Summary
Neutrophils are a major component of the innate host response, and the outcome of the interaction between the oral microbiota and neutrophils is a key determinant of oral health status. The ...composition of the oral microbiome is very complex and different in health and disease. Neutrophils are constantly recruited to the oral cavity, and their protective role is highlighted in cases where their number or functional responses are impeded, resulting in different forms of periodontal disease. Periodontitis, one of the more severe and irreversible forms of periodontal disease, is a microbial‐induced chronic inflammatory disease that affects the gingival tissues supporting the tooth. This chronic inflammatory disease is the result of a shift of the oral bacterial symbiotic community to a dysbiotic more complex community. Chronic inflammatory infectious diseases such as periodontitis can occur because the pathogens are able to evade or disable the innate immune system. In this review, we discuss how human neutrophils interact with both the symbiotic and the dysbiotic oral community; an understanding of which is essential to increase our knowledge of the periodontal disease process.
Exposure to pro-inflammatory cytokines, chemokines, mitochondrial contents, and bacterial and viral products induces neutrophils to transition from a basal state into a primed one, which is currently ...defined as an enhanced response to activating stimuli. Although, typically associated with enhanced generation of reactive oxygen species (ROS) by the NADPH oxidase, primed neutrophils show enhanced responsiveness of exocytosis, NET formation, and chemotaxis. Phenotypic changes associated with priming also include activation of a subset of functions, including adhesion, transcription, metabolism, and rate of apoptosis. This review summarizes the breadth of phenotypic changes associated with priming and reviews current knowledge of the molecular mechanisms behind those changes. We conclude that the current definition of priming is too restrictive. Priming represents a combination of enhanced responsiveness and activated functions that regulate both adaptive and innate immune responses.
Neutrophils are phagocytic innate immune cells essential for killing bacteria via activation of a wide variety of effector responses and generation of large amounts of reactive oxygen species (ROS). ...Majority of the ROS in neutrophils is generated by activation of the superoxide‐generating enzyme nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. Independent of their anti‐microbial function, NADPH oxidase‐derived ROS have emerged as key regulators of host immune responses and neutrophilic inflammation. Data from patients with inherited defects in the NADPH oxidase subunit alleles that ablate its enzyme function as well as mouse models demonstrate profound dysregulation of host inflammatory responses, neutrophil hyper‐activation and tissue damage in response to microbial ligands or tissue trauma. A large body of literature now demonstrates how oxidants function as essential signaling molecules that are essential for the regulation of neutrophil responses during priming, degranulation, neutrophil extracellular trap formation, and apoptosis, independent of their role in microbial killing. In this review we summarize how NADPH oxidase‐derived oxidants modulate neutrophil function in a cell intrinsic manner and regulate host inflammatory responses. In addition, we summarize studies that have elucidated possible roles of oxidants in neutrophilic responses within the oral mucosa and periodontal disease.
Activation of neutrophil NADPH oxidase (NOX2) enzyme complex generates reactive oxygen species (ROS). ROS generated play critical roles in the activation and redox modulation of neutrophil antimicrobial capacity and effector functions.
Variable power sources are becoming increasingly common in low-inertia microgrids. Inadequate amounts, however, can disrupt electric service if ramped events occur too quickly. The authors introduce ...an approach to predict how long microgrids can withstand ramped events as a function of local inertia. Although microgrids can ride through disturbances using local inertia and other technologies, it is not clear for how long disturbances can be tolerated-particularly when in progress. The estimated reaction times are presented, first, as stability margins to illustrate how ramp-rate magnitudes relate to local inertia. Then, use of the reaction times is demonstrated as a forward-looking capability to anticipate frequency deviation times as a microgrid model undergoes large solar ramp rates. It is shown that the available remaining times can be estimated even as disturbances and remedial actions take place.
Filifactor alocis is a gram positive anaerobe that is emerging as an important periodontal pathogen. In the oral cavity F. alocis colonizes polymicrobial biofilm communities; however, little is known ...regarding the nature of the interactions between F. alocis and other oral biofilm bacteria. Here we investigate the community interactions of two strains of F. alocis with Streptococcus gordonii, Fusobacterium nucleatum, Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans, organisms with differing pathogenic potential in the oral cavity. In an in vitro community development model, S. gordonii was antagonistic to the accumulation of F. alocis into a dual species community. In contrast, F. nucleatum and the type strain of F. alocis formed a synergistic partnership. Accumulation of a low passage isolate of F. alocis was also enhanced by F. nucleatum. In three species communities of S. gordonii, F. nucleatum and F. alocis, the antagonistic effects of S. gordonii superseded the synergistic effects of F. nucleatum toward F. alocis. The interaction between A. actinomycetemcomitans and F. alocis was strain specific and A. actinomycetemcomitans could either stimulate F. alocis accumulation or have no effect depending on the strain. P. gingivalis and F. alocis formed heterotypic communities with the amount of P. gingivalis greater than in the absence of F. alocis. However, while P. gingivalis benefited from the relationship, levels of F. alocis in the dual species community were lower compared to F. alocis alone. The inhibitory effect of P. gingivalis toward F. alocis was dependent, at least partially, on the presence of the Mfa1 fimbrial subunit. In addition, AI-2 production by P. gingivalis helped maintain levels of F. alocis. Collectively, these results show that the pattern of F. alocis colonization will be dictated by the spatial composition of microbial microenvironments, and that the organism may preferentially accumulate at sites rich in F. nucleatum.
is a gram-negative facultative anaerobe and an opportunistic oral pathogen, strongly associated with periodontitis and other inflammatory diseases. Periodontitis is a chronic inflammation of the ...periodontium resulting from the inflammatory response of the host towards the dysbiotic microbial community present at the gingival crevice. Previously, our group identified catecholamines and iron as the signals that activate the QseBC two-component system in
, necessary for the organism to acquire iron as a nutrient to survive in the anaerobic environment. However, the source of catecholamines has not been identified. It has been reported that mouse neutrophils can release catecholamines. In periodontitis, large infiltration of neutrophils is found at the subgingival pocket; hence, we wanted to test the hypothesis that
exploits human neutrophils as a source for catecholamines. In the present study, we showed that human neutrophils synthesize, store, and release epinephrine, one of the three main types of catecholamines. Human neutrophil challenge with
induced exocytosis of neutrophil granule subtypes: secretory vesicles, specific granules, gelatinase granules, and azurophilic granules. In addition, by selectively inhibiting granule exocytosis, we present the first evidence that epinephrine is stored in azurophilic granules. Using QseC mutants, we showed that the periplasmic domain of the QseC sensor kinase is required for the interaction between
and epinephrine. Finally, epinephrine-containing supernatants collected from human neutrophils promoted
growth and induced the expression of the
operon under anaerobic conditions. Based on our findings, we propose that
promotes azurophilic granule exocytosis by neutrophils as an epinephrine source to promote bacterial survival.
Summary Inflammation is a double-edged sword in the outcome of pneumonia. On the one hand, an effective and timely inflammatory response is required to eliminate the invading respiratory pathogen. On ...the other, a toxic and prolonged inflammatory response may result in lung injury and poor outcomes, even in those receiving advanced medical care. This review focuses on recent understanding of the dynamics of the cytokine response, neutrophil activity, and responsiveness to cytokines and neutrophil lifespan as major elements of lung inflammation resulting in favorable or poor outcomes in lung infection primarily due to pneumococcus and influenza virus. Although some progress has been made in our understanding of the molecular mechanisms of the pneumonia inflammation axis composed of cytokines modulating neutrophil activation and neutrophil apoptosis, important questions remain to be answered. The degree of neutrophil activation, generation of reactive oxygen species, and the release of granule antimicrobial peptides play a key role in microbial pathogen clearance; however, prolonged neutrophil activation may contribute to lung injury and poor outcomes in pneumonia. Molecular markers of the mechanisms regulating neutrophil survival and apoptosis may help in the identification of novel therapeutic targets to modulate inflammation by inducing timely neutrophil apoptosis. A major task is to identify the mechanisms of dysregulation in inflammation leading to toxic responses, thereby targeting a biomarker and enabling timely therapies to modulate inflammation.
Two photoswitchable compounds that can operate under visible light irradiation are prepared and investigated using spectroscopic and computational studies. These all-visible systems are based on the ...dimethyldihydropyrene (DHP)/cyclophanediene (CPD) photochromic couple connected either to a bipyridine (bpy) unit or to a (tris(bpy)ruthenium(II)) complex through a pyridinium bridge. In these compounds, the DHP to CPD isomerization and the reverse CPD to DHP conversion can be triggered by illumination with red (>630 nm) and blue (460 nm) lights, respectively. The unambiguous and reversible response of these systems triggered by visible light make them potential candidates for biological purposes and electronic devices.
Subverting the host immune response to inhibit inflammation is a key virulence strategy of Yersinia pestis. The inflammatory cascade is tightly controlled via the sequential action of lipid and ...protein mediators of inflammation. Because delayed inflammation is essential for Y. pestis to cause lethal infection, defining the Y. pestis mechanisms to manipulate the inflammatory cascade is necessary to understand this pathogen's virulence. While previous studies have established that Y. pestis actively inhibits the expression of host proteins that mediate inflammation, there is currently a gap in our understanding of the inflammatory lipid mediator response during plague. Here we used the murine model to define the kinetics of the synthesis of leukotriene B4 (LTB4), a pro-inflammatory lipid chemoattractant and immune cell activator, within the lungs during pneumonic plague. Furthermore, we demonstrated that exogenous administration of LTB4 prior to infection limited bacterial proliferation, suggesting that the absence of LTB4 synthesis during plague contributes to Y. pestis immune evasion. Using primary leukocytes from mice and humans further revealed that Y. pestis actively inhibits the synthesis of LTB4. Finally, using Y. pestis mutants in the Ysc type 3 secretion system (T3SS) and Yersinia outer protein (Yop) effectors, we demonstrate that leukocytes recognize the T3SS to initiate the rapid synthesis of LTB4. However, several Yop effectors secreted through the T3SS effectively inhibit this host response. Together, these data demonstrate that Y. pestis actively inhibits the synthesis of the inflammatory lipid LTB4 contributing to the delay in the inflammatory cascade required for rapid recruitment of leukocytes to sites of infection.
Increased prevalence and abundance of Selenomonas sputigena have been associated with periodontitis, a chronic inflammatory disease of tooth-supporting tissues, for more than 50 years. Over the past ...decade, molecular surveys of periodontal disease using 16S and shotgun metagenomic sequencing approaches have confirmed the disease association of classically recognized periodontal pathogens such as Porphyromonas gingivalis, Treponema denticola, and Tannerella forsythia while highlighting previously underappreciated organisms such as Filifactor alocis and S. sputigena. Despite abundant clinical association between
and periodontal disease, we have little to no understanding of its pathogenic potential, and virulence mechanisms have not been studied. In this study, we sought to characterize the response of gingival epithelial cells to infection with
. Here, we show that
attaches to gingival keratinocytes and induces expression and secretion of cytokines and chemokines associated with inflammation and leukocyte recruitment. We demonstrate that
induces signaling through Toll-like receptor 2 (TLR2) and TLR4 but evades activation of TLR5. Cytokines released from
-infected keratinocytes induced monocyte and neutrophil chemotaxis. These results show that S.
-host interactions have the potential to contribute to bacterially driven inflammation and tissue destruction, the hallmark of periodontitis. Characterization of previously unstudied pathogens may provide novel approaches to develop therapeutics to treat or prevent periodontal disease.
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