Staphylococcus aureus Manipulates Innate Immunity through Own and Host-Expressed Proteases

REVIEW published: 05 May 2017 doi: 10.3389/fcimb.2017.00166 Staphylococcus aureus Manipulates Innate Immunity through Own and Host-Expressed Proteases Giampiero Pietrocola, Giulia Nobile, Simonetta Rindi and Pietro Speziale * Unit of Biochemistry, Department of Molecular Medicine, University of Pavia, Pavia, Italy Neutrophils, complement system and skin collectively represent the main elements of the innate immune system, the first line of defense of the host against many common microorganisms. Bacterial pathogens have evolved strategies to counteract all these defense activities. Specifically, Staphylococcus aureus, a major human pathogen, secretes a variety of immune evasion molecules including proteases, which cleave components of the innate immune system or disrupt the integrity of extracellular matrix and intercellular connections of tissues. Additionally, S. aureus secretes proteins that can activate host zymogens which, in turn, target specific defense components. Secreted proteins can also inhibit the anti-bacterial function of neutrophils or complement system proteases, potentiating S. aureus chances of survival. Here, we review the current understanding of these proteases and modulators of host proteases in the functioning of innate immunity and describe the importance of these mechanisms in the pathology of staphylococcal diseases. Edited by: Francois Vandenesch, University of Lyon, France Reviewed by: Peter Verhamme, Universitaire Ziekenhuizen Leuven, Belgium Fabrice Cognasse, The Rhone-Alpes-Auvergne Regional Branch of the French National Blood System, France *Correspondence: Pietro Speziale Received: 29 December 2016 Accepted: 18 April 2017 Published: 05 May 2017 Citation: Pietrocola G, Nobile G, Rindi S and Speziale P (2017) Staphylococcus aureus Manipulates Innate Immunity through Own and Host-Expressed Proteases. Front. Cell. Infect. Microbiol. 7:166. doi: 10.3389/fcimb.2017.00166 Keywords: Staphylococcus aureus, secreted virulence factors, innate immunity, immune evasion molecules, protease, host protease modulator INTRODUCTION Staphylococcus aureus is a human pathogen known for its ability to cause both communityand nosocomial-acquired diseases ranging from mild skin infections, such as impetigo to severe diseases, such as endocarditis, pneumonia, sepsis and toxic shock syndrome (David and Daum, 2010). Treatment of S. aureus infections with antibiotics is often ineffective due to the development of antibiotic-resistance strains, such as methicillin-resistant S. aureus (MRSA). Therefore, alternative treatment options and vaccination are now being explored (Bagnoli et al., 2012; Pozzi et al., 2015). The success of S. aureus as a pathogen depends on the production of several virulence factors. S. aureus can express up to 24 cell wall-anchored proteins, which promote adhesion to extracellular matrices, invasion of non-phagocytic cells, biofilm formation (Foster et al., 2014) and interference with neutralization of the innate immune system (Sjodahl, 1977; Cary et al., 1999; Kang et al., 2013). S. aureus also produces a wide variety of peptides that inhibit specific steps of the innate immune system, which represents the first line of defense of the host (Rooijakkers et al., 2005a; Itoh et al., 2010; Thammavongsa et al., 2015) (For more details see below). Potentiation of S. aureus pathogenesis is determined by secretion of proteases that cleave specific components of the host immune system or disrupt the integrity of extracellular matrix and intercellular connections, compromising the stability of the host tissues and contributing to the dissemination of the infection (Koziel and Potempa, 2013). S. aureus also secretes proteins that can Frontiers in Cellular and Infection Microbiology | www.frontiersin.org 1 May 2017 | Volume 7 | Article 166 Pietrocola et al. Modulation of Innate Immunity by Proteases inflammatory challenge is processed by proteinase 3 to generate the active peptide LL-37 (Sørensen et al., 1997) that possesses considerable anti-staphylococcal activity (Tkalcevic et al., 2000; Travis et al., 2000). S. aureus uses several mechanisms to counteract the epithelia defense actions. Adhesion to epithelia is a multifactorial process that involves the host as well as bacterial factors. One key factor is the glycopolymer cell wall teichoic acid of S. aureus, which directly interacts with nasal epithelial surface through a type F scavenger receptor named SREC-I (Baur et al., 2014). Another important surface factor with a role in nasal and possibly skin epithelia colonization is the cell wall-anchored protein clumping factor B, which binds to fibrinogen, cytokeratin, the dominant component of the interior of squamous cells and loricrin, the most abundant protein of the cornified envelop of squames (Lacey et al., 2016). Iron-regulated surface determinant A protein also promotes the adhesion of S. aureus to squames cooperating in binding to cornified cell envelop loricrin, involucrin, and cytokeratin. Other cell wall-anchored proteins such serine-aspartate dipeptide repeat proteins SdrC, SdrD, and SasG promote adhesion to squames but their ligands are unknown (Foster et al., 2014; Figure 1). Although S. aureus is not considered an intracellular pathogen, it can govern its uptake into non-phagocytic cells. Bacterial internalization is promoted by fibronectin-binding proteins A and B. Binding of fibronectin to fibronectin-binding proteins and its subsequent recognition by integrin a5 b1 leads to internalization of the bacterium into epithelial and endothelial cells (Foster et al., 2014). Recently, it has been shown that clumping factor A binds annexin A2, a calcium-regulated membrane-binding protein, and it has been proposed that this interaction could also mediate S. aureus invasion into bovine mammary epithelial cells (Bonora et al., 2015; Figure 1). In lung epithelial cells S. aureus internalization also involves the efflux pump Tet38 via interaction with CD36 (Truong-Bolduc et al., 2015, 2017). To disturb the defensive barrier function of the airway epithelium, S. aureus α-hemolysin disrupts cell-matrix adhesion by activating Fak signaling with the consequent acceleration of focal contact turnover (Hermann et al., 2015). Additionally, treatment of airway epithelial cells with recombinant αhemolysin results in plasma membrane depolarization, and increased phosphorylation of paxillin and p38 MAP kinase, a signal transduction module involved in host defensive actions (Eiffler et al., 2016). Lastly, staphylococcal EsxA protein interferes with epithelial cell apoptotic pathways and, together with EsxB, mediates the release of intracellular staphylococci from the host cells (Truong-Bolduc et al., 2015). bind and modulate host protease precursors which, in turn, can target specific defense components, providing the bacterium with additional tools to establish colonization of the tissues (McAdow et al., 2012). Lastly, some S. aureus secreted mol (...truncated)