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(A) Recombinant CAMP factor (arrowheads) of P. acnes was expressed in E. coli. The protein expression was incubated without (lane 1) or with (lane 2) IPTG. Purified recombinant CAMP factor is shown (lane 3). (B) The identity of recombinant CAMP factor was analyzed by NanoLC-LTQ MS/MS mass spectrometry. A sequenced internal peptide (AVLLTANPASTAK) of CAMP factor is presented. (C) Co-hemolytic activity of recombinant CAMP factor was examined on a sheep blood agar plate. Recombinant CAMP factor (2.5 µg) or a GFP control protein (2.5 µg) was spotted beside the S. aureus streak. (D) Immunogenicity of CAMP factor was evaluated by Western blotting. ICR mice were intranasally vaccinated with UV-inactivated E. coli over-expressing CAMP factor or GFP. Sera were collected 14 days after the vaccination. Anti-CAMP factor (1∶2,000 dilution; lanes 1 and 2) or anti-GFP antiserum (lanes 3 and 4) was reacted with recombinant CAMP factor (0.2 µg; lanes 1 and 3) or GFP (lanes 2 and 4). (E) The antibody titer of CAMP factor was quantified by ELISA. The antisera (1∶10,000 dilution) were reacted with purified recombinant CAMP factor immobilized on a microtiter ELISA plate. The captured antibodies were detected by an OptEIA™ Reagent Set consisting of a goat-anti-mouse IgG (H+L)-HRP conjugate. The OD of each well was measured at 450 nm. Horizontal bar represents average of 10 individual assays. (F) CAMP factor was detectable in P. acnes culture medium by Western blotting. Recombinant CAMP factor (0.2 µg; lane 1) as a positive control, P. acnes culture medium (70 µg; lane 2), and RCM (70 µg; lane 3) as a negative control were reacted with mouse anti-CAMP factor antiserum (1∶1,000 dilution, left panel) or anti-GFP antiserum (right panel). The 6×HN tag linked to recombinant CAMP factor was removed by enterokinase before loading into a SDS-PAGE.
Source publication
In the progression of acne vulgaris, the disruption of follicular epithelia by an over-growth of Propionibacterium acnes (P. acnes) permits the bacteria to spread and become in contact with various skin and immune cells.
We have demonstrated in the present study that the Christie, Atkins, Munch-Peterson (CAMP) factor of P. acnes is a secretory prot...
Citations
... Although our data support the prominence of HylA virulence, several other C. acnes virulence factors have been reported. These include toxic porphyrin biosynthesis genes that are upregulated with vitamin B12 supplementation 32 , and CAMP factor which enlist cytotoxic host sphingomyelinase 33 . ...
Acne is a dermatologic disease with a strong pathologic association with human commensal Cutibacterium acnes. Conspicuously, certain C. acnes phylotypes are associated with acne, whereas others are associated with healthy skin. Here we investigate if the evolution of a C. acnes enzyme contributes to health or acne. Two hyaluronidase variants exclusively expressed by C. acnes strains, HylA and HylB, demonstrate remarkable clinical correlation with acne or health. We show that HylA is strongly pro-inflammatory, and HylB is modestly anti-inflammatory in a murine (female) acne model. Structural and phylogenic studies suggest that the enzymes evolved from a common hyaluronidase that acquired distinct enzymatic activity. Health-associated HylB degrades hyaluronic acid (HA) exclusively to HA disaccharides leading to reduced inflammation, whereas HylA generates large-sized HA fragments that drive robust TLR2-dependent pathology. Replacing an amino acid, Serine to Glycine near the HylA catalytic site enhances the enzymatic activity of HylA and produces an HA degradation pattern intermediate to HylA and HylB. Selective targeting of HylA using peptide vaccine or inhibitors alleviates acne pathology. We suggest that the functional divergence of HylA and HylB is a major driving force behind C. acnes health- and acne- phenotype and propose targeting of HylA as an approach for acne therapy.
... This model proposed that increased sebum production in the pores promoted C. acnes overgrowth that physically "plugged" the hair follicle and sebaceous gland, thereby inducing inflammation in surrounding skin cells. Other work has suggested that disease in acne can come from cooperation between C. acnes and other inhabitants of the follicular microbiome, resulting in cell damage from a Christie, Atkins, Munch-Peterson (CAMP) reaction (113). Multiple studies have concluded that C. acnes is the predominant bacterium within most individuals' skin microbial communities, both in healthy and diseased skin, and can account for nearly 90% of the skin pore microbiota, while its oxygen detoxification abilities allow it also to inhabit the skin surface (67,79,86). ...
Despite its harsh and dry environment, human skin is home to diverse microbes, including bacteria, fungi, viruses, and microscopic mites. These microbes form communities that may exist at the skin surface, deeper skin layers, and within microhabitats such as the hair follicle and sweat glands, allowing complex interactions with the host immune system. Imbalances in the skin microbiome, known as dysbiosis, have been linked to various inflammatory skin disorders, including atopic dermatitis, acne, and psoriasis. The roles of abundant commensal bacteria belonging to Staphylococcus and Cutibacterium taxa and the fungi Malassezia, where particular species or strains can benefit the host or cause disease, are increasingly appreciated in skin disorders. Furthermore, recent research suggests that the interactions between microorganisms and the host’s immune system on the skin can have distant and systemic effects on the body, such as on the gut and brain, known as the “skin-gut” or “skin-brain” axes. Studies on the microbiome in skin disease have typically relied on 16S rRNA gene sequencing methods, which cannot provide accurate information about species or strains of microorganisms on the skin. However, advancing technologies, including metagenomics and other functional ‘omic’ approaches, have great potential to provide more comprehensive and detailed information about the skin microbiome in health and disease. Additionally, inter-species and multi-kingdom interactions can cause cascading shifts towards dysbiosis and are crucial but yet-to-be-explored aspects of many skin disorders. Better understanding these complex dynamics will require meta-omic studies complemented with experiments and clinical trials to confirm function. Evolving how we profile the skin microbiome alongside technological advances is essential to exploring such relationships. This review presents the current and emerging methods and their findings for profiling skin microbes to advance our understanding of the microbiome in skin disease.
... Although generally regarded as a low-virulence bacterium and a human skin commensal, C. acnes can be considered an opportunistic pathogen associated with invasive skin and soft tissue infections and implant-associated infections [16][17][18] . Indeed, C. acnes, by producing multiple virulence factors such as lipases, proteases, and the Christine Atkins Munch-Petersen (CAMP) factors, can trigger inflammation and host tissue damage [19][20][21][22][23][24] . Besides, C. acnes proliferation in the pilosebaceous unit can induce the upregulation of different proinflammatory cytokines by keratinocytes, sebocytes, or peripheral blood mononuclear cells 25-28 . ...
... C. acnes isolates were frozen and stored at − 80 °C. The co-hemolytic reaction of the CAMP factor on blood agar plates (bioMérieux) was performed using S. aureus strain ATCC 25923, according to the previous method 23 . ...
Acne vulgaris is a common inflammatory disorder affecting more than 80% of young adolescents. Cutibacterium acnes plays a role in the pathogenesis of acne lesions, although the mechanisms are poorly understood. The study aimed to explore the microbiome at different skin sites in adolescent acne and the role of biofilm production in promoting the growth and persistence of C. acnes isolates. Microbiota analysis showed a significantly lower alpha diversity in inflammatory lesions (LA) than in non-inflammatory (NI) lesions of acne patients and healthy subjects (HS). Differences at the species level were driven by the overabundance of C. acnes on LA than NI and HS. The phylotype IA1 was more represented in the skin of acne patients than in HS. Genes involved in lipids transport and metabolism, as well as potential virulence factors associated with host-tissue colonization, were detected in all IA1 strains independently from the site of isolation. Additionally, the IA1 isolates were more efficient in early adhesion and biomass production than other phylotypes showing a significant increase in antibiotic tolerance. Overall, our data indicate that the site-specific dysbiosis in LA and colonization by virulent and highly tolerant C. acnes phylotypes may contribute to acne development in a part of the population, despite the universal carriage of the microorganism. Moreover, new antimicrobial agents, specifically targeting biofilm-forming C. acnes, may represent potential treatments to modulate the skin microbiota in acne.
... These patients were classified as definitively infected due to the presence of a sinus tract or gross intra-articular pus. This difference in pathogenic potential and level of host inflammatory response might be caused by different phylotypes of C. acnes with varying virulence properties [26][27][28]. Boyle et al. were recently able to show that hemolytic strains of C. acnes exhibit enhanced pathogenicity to their host by eliciting a more prominent systemic inflammatory response and severe clinical course [26]. Furthermore, they reported a significantly higher median serum CRP level (17.9 mg/l) in the hemolytic C. acnes group compared to the nonhemolytic group (3.5 mg/l). ...
Introduction
There is a paucity of literature regarding serum C-reactive protein (CRP) in the evaluation of a shoulder periprosthetic joint infection (PJI). The purpose of the current study was to establish cutoff values for diagnosing shoulder PJI and evaluate the influence of the type of infecting microorganism and the classification subgroups according to last proposed International Consensus Meeting (ICM) criteria on the CRP level.
Materials and methods
A retrospective analysis of all 136 patients, who underwent septic or aseptic revision shoulder arthroplasty in our institution between January 2010 and December 2019, was performed. Shoulder PJI was defined according to the last proposed definition criteria of the ICM. Serum CRP levels were compared between infected and non-infected cases, between infection subgroups, as well as between different species of infecting microorganisms. A receiver-operating characteristic (ROC) analysis was performed to display sensitivity and specificity of serum CRP level for shoulder PJI.
Results
A total of 52 patients (38%) were classified as infected, 18 meeting the criteria for definitive infection, 26 for probable infection and 8 for possible infection. According to the ROC curve, an optimized serum CRP threshold of 7.2 mg/l had a sensitivity of 69% and specificity of 74% (area under curve = 0.72). Patients with definitive infection group demonstrated significantly higher median serum CRP levels (24.3 mg/l), when compared to probable, possible infection groups and PJI unlikely group (8 mg/l, 8.3 mg/l, 3.6 mg/l, respectively, p < 0.05). The most common isolated microorganism was Cutibacterium acnes in 25 patients (48%) followed by coagulase-negative staphylococci (CNS) in 20 patients (39%). Patients with a PJI caused by high-virulent microorganisms had a significantly higher median serum CRP level compared to patients with PJI caused by low-virulent microorganisms (48 mg/l vs. 11.3 mg/l, p = 0.04).
Conclusions
Serum CRP showed a low sensitivity and specificity for the diagnosis of shoulder PJI, even applying cutoffs optimized by receiver-operating curve analysis. Low-virulent microorganisms and patients with probable and possible infections are associated with lower CRP levels compared to patients with definitive infection and infections caused by high-virulent microorganisms.
Level of evidence
Diagnostic Level III.
... While sparse, there is some literature highlighting the usefulness of aSMase inhibitors within the dermis. Nakatsuji and collaborators found that C.acnes Christie, Atkins, Munch-Peterson (CAMP) factor may hijack host aSMase to increase bacterial virulence in order to impair and invade host cells (155). Similarly, Ma and colleagues demonstrated how S.aureus a-toxin activates aSMase in macrophages and precipitates the release of ceramides, which activate the inflammasome and mediate the generation and release of cytokines (156). ...
Ultraviolet B radiation (UVB) has profound effects on human skin that results in a broad spectrum of immunological local and systemic responses and is the major cause of skin carcinogenesis. One important area of study in photobiology is how UVB is translated into effector signals. As the skin is exposed to UVB light, subcellular microvesicle particles (MVP), a subtype of bioactive extracellular vesicles, are released causing a variety of local and systemic immunological effects. In this review, we highlight keratinocyte MVP release in keratinocytes in response to UVB. Specifically, Platelet-activating factor receptor agonists generated by UVB result in MVP released from keratinocytes. The downstream effects of MVP release include the ability of these subcellular particles to transport agents including the glycerophosphocholine-derived lipid mediator Platelet-activating factor (PAF). Moreover, even though UVB is only absorbed in the epidermis, it appears that PAF release from MVPs also mediates systemic immunosuppression and enhances tumor growth and metastasis. Tumor cells expressing PAF receptors can use this mechanism to evade chemotherapy responses, leading to treatment resistance for advanced cancers such as melanoma. Furthermore, novel pharmacological agents provide greater insight into the UVB-induced immune response pathway and a potential target for pharmacological intervention. This review outlines the need to more clearly elucidate the mechanism linking UVB-irradiation with the cutaneous immune response and its pathological manifestations. An improved understanding of this process can result in new insights and treatment strategies for UVB-related disorders from carcinogenesis to photosensitivity.
... An analysis of the C. acnes genome has revealed the presence of five CAMP factor genes (camp1, camp2, camp3, camp4 and camp5), all considered to be putative virulence factors [29]. The hemolytic properties of C. acnes in situ in cases of acne remain unclear, but it has been shown that C. acnes can use the host SMase to enhance its virulence [30], and that C. acnes strains displaying hemolytic activity have been isolated from the intervertebral discs of patients with chronic lower back pain [31]. C. acnes CAMP factor 2 is considered to be a virulence factor because it can induce inflammation in vivo and has been used Figure 10. ...
... An analysis of the C. acnes genome has revealed the presence of five CAMP factor genes (camp1, camp2, camp3, camp4 and camp5), all considered to be putative virulence factors [29]. The hemolytic properties of C. acnes in situ in cases of acne remain unclear, but it has been shown that C. acnes can use the host SMase to enhance its virulence [30], and that C. acnes strains displaying hemolytic activity have been isolated from the intervertebral discs of patients with chronic lower back pain [31]. C. acnes CAMP factor 2 is considered to be a virulence factor because it can induce inflammation in vivo and has been used as an antigen to elicit monoclonal antibodies, decreasing the production of CXCL8/IL-8 and IL-1β in ex vivo skin explants from patients with acne [32,33]. ...
Cutibacterium acnes (C. acnes) has been implicated in inflammatory acne where highly mutated Christie–Atkins–Munch–Petersen factor (CAMP)1 displays strong toll like receptor (TLR)-2 binding activity. Using specific antibodies, we showed that CAMP1 production was independent of C. acnes phylotype and involved in the induction of inflammation. We confirmed that TLR-2 bound both mutated and non-mutated recombinant CAMP1, and peptide array analysis showed that seven peptides (A14, A15, B1, B2, B3, C1 and C3) were involved in TLR-2 binding, located on the same side of the three-dimensional structure of CAMP1. Both mutated and non-mutated recombinant CAMP1 proteins induced the production of C-X-C motif chemokine ligand interleukin (CXCL)8/(IL)-8 in vitro in keratinocytes and that of granulocyte macrophage-colony stimulating factor (GM-CSF), tumor necrosis factor (TNF)-α, IL-1β and IL-10 in ex vivo human skin explants. Only A14, B1 and B2 inhibited the production of CXCL8/IL-8 by keratinocytes and that of (GM-CSF), TNF-α, IL-1β and IL-10 in human skin explants stimulated with rCAMP1 and C. acnes. Following pretreatment with B2, RNA sequencing on skin explants identified the 10 genes displaying the strongest differential expression as IL6, TNF, CXCL1, CXCL2, CXCL3, CXCL8, IL-1β, chemokine ligand (CCL)2, CCL4 and colony stimulating factor (CSF)2. We, thus, identified a new CAMP1-derived peptide as a TLR-2 modulator likely to be a good candidate for clinical evaluation.
... Moreover, the application of acneassociated C. acnes strains in murine models develop moderateto-severe skin pathology ( Kolar et al. 2019 ) . In the study using cultural cells, the Christie, Atkins, Munch-Peterson ( CAMP ) factor of C. acnes , which is a secretory protein with co-hemolytic activity, has been reported to contribute to bacterial virulence ( Nakatsuji et al. 2011 ) . ...
Cutibacterium acnes plays roles in both acne disease and healthy skin ecosystem. We observed that mutations in the tir-1/SARM1 and p38 MAPK cascade genes significantly shortened Caenorhabditis elegans lifespan upon Cutibacterium acnes SK137 infection. Antimicrobial molecules were induced by SK137 in a TIR-1-dependent manner. These results suggest that defense responses against SK137 involve the TIR-1-p38 MAPK pathway in Caenorhabditis elegans.
... P. acnes CAMP factor has been shown to have cytotoxic properties against keratinocyte (HaCaT) and macrophage (RAW264.7) cell lines (52). Thus, we investigated whether GBS CAMP factor reduced cell viability of VK2 cells in the absence or presence of S. aureus. ...
... Additionally, the CAMP test is temperature dependent and occurs most optimally at 15°C to 30°C (19) and thus is not reflective of animal or human environments, except for perhaps the skin. Host acid sphingomyelinase enhances cytotoxic and inflammatory properties of P. acnes CAMP factor in vitro and in skin infection models (52). However, we did not quantify host sphingomyelinase in our assays. ...
Group B Streptococcus (GBS) remains a pervasive pathogen for pregnant women and their newborns. Maternal screening and intrapartum antibiotic prophylaxis to GBS-positive mothers have reduced, but not eliminated GBS neonatal disease, and have not impacted GBS-associated preterm birth or stillbirth.
... Les différents facteurs de virulence peuvent également interagir avec l'oxygène moléculaire, puis générer des ROS et des radicaux libres qui à leur tour endommagent les kératinocytes et favorisent ainsi l'inflammation périfolliculaire dans l'acné (Liu et al., 2011 ;Nakatsuji et al., 2011 ;Beylot et al., 2014). Ce processus de dommages aux kératinocytes et à la MEC via la virulence de C. acnes pourrait être impliqué dans la voie du vieillissement cutané (Fournière et al., 2020). ...
... et les porphyrines contribuant à la réaction d'inflammation périfolliculaire(Shu et al., 2013b ;Oyewole & Birch-Machin, 2015 ;Johnson et al., 2016), et la hyaluronate lyase impliquée dans l'adhérence et l'invasion qui dégrade le derme et les composants de la MEC(Cogen et al., 2008 ;Nazipi et al., 2017) (Figure 55). Les CAMP (« Christie-Atkins-Munch-Petersen »), notamment CAMP1(Jahns et al., 2012), protéines agissant comme des enzymes de dégradation des tissus de l'hôte via la formation de pores dans les membranes des cellules(Liu et al., 2011 ;Nakatsuji et al., 2011) sont également considérés comme des facteurs de virulence (Figure 55). ...
Les ulvanes sont des polysaccharides matriciels sulfatés constitutifs de la paroi de l’algue verte Ulva sp.. Bien que proliférative et quantitativement disponible, Ulva sp. est peu valorisée avec des applications dans des domaines à faible valeur ajoutée. Ce projet de thèse a pour objectif la production de fractions enrichies en ulvanes et en oligo-ulvanes dans le but d’évaluer leurs propriétés biologiques sur le système cutané. Les fractions d’ulvanes ont été produites par macération et extraction assistée par enzyme suivie de différents procédés de purification : précipitation éthanolique et dialyse. Des dépolymérisations radicalaire et acide ont permis d’obtenir des fractions d’oligo-ulvanes. Ces fractions d’ulvanes et d’oligo-ulvanes stimulent la prolifération de fibroblastes dermiques humains. Une augmentation de la synthèse protéique de composants matriciels dont les collagènes de type I et III, et les glycosaminoglycanes a été mise en évidence. Les fractions stimulent également l’expression, la synthèse et l’activité enzymatique de MMP-1. Au niveau du microbiote cutané, ces fractions n’altèrent pas la croissance des bactéries commensales S. epidermidis, S. aureus et C. acnes, mais peuvent modifier la formation de biofilm. Les fractions d’ulvanes et d’oligo-ulvanes diminuent également le potentiel inflammatoire des kératinocytes HaCaT induit par C. acnes. Ainsi, les travaux ont démontré que les fractions d’ulvanes et d’oligo-ulvanes présentent des activités biologiques prometteuses pour des applications dermo-cosmétiques dans le cadre de stratégies de réparation tissulaire, anti-vieillissement, ou anti-inflammatoire, dans le respect du microbiote commensal cutané.
... Functional studies on CAMP factors of group B streptococci indicate that they are able to form micropores in eukaryotic membranes (Lang and Palmer, 2003). For the CAMP2 of C. acnes it was shown that is has cytotoxic effects in keratinocytes and macrophages if applied as recombinant protein (Nakatsuji et al., 2011). Another study reported that Toll-like receptor 2 (TLR-2) can recognize CAMP1 (Lheure et al., 2016). ...
The bacterial species Cutibacterium acnes (formerly known as Propionibacterium acnes) is tightly associated with humans. It is the dominant bacterium in sebaceous regions of the human skin, where it preferentially colonizes the pilosebaceous unit. Multiple strains of C. acnes that belong to phylogenetically distinct types can co-exist. In this review we summarize and discuss the current knowledge of C. acnes regarding bacterial properties and traits that allow host colonization and play major roles in host-bacterium interactions and also regarding the host responses that C. acnes can trigger. These responses can have beneficial or detrimental consequences for the host. In the first part of the review, we highlight and critically review disease associations of C. acnes, in particular acne vulgaris, implant-associated infections and native infections. Here, we also analyse the current evidence for a direct or indirect role of a C. acnes-related dysbiosis in disease development or progression, i.e., reduced C. acnes strain diversity and/or the predominance of a certain phylotype. In the second part of the review, we highlight historical and recent findings demonstrating beneficial aspects of colonization by C. acnes such as colonization resistance, immune system interactions, and oxidant protection, and discuss the molecular mechanisms behind these effects. This new insight led to efforts in skin microbiota manipulation, such as the use of C. acnes strains as probiotic options to treat skin disorders.
