Bacterial Moonlighting Proteins that Function as Cytokine Binders/Receptors

Miscellaneous IL-10-Binding Proteins of Aggregatibacter actinomycetemcomitans

Riikka Ihalin

Department of Biochemistry, University of Turku, Turku, Finland


The Gram-negative capnophilic bacterium Aggregatibacter actinomycetemcomitans forms robust biofilms on a variety of surfaces by producing long fimbriae that are encoded by its ta^-locus (Schreiner et al. 2003; Tomich et al. 2007). A. actinomycetemcomitans’ main ecological niche is the oral cavity where it thrives in gingival pockets, but it can also be found in the epithelium, where it has the potential to invade epithelial cells (Meyer et al. 1991). In subgingival biofilm, the opportunistic pathogen is involved in the etiology of periodontitis, especially the localized aggressive form of the disease (Zambon et al. 1985; Haffajee and Socransky 1994; Aberg et al. 2015) in which the host response destroys the tooth-supporting tissues. Because A. actinomycetemcomitans can be found in the oral microbiota of healthy individuals, host-microbe interactions as well as microbe-microbe interactions (Fine et al. 2013) are likely to play an important role in the progression of the disease.

Although the species primarily colonizes the oral cavity, A. actinomycetemcom- itans may cause health problems in distant sites from its main ecological niche. A. actinomycetemcomitans may promote the development of cardiovascular diseases (Kozarov et al. 2005; Hyvarinen et al. 2012) and, as a member of the HACEK group of Gram-negative bacteria, it can cause endocarditis (Das et al. 1997). Moreover, it has been found in abscesses in the brain (Rahamat-Langendoen et al. 2011), demonstrating its potential to spread from the oral cavity.

A. actinomycetemcomitans uses various virulence mechanisms when colonizing and causing disease in humans. The most well-known virulence factors of the species are the repeat-in-toxin (RTX) leukotoxin and cytolethal distending toxin (CDT). Leukotoxin is coded by the ltxCABD operon in which ltxA codes for the toxin, ltxC is needed for post-translational modifications, and the products of ltxB and ltxD take part in the transport of the toxin (Johansson 2011). Modifications in the promoter region of ltxCABD have been shown to change

Moonlighting Proteins: Novel Virulence Factors in Bacterial Infections, First Edition. Edited by Brian Henderson.

© 2017 John Wiley & Sons, Inc. Published 2017 by John Wiley & Sons, Inc.

the expression levels of leukotoxin in some clinical isolates of A. actinomycetem- comitans (Brogan et al. 1994; He et al. 1999). In the highly leukotoxic strain JP2, the ItxCABD promoter has a 530 bp deletion (Haubek 2010). Leukotoxin can kill various human cells, although its primary targets are polymorphonuclear leukocytes (Johansson et al. 2000) and monocytes/macrophages (Tsai et al. 1979). Lymphocytes (Simpson et al. 1988; Rabie et al. 1988; Mangan et al. 1991; Shenker et al. 1994) and erythrocytes (Balashova et al. 2006) are also affected by leukotoxin, making it a versatile factor for manipulating the immune response. Monocytes are especially sensitive to the cytotoxic effect of leukotoxin, which lyses the cells in a caspase- 1-dependent manner (Kelk et al. 2003). This result is in accordance with the finding that LtxA-treated macrophages rapidly secrete bioactive interleukin (IL)-1p, which requires caspase-1 activation for maturation (Kelk et al. 2005). The main toxic function of CDT is to prevent eukaryotic cells from entering mitosis, thus leading to the eventual apoptosis of the host cell (Shenker et al. 1999). In addition to preventing cell proliferation, A. actinomycetemcomitans CDT disturbs cell-cell contacts in the epithelium (Damek-Poprawa et al. 2013), facilitating the entrance of bacteria into the deeper layers of gingival tissue.

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