Infectious Disorders - Drug Targets (Formerly Current Drug Targets - Infectious Disorders) - Volume 8, Issue 3, 2008

With increasing interest in new drug and/or vaccine targets for the treatments of skin infectious diseases, this special issue is focused specifically on current advancements in antimicrobial peptides, vaccines as well as novel technologies for detection of skin microbiota [1]. The first paper, by Brigit Schittek, in this issue exemplifies various antimicrobial peptides or proteins (AMPs) in human skins and discusses their roles in a range of skin diseases. These human AMPs are either expressed constitutively like RNase 7, psoriasin or dermcidin or after an inflammatory stimulus like the β-defensins-2 and -3 or the cathelicidin LL-37. The author suggests that AMPs have a therapeutical potential as topical anti-infectives in several skin diseases. The second paper, by Richard L. Gallo, discusses the involvement of Toll-like receptors (TLRs) in the expansion of skin infections and inflammatory diseases, and draws attention to the potential application of TLR agonists or antagonists in various skin diseases. Tom Coenye highlights the biofilm formation of Propionibacterium acnes (P. acnes) and their possible roles in the pathogenesis of acne vulgaris, a common disorder of the pilosebaceous follicles. In the fourth paper, Chun-Ming “Eric” Huang introduces a novel therapy for acne vulgaris. A vaccine targeting a cell wall-anchored sialidase of P. acnes effectively suppresses the P. acnes-induced inflammation, suggesting that the vaccine may be a new modality for treatments of P. acnesassociated diseases. Most importantly, the review introduces a protein molecule (a surface sialidase) that potentially can serve as an anti-acne drug target. The fifth paper, by Yen-Peng Ho, offers specific guidance on the detection of proteins of Staphylococcus species by mass spectrometry-based approaches. The paper emphasizes a direct mass spectrometric analysis of whole pathogenic bacterial cells taken directly from a colony. The paper by Yu-Tsueng Liu reviews the applications of microarray and ultra high throughput sequencing technologies for diagnostic microbiology. The seventh paper, by Jianfeng Zhang, introduces a new vaccine vector using non-replicating Escherichia coli (E. coli) particles overproducing pathogen-derived antigens. The E. coli-vectored vaccines may benefit developing countries since they eliminate the time-consuming and deleterious requirement for the biochemical purification of antigens, the hazard of contemporary adjuvants, and the intrinsic problems associated with needle injections. The final paper in the special issue discusses the antimicrobial activity of histones. The authors speculate that histones may play critical roles as an ancient innate host defense system against pathogens prior to their integration as elements of chromatin structure in eukaryotic organisms. We hope you enjoy reading these papers as we did. Special thanks must go to our reviewers for the special issue. We set ourselves a tight timetable for publication, and this put additional pressure on the reviewers to complete their reviews in a timely fashion. [1] Cogen, A.L.; Nizet, V.; Gallo, R.L. Br. J. Dermatol., 2008, 158, 442-455.

Antimicrobial peptides or proteins (AMPs) represent an ancient and efficient innate defense mechanism which protects interfaces from infection with pathogenic microorganisms. In human skin AMPs are produced mainly by keratinocytes, neutrophils, sebocytes or sweat glands and are either expressed constitutively or after an inflammatory stimulus. In several human skin diseases there is an inverse correlation between severity of the disease and the level of AMP production. Skin lesions of patients with atopic dermatitis show a diminished expression of the β-defensins and the cathelicidin LL-37. Furthermore, these patients have a reduced amount of the AMP dermcidin in their sweat which correlates with an impaired innate defense of human skin in vivo. In addition, decreased levels of AMPs are associated with burns and chronic wounds. In contrast, overexpression of AMPs can lead to increased protection against skin infections as seen in patients with psoriasis and rosacea, inflammatory skin-diseases which rarely result in superinfection. In other skin diseases, e.g. in patients with acne vulgaris, increased levels of AMPs are often found in inflamed or infected skin areas indicating a role of these peptides in the protection from infection. These data indicate that AMPs have a therapeutical potential as topical anti-infectives in several skin diseases. The broad spectrum of antimicrobial activity, the low incidence of bacterial resistance and their function as immunomodulatory agents are attractive features of AMPs for their clinical use.

The skin is the ultimate example of the function of innate immunity, it alerts the host of danger by many systems including sensing pathogen-associated molecule patterns (PAMPs) through Toll-like receptors and other pattern recognition receptors (PRRs), yet normally provides defense without inflammation. The skin responds rapidly to invading microbes by producing antimicrobial peptides or other antimicrobial intermediates before cytokine release results in inflammation. To achieve maximal immune responses for clearing invading microbes, the activation of select PRRs in skin then initiates and shapes adaptive immune responses through the activation of dendritic cells and recruitment of T cell subsets. Importantly, cross-talk between TLRs can influence this system in several ways including augmenting or suppressing the immune response. As a consequence of their pivotal role, TLR responses need to be tightly controlled by associated negative regulators or negative feedback loops to prevent detrimental effects from TLRs overactivation. This review focuses on describing the involvement of TLRs in the development of skin infections and inflammatory diseases, and highlights the potential application of TLR agonists or antagonists in these skin diseases.

It is generally accepted that many human infections are biofilm-related and that sessile (biofilm-grown) cells are highly resistant against antimicrobial agents. Propionibacterium acnes plays a role in the pathogenesis of acne vulgaris, a common disorder of the pilosebaceous follicles and it has been suggested that P. acnes cells residing within the follicles grow as a biofilm. Although P. acnes biofilms have not been observed directly in the pilosebaceous unit, the observation that P. acnes readily forms biofilm in vitro as well as on various medical devices in vivo, combined with the high resistance of sessile P. acnes cells and the increased production of particular virulence factors and qourum sensing molecules in sessile cells point in this direction. In addition, in vitro and in vivo biofilm formation has also been demonstrated for other microorganisms involved in skin diseases (including Staphylococcus aureus and Streptococcus pyogenes).

Recent studies have afforded abundant evidences showing that Propionibacterium acnes (P. acnes) is involved not only in acne vulgaris, but also in many diseases, including endocarditis, endophthalmitis, osteomyelitis, joint, nervous system, cranial neurosurgery infections, and implanted biomaterial contamination. In spite of a range of P. acnes pathogenicity, its vaccine therapies have been studied much less intensively than antibiotic therapies which have been mainstay of treatment for P. acnes-associated diseases. Therefore, we have recently developed effective vaccines for P. acnes-associated inflammatory acne, consisting of a cell wall-anchored sialidase of P. acnes or killed-whole organism of P. acnes. Our data strongly show that immunization of ICR mice with the vaccines provides in vivo protective immunity against P. acnes challenge and decreases P. acnes-induced elevation of cytokine production. This review highlights the potential functions of killed P. acnes- and sialidase-based vaccines as novel treatments for P. acnes-associated diseases.

Mass spectrometry (MS) has become a powerful and popular method to analyze macromolecules from biological systems towards the application of clinical chemistry. Disease markers related to infections can be identified with MS analysis in combination with electrophoresis or chromatographic separations. Further, direct analysis of whole pathogenic bacterial cells (taken directly from a colony) by MS can reveal specific biomarkers that can be used for taxonomy. A brief introduction to the two advanced ionization techniques, electrospray ionization and matrix-assisted laser desorption/ionization, for MS is provided in this review. Sample preparation, separation and MS-related techniques for staphylococcal proteins analysis are summarized. The review is concluded with some current clinical applications of mass spectrometry in the area of biomarker research, vaccine development, diagnosis and strain typing of infectious Staphylococci.

Identification of a causative pathogen is essential for the choice of treatment for most infectious diseases. Many FDA approved molecular assays; usually more sensitive and specific compared to traditional tests, have been developed in the last decade. A new trend of high throughput and multiplexing assays are emerging thanks to technological developments for the human genome sequencing project. The applications of microarray and ultra high throughput sequencing technologies for diagnostic microbiology are reviewed. The race for the $1000 genome technology by 2014 will have a profound impact in diagnosis and treatment of infectious diseases in the near future.

The development of a new generation of vaccines that can be produced rapidly at low costs and massadministered noninvasively by non-medical personnel is crucial for boosting vaccine coverage in response to an escalation in demand. The demonstration that topical application of bioengineered nonreplicating Escherichia coli particles overproducing pathogen-derived antigens can mobilize the immune repertoire toward beneficial immune protection against relevant pathogens holds promise for enabling mass-immunization without pain, fear and perceivable tissue damage. Moreover, this noninvasive regimen using E. coli epitopes as a natural adjuvant is in compliance with evolutionary medicine.

Antimicrobial peptides (AMPs), which are widely distributed in various organisms, comprise part of the host innate defense system to kill or damage bacterial and fungal pathogens. Amphibian skin is known to produce various AMPs, and is used as a source material in attempts to identify novel therapeutic AMPs. More than one hundred frog AMPs have been identified to date. In our previous study, we isolated histone H2B with antibacterial properties from the skin of the Schlegel's green tree frog Rhacophorus schlegelii. Although antimicrobial histone H2B has not been obtained from the skin of any species other than R. schlegelii, histones and histone-derived fragments with antimicrobial activities have been found in some specific cells of a diverse range of organisms from shrimps to humans. At least a portion of these fragments are known to be produced from “precursor histones” via specific cleavage by endogenous proteases. These antimicrobial histones and the fragments that act as physiological barriers of cells have a variety of antimicrobial actions and functions, including bacterial cell membrane permeabilization, penetration into the membrane followed by binding to bacterial DNA and/or RNA, binding to bacterial lipopolysaccharide (LPS) in the membrane, neutralizing the toxicity of bacterial LPS, and entrapping pathogens as a component of neutrophil extracellular traps (NETs). This review discusses the literature regarding the isolation, antimicrobial properties, and modes of action of antimicrobial histones and fragmented histones along with a brief introduction of typical amphibian skin AMPs.