Pei-Feng Liu

Passive Immunoprotection Targeting a Secreted CAMP Factor of Propionibacterium acnes as a Novel Immunotherapeutic for Acne Vulgaris

Propionibacterium acnes (P. acnes) bacteria play a key role in the pathogenesis of acne vulgaris. Although our previous studies have demonstrated that vaccines targeting a surface sialidase or bacterial particles exhibit a preventive effect against P. acnes, the lack of therapeutic activities and incapability of neutralizing secretory virulence factors motivate us to generate novel immunotherapeutics. In this study, we develop an immunotherapeutic antibody to secretory Christie-Atkins-Munch-Peterson (CAMP) factor of P. acnes. Via agroinfiltration, P. acnes CAMP factor was encapsulated into the leaves of radishes. ICR mice intranasally immunized with whole leaves expressing CAMP factor successfully produced neutralizing antibodies that efficiently attenuated P. acnes-induced ear swelling and production of macrophage-inflammatory protein-2. Passive neutralization of CAMP factor enhanced immunity to eradicate P. acnes at the infection site without influencing bacterial growth elsewhere. We propose that CAMP factor is a novel therapeutic target for the treatment of various P. acnes-associated diseases and highlight the concept of neutralizing P. acnes virulence without disturbing the bacterial commensalism in human microbiome.

Vaccination targeting surface FomA of Fusobacterium nucleatum against bacterial co-aggregation: Implication for treatment of periodontal infection and halitosis.

The mechanical therapy with multiple doses of antibiotics is one of modalities for treatment of periodontal diseases. However, treatments using multiple doses of antibiotics carry risks of generating resistant strains and misbalancing the resident body flora. We present an approach via immunization targeting an outer membrane protein FomA of Fusobacterium nucleatum (F. nucleatum), a central bridging organism in the architecture of oral biofilms. Neutralization of FomA considerably abrogated the enhancement of bacterial co-aggregation, biofilms and production of volatile sulfur compounds mediated by an inter-species interaction of F. nucleatum with Porphyromonas gingivalis (P. gingivalis). Vaccination targeting FomA also conferred a protective effect against co-infection-induced gum inflammation. Here, we advance a novel infectious mechanism by which F. nucleatum co-opts P. gingivalis to exacerbate gum infections. FomA is highlighted as a potential target for development of new therapeutics against periodontal infection and halitosis in humans.

The essentiality of α‐2‐macroglobulin in human salivary innate immunity against new H1N1 swine origin influenza A virus

A novel strain of influenza A H1N1 emerged in the spring of 2009 and has spread rapidly throughout the world. Although vaccines have recently been developed that are expected to be protective, their availability was delayed until well into the influenza season. Although anti‐influenza drugs such as neuraminidase inhibitors can be effective, resistance to these drugs has already been reported. Although human saliva was known to inhibit viral infection and may thus prevent viral transmission, the components responsible for this activity on influenza virus, in particular, influenza A swine origin influenza A virus (S‐OIV), have not yet been defined. By using a proteomic approach in conjunction with beads that bind α‐2,6‐sialylated glycoprotein, we determined that an α‐2‐macroglobulin (A2M) and an A2M‐like protein are essential components in salivary innate immunity against hemagglutination mediated by a clinical isolate of S‐OIV (San Diego/01/09 S‐OIV). A model of an A2M‐based “double‐edged sword” on competition of α‐2,6‐sialylated glycoprotein receptors and inactivation of host proteases is proposed. We emphasize that endogenous A2M in human innate immunity functions as a natural inhibitor against S‐OIV.

Vaccines and photodynamic therapies for oral microbial-related diseases.

The mouth is a favorable habitat for a great variety of bacteria. Microbial composition of dental plaque is the usual cause of various oral diseases in humans, including dental caries, periodontal disease and halitosis. In general, oral antibacterial agents such as antibiotics are commonly used to treat oral bacterial infection. Traditional periodontal surgery is painful and time-consuming. In addition, bacterial resistance and toxicity of antibiotics have become a global pandemic and unavoidable. Recently, vaccines for dental caries and periodontal disease have been developed and applied. Moreover, the use of photodynamic therapy has become an alternative to antibiotic drugs. The purpose of this article is to highlight the advantages of vaccine therapy and photodynamic therapy for oral microbial-related diseases compared to treatments with antimicrobial agents and traditional periodontal surgery.

Use of nanoparticles as therapy for methicillin-resistant staphylococcus aureus infections

Staphylococcal infection can cause a wide range of diseases resulting either from staphylococcal bacteria invasion or through toxin production. The majority of infections caused by staphylococci are due to Staphylococcus aureus. Moreover, methicillin-resistant Staphylococcus aureus has recently been considered to be one of the major causes of hospital-acquired infections. The treatment of staphylococci infections is difficult because increased antibiotic resistant strains have become more common, increasing the risk of serious health penalty. Delivery of antibiotics via nanoparticles is a promising therapy, as a drug delivery mechanism, particularly for controlled release or depot delivery of drugs to decrease the number of doses required to achieve a clinical effect. This review emphasized the potential of nanoparticles in the targeted antibiotics for therapy of staphylococcal infections.

A novel vaccine targeting Fusobacterium nucleatum against abscesses and halitosis

An abscess in a gum pocket, resulting from bacterial infection, is a common source of chronic halitosis. Although antibiotics are generally prescribed for abscesses, they require multiple treatments with risks of creating resistant bacterial strains. Here we develop a novel vaccine using ultraviolet-inactivated Fusobacterium nucleatum (F. nucleatum), a representative oral bacterium for halitosis. A gum pocket model, established by continuous inoculation of F. nucleatum, was employed to validate the vaccine potency. Mice immunized with inactivated F. nucleatum effectively minimized the progression of abscesses, measured by swollen tissues of gum pockets. Most notably, the immunized mice were capable of eliciting neutralizing antibodies against the production of volatile sulfur compounds of F. nucleatum. The novel vaccine inducing protective immunity provides an alternative option to conventional antibiotic treatments for chronic halitosis associated with abscesses.

High Throughput Screening for Drug Discovery of Autophagy Modulators

Autophagy is an evolutionally conserved process in cells for cleaning abnormal proteins and organelles in a lysosome dependent manner. Growing studies have shown that defects or induced autophagy contributes to many diseases including aging, neurodegeneration, pathogen infection, and cancer. However, the precise involvement of autophagy in health and disease remains controversial because the theories are built on limited assays and chemical modulators, indicating that the role of autophagy in diseases may require further verification. Many food and drug administration (FDA) approved drugs modulate autophagy signaling, suggesting that modulation of autophagy with pharmacological agonists or antagonists provides a potential therapy for autophagy-related diseases. This suggestion raises an attractive issue on drug discovery for exploring chemical modulators of autophagy. High throughput screening (HTS) is becoming a powerful tool for drug discovery that may accelerate screening specific autophagy modulators to clarify the role of autophagy in diseases. Herein, this review lays out current autophagy assays to specifically measure autophagy components such as LC3 (mammalian homologue of yeast Atg8) and Atg4. These assays are feasible or successful for HTS with certain chemical libraries, which might be informative for this intensively growing field as research tools and hopefully developing new drugs for autophagy-related diseases.

IsaB Inhibits Autophagic Flux to Promote Host Transmission of Methicillin-Resistant Staphylococcus aureus

Methicillin-resistant Staphylococcus aureus (MRSA) has emerged as a major nosocomial pathogen that is widespread in both health care facilities and the community at large as a result of direct host-to-host transmission. Several virulence factors are associated with pathogen transmission to naive hosts. Immunodominant surface antigen B (IsaB) is a virulence factor that helps Staphylococcus aureus to evade the host defense system. However, the mechanism of IsaB on host transmissibility remains unclear. We found that IsaB expression was elevated in transmissible MRSA. Wild-type isaB strains inhibited autophagic flux to promote bacterial survival and elicit inflammation in THP-1 cells and mouse skin. MRSA isolates with increased IsaB expression showed decreased autophagic flux, and the MRSA isolate with the lowest IsaB expression showed increased autophagic flux. In addition, recombinant IsaB rescued the virulence of the isaB deletion strain and increased the Group A streptococcus (GAS) virulence in vivo. Together, these results reveal that IsaB diminishes autophagic flux, thereby allowing MRSA to evade host degradation. These findings suggest that IsaB is a suitable target for preventing or treating MRSA infection.

Nasal commensal Staphylococcus epidermidis counteracts influenza virus

Several microbes, including Staphylococcus epidermidis (S. epidermidis), a Gram-positive bacterium, live inside the human nasal cavity as commensals. The role of these nasal commensals in host innate immunity is largely unknown, although bacterial interference in the nasal microbiome may promote ecological competition between commensal bacteria and pathogenic species. We demonstrate here that S. epidermidis culture supernatants significantly suppressed the infectivity of various influenza viruses. Using high-performance liquid chromatography together with mass spectrometry, we identified a giant extracellular matrix-binding protein (Embp) as the major component involved in the anti-influenza effect of S. epidermidis. This anti-influenza activity was abrogated when Embp was mutated, confirming that Embp is essential for S. epidermidis activity against viral infection. We also showed that both S. epidermidis bacterial particles and Embp can directly bind to influenza virus. Furthermore, the injection of a recombinant Embp fragment containing a fibronectin-binding domain into embryonated eggs increased the survival rate of virus-infected chicken embryos. For an in vivo challenge study, prior Embp intranasal inoculation in chickens suppressed the viral titres and induced the expression of antiviral cytokines in the nasal tissues. These results suggest that S. epidermidis in the nasal cavity may serve as a defence mechanism against influenza virus infection.

Propionibacterium acnes in the Pathogenesis and Immunotherapy of Acne Vulgaris

Acne vulgaris, a multi-factorial disease, is one of the most common skin diseases, affecting an estimated 80% of Americans at some point during their lives. The gram-positive and anaerobic Propionibacterium acnes (P. acnes) bacterium has been implicated in acne inflammation and pathogenesis. Therapies for acne vulgaris using antibiotics generally lack bacterial specificity, promote the generation of antibiotic-resistant bacterial strains, and cause adverse effects. Immunotherapy against P. acnes or its antigens (sialidase and CAMP factor) has been demonstrated to be effective in mice, attenuating P. acnes-induced inflammation; thus, this method may be applied to develop a potential vaccine targeting P. acnes for acne vulgaris treatment. This review summarizes reports describing the role of P. acnes in the pathogenesis of acne and various immunotherapy-based approaches targeting P. acnes, suggesting the potential effectiveness of immunotherapy for acne vulgaris as well as P. acnes-associated diseases.