Science - USA (2019-01-18)

INSIGHTS | PERSPECTIVES

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compete by producing antimicrobials, usu-
ally peptides, that directly kill specific spe-
cies or strains (bacteriocins) ( 3 ) or interfere
with their coordination of microbial group
behaviors (quorum-sensing inhibitors) ( 10 ).
In a systematic analysis of nasal isolates, S.
epidermidis was identified as an especially
frequent producer of antimicrobials ( 11 ). As
such, S. epidermidis may play a dominant
role in shaping the microbiota in defined
settings. This is illustrated by the microbiota
associated with atopic dermatitis (AD), a
type of eczema that is characterized by re-
curring flares of dry, itchy skin. These flares
are thought to be driven by colonization with

S. aureus and are associated with a loss of S.
epidermidis strains that produce S. aureus–
targeting bacteriocins. Reintroduction of a
cocktail of bacteriocin-producing microbes
decolonizes AD-affected sites of S. aureus
( 12 ), which suggests that this condition may
represent a target for ecology-based ther-
apy. This type of therapy, rather than elimi-
nating pathogens by brute force, leverages
understanding of the preferred niche of a
pathogen in order to make it less habitable.
The appeal of this approach is that, com-
pared to antibiotic therapy, it is much less
likely to harm the indigenous microbiota in
a patient. Such an approach could also pro-

vide an important strategy for the control of

antibiotic-resistant pathogens.

However, S. epidermidis does not always

act in the host’s interest. Although S. aureus

predominantly colonizes strong AD flares,

mixed populations of S. epidermidis strains

prevail in less severe flares ( 13 ). These strains

are genetically related to strains acquired in

hospitals, where S. epidermidis is one of the

most frequent causes of sepsis in newborns

( 9 ). A hallmark of these strains is the pres-

ence of staphylococcal chromosome cassette

(SCC) mec genetic elements that can encode

not only methicillin antibiotic resistance but

also a potent peptide toxin, the phenol-sol-

uble modulin PSM-mec. During sepsis, this

toxin mediates the killing of neutrophils (cru-

cial inflammatory immune cells), the survival

of S. epidermidis in blood, and ultimately

host death ( 14 ).

Furthermore, the ability of S. epidermidis

to limit inflammation can be exploited to the

advantage of pathogens such as S. aureus. In

the liver, macrophage uptake of the cell wall

polymer peptidoglycan from S. epidermidis

or other defined skin microbes strongly sup-

presses production of antimicrobial reactive

oxygen species. Because of this, bloodstream

infection by S. aureus and S. epidermidis—

for example, as a consequence of intravas-

cular catheterization—promotes S. aureus

survival in the liver and reduces its infectious

dose ( 15 ).

Although many of the products made

by S. epidermidis likely evolved for its sur-

vival on skin, these products can also have

unexpected, off-target effects. Remarkably,

one such product, 6-N-hydroxyaminopu-

rine (6-HAP), an antimicrobial that nor-

mally targets skin pathogens, has recently

been shown to inhibit tumor cell growth.

6-HAP, an analog of the DNA nucleotide

base adenine, interferes with the essential

process of DNA replication. Keratinocytes,

however, are resistant to 6-HAP because,

unlike tumor cells, they highly express en-

zymes that can detoxify 6-HAP. In mice,

topical application of 6-HAP–producing

strains of S. epidermidis protects against

ultraviolet-induced skin tumors ( 16 ). In-

triguingly, such strains are commonly

found on the skin of healthy human indi-

viduals, which suggests that the composi-

tion of the skin microbiota could affect the

development of skin tumors.

S. epidermidis has emerged as an influen-

tial, keystone member of the skin microbiota.

Although particular strains are contextually

pathogenic, their multifarious roles in skin

immunity and antimicrobial defense sug-

gest that most S. epidermidis strains bolster

our skin health overall. Much remains to be

learned about the beneficial role of the nu-

merous other microbes that constitute the

skin microbiota. Precise editing of the micro-

biota, such as by providing nutrients targeted

at promoting the growth of defined members

of the skin microbiota such as S. epidermi-

dis, or the direct application of purified mi-

crobiota-derived products may one day hold

strong therapeutic value in the fight against

skin inflammatory disorders, infections,

wounds, and cancer. j

REFERENCES AND NOTES

1. S. Naik et al., Nature 520 , 104 (2015).


2. R. L. Gallo, T. Nakatsuji, J. Invest. Dermatol. 131 , 1974 (2011).


3. B. Krismer et al., Nat. Rev. Microbiol. 15 , 675 (2017).


4. T. C. Scharschmidt et al., Cell Host Microbe 22 , 1 (2017).


5. J. A. Sanford et al., Sci. Immunol. 1 , eaah4609 (2016).


6. X. Xia et al., J. Invest. Dermatol. 136 , 621 (2016).


7. J. L. Linehan et al., Cell 172 , 784 (2018).


8. S. Naik et al., Science 337 , 1115 (2012).


9. M. Otto, Nat. Rev. Microbiol. 7 , 555 (2009).


10. A. E. Paharik et al., Cell Host Microbe 22 , 746 (2017).


11. D. Janek et al., PLOS Pathog. 12 , e1005812 (2016).


12. T. Nakatsuji et al., Sci. Transl. Med. 9 , eaah4680 (2017).


13. A. L. Byrd et al., Sci. Transl. Med. 9 , eaal4651 (2017).


14. L. Qin et al., PLOS Pathog. 13 , e1006153 (2017).


15. E. Boldock et al., Nat. Microbiol. 3 , 881 (2018).


16. T. Nakatsuji et al., Sci. Adv. 4 , eaao4502 (2018).

ACKNOWLEDGMENTS

Supported by the Intramural Research Program of the National

Institute of Allergy and Infectious Diseases (project number

1ZIAAI001115-09) (A.S. and Y.B.) and by a Postdoctoral

Research Associate Training fellowship from the National

Institute of General Medical Sciences (project number

1FI2GM128736-01) (A.S.).

10.1126/science.aat4326

Infammation

To x i n

(e.g., PSM)

Infammation

Promotion of

infection

Metabolic

by-products

(e. g. , S C FA s)

Control of infammation

Wound repair

AMPs

Innate receptor

(e.g., TLR2)

Cell wall

structures

(e.g., lipoprotein)

Pathogens

(e.g., S. aureus) Dendritic cell

Control of atopic

dermatitis

Control of

infection

Control of cancer

S. epidermidis

Keratinocyte

Keratinocyte

Antimicrobials

Pathogens

(e.g., S. aureus,

S. pyogenes)

Antigens

(e.g.,

formylated

peptides)

Treg

T cell

6 -HAP

228 18 JANUARY 2019 • VOL 363 ISSUE 6424

The multifaceted roles of S. epidermidis in skin physiology
S. epidermidis guards skin against inflammation, infections, and cancer through interactions with
keratinocytes, T cells, and other members of the skin microbiota. These interactions are strain- and context-
dependent, with some leading to negative outcomes for the host, including inflammation and infection.

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