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Infectious
Disorders - Drug Targets
(Formerly 'Current Drug Targets - Infectious Disorders')
ISSN: 1871-5265
Infectious Disorders
– Drug Targets
Volume 8, Number 3, September 2008
Contents
Editorial:
Pp. 134
The Role of Antimicrobial Peptides in Human Skin and in Skin
Infectious Diseases Pp. 135-143
Birgit Schittek, Maren Paulmann, Ilknur Senyürek and
Heiko Steffen
[Abstract]
Toll-Like Receptors in Skin Infections
and Inflammatory Diseases
Pp. 144-155
Yuping Lai and Richard L. Gallo
[Abstract]
Biofilms in Skin Infections: Propionibacterium
acnes and Acne Vulgaris Pp. 156-159
T. Coenye, K. Honraet, B. Rossel and H.J. Nelis
[Abstract]
Vaccine Therapy for P. acnes-Associated
Diseases Pp. 160-165
Teruaki Nakatsuji, Lada Rasochova and Chun-Ming Huang
[Abstract]
Mass Spectrometry-Based Approaches for
the Detection of Proteins of Staphylococcus Species
Pp. 166-182
Yen-Peng Ho and P. Muralidhar Reddy
[Abstract]
A Technological Update of Molecular Diagnostics
for Infectious Diseases Pp. 183-188
Yu-Tsueng Liu
[Abstract]
Topical Application of Escherichia
coli Particles Over-Producing Pathogen-Derived Antigens
as a Simple Vaccination Modality in Compliance with Evolutionary
Medicine Pp. 189-194
Jianfeng Zhang and De-chu C. Tang
[Abstract]
Potential Roles of Histones in Host Defense as
Antimicrobial Agents Pp. 195-205
H. Kawasaki and S. Iwamuro
[Abstract]
Abstracts
[Back to top]
Editorial:
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. acnes-associated 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.
Chun-Ming Huang
Associate Professor
Division of Dermatology
University of Califorlina, San Diego
Tel: 858 552 8585 x 3708
Fax: 858 642 1435
Email: chunming@ucsd.edu
[Back to top]
The Role of Antimicrobial Peptides in Human
Skin and in Skin Infectious Diseases
Birgit Schittek, Maren Paulmann, Ilknur
Senyürek and Heiko Steffen
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.
[Back to top]
Toll-Like Receptors in Skin Infections and Inflammatory Diseases
Yuping Lai and Richard L. Gallo
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.
[Back to top]
Vaccine Therapy for P. acnes-Associated Diseases
Teruaki Nakatsuji, Lada Rasochova and Chun-Ming Huang
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.
[Back to top]
Biofilms in Skin Infections: Propionibacterium acnes
and Acne Vulgaris
T. Coenye, K. Honraet, B. Rossel and
H.J. Nelis
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).
[Back to top]
Mass Spectrometry-Based Approaches for the Detection of Proteins
of Staphylococcus Species
Yen-Peng Ho and P. Muralidhar Reddy
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.
[Back to top]
A Technological Update of Molecular Diagnostics for Infectious
Diseases
Yu-Tsueng Liu
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.
[Back to top]
Topical Application of Escherichia coli Particles
Over-Producing Pathogen-Derived Antigens as a Simple Vaccination
Modality in Compliance with Evolutionary Medicine
Jianfeng Zhang and De-chu C. Tang
The development of a new generation of vaccines that
can be produced rapidly at low costs and mass-administered
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.
[Back to top]
Potential Roles of Histones in Host Defense as Antimicrobial
Agents
H. Kawasaki and S. Iwamuro
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.
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