Abstract
The complement system is an ancient part of the innate immune system important for both tissue homeostasis and host defense. However, bacteria like Staphylococcus aureus (SA) possess elaborative mechanisms for evading both the complement system and other parts of the immune system. One of these evasive mechanisms—important in causing chronic and therapy resistant infections—is the intracellular persistence in non-immune cells. The objective of our study was to investigate whether persistent intracellular SA infection of epidermal keratinocytes resulted in complement activation. Using fluorescence microscopy, we found that persistent SA, surviving intracellularly in keratinocytes, caused activation of the complement system with formation of the terminal complement complex (TCC) at the cell surface. Skin samples from atopic dermatitis patients analyzed by bacterial culture and microscopy, demonstrated that SA colonization was associated with the presence of intracellular bacteria and deposition of the TCC in epidermis in vivo. Complement activation on keratinocytes with persistent intracellular bacteria was found with sera deficient/depleted of the complement components C1q, Mannan-binding lectin, or complement factor B, demonstrating involvement of more than one complement activation pathway. Viable bacterial counts showed that complement activation at the cell surface initiated cellular responses that significantly reduced the intracellular bacterial burden. The use of an inhibitor of the extracellular signal-regulated kinase (ERK) abrogated the complement-induced reduction in intracellular bacterial load. These data bridge the roles of the complement system in tissue homeostasis and innate immunity and illustrate a novel mechanism by which the complement system combats persistent intracellular bacteria in epithelial cells.
Highlights
Encompassing more than 30 proteins, the complement system is an ancient part of innate immunity [1], and it was originally described for its ability to complement phagocytes and antibodies in microbial killing [2]
Since persistent intracellular bacteria presumably result in changes of cellular homeostasis, we investigated whether persistent intracellular Staphylococcus aureus (SA) in epidermal keratinocytes could alert the body’s intricate surveillance system, the complement system
We found no significant difference in light chain 3 (LC3) or lysosomal-associated membrane protein 1 (LAMP-1) staining, nor in Atg 5 and beclin-1 expression when comparing cells with intracellular SA treated with normal human serum (NHS) or heat-inactivated serum (HIS) (Figures S4B,C in Supplementary Material)
Summary
Encompassing more than 30 proteins, the complement system is an ancient part of innate immunity [1], and it was originally described for its ability to complement phagocytes and antibodies in microbial killing [2]. The complement system combats infections by detection of microbial intruders followed by lysis or opsonization to facilitate microbial clearance. The complement system plays a role as an intricate surveillance system by detecting altered host cells and facilitates clearance of dead or altered cells [1, 3]. Deficiency of C1q, which is important for clearance of apoptotic cells, is associated with systemic lupus erythematosus [5]. SA is commonly associated with skin infections [8], for example in diseases like atopic dermatitis (AD) [9], a chronic inflammatory pruritic skin disease characterized by dry skin, pruritus, erythema, edema, scaling, excoriations, oozing, and lichenification [9]. Disease flares of AD are associated with a microbial dysbiosis with abundance of SA [10, 11] suggested to drive inflammation [12]
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