Porphyrin Production and Regulation in Cutaneous Propionibacteria

ABSTRACT Porphyrins are intermediate metabolites in the biosynthesis of vital molecules, including heme, cobalamin, and chlorophyll. Bacterial porphyrins are known to be proinflammatory, with high levels linked to inflammatory skin diseases. Propionibacterium species are dominant skin commensals and play essential roles in defending against pathogens and in triggering an inflammatory response. To better understand how the inflammatory potential of the skin microbiome may vary depending on its propionibacterial composition, we compared the production levels of porphyrins among Propionibacterium acnes, Propionibacterium granulosum, Propionibacterium avidum, and Propionibacterium humerusii strains. We found that porphyrin production varied among these species, with P. acnes type I strains producing significantly larger amounts of porphyrins than P. acnes type II and III strains and other Propionibacterium species. P. acnes strains that are highly associated with the common skin condition acne vulgaris responded to vitamin B12 supplementation with significantly higher porphyrin production. In contrast, vitamin B12 supplementation had no effect on the porphyrin production of health-associated P. acnes strains and other propionibacteria. We observed low-level porphyrin production in most Propionibacterium strains harboring the deoR repressor gene, with the exception of P. acnes strains belonging to type I clades IB-3 and IC. Our findings shed light on the proinflammatory potential of distinct phylogenetic lineages of P. acnes as well as other resident skin propionibacteria. We demonstrate that the overall species and strain composition is important in determining the metabolic output of the skin microbiome in health and disease. IMPORTANCE Porphyrins are a group of metabolites essential to the biosynthesis of heme, cobalamin, and chlorophyll in living organisms. Bacterial porphyrins can be proinflammatory, with high levels linked to human inflammatory diseases, including the common skin condition acne vulgaris. Propionibacteria are among the most abundant skin bacteria. Variations in propionibacteria composition on the skin may lead to different porphyrin levels and inflammatory potentials. This study characterized porphyrin production in all lineages of Propionibacterium acnes, the most dominant skin Propionibacterium, and other resident skin propionibacteria, including P. granulosum, P. avidum, and P. humerusii. We revealed that P. acnes type I strains produced significantly more porphyrins than did type II and III strains and other Propionibacterium species. The findings from this study shed light on the proinflammatory potential of the skin microbiome and can be used to guide the development of effective acne treatments by modulating the skin microbiome and its metabolic activities

Anti-Melanoma immunity and local regression of cutaneous metastases in melanoma patients treated with monobenzone and imiquimod; a phase 2 a trial

Vitiligo development in melanoma patients during immunotherapy is a favorable prognostic sign and indicates breakage of tolerance against melanocytic/melanoma antigens. We investigated a novel immunotherapeutic approach of the skin-depigmenting compound monobenzone synergizing with imiquimod in inducing antimelanoma immunity and melanoma regression. Stage III-IV melanoma patients with non-resectable cutaneous melanoma metastases were treated with monobenzone and imiquimod (MI) therapy applied locally to cutaneous metastases and adjacent skin during 12 weeks, or longer. Twenty-one of 25 enrolled patients were evaluable for clinical assessment at 12 weeks. MI therapy was well-tolerated. Partial regression of cutaneous metastases was observed in 8 patients and stable disease in 1 patient, reaching the statistical endpoint of treatment efficacy. Continued treatment induced clinical response in 11 patients, including complete responses in three patients. Seven patients developed vitiligo-like depigmentation on areas of skin that were not treated with MI therapy, indicating a systemic effect of MI therapy. Melanoma-specific antibody responses were induced in 7 of 17 patients tested and melanoma-specific CD8+T-cell responses in 11 of 15 patients tested. These systemic immune responses were significantly increased during therapy as compared to baseline in responding patients. This study shows that MI therapy induces local and systemic anti-melanoma immunity and local regression of cutaneous metastases in 38% of patients, or 52% during prolonged therapy. This study provides proof-of-concept of MI therapy, a low-cost, broadly applicable and well-tolerated treatment for cutaneous melanoma metastases, attractive for further clinical investigation

Doxorubicin and paclitaxel enhance the antitumor efficacy of vaccines directed against HER 2/neu in a murine mammary carcinoma model

INTRODUCTION: The purpose of the present study was to determine whether cytotoxic chemotherapeutic agents administered prior to immunotherapy with gene vaccines could augment the efficacy of the vaccines. METHODS: Mice were injected in the mammary fat pad with an aggressive breast tumor cell line that expresses HER2/neu. The mice were treated 3 days later with a noncurative dose of either doxorubicin or paclitaxel, and the following day with a gene vaccine to HER2/neu. Two more doses of vaccine were given 14 days apart. Two types of gene vaccines were tested: a plasmid vaccine encoding a self-replicating RNA (replicon) of Sindbis virus (SINCP), in which the viral structural proteins were replaced by the gene for neu; and a viral replicon particle derived from an attenuated strain of Venezuelan equine encephalitis virus, containing a replicon RNA in which the Venezuelan equine encephalitis virus structural proteins were replaced by the gene for neu. RESULTS: Neither vaccination alone nor chemotherapy alone significantly reduced the growth of the mammary carcinoma. In contrast, chemotherapy followed by vaccination reduced tumor growth by a small, but significant amount. Antigen-specific CD8(+ )T lymphocytes were induced by the combined treatment, indicating that the control of tumor growth was most probably due to an immunological mechanism. The results demonstrated that doxorubicin and paclitaxel, commonly used chemotherapeutic agents for the treatment of breast cancer, when used at immunomodulating doses augmented the antitumor efficacy of gene vaccines directed against HER2/neu. CONCLUSIONS: The combination of chemotherapeutic agents plus vaccine immunotherapy may induce a tumor-specific immune response that could be beneficial for the adjuvant treatment of patients with minimal residual disease. The regimen warrants further evaluation in a clinical setting

Progressive macular hypomelanosis (PMH) treatable but often misdiagnosed

The results of the studies presented in this thesis confirm the opinion that PMH is a separate, treatable and relatively new entity, which if the right diagnostic tests are performed can easily be distinguished from other hypopigmented skin disorders. Although the precise pathogenesis is still unknown, we gained more insight and gave a more accurate description of PMH. The investigations demonstrating the relation between Propioni bacteria and PMH provide the strongest evidence in confirming the idea that it is a separate entity. We propose that the clinical characteristics of PMH in combination with red, follicular fluorescence in lesional skin and/or gram-positive bacteria with a rod-like structure in the pilosebaceous glands of lesional skin, should be considered as diagnostic criteria for PMH. It is obvious that further research is necessary, for instance to consolidate the diagnostic criteria, to develop additional treatment modalities and to identify the postulated factor that is produced by the bacteria, influencing melanogenesis