Abstract
Aggregatibacter actinomycetemcomitans 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 A. actinomycetemcomitans, 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 A. actinomycetemcomitans 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 A. actinomycetemcomitans 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 A. actinomycetemcomitans and epinephrine. Finally, epinephrine-containing supernatants collected from human neutrophils promoted A. actinomycetemcomitans growth and induced the expression of the qseBC operon under anaerobic conditions. Based on our findings, we propose that A. actinomycetemcomitans promotes azurophilic granule exocytosis by neutrophils as an epinephrine source to promote bacterial survival.
Highlights
In the oral cavity, when host microbe homeostasis is broken, bacterial communities accumulate at the sub-gingival pocket and form biofilms that lead to oral diseases such as periodontitis [1]
We examined the ability of Aa to induce epinephrine release by human neutrophils
Epinephrine levels in cell lysates of human neutrophils treated with latrunculin A + fMLF had significantly reduced levels of epinephrine compared to basal (Figure 1D); this correlates the significant increase release of epinephrine observed in supernatants (Figure 1C)
Summary
In the oral cavity, when host microbe homeostasis is broken, bacterial communities accumulate at the sub-gingival pocket and form biofilms that lead to oral diseases such as periodontitis [1]. Periodontitis consists of a chronic inflammation of the periodontium caused by the inflammatory response of the host to plaque biofilm. Recurring inflammation of the periodontium has been associated with the initiation, exacerbation, and pathogenesis of a number of other inflammatory diseases [2]. A. actinomycetemcomitans contributes to tissue inflammation, destruction, and bone resorption by expressing a number of virulence factors such as cytolethal disentin toxin, leukotoxin A of the RTX family of bacterial toxins, and collagenase [11,12,13,14]
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