the
modA2
OFF subpopulation in an
ex vivo
survival assay. These findings highlight the importance of the ModA2 phasevarion in adaptation to innate host defences and reveal an additional microenvironmental pressure that selected for a specific ModA2 subpopulation.