Propionibacterium acnes and Acne Vulgaris: New Insights from the Integration of Population Genetic, Multi-Omic, Biochemical and Host-Microbe Studies

Abstract

The anaerobic bacterium Propionibacterium acnes is believed to play an important role in the pathophysiology of the common skin disease acne vulgaris. Over the last 10 years our understanding of the taxonomic and intraspecies diversity of this bacterium has increased tremendously, and with it the realisation that particular strains are associated with skin health while others appear related to disease. This extensive review will cover our current knowledge regarding the association of P. acnes phylogroups, clonal complexes and sequence types with acne vulgaris based on multilocus sequence typing of isolates, and direct ribotyping of the P. acnes strain population in skin microbiome samples based on 16S rDNA metagenomic data. We will also consider how multi-omic and biochemical studies have facilitated our understanding of P. acnes pathogenicity and interactions with the host, thus providing insights into why certain lineages appear to have a heightened capacity to contribute to acne vulgaris development, while others are positively associated with skin health. We conclude with a discussion of new therapeutic strategies that are currently under investigation for acne vulgaris, including vaccination, and consider the potential of these treatments to also perturb beneficial lineages of P. acnes on the skin.

Keywords: Cutibacterium; MLST; Propionibacterium acnes; clonal complex; host-microbe interactions; multi-omic analyses; novel therapeutics; phylogroups; sequence types; vaccination; virulence factors.

Figure 1

Key requirements for cutaneous propionibacteria, especially P. acnes, to cause an opportunistic infection.

Figure 2

Minimum evolution phylogenetic tree of concatenated gene sequences (4253 bp) from all current STs in the MLST₈ database. Bootstrapping statistics were performed using 500 data sets, and only bootstrap values ≥70% are shown. Clonal complexes (CC) are indicated.

Figure 3

A 14-year-old adolescent boy who presented with moderate inflammatory and non-inflammatory acne lesions (A). After consultation and initial treatment for three months with oral minocycline (100 mg/d) and a topical antimicrobial gel, his condition was greatly improved (B).

Figure 4

Association of P. acnes phylogroups with acneic and healthy skin. Data was analysed from the current MLST₈ isolate database. Statistically significant differences (p < 0.001, Fisher’s exact test) were observed for type IA₁ and type III distributions between acneic and healthy skin based on this isolate cohort (type IC numbers too small for statistical analysis).

Figure 5

Principal component analysis (PCA) plot of P. acnes STs associated with acneic and healthy skin. Data is from the MLST₈ isolate database. Using the presence or absence of an allele at each specific gene locus as a separate coordinate, each ST is represented here as a point in a 111 dimensional space. The PCA plot separates STs into four clusters representing types IA₁/IA₂/IB, type IC, type II and type III. Note: phylogroup III has never been associated with acne.

Figure 6

Association of type IA₁ (CC1, CC3, CC4) and type IC (CC107) CCs (A), as well as ST1, ST3 and ST4 genotypes (B), with acneic and healthy skin. Data was analysed from the MLST₈ isolate database. p-values were calculated using N-1 Chi squared test for independent proportions.

Figure 7

Association of antibiotic resistance with P. acnes phylogroups (A). Data is combined from the MLST₈ studies of McDowell et al. [22] and Giannopoulos et al. [74]. Countries to date in which inter-continental spread of multi-resistant forms of the ST3 lineage (CC3) of P. acnes have been reported based on MLST analysis (B) (other countries are also likely to contain this multi-resistant lineage).

Figure 8

Circular map of the KPA171202 genome. From the outside to the centre: ORFs in the positive (red) and negative (green) strands, pseudogenes, tRNA (blue), rRNA (green), %GC plot and GC skew (purple and green equates to negative and positive values, respectively).

Figure 9

Clustering of noncore genomic regions present in 82 P. acnes genomes. Rows represent genomes, and columns represent 314 noncore regions that are longer than 500 bp. The presence of a noncore region is coloured in yellow, and the absence is coloured in blue. Taken from Tomida et al. [67].

Figure 10

Homopolymeric C tract within the 5’ end of the ORF for DsA1 (PPA2127) leading to putative differences in phylogroup expression due to frameshift mutations.

Figure 11

Key secreted (A) and cell-wall (B) proteins (fmol/µg total protein) produced by representative strains of phylogroups IA₁ (CC1, CC3, CC4), IA₂, II and III. Organisms were grown in reinforced clostridial media before mass spectrometry analysis. Secreted and cell wall protein concentration data is taken from the study of Yu et al. [51]. Endogly = Endoglycoceramidase. HL005PA1 (normal skin; ST11, CC1), HL043PA1 (acne; ST3, CC3), HL110PA1 (acne; ST4, CC4), HL013PA1 (acne; ST2, CC2), HL110PA4 (acne; ST7, CC6), Asn12 (cervical disc; ST33, CC33).

Figure 12

Summary of key virulence determinants expressed by type IA₁ strains that, collectively, may help to explain, alongside host response, their dominant association with acne versus other phylogroups. Data is compiled from genomic, proteomic, transcriptomic and biochemical studies.