Teruaki Nakatsuji, Tiffany H. Chen, Anna M. Butcher, Lynnie L. Trzoss, Sang-Jip Nam,, Karina T. Shirakawa, Wei Zhou, Julia Oh, Michael Otto, William Fenical, and Richard L. Gallo
We report the discovery that strains of Staphylococcus epidermidis produce 6-N-hydroxyaminopurine (6-HAP), a molecule that inhibits DNA polymerase activity. In culture, 6-HAP selectively inhibited proliferation of tumor lines but did not inhibit primary keratinocytes. Resistance to 6-HAP was associated with the expression of mitochondrial amidoxime reducing components, enzymes that were not observed in cells sensitive to this compound. Intravenous injection of 6-HAP in mice suppressed the growth of B16F10 melanoma without evidence of systemic toxicity. Colonization of mice with an S. epidermidis strain producing 6-HAP reduced the incidence of ultraviolet-induced tumors compared to mice colonized by a control strain that did not produce 6-HAP. S. epidermidis strains producing 6-HAP were found in the metagenome from multiple healthy human subjects, suggesting that the microbiome of some individuals may confer protection against skin cancer. These findings show a new role for skin commensal bacteria in host defense.
Sci Adv. 2018 Feb; 4(2): eaao4502.
Published online 2018 Feb 28.
Ling-juan Zhang, Stella Xiang Chen, Christian F. Guerrero-Juarez, Fengwu Li, Yun Tong, Yuqiong Liang, Marc Liggins, Xu Chen, Hao Chen, Min Li, Tissa Hata, Ye Zheng, Maksim V. Plikus, Richard L.Gallo
Dermal fibroblasts (dFBs) resist infection by locally differentiating into adipocytes and producing cathelicidin antimicrobial peptide in response to Staphylococcus aureus (S. aureus). Here, we show that neonatal skin was enriched with adipogenic dFBs and immature dermal fat that highly expressed cathelicidin. The pool of adipogenic and antimicrobial dFBs declined after birth, leading to an age-dependent loss of dermal fat and a decrease in adipogenesis and cathelidicin production in response to infection. Transforming growth factor beta (TGF-β), which acted on uncommitted embryonic and adult dFBs and inhibited their adipogenic and antimicrobial function, was identified as a key upstream regulator of this process. Furthermore, inhibition of the TGF-β receptor restored the adipogenic and antimicrobial function of dFBs in culture and increased resistance of adult mice to S. aureus infection. These results provide insight into changes that occur in the skin innate immune system between the perinatal and adult periods of life.
• Neonatal skin is enriched with immature fat and adipogenic dermal fibroblasts
• Dermal immature fat and adipogenic-antimicrobial dFBs are lost with age
• TGF-β pathway promotes the age-related adipogenic-to-fibrotic switch of dFBs
• Inhibition of TGFBR restores antimicrobial function of dFBs in adult mice
Volume 50, Issue 1, 15 January 2019, Pages 121-136.e5
Michael R. Williams, Stephen K. Costa, Livia S. Zaramela, Shadi Khalil, Daniel A. Todd, Heather L. Winter, James A. Sanford, Alan M. O’Neill, Marc C. Liggins, Teruaki Nakatsuji, Nadja B. Cech, Ambrose L. Cheung, Karsten Zengler, Alexander R. Horswill, and Richard L. Gallo
Staphylococcus aureus is both a normal skin-resident species and a common bad actor in inflammatory skin conditions. Williams et al. showed that S. aureus relies on quorum sensing to secrete certain toxins and proteases that can cause epithelial barrier damage. Coagulase-negative staphylococci (CoNS) normally present on human skin, however, secreted autoinducing peptides that inhibited quorum sensing in S. aureus and hence secretion of these virulence factors. A CoNS autoinducing peptide also reduced S. aureus–induced skin inflammation in mice. Analysis of the skin microbiome of patients with atopic dermatitis suggested that the ratio of protective CoNS to S. aureus may be a factor in the pathogenesis of this condition.
Colonization of the skin by Staphylococcus aureus is associated with exacerbation of atopic dermatitis (AD), but any direct mechanism through which dysbiosis of the skin microbiome may influence the development of AD is unknown. Here, we show that proteases and phenol-soluble modulin α (PSMα) secreted by S. aureus lead to endogenous epidermal proteolysis and skin barrier damage that promoted inflammation in mice. We further show that clinical isolates of different coagulase-negative staphylococci (CoNS) species residing on normal skin produced autoinducing peptides that inhibited the S. aureus agr system, in turn decreasing PSMα expression. These autoinducing peptides from skin microbiome CoNS species potently suppressed PSMα expression in S. aureus isolates from subjects with AD without inhibiting S. aureus growth. Metagenomic analysis of the AD skin microbiome revealed that the increase in the relative abundance of S. aureus in patients with active AD correlated with a lower CoNS autoinducing peptides to S. aureus ratio, thus overcoming the peptides’ capacity to inhibit the S. aureus agr system. Characterization of a S. hominis clinical isolate identified an autoinducing peptide (SYNVCGGYF) as a highly potent inhibitor of S. aureus agr activity, capable of preventing S. aureus–mediated epithelial damage and inflammation on murine skin. Together, these findings show how members of the normal human skin microbiome can contribute to epithelial barrier homeostasis by using quorum sensing to inhibit S. aureus toxin production.
Science Translational Medicine 01 May 2019:
Vol. 11, Issue 490, eaat8329
- Science Translational Medicine article
S. aureus aggravates skin conditions such as atopic dermatitis. Photo courtesy of NIAID.
Teruaki Nakatsuji, Tiffany H. Chen, Saisindhu Narala, Kimberly A. Chun, Aimee M. Two, Tong Yun, Faiza Shafiq, Paul F. Kotol, Amina Bouslimani, Alexey V. Melnik, Haythem Latif, Ji-Nu Kim, Alexandre Lockhart, Keli Artis, Gloria David, Patricia Taylor, Joanne Streib, Pieter C. Dorrestein, Alex Grier, Steven R. Gill, Karsten Zengler, Tissa R. Hata, Donald Y. M. Leung and Richard L. Gallo
The microbiome can promote or disrupt human health by influencing both adaptive and innate immune functions. We tested whether bacteria that normally reside on human skin participate in host defense by killing Staphylococcus aureus, a pathogen commonly found in patients with atopic dermatitis (AD) and an important factor that exacerbates this disease. High-throughput screening for antimicrobial activity against S. aureus was performed on isolates of coagulase-negative Staphylococcus (CoNS) collected from the skin of healthy and AD subjects. CoNS strains with antimicrobial activity were common on the normal population but rare on AD subjects. A low frequency of strains with antimicrobial activity correlated with colonization by S. aureus. The antimicrobial activity was identified as previously unknown antimicrobial peptides (AMPs) produced by CoNS species including Staphylococcus epidermidis and Staphylococcus hominis. These AMPs were strain-specific, highly potent, selectively killed S. aureus, and synergized with the human AMP LL-37. Application of these CoNS strains to mice confirmed their defense function in vivo relative to application of nonactive strains. Strikingly, reintroduction of antimicrobial CoNS strains to human subjects with AD decreased colonization by S. aureus. These findings show how commensal skin bacteria protect against pathogens and demonstrate how dysbiosis of the skin microbiome can lead to disease.
reprint here and full text here
Science Translational Medicine 22 Feb 2017:
Vol. 9, Issue 378,
James A. Sanford, Ling-Juan Zhang, Michael R. Williams, Jon A. Gangoiti,
Chun-Ming Huang, Richard L. Gallo
Epidermal keratinocytes participate in immune defense through their capacity to recognize danger, trigger inflammation,
and resist infection. However, normal skin immune function must tolerate contact with an abundant community
of commensal microbes without inflammation. We hypothesized that microbial environmental conditions dictate the
production of molecules that influence epigenetic events and cause keratinocytes to break innate immune tolerance.
Propionibacterium acnes, a commensal skin bacterium, produced the short-chain fatty acids (SCFAs) propionate and
valerate when provided a lipid source in hypoxic growth conditions, and these SCFAs inhibited histone deacetylase
(HDAC) activity. Inhibition of HDAC activity in keratinocytes promoted cytokine expression in response to Toll-like
receptor (TLR) ligands for TLR2 or TLR3. This response was opposite to the action of HDAC inhibition on production
of inflammatory cytokines bymonocytes and involved HDAC8 and HDAC9 because small interfering RNA silencing of
these HDACs recapitulated the activity of SCFAs. Analysis of cytokine expression in mice confirmed the response of the
epidermis where application of SCFA on the skin surface promoted cytokine expression, whereas subcutaneous
administration was inhibitory. These findings show that the products of commensal microbes made under specific
conditions will inhibit HDAC activity and break tolerance of the epidermis to inflammatory stimuli.
Sanford et al., Sci. Immunol. 1, eaah4609 (2016) 28 October 2016
Zhang LJ, Gallo RL
Antimicrobial peptides and proteins (AMPs) are a diverse class of naturally occurring molecules that are produced as a first line of defense by all multicellular organisms. These proteins can have broad activity to directly kill bacteria, yeasts, fungi, viruses and even cancer cells. Insects and plants primarily deploy AMPs as an antibiotic to protect against potential pathogenic microbes, but microbes also produce AMPs to defend their environmental niche. In higher eukaryotic organisms, AMPs can also be referred to as 'host defense peptides', emphasizing their additional immunomodulatory activities. These activities are diverse, specific to the type of AMP, and include a variety of cytokine and growth factor-like effects that are relevant to normal immune homeostasis. In some instances, the inappropriate expression of AMPs can also induce autoimmune diseases, thus further highlighting the importance of understanding these molecules and their complex activities. This Primer will provide an update of our current understanding of AMPs.
Copyright © 2016 Elsevier Ltd. All rights reserved.
Curr Biol. 2016 Jan 11;26(1):R14-9.
PubMed (NCBI) References (link)