The Complete Genome Sequence of Propionibacterium Acnes, a Commensal of Human Skin

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Science  30 Jul 2004:
Vol. 305, Issue 5684, pp. 671-673
DOI: 10.1126/science.1100330


Propionibacterium acnes is a major inhabitant of adult human skin, where it resides within sebaceous follicles, usually as a harmless commensal although it has been implicated in acne vulgaris formation. The entire genome sequence of this Gram-positive bacterium encodes 2333 putative genes and revealed numerous gene products involved in degrading host molecules, including sialidases, neuraminidases, endoglycoceramidases, lipases, and pore-forming factors. Surface-associated and other immunogenic factors have been identified, which might be involved in triggering acne inflammation and other P. acnes–associated diseases.

The details of the involvement of Propionibacterium acnes in acne—the most common skin disease, affecting up to 80% of all adolescents in the United States—are still obscure. Several mechanisms have been proposed to account for its role in the disease (15). First, damage to host tissues and cells might be accomplished by bacterial enzymes with degradative properties, such as lipases (2). Second, immunogenic factors of P. acnes such as surface determinants or heat shock proteins (HSPs) might trigger inflammation (46). Other diseases are also associated with P. acnes, including corneal ulcers; endocarditis; sarcoidosis; cholesterol gallstones; allergic alveolitis; pulmonary angitis; and synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome (7, 8). Its genome sequence may provide a basis for finding alternative targets in therapy for acne and other P. acnes–associated diseases.

The genome of P. acnes strain KPA171202 (no. DSM 16379) consists of a single circular chromosome of 2,560,265 base pairs (9, 10) (supporting online text and fig. S1). We predicted and annotated 2333 putative genes. The sequenced strain exhibited 100% identity on the 16S ribosomal RNA level to several clinical P. acnes isolates, as well as to the well-studied laboratory strain P-37. The main features of the genome sequence and comparative analyses are described in the supporting online material (supporting online text and fig. S2).

The genome sequence offers insights into the traits that favor P. acnes as a ubiquitous commensal on human skin. Metabolic reconstruction reveals a capacity to cope with changing oxygen tensions, which confirms observations that strains of P. acnes can grow under microaerobic as well as anaerobic conditions. The genome sequence encodes all key components of oxidative phosphorylation that employs two terminal oxidases, a cytochrome aa3 oxidase (PPA701/702) and a cytochrome d oxidase (PPA173-176), and a F0F1-type adenosine triphosphate synthase (PPA1238-1245). All genes of the Embden-Meyerhof pathway, the pentose phosphate pathway, and the tricarboxylic acid cycle are present. Under anaerobic conditions, strain KPA171202 can grow on several substrates such as glucose, ribose, fructose, mannitol, trehalose, mannose, N-acetylglucosamine, erythritol, and glycerol (11). In addition, several amino acid degrading pathways, similar to those of fermentative organisms, are present. Fermentative products are short-chain fatty acids, in particular propionic acid (11), whose production from pyruvate and methylmalonyl–coenzyme (CoA) is initialized by the methylmalonyl-CoA carboxyltransferase (PPA2005-2008). In addition to fermentative energy conservation, P. acnes possesses systems involved in anaerobic respiration such as nitrate reductase (PPA507-511), dimethyl sulfoxide reductase (PPA515-517), sn-glycerol-3-phosphate dehydrogenase (PPA2248-2250), and fumarate reductase (PPA950-952 and PPA1437-1439). Factors that might be involved in the life-style switch related to oxygen availability, as well as further aspects of the biology and biochemistry of P. acnes, are presented in the supporting online text.

Numerous genes have been found that can degrade and use host-derived substances (Table 1 and fig. S3). It has been proposed that free fatty acids, produced by P. acnes lipase activity on sebum, assist bacterial adherence and colonization of the sebaceous follicle (2, 12). In addition to the previously identified gene for the secreted triacylglycerol lipase (PPA2105), various other lipase/esterase genes can be found in the genome. Three of these possess a C-terminal Leu-Pro-X-Thr-Gly (LPXTG)–type cell-wall sorting signal. As previously known, a hyaluronate lyase (PPA380) degrades hyaluronan, an important constituent of the extracellular matrix of connective tissues, and presumably aids bacterial invasion (13, 14). Genome sequencing revealed numerous additional enzymes putatively involved in host tissue degradation, such as two endoglycoceramidases (PPA644 and PPA2106) and four sialidases, two of them possessing a LPXTG motif (PPA1560 and PPA1569). Other degradative enzymes include a putative endo-β-N-acetylglucosaminidase (PPA990) and various extracellular peptidases. Five highly similar genes encoding homologs to CAMP (Christie, Atkins, Munch-Peterson) factors are also present in the genome of P. acnes (fig. S4). These factors are secreted proteins characteristic of some streptococcal species. CAMP factors have been shown to bind to immunoglobulins of the G and M classes and have long been known as pathogenic determinants. Recently, it was reported that CAMP factors can act as pore-forming toxins (15). These proteins could explain previously observed cytotoxic effects of P. acnes strains (16).

Table 1.

Selected factors of P. acnes that are putatively involved in degrading host molecules, conferring cell adhesion and/or mediating inflammation. ORF, open reading frame.

ORF number(s) Function Comment Homology
380 Hyaluronate lyase Polysaccharide lyase family protein 94% identity to P. acnes clone 49/51
570, 1035, 1101, 1224, 1425, 1631, 1745, 1761, 1839, 1953, 1967, 2036, 2142, 2150, etc. Putative lipases/esterases ORFs 570, 1745, and 2150 have a C-terminal LPXTG motif Diverse
644, 2106 Endoglycoceramidases Hydrolyzes glycosphingolipids Rhodococcus sp., Cyanea nozakii
684 Sialidase L Trans-sialidase Macrobdella decora (leech)
685 Sialidase A Exo-α-sialidase Clostridium perfringens, C. septicum
687, 1198, 1231, 1340, 2108 CAMP factors Immunoglobulin-binding, pore-forming toxin Streptococcus species
990 Endo-β-N-acetylglucosaminidase Streptomyces plicatus
1396 Putative hemolysin M. ulcerans, M. leprae
1560, 1569 Sialidases/neuraminidases With LPXTG motif Micromonospora viridifaciens
1796, 2105 Triacylglycerol lipases ORF 2105 is 100% identical to gehA P. acnes P-37
1819-1821 Putative chitobiase/β-N-acetylhexosaminidase Possible frameshift, with LPXTG motif Arthrobacter
2139 Putative cutinase Botryotinia fuckeliana
109 Myosin-crossreactive antigen Rhodopseudomonas palustris
125-134, 145-150, 1692-1700, 1185, 1791, 2181 Glycosyltransferases, uridine diphosphate—N-acetylglucosamine 2-epimerase, polysaccharide biosynthesis proteins Slime/capsular polysaccharide biosynthesis Staphylococcus aureus and others
453, 1772, 1773 GroEL, Cpn10 The homolog of ORF 737 is a major immune reactive protein in mycobacteria 100% identity to GroEL and DnaK of P. acnes strain P-37
916, 2038 DnaJ2, DnaJ
2039 GrpE
2040, 1098 DnaK
737 18-kD antigen
721, 1962 Homologs of invasion-associated protein p60 NlpC/P60 family Listeria welshimeri
571 Putative secreted surface protein WD domain, senescence marker protein-30 domain
765 Immunogenic protein, antigen 84 divIVA domain Corynebacterium efficiens, M. leprae, M. tuberculosis
1983, 1984, 1906-1908, 1663-1666 Putative adhesions Thrombospondin type 3 repeats, PKD and SEST domains
1955 Surface-associated protein RTX toxin domain, LPXTG motif
1879, 1880, 1881, 2127 PTRPs Putatively regulated by phase variation, LPXTG motifs
1715, 2210, 2270 PTRPs ORF 2210 has a LPXTG motif
2130 Outer membrane protein A family protein Putatively regulated by phase variation

In several studies, the capability of P. acnes to interact with and stimulate the immune system has been investigated. Increased cellular, as well as humoral, immunity to P. acnes has been detected in patients with severe acne (35). The genome sequence encodes many factors with antigenic potential, for example, cell surface proteins that may also exhibit cell-adherent properties (Table 1 and fig. S3). Several of these (PPA1879-1881, PPA1955, PPA2127, and PPA2210) possess a C-terminal LPXTG-type cell-wall sorting signal that is required for attaching surface proteins to the cell-wall through the action of sortase (possibly encoded by candidate: PPA777), a mechanism employed by many Gram-positive bacteria (17). In all, 25 genes encoding proteins with a C-terminal LPXTG motif could be found in the genome. A few of these (PPA1880, PPA2127, and PPA2130) possess contiguous stretches of guanidine (G) or cytosine (C) residues, either in the putative promoter region or within the 5′ end. The sequences of several plasmids (of the shotgun library) that cover these regions were ambiguous with respect to the length of the poly(C)/(G) stretches (supporting online text and figs. S5 and S6). Such variable homopolymeric C or G stretches, generated in the course of replication because of slipped-strand mispairing, have been reported in other species to be involved in phase variation, an adaptation strategy to generate phenotypic variation (18) (supporting online text). Although showing no similarity to database entries, PPA1880 and PPA2127 both contain characteristic multiple repeats of the dipeptide proline-threonine [PT repetitive protein (PTRP)]. Such PT repeats have been detected in antigenic proteins of Mycobacterium tuberculosis (19). Additional PTRPs (PPA1715, PPA2210, and PPA2270) were found in P. acnes with characteristics of surface proteins, which may represent further host-interacting factors (Table 1 and supporting online text).

Several HSPs have been identified as major targets of the immune response in bacterial pathogens. Homologs of GroEL and DnaK were found and characterized in P. acnes (6). The genome sequence contains several more HSPs, such as DnaJ (PPA916 and PPA2038), GrpE (PPA2039), and an 18-kD protein (PPA737), the homologs of which in mycobacteria are major immune reactive proteins (20). Further proteins show similarities to known bacterial immunogenic factors, such as PPA765, to antigen 84 of M. tuberculosis and M. leprae, which is a highly immunogenic protein involved in the symptoms of multibacillary leprosy (21). Porphyrins are produced by P. acnes in high amounts, and these are also thought to be involved in inflammation (1) (supporting online text). In the presence of increasing oxygen tension, the interaction of molecular oxygen with released porphyrins generates toxic, reduced oxygen species, which can damage keratinocytes and lead to cytokine release (fig. S7).

In summary, the genome sequence clearly reveals many proteins involved in the ability of P. acnes to colonize and reside in human skin sites as well as a pronounced potential to survive a spectrum of environments. This capacity helps to explain the ubiquity of P. acnes and also its potential hazards, for example, the public health problems associated with Blood Bank contaminations, or the contamination of the human genome sequence database with P. acnes sequence. The GenBank entry AAH14236.1, a proposed human protein, is in fact a P. acnes protein (PPA1069).

Supporting Online Material

Materials and Methods

SOM Text

Figs. S1 to S7

Table S1

References and Notes

References and Notes

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