Epigenetic Regulation Alters Biofilm Architecture and Composition in Multiple Clinical Isolates of Nontypeable Haemophilus influenzae

Brockman, Kenneth L.; Azzari, Patrick N.; Branstool, M. Taylor; Atack, John M.; Schulz, Benjamin L.; Jen, Freda E.-C.; Jennings, Michael P.; Bakaletz, Lauren O.

doi:10.1128/mbio.01682-18

Cited by 35 publications

(36 citation statements)

References 53 publications

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“…Subsequent work demonstrated that the switch from modA2 OFF to modA2 ON results in more severe middle ear infections [80], indicating that an as yet uncharacterized interaction likely occurs between modA2 ON and modA2 OFF sub-populations in the middle ear to increase disease severity. Further work with modA-controlled phasevarions in NTHi demonstrated that they influence important pathobiological traits, such as resistance to oxidative stress [81] and biofilm formation [82].…”

Section: Many Important Human-adapted Bacterial Pathogens Contain Phamentioning

confidence: 99%

Phasevarions of bacterial pathogens – phase-variable epigenetic regulators evolving from restriction–modification systems

et al. 2019

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Phase-variable DNA methyltransferases control the expression of multiple genes via epigenetic mechanisms in a wide variety of bacterial species. These systems are called phasevarions, for phase-variable regulons. Phasevarions regulate genes involved in pathogenesis, host adaptation and antibiotic resistance. Many human-adapted bacterial pathogens contain phasevarions. These include leading causes of morbidity and mortality worldwide, such as non-typeable Haemophilus influenzae, Streptococcus pneumoniae and Neisseria spp. Phase-variable methyltransferases and phasevarions have also been discovered in environmental organisms and veterinary pathogens. The existence of many different examples suggests that phasevarions have evolved multiple times as a contingency strategy in the bacterial domain, controlling phenotypes that are important in adapting to environmental change. Many of the organisms that contain phasevarions have existing or emerging drug resistance. Vaccines may therefore represent the best and most cost-effective tool to prevent disease caused by these organisms. However, many phasevarions also control the expression of current and putative vaccine candidates; variable expression of antigens could lead to immune evasion, meaning that vaccines designed using these targets become ineffective. It is therefore essential to characterize phasevarions in order to determine an organism's stably expressed antigenic repertoire, and rationally design broadly effective vaccines.

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Section: Many Important Human-adapted Bacterial Pathogens Contain Phamentioning

confidence: 99%

Phasevarions of bacterial pathogens – phase-variable epigenetic regulators evolving from restriction–modification systems

et al. 2019

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“…Examples of such evasion mechanisms include coexisting viral infections resulting in a negative pressure buildup in the Eustachian tube, exaggerated cytokine production leading to increased inflammation, and a build‐up of mucin, which decreases mucociliary clearance and hence results in OM infections that are less likely to be cleared (Table ) . Bacteria are even able to manipulate their gene expression through phase variation and interact with other pathogens, increasing their virulence and decreasing the chances of host clearance . Immunologic evasion is multifactorial, and often depends on damage to the host mucociliary tract, genetic regulatory changes within otopathogens, the number as well as a variety of different otopathogens that have colonized the nasopharynx, and finally, the delicate interplay between the host's adaptive and innate immune response (Table ).…”

Section: Immunologic Evasionmentioning

confidence: 99%

“…NTHi ModA allele phaseversion was studied in animal models that specifically investigated OM. It has been demonstrated that animals with the “on” modA2 phaseversion had a higher burden of disease . Tetranucleotide repeats that influence phase variation in lipo‐oligosaccharide genes have also been studied.…”

Section: Immunologic Evasionmentioning

confidence: 99%

Subversion of host immune responses by otopathogens during otitis media

Parrish

Soni

Mittal

2019

Journal of Leukocyte Biology

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Otitis media (OM) is one of the most common ear diseases affecting humans. Children are at greater risk and suffer most frequently from OM, which can cause serious deterioration in the quality of life. OM is generally classified into two main types: acute and chronic OM (AOM and COM). AOM is characterized by tympanic membrane swelling or otorrhea and is accompanied by signs or symptoms of ear infection. In COM, there is a tympanic membrane perforation and purulent discharge. The most common pathogens that cause AOM are Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis whereas Pseudomonas aeruginosa and Staphylococcus aureus are commonly associated with COM. Innate and adaptive immune responses provide protection against OM. However, pathogens employ a wide arsenal of weapons to evade potent immune responses and these mechanisms likely contribute to AOM and COM. Immunologic evasion is multifactorial, and involves damage to host mucociliary tract, genetic polymorphisms within otopathogens, the number and variety of different otopathogens in the nasopharynx as well as the interaction between the host's innate and adaptive immune responses. Otopathogens utilize host mucin production, phase variation, biofilm production, glycans, as well as neutrophil and eosinophilic extracellular traps to induce OM. The objective of this review article is to discuss our current understanding about the mechanisms through which otopathogens escape host immunity to induce OM. A better knowledge about the molecular mechanisms leading to subversion of host immune responses will provide novel clues to develop effective treatment modalities for OM.

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“…These two subpopulations are referred to as ON and OFF, for review see (Srikhanta et al, 2010;Tan et al, 2016;Atack et al, 2018). Recent work has shown that each of these distinct subpopulations differ in the expression of known virulence factors and responses to disease-related stresses in vitro (Atack et al, 2015a(Atack et al, , 2019aBrockman et al, 2017Brockman et al, , 2018Srikhanta et al, 2017b). Phasevarionmediated changes in gene expression not only impact bacterial physiology, but also present an important challenge for vaccine development.…”

Section: Introductionmentioning

confidence: 99%

“…Initial studies into the phasevarion of NTHi found that within multiple diverse collections of clinical isolates, up to two-thirds of NTHi had an active phasevarion (Atack et al, 2015a). Since then, NTHi phasevarions were shown to regulate numerous diseaserelated processes, which include biofilm formation, resistance to oxidative stress, opsonization and antibiotic sensitivity (Atack et al, 2015a;VanWagoner et al, 2016;Brockman et al, 2017Brockman et al, , 2018. The NTHi phasevarion has also been studied in vivo, where NTHi strain 723 was shown to regulate pathogenesis and disease severity in a chinchilla model of experimental otitis media (Atack et al, 2015a;Brockman et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

A Bacterial Epigenetic Switch in Non-typeable Haemophilus influenzae Modifies Host Immune Response During Otitis Media

Robledo‐Avila

Ruíz-Rosado

Partida-Sánchez

et al. 2020

Front. Cell. Infect. Microbiol.

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Non-typeable Haemophilus influenzae (NTHi) causes multiple diseases of the human airway and is a predominant bacterial pathogen of acute otitis media and otitis media in which treatment fails. NTHi utilizes a system of phase variable epigenetic regulation, termed the phasevarion, to facilitate adaptation and survival within multiple sites of the human host. The NTHi phasevarion influences numerous disease-relevant phenotypes such as biofilm formation, antibiotic resistance, and opsonization. We have previously identified an advantageous selection for a specific phasevarion status, which significantly affects severity and chronicity of experimental otitis media. In this study, we utilized pure cultures of NTHi variants in which modA was either locked ON or locked OFF, and thus modA was unable to phase vary. These locked variants were used to assess the progression of experimental otitis media and define the specific immune response induced by each subpopulation. Although the initial disease caused by each subpopulation was similar, the immune response elicited by each subpopulation was unique. The modA2 OFF variant induced significantly greater activation of macrophages both in vitro and within the middle ear during disease. In contrast, the modA2 ON variant induced a greater neutrophil extracellular trap response, which led to greater killing of the modA2 ON variant. These data suggest that not only does the NTHi phasevarion facilitate adaptation, but also allows the bacteria to alter immune responses during disease. Understanding these complex bacterial-host interactions and the regulation of bacterial factors responsible is critical to the development of better diagnostic, treatment, and preventative strategies for these bacterial pathogens.

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Epigenetic Regulation Alters Biofilm Architecture and Composition in Multiple Clinical Isolates of Nontypeable Haemophilus influenzae

Cited by 35 publications

References 53 publications

Phasevarions of bacterial pathogens – phase-variable epigenetic regulators evolving from restriction–modification systems

Phasevarions of bacterial pathogens – phase-variable epigenetic regulators evolving from restriction–modification systems

Subversion of host immune responses by otopathogens during otitis media

A Bacterial Epigenetic Switch in Non-typeable Haemophilus influenzae Modifies Host Immune Response During Otitis Media

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