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Lucky Number Seven: RNase 7 Can Prevent Staphylococcus aureus Skin Colonization

      Staphylococcus aureus colonization is a major risk factor for infection. In this issue, Simanski et al. demonstrate that the antimicrobial peptide RNase 7 is essential for preventing S. aureus colonization in human skin. These findings suggest that therapeutic interventions aimed at targeting RNase 7 production in the skin may be a novel strategy to protect against S. aureus infections.

      Antimicrobial peptides and skin host defense

      Human skin presents both a physical and an immunological barrier against invading microbial pathogens. In addition to contributing to the physical barrier, the stratum corneum contains antimicrobial peptides that act as a first line of defense against pathogenic microbial colonization and infection by pathogens such as bacteria, fungi, and viruses (
      • Lai Y.
      • Gallo R.L.
      AMPed up immunity: how antimicrobial peptides have multiple roles in immune defense.
      ). Whereas certain antimicrobial peptides are present in normal skin, others are induced upon exposure to pathogens or in response to skin wounding (
      • Miller L.S.
      • Sorensen O.E.
      • Liu P.T.
      • et al.
      TGF-alpha regulates TLR expression and function on epidermal keratinocytes.
      ;
      • Sorensen O.E.
      • Thapa D.R.
      • Roupe K.M.
      • et al.
      Injury-induced innate immune response in human skin mediated by transactivation of the epidermal growth factor receptor.
      ).
      The importance of antimicrobial peptides in preventing skin infections is highlighted in a study by Gallo and colleagues demonstrating that mice lacking expression of CRAMP, the mouse ortholog of human cathelicidin, are highly susceptible to cutaneous infection by Group A Streptococcus (
      • Nizet V.
      • Ohtake T.
      • Lauth X.
      • et al.
      Innate antimicrobial peptide protects the skin from invasive bacterial infection.
      ). Further evidence comes from a study by Gläser et al., which showed that the antimicrobial peptide psoriasin (S100A7) is essential for controlling Escherichia coli colonization on skin (
      • Gläser R.
      • Harder J.
      • Lange H.
      • et al.
      Antimicrobial psoriasin (S100A7) protects human skin from Escherichia coli infection.
      ). Gläser et al. found that inhibition of psoriasin on the surface of healthy human skin promoted the persistence of E. coli, indicating that psoriasin acts as a primary bactericidal factor against E. coli colonization. Thus, the production of specific antimicrobial peptides on the surface of the skin is essential to prevent pathogenic colonization and infection.

      A role for RNase 7 in the prevention of Staphylococcus aureus colonization

      S. aureus is a bacterial pathogen that has emerged as a leading cause of skin and soft tissue infections, including cellulitis, folliculitis, and impetigo (
      • Daum R.S.
      Clinical practice. Skin and soft-tissue infections caused by methicillin-resistant Staphylococcus aureus.
      ;
      • McCaig L.F.
      • McDonald L.C.
      • Mandal S.
      • et al.
      Staphylococcus aureus-associated skin and soft tissue infections in ambulatory care.
      ). In addition, the widespread prevalence of antibiotic-resistant strains, such as methicillin-resistant S. aureus, complicate treatment, creating serious public health concerns (
      • Klevens R.M.
      • Morrison M.A.
      • Nadle J.
      • et al.
      Invasive methicillin-resistant Staphylococcus aureus infections in the United States.
      ;
      • Moran G.J.
      • Krishnadasan A.
      • Gorwitz R.J.
      • et al.
      Methicillin-resistant S. aureus infections among patients in the emergency department.
      ). At any given time, approximately one-third of healthy individuals in the United States are colonized with S. aureus (
      • Graham III, P.L.
      • Lin S.X.
      • Larson E.L.
      A U.S. population-based survey of Staphylococcus aureus colonization.
      ). In addition, colonization is a risk factor for developing S. aureus infections, including skin infections as well as more invasive and potentially life-threatening infections such as pneumonia, bacteremia, and sepsis (
      • von Eiff C.
      • Becker K.
      • Machka K.
      • et al.
      Nasal carriage as a source of Staphylococcus aureus bacteremia. Study Group.
      ). Indeed, eradicating S. aureus colonization has proven to be an effective strategy to prevent postoperative S. aureus infections (
      • Bode L.G.
      • Kluytmans J.A.
      • Wertheim H.F.
      • et al.
      Preventing surgical-site infections in nasal carriers of Staphylococcus aureus.
      ;
      • Darouiche R.O.
      • Wall Jr, M.J.
      • Itani K.M.
      • et al.
      Chlorhexidine–alcohol versus povidone–iodine for surgical-site antisepsis.
      ). To develop immune-based therapeutic or preventative strategies against S. aureus colonization and infection, a greater understanding of the protective functions of antimicrobial peptides in human skin is essential. In the current issue, Simanski et al. report on the role of the antimicrobial peptide RNase 7 in the prevention of S. aureus colonization of human skin (
      • Simanski M.
      • Dressel S.
      • Gläser R.
      • et al.
      RNase 7 protects healthy skin from Staphylococcus aureus colonization.
      ).
      • Harder J.
      • Schroder J.M.
      RNase 7, a novel innate immune defense antimicrobial protein of healthy human skin.
      first identified RNase 7 by extracting it from human skin. They demonstrated that this antimicrobial peptide exhibited broad-spectrum antimicrobial activity in vitro against microorganisms, including S. aureus and E. coli. RNase 7 is constitutively expressed throughout the epidermis but is also present in abundant quantities in the stratum corneum of healthy human skin (
      • Koten B.
      • Simanski M.
      • Glaser R.
      • et al.
      RNase 7 contributes to the cutaneous defense against Enterococcus faecium.
      ). Its expression by cultured primary keratinocytes can be further induced by IL-1β, IFN-γ, and bacterial challenge (
      • Harder J.
      • Schroder J.M.
      RNase 7, a novel innate immune defense antimicrobial protein of healthy human skin.
      ). To evaluate the potential role of RNase 7 in protecting against S. aureus skin colonization,
      • Simanski M.
      • Dressel S.
      • Gläser R.
      • et al.
      RNase 7 protects healthy skin from Staphylococcus aureus colonization.
      ) investigated RNase 7 production in human skin explants in the context of bacterial challenge with S. aureus. They demonstrate that skin extracts derived from the stratum corneum of healthy skin contain significant concentrations of active RNase 7 with bactericidal activity against S. aureus (Figure 1). Furthermore, RNase 7 was produced rapidly within 2 hours after S. aureus bacterial challenge, resulting in high levels of RNase 7 in the stratum corneum. These high levels were sufficient to control S. aureus growth effectively on the surface of the skin, preventing colonization. Additionally, bactericidal activity could be blocked by an RNase 7–specific neutralizing antibody, confirming that RNase 7 is an essential antimicrobial peptide produced by human skin to control S. aureus growth. These findings are consistent with a previous report demonstrating that lower baseline levels of RNase 7 expression were associated with S. aureus skin infections in previously healthy individuals (
      • Zanger P.
      • Holzer J.
      • Schleucher R.
      • et al.
      Constitutive expression of the antimicrobial peptide RNase 7 is associated with Staphylococcus aureus infection of the skin.
      ). Taken together, these studies provide evidence that the expression level of RNase 7 in the skin is an important factor that contributes to the susceptibility of human skin to S. aureus colonization.
      Figure thumbnail gr1
      Figure 1RNase 7 protects against Staphylococcus aureus skin colonization. RNase 7 is expressed constitutively in the epidermis of normal skin and can act as a chemical shield to prevent the growth of S. aureus (left). Upon exposure to S. aureus, keratinocytes produce large amounts of RNase 7, which accumulate at high levels in the stratum corneum and prevent colonization by S. aureus (center). Addition of an RNase 7–specific neutralizing antibody blocked the killing of S. aureus in the stratum corneum, demonstrating the key role of RNase 7 in preventing colonization (right).

      Other cutaneous immune responses that inhibit S. aureus colonization

      Although this study points to a key role for RNase 7 in preventing S. aureus colonization, other antimicrobial peptides have also been implicated in inhibiting S. aureus colonization and infection in skin. Specifically, β-defensin 3 (hBD-3) and cathelicidin have potent bactericidal activity against S. aureus, and β-defensin 2 (hBD-2) has bacteriostatic activity against S. aureus (
      • Braff M.H.
      • Zaiou M.
      • Fierer J.
      • et al.
      Keratinocyte production of cathelicidin provides direct activity against bacterial skin pathogens.
      ;
      • Harder J.
      • Bartels J.
      • Christophers E.
      • et al.
      A peptide antibiotic from human skin.
      ,
      • Harder J.
      • Bartels J.
      • Christophers E.
      • et al.
      Isolation and characterization of human beta-defensin-3, a novel human inducible peptide antibiotic.
      ). Much of the evidence that these antimicrobial peptides are important in host defense against S. aureus skin infection in vivo has come from studying two chronic inflammatory skin diseases that represent extremes in the spectrum of susceptibility to S. aureus. Patients suffering from atopic dermatitis are highly susceptible to S. aureus infection, whereas those with psoriasis are resistant to infection (
      • Ong P.Y.
      • Ohtake T.
      • Brandt C.
      • et al.
      Endogenous antimicrobial peptides and skin infections in atopic dermatitis.
      ). Although many factors likely contribute to this difference, a strong association between susceptibility and the expression of antimicrobial peptides in human skin has been observed. In particular, the antimicrobial peptides hBD-2, hBD-3, and cathelicidin have all been shown to be present at significantly lower concentrations in skin lesions of patients with atopic dermatitis compared with the levels found in skin lesions of patients with psoriasis (
      • Ong P.Y.
      • Ohtake T.
      • Brandt C.
      • et al.
      Endogenous antimicrobial peptides and skin infections in atopic dermatitis.
      ;
      • Kisich K.O.
      • Carspecken C.W.
      • Fieve S.
      • et al.
      Defective killing of Staphylococcus aureus in atopic dermatitis is associated with reduced mobilization of human beta-defensin-3.
      ). This reduction in antimicrobial peptides has been proposed to contribute to the increased susceptibility to S. aureus colonization and infection in atopic dermatitis patients. Although it is tempting to speculate that decreased RNase 7 expression may also contribute to the increased susceptibility to S. aureus in atopic dermatitis, this may not be the case because a recent study found a lack of correlation between RNase 7 expression and S. aureus colonization in atopic dermatitis (
      • Harder J.
      • Dressel S.
      • Wittersheim M.
      • et al.
      Enhanced expression and secretion of antimicrobial peptides in atopic dermatitis and after superficial skin injury.
      ).
      Figure thumbnail fx1
      There is growing evidence that T-cell responses may also play a role in controlling S. aureus colonization and infection. In the skin of patients with atopic dermatitis, the predominance of Th2 cytokines inhibits the production of certain antimicrobial peptides, especially hBD-2 and hBD-3, which likely contributes to increased susceptibility to S. aureus colonization (
      • Nomura I.
      • Goleva E.
      • Howell M.D.
      • et al.
      Cytokine milieu of atopic dermatitis, as compared to psoriasis, skin prevents induction of innate immune response genes.
      ). More recently, expression of the Th17 cytokines IL-17A and IL-22 have been demonstrated to upregulate the production of several antimicrobial peptides, including hBD-2, S100A7 (psoriasin), S100A8, and S100A9, in primary keratinocytes (
      • Liang S.C.
      • Tan X.Y.
      • Luxenberg D.P.
      • et al.
      Interleukin (IL)-22 and IL-17 are coexpressed by Th17 cells and cooperatively enhance expression of antimicrobial peptides.
      ). Additionally, a role for Th17 cells is supported by studies in mice and humans demonstrating that a deficiency in IL-17-producing T cells results in an increased susceptibility to cutaneous S. aureus infection (
      • Cho J.S.
      • Pietras E.M.
      • Garcia N.C.
      • et al.
      IL-17 is essential for host defense against cutaneous Staphylococcus aureus infection in mice.
      ;
      • Milner J.D.
      • Brenchley J.M.
      • Laurence A.
      • et al.
      Impaired T(H)17 cell differentiation in subjects with autosomal dominant hyper-IgE syndrome.
      ;
      • Ma C.S.
      • Chew G.Y.
      • Simpson N.
      • et al.
      Deficiency of Th17 cells in hyper IgE syndrome due to mutations in STAT3.
      ;
      • Renner E.D.
      • Rylaarsdam S.
      • nover-Sombke A.
      • et al.
      Novel signal transducer and activator of transcription 3 (STAT3) mutations, reduced T(H)17 cell numbers, and variably defective STAT3 phosphorylation in hyper-IgE syndrome.
      ). However, a role for T-cell responses in modulating the expression of RNase 7 in the skin has not been described. Further investigation will be required to determine whether T-cell-derived cytokines can regulate RNase 7 expression, thereby influencing susceptibility to S. aureus colonization and infection in the skin.

      Perspectives

      With the epidemic of S. aureus infections and the widespread emergence of antibiotic-resistant strains, there is considerable urgency to identify novel therapeutic approaches that combat this important human pathogen. Because colonization represents a major risk factor for infection, decreasing colonization by S. aureus may be an effective preventative strategy. Research into the natural antimicrobial peptide defense system in human skin has yielded promising candidates. The work of
      • Simanski M.
      • Dressel S.
      • Gläser R.
      • et al.
      RNase 7 protects healthy skin from Staphylococcus aureus colonization.
      ) highlights the potential of one such molecule, RNase 7, an antimicrobial peptide that is constitutively present at sufficient levels in healthy human skin to prevent S. aureus colonization. Improved understanding of how the expression of this molecule is regulated will be crucial in developing new strategies to prevent pathogenic microbial colonization of skin. As such, RNase 7 warrants further investigation as a target for future immune-based therapeutic strategies against cutaneous S. aureus colonization and infection.

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