In general, knowledge about the molecular mechanisms of biofilm formation and its regulation in S. Furthermore, there is evidence indicating that important biofilm factors are expressed in vivo 58 , Nevertheless, there is an urgent need for more detailed in vivo research providing mechanistic insight into S. A recently constructed bioluminescent strain of a biofilm-forming clinical isolate of S.
The pseudopeptide polymer PGA, which is synthesized by the gene products of the cap locus, is crucial for S. Except for Bacillus anthracis 50 , S. Furthermore, PGA promotes growth of S. Finally, expression of the cap genes appears to be increased during the biofilm mode of growth It may thus also work by sequestering oppositely charged AMPs in a way similar to the proposed mechanism of protection from tobramycin by Pseudomonas aeruginosa alginate Pathogen-associated molecular patterns PAMPs are structures on the bacterial surface that the innate immune system recognizes as non-self via dedicated pathogen recognition receptors PRRs , such as the Toll-like receptors TLRs Recognition of PAMPs acivates host defense mechanisms that include phagocytosis and cytokine release PAMPs such as lipoproteins and lipoteichoic acids are common in Gram-positive bacteria.
Furthermore, there are reports suggesting that several additional molecules that are specific to S. However, this has not been confirmed using genetic deletion mutants, which is important to rule out that contaminating strongly pro-inflammatory substances such as lipoproteins were the basis of the observed effect, a situation that has led to frequent misidentification of alleged TLR2 stimulators — Similarly, pro-inflammatory capacities of S. However, their similarity to S.
Finally, an unusual short-chain pro-inflammatory lipoteichoic acid has been described in S. However, the chemical characterization of the purified molecule does not indicate a teichoic acid-related polymer, and thus the identity of this molecule and the reported pro-inflammatory activity certainly require confirmation. Thus, there is a clear need for further characterization of S. In a way similar to the recognition of S. Specifically, an AMP-sensing system has been identified, termed aps , that is activated by a variety of AMPs and triggers up-regulation of staphylococcal AMP-defensive systems 59 , including D-alanylation of teichoic acids 60 , lysylation of phospholipids by the MprF enzyme , and the VraFG proteins 61 Fig.
Importantly, activation and protective response of the aps system is limited to cationic AMPs. Cationic AMPs attach to the negatively charged bacterial surface and membrane by electrostatic interaction, a prerequisite for AMP antimicrobial activity, which is often based on pore formation in the bacterial cytoplasmic membrane.
Transduction of this signal via ApsS and the accessory, essential ApsX, which has a yet unknown function, triggers expression of key AMP resistance mechanisms. The D-alanylation of teichoic acids, encoded by the products of the dlt operon, and lysylation of phosphatidylglycerol, catalyzed by the MprF enzyme, result in a decreased negative charge of the cell surface and membrane, respectively, leading to decreased attraction, or repulsion, of cationic AMPs.
In contrast to the vast toxin repertoire of S. While strain-specific production of enterotoxins has been described , , S. In contrast, all except naturally agr dysfunctional S.
Some S. However, the PSM production pattern in S. Thus, the PSM production pattern, in addition to the general absence of highly aggressive toxins in S. This underpins the Massey et al. Several studies have attempted to identify determinants that distinguish S. These studies focused on putative virulence determinants or used genome-wide approaches such as comparative genomic hybridization 14 — 16 , Two main putative determinants of S.
IS is believed to contribute to genetic adaptation that may play a role during infection In addition, results from a human colonization model indicate that ica -negative strains may even have a selective advantage over ica -positive strains on the skin However, there is also evidence suggesting that when corrected for clonal relatedness, there may not be any differences between commensal and infectious strains Furthermore, intercellular adhesion by PIA and biofilm-related proteins can be assumed to be vital in an environment such as the skin, where there is considerable mechanical stress for the bacteria.
Finally, the role of PGA in osmotolerance 49 suggests an original function of this polymer in the non-infectious lifestyle of S. Moreover, there is no clear evidence indicating differences between infectious and commensal strains for the multitude of S.
This makes sense, as adhesion to host tissue is considered imperative during both these lifestyles. Together, this suggests that S. Determinants that are believed to contribute to both S. Other roles are based on in vitro experiments and environmental challenges during colonization and infection. Not shown are regulators such as agr or sigB that control many of the depicted determinants and may thus also have important functions during both S.
Specific antibiotic resistance genes are widespread in S. High-level resistance to methicillin is encoded on mobile genetic elements MGEs , namely the staphylococcal cassette chromosome mec SCC mec , which contains the mecA gene encoding a penicillin-binding protein, PBP2a, with decreased affinity for methicillin compared to other PBPs SCC mec type IV poses a particular problem, as it does not impose a fitness cost to its host and may thus spread without selective antibiotic pressure Interestingly, closely related strains may carry different SCC mec types, indicating frequent loss and acquisition of SCC mec elements by S.
In addition to methicillin resistance, S. Very rarely, there is resistance to streptogramins, linezolid, and tigecycline. Most antibiotic resistance genes are plasmid-encoded and more often found in methicillin-resistant than methicillin-susceptible strains This likely has no molecular reasons, but is due to the fact that both resistance to methicillin and other antibiotics is frequent among endemic nosocomial strains. However, intermediate resistance to vancomycin has been described Additionally, staphylococcal biofilm formation significantly decreases the activity of vancomycin and other antibiotics — The frequency of antibiotic resistance in S.
Furthermore, the ubiquity of S. Accordingly, there is evidence suggesting that methicillin resistance cassettes were transferred from S. It enabled the combination of methicillin resistance at no cost for fitness paired with exceptional virulence, which is the main molecular basis of the epidemic caused by CA-MRSA These findings emphasize an important role of S.
Together, these considerations highlight the need for prophylactic measures against S. Vaccination and decolonization, often discussed for other pathogens including S.
First, there is no anti-staphylococcal vaccine and several lines of evidence indicate that it may be very difficult to use traditional active immunization for staphylococci , Second, eradication of S.
Thus, it is commonly agreed upon that the best way to deal with S. Interestingly, while S. The recent investigation of CRISPR Clustered Regularly Interspaced Short Palindromic Repeats sequences, short repeats that are involved in preventing uptake of conjugative elements such as phages and conjugative plasmids, may provide an explanation of why the transfer of MGEs between S. These sequences have only been found in S.
To evaluate potential novel strategies to combat S. To that end, we should more thoroughly investigate determinants that ensure survival of S. Furthermore, the interaction of S. For several of these tasks, it would be helpful to determine the genome sequence of additional S. Finally, the molecular mechanisms influencing biofilm-associated infection of S. National Center for Biotechnology Information , U.
Nat Rev Microbiol. Author manuscript; available in PMC Aug 1. Michael Otto , Ph. Author information Copyright and License information Disclaimer.
Copyright notice. The publisher's final edited version of this article is available at Nat Rev Microbiol. See other articles in PMC that cite the published article. An opportunistic pathogen As part of the human epithelial microflora, S. The staphylococcal accessory gene regulator agr quorum-sensing system and cross-inhibition by agr autoinducing peptides AIPs Quorum-sensing in staphylococci is accomplished by the agr system, which consists of an AIP precursor peptide maturation and export enzyme AgrB and a two-component signal transduction system AgrC, AgrA Evasion of host defenses Pathogen survival in the human body requires evasion of host defenses.
Biofilm formation Biofilms are multicellular, surface-attached agglomerations of microorganisms. Open in a separate window. Figure 1. Biofilm development in S. Figure 2. Figure 3. Biofilm detachment In contrast to intercellular aggregation, S. Figure 4. Phenol-soluble modulins Sequence alignment of S.
Protective exopolymers S. Pathogen-associated molecular patterns Pathogen-associated molecular patterns PAMPs are structures on the bacterial surface that the innate immune system recognizes as non-self via dedicated pathogen recognition receptors PRRs , such as the Toll-like receptors TLRs Sensing of antimicrobial peptides In a way similar to the recognition of S. Figure 5. Toxins In S. Colonization and pathogenesis Several studies have attempted to identify determinants that distinguish S.
Figure 6. Antibiotic resistance and prophylaxis Specific antibiotic resistance genes are widespread in S. Unidirectional horizontal gene transfer? Outlook To evaluate potential novel strategies to combat S.
Glossary Biofilms Multicellular agglomerations of microorganisms on a surface with a characteristic three-dimensional structure and physiology. Quorum-sensing Cell density-dependent gene regulation in bacteria. Quorum-sensing systems in Gram-positive bacteria commonly contain peptide-based secreted signals and a membrane-located sensor. The staphylococcal quorum-sensing system is termed agr accessory gene regulator and controls a series of genes involved in metabolism and virulence.
Innate host defense Part of the immune system that provides first line of defense, fast response to invading microorganisms, based on recognition of pathogen-associated molecular patterns PAMPs.
Consists mainly of phagocytes, platelets, and secreted antimicrobial peptides AMPs. PAMPs or pathogen-associated molecular patterns. Surface structures on pathogens that the innate immune system recognizes as non-self and which trigger activation of innate host defense commonly by binding to toll-like receptors TLRs. Acquired host defense Part of the immune system that depends on antigen-dependent clonal expansion of T and B cells after antigen presentation by professional antigen-presenting cells.
Provides long-term humoral e. Neutrophils short for neutrophil granulocytes or polymorphonuclear leukocytes - PMNs , the most abundant leukocytes in human blood. Neutrophils are the primary cells in charge of eliminating invading microorganisms by uptake and subsequent killing via reactive oxygen species and antimicrobial proteins and peptides. Antimicrobial peptides or AMPs, peptides with antimicrobial activity, such as defensins, cathelicidins, etc.
Sortase Enzyme that covalently links secreted bacterial surface proteins to peptidoglycan. Teichoic acids Anionic cell envelope glycopolymer in Gram-positive bacteria composed of many identical sugar-phosphate repeating units. May be linked to peptidoglycan wall teichoic acids or the cytoplasmic membrane via a lipid anchor lipoteichoic acids. Two-component system or TCS, bacterial sensory system composed of a membrane-located sensor histidine kinase and a cytoplasmic DNA-binding regulatory protein response regulator , whose autophosphorylation-dependent activation is triggered by an extracellular signal.
Enterotoxin a protein toxin released by a microorganism into the intestine. Methicillin Penicillin derivative that is resistant to penicillinase an enzyme widespread in staphylococci providing resistance to penicillin. Mobile genetic elements or MGEs, DNA such as plasmids or transposons that may be exchanged between bacteria by horizontal gene transfer, and which often carry virulence or antibiotic resistance genes. References 1.
Am J Infect Control. Uckay I, et al. Foreign body infections due to Staphylococcus epidermidis. Ann Med. Bacterial biofilms: a common cause of persistent infections.
Kloos W, Schleifer KH. In: Bergey's Manual of Systematic Bacteriology. Most colonies appear relatively smooth, glossy, butyrous, and sometimes appearing wet. Colonies of most strains are usually opaque and may be pigmented white or cream and sometimes yellow to orange. Facultatively anaerobic. Chemoorganotrophic, having both a fermentative and respiratory type metabolism. Mainly associated with skin, glands and mucous membranes of mammals and birds. Often found in the mouth, blood, mammary glands, intestinal and respiratory tracts of humans and warm-blooded animals.
Frequently, non-human primates carry large populations of S. Species have been isolated from food products, dust, and water. Some species produce extracellular toxins. Some of the major infections involve the skin and include furuncles or boils, cellulitis, impetigo, toxic epidermal necrolysis, scalded skin syndrome, and postoperative wound infections or of various sites.
Other major infections produced by S. Food poisoning is often attributed to staphylococcal enterotoxin. Holt, J. Bergey's Manual of Determinative Bacteriology , 9th ed. Possibly, local concentrations in epithelial microenvironments may be higher than what expression levels would suggest, and sufficient to kill microorganisms in vivo. Furthermore, the conditions used in minimal inhibitory concentration or killing assays in vitro are not standardized, may vary significantly, and very likely do not adequately reflect the physiological conditions on the skin.
On the other hand, growth in low-nutrient media with serum components and carbonate, which probably better resembles skin conditions, appears to increase bacterial susceptibility to AMPs [ ]. This indicates that physiological components that may increase the activity of AMPs in vivo might be lacking from most in vitro assays being used. Thus, while the physiological conditions present in the microenvironments on the human skin can only be guessed and hardly reproduced in vitro , in vitro assays used so far may have led to an underestimation of AMP potency in vivo.
Some, although circumstantial, evidence for a key role of AMPs in controlling bacterial colonization and infection of the skin is derived from differential AMP expression in certain diseases, such as atopic dermatitis, psoriasis and acne vulgaris [ ]. Atopic dermatitis is a chronic inflammatory skin disease that is associated with recurrent infections. Lesions and unaffected skin in atopic dermatitis patients are colonized by S.
Furthermore, in the inflammatory skin disease psoriasis, many AMPs are overexpressed, which has not only facilitated purification of many AMPs [ ], but may also explain the lower risk for bacterial infection observed in psoriatic skin [ ]. Finally, the most important bacterial causative agent of acne vulgaris, Propionibacterium acnes , triggers overexpression of some AMPs such as hBD-1 and hBD-2 [ , ]. Together, these observations suggest that differential expression of certain AMPs may be triggered by bacterial pathogens and affect bacterial colonization and infection.
Furthermore, evidence for AMP importance in vivo has been achieved using knockout mice. This approach is difficult and only works for some selected AMPs, as AMP production and genes are very different between mice and men. In an important study, it has been shown that mice deleted in the Cnlp genes have increased susceptibility for infection by Group A streptococci, representing the first evidence from knockout mice indicating a key role of AMPs in bacterial infection [ ].
Moreover, the AMPs hBD-2 and hBD-3 likely play a key role during selection of carrier versus noncarrier strains during nasal colonization. It has been suggested that S. Finally, the fact that bacteria have developed specific resistance mechanisms to AMPs [ ], which will be presented in the next paragraph, clearly underlines the importance of AMPs in battling bacterial colonizers. Thus, although direct evidence has been hard to achieve, AMPs are now commonly agreed to form a key part of innate host defense on the human skin.
Bacteria have developed several efficient mechanisms to combat the activity of AMPs [ ]. Secreted bacterial proteases may degrade AMPs. Specific secreted bacterial proteins can sequester AMPs, and thus prevent them from reaching their cellular target. In addition, there are many membrane-located transporters that export AMPs in a drug exporter-like fashion. Moreover, many mechanisms alter the bacterial cell surface net charge to minimize attraction of the commonly cationic AMPs.
Staphylococci, as the most important bacterial colonizers of the human skin, have developed mechanisms belonging to all of these four categories Table 2. For example, the S. The homologous S. Finally, there are many AMP resistance mechanisms in staphylococci that involve alteration of surface charge. Usually, these lead to a decrease of the anionic character of surface or cytoplasmic membrane structures, thus preventing attraction of cationic AMPs.
Several of these mechanisms have first been described in staphylococci. The enzyme MprF produces lysinylated phospholipids, whose integration into the cytoplasmic membrane decreases the overall negative charge of this direct target structure for many AMPs [ ]. The proteins encoded in the dlt locus are responsible for introducing alanyl residues in teichoic acids [ ]. The free amino groups of the carboxy-esterified alanyl residues act to partially counterbalance the strongly anionic character of teichoic acids, thus minimizing AMP attraction [ ].
However, surface polymers may also act to eliminate AMPs using different mechanisms. Thus, it may function either by repulsion or sequestration, or possibly by providing a structural barrier. Finally, some AMP resistance mechanisms may also provide protection from specific antibiotics, which is likely due to structural and physico—chemical similarities with AMPs, for example in the case of the cationic cyclic lipopeptide daptomycin [ ].
Host adaptations to bacterial AMP resistance mechanisms exemplify the interplay between innate host defense and bacteria during evolution [ ]. These include, for example, the production of anionic AMPs, such as DCD, to subvert bacterial resistance mechanisms that exclusively target cationic AMPs, or the development of protease-resistant AMPs such as the heavily bridged defensins.
Bacteria, in addition to having developed AMP resistance mechanisms, have learned to sense the presence of sub-lethal concentrations of AMPs [ ]. This means that expression of resistance genes can be limited to times when they are needed, which is beneficial for the bacteria, because expression of AMP resistance genes often involves significant physiological changes that likely represent a considerable energetic burden.
The Aps system, which has also been investigated in S. While genes similar to apsS and apsR exist in other bacteria, apsX homologs are found only in staphylococci, indicating that the aps -based sensing of AMPs may be a unique staphylococcal property [ ]. Furthermore, AMPs trigger in an apparently less specific way the altered expression of global regulatory systems including agr , sarA and saeRS , leading to increased secretion of proteases, such as of S.
Thus, the capacities to express a broad series of AMP resistance mechanisms and respond to the presence of AMPs may contribute to the exceptional ability of staphylococci to colonize human epithelia. Progress in our understanding of staphylococcal colonization of the skin and the molecular factors involved therein is linked to the development and use of suitable animal colonization models.
Quite understandably, the staphylococcal research community has mostly been focused on infection and infection models. However, colonization has recently been recognized as an important area of research, predominantly owing to the occurrence of CA-MRSA and the likely high importance of colonization as a prerequisite for infection with these strains.
Several researchers have proposed decolonization strategies to prevent staphylococcal infections [ , ]. To find targets for vaccine development aimed at preventing colonization, we need to better understand which molecular factors staphylococci rely on to colonize the human skin and mucous membranes. While decolonization of coagulase-negative staphylococci, such as S. Animal models for staphylococcal colonization are in their infancy.
Models for nasal colonization have been used in mice and cotton rats [ , ]. However, prolonged colonization is difficult to achieve, and the time the animals need to clear staphylococci from the nose in these models is relatively short, with cotton rats showing longer colonization than mice.
Monitoring permanent colonization, such as is seen in humans, is therefore so far not possible. However, with more laboratories using these models, they may become optimized over time.
Rarely, human subjects have been used to monitor colonization [ ], but for obvious reasons, this approach is limited to less virulent species such as S. Tissue culture studies may provide some insight into the interaction of staphylococci with, for example, keratinocytes, but such in vitro systems lack the complicated build-up of real skin to adequately reflect the complexity of that interaction.
The relative importance of AMPs in determining staphylococcal colonization and for the interplay between the innate immune system and bacteria in general is still a mystery. As discussed above, evidence to support a key role of AMPs in the cutaneous defense against microorganisms is mainly circumstantial.
To better judge the relative importance of AMPs, in vitro assay conditions should be standardized and adjusted to reflect physiological settings more closely. While the use of animals is difficult in this area owing to the differences with humans regarding AMP genes, the immense progress in human genetics may provide evidence in the future derived from the investigation of gene composition in individuals prone to develop skin diseases.
Whether direct bacterial interference, such as most notably between S. Bacteriocins as the most obvious candidates for bacterial interference seem to be limited to specific strains, for which no clear colonization advantage could be established. While the molecular basis of competition is quite easy to investigate in vitro , similarly to AMPs, only in vivo research and epidemiology will provide clear answers in this field.
Altogether, it appears that while much in vitro research still needs to be performed, classic laboratory microbiology is at its limits to further our understanding of the interplay between staphylococci and their host. Integrative efforts comprised of molecular biology, animal colonization models, human genetics and epidemiology will be needed.
Furthermore, the presence of AMP resistance mechanisms in many bacteria, including staphylococci, indicates that the frequently suggested development of AMPs into therapeutics [ 99 , ] may be problematic. On the other hand, efficient AMPs have evolved despite those mechanisms [ ], and may thus provide a basis for the development of valuable alternatives to antibiotics, for example in the topical treatment of staphylococcal skin infections.
The CA-MRSA epidemic will probably drive the investigation of molecular factors enabling these strains to better colonize, and possibly compete with other strains. It is to be expected that these endeavors will also lead to a better understanding of staphylococcal colonization in general.
Researchers will focus more on using animal models of colonization. In contrast, achieving more direct evidence for a role of AMPs in controlling staphylococcal skin colonization is expected to take longer.
In the meantime, the field will likely provide more detailed insight into the mechanisms of AMP resistance in staphylococci and their regulation. Staphylococci are frequent colonizers of human epithelia. Many strains are permanent colonizers, while the human population is split into carriers and noncarriers with regard to Staphylococcus aureus. What distinguishes S. The species S. Colonization is usually a prerequisite for infection.
Staphylococci produce many molecular factors that may play a role in colonization, such as surface-binding proteins and exopolymers. Furthermore, staphylococci show gene composition and expression aimed to withstand the harsh environmental conditions on human skin. However, the role of most of these components in colonization is hypothetical.
There is no evidence so far that direct bacterial interference favors colonization by one staphylococcal strain over another, or other bacteria. Antimicrobial peptides are believed to play a key role in innate host defense on the human skin and in controlling bacterial colonization. Staphylococci have many mechanisms to subvert antimicrobial peptide activity, many of which are triggered by the presence of antimicrobial peptides.
Colonization models will need to be used together with molecular biology approaches to provide direct evidence for a role of antimicrobial peptides AMPs in controlling staphylococcal colonization and a function of AMP resistance mechanisms in evading AMP activity in vivo , which is at present lacking.
For reprint orders, please contact moc. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript. National Center for Biotechnology Information , U. Expert Rev Dermatol. Author manuscript; available in PMC Feb 1. Michael Otto. Author information Copyright and License information Disclaimer.
Michael Otto: vog. Copyright notice. See other articles in PMC that cite the published article. Abstract Staphylococci are the most abundant skin-colonizing bacteria and the most important causes of nosocomial infections and community-associated skin infections.
Keywords: antimicrobial peptides, colonization, innate host defense, Staphylococcus aureus , Staphylococcus epidermidis. Molecular factors involved in colonization Both bacterial and host factors are believed to play a role in colonization. Bacterial interference Before turning to the interaction of staphylococci with the human host, it should be discussed whether bacterial interference — either between staphylococcal strains or between staphylococci and other bacteria — determines colonization independently of host contribution.
Interaction with host defenses during colonization The human immune system comprises two major parts. AMPs on the human skin Antimicrobial peptides are part of the innate immune system in many organisms from almost all phyla, and developed early in evolution [ 96 — 98 ].
Table 1 Human antimicrobial peptides and proteins on the skin. Open in a separate window. Parentheses indicate reduced activity. Antimicrobial peptide resistance mechanisms in staphylococci Bacteria have developed several efficient mechanisms to combat the activity of AMPs [ ]. Table 2 Prominent antimicrobial peptide resistance mechanisms in staphylococci. Name Gene s Function Present in S. Sensing antimicrobial peptides Host adaptations to bacterial AMP resistance mechanisms exemplify the interplay between innate host defense and bacteria during evolution [ ].
Expert commentary Progress in our understanding of staphylococcal colonization of the skin and the molecular factors involved therein is linked to the development and use of suitable animal colonization models. Five-year view The CA-MRSA epidemic will probably drive the investigation of molecular factors enabling these strains to better colonize, and possibly compete with other strains.
Key issues Staphylococci are frequent colonizers of human epithelia. Footnotes For reprint orders, please contact moc. References 1. Kloos W, Schleifer KH. In: Holt JG, editor. Staphylococcus auricularis sp nov. Int J Syst Bacteriol. Williams RE. Healthy carriage of Staphylococcus aureus : its prevalence and importance.
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Antimicrob Agents Chemother. Carriage of Staphylococcus aureus among healthy persons during a month period. Epidemiol Infect. Nasal carriage of Staphylococcus aureus and prevention of nosocomial infections. The role of nasal carriage in Staphylococcus aureus infections.
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Chambers HF. The changing epidemiology of Staphylococcus aureus? Emerg Infect Dis. Invasive methicillin-resistant Staphylococcus aureus infections in the United States. Staphylococcus epidermidis : emerging resistance and need for alternative agents.
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