Understanding virulence is vital for the development of novel therapeutics to target infections with community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA), which cause an ongoing epidemic in the United States and are on a global rise. However, what defines virulence particularly of global CA-MRSA lineages is poorly understood. Threatening a vast population, the predominant Asian CA-MRSA lineage ST59 is of major epidemiological importance. However, there have been no molecular analyses using defined virulence gene deletion mutants in that lineage as of yet. Here, we compared virulence in skin, lung, and blood infection models of ST59 CA-MRSA isolates with geographically matched hospital-associated MRSA isolates. We selected a representative ST59 CA-MRSA isolate based on toxin expression and virulence characteristics, and produced isogenic gene deletion mutants of important CA-MRSA virulence determinants (α-toxin, PSM α, Agr) in that isolate for in-vitro and in-vivo analyses. Our results demonstrate strongly enhanced virulence of ST59 CA-MRSA over hospital-associated lineages, supporting the notion that enhanced virulence is characteristic for CA-MRSA. Furthermore, they show strong and significant contribution of Agr, α-toxin, and PSMα to pathogenesis of ST59 CA-MRSA skin, lung, and blood infection, emphasizing the value of drug development efforts targeted toward those virulence determinants.

The highly successful epidemic of healthcare-associated methicillin-resistant Staphylococcus aureus (HA-MRSA) ST239 is a growing concern worldwide, due to its progressive adaptation to the highly selective environment of the healthcare system. HA-MRSA ST239 display the reduced virulence and successfully colonize in hospital settings, while the emergent community-associated MRSA (CA-MRSA) maintain full virulence and cause infections in the community environment. Our aim was to investigate what enables S. aureus ST239 to be highly adaptive under hospital circumstances and gradually progress to a series of widespread invasive infections. We found that spa expression of HA-MRSA ST239 is much higher than that of CA-SA ST398. And we discovered that the highly production of staphylococcal protein A (SpA), having no concern with spa gene structure, enhances nasal colonization and cell adhesion in ST239. S. aureus ST239 defends against the adaptive immune response by resisting phagocytosis and inducing apoptosis of B cells through expression of surface-anchored and released protein A, facilitating its dissemination within the circulatory system to other organs. Protein A also plays another key role in subverting the host immune response through its ability to induce early shedding of TNF-α receptor 1 (TNFR1) from phagocytic cells. The increased levels of soluble TNFR1 present during experimental S. aureus ST239 infection may neutralize circulating TNF-α and impair the host inflammatory response. Protein A is also a virulence factor, as tested in our bacteremia model in mice, contributing to the durative tissue damage of abscess formation sites in ST239 infection. These functions of protein A eventually benefit to widespread infections of S. aureus ST239. We draw the conclusion that Staphylococcal Protein A may be a crucial determinant in the colonization and immune evasion of ST239 infections, contributing to persistent spread in the hospital settings. These results suggest that antibodies against protein A may provide insights into the development of novel treatments against S. aureus, especially HA-MRSA.

No abstract

c SasX is a recently described surface protein of Staphylococcus aureus that is linked to the epidemic success of hospital-associated methicillin-resistant clones, in particular in Asia. It enhances nasal colonization and virulence in skin and lung infection models. Here, we evaluated the potential of SasX as a vaccine component in passive and active immunization efforts using mouse infection models. We found that SasX induced a specific immune response predominantly based on IgG1 antibodies. Active immunization with recombinant SasX or passive immunization with rabbit polyclonal anti-SasX IgG significantly decreased the size of lesions caused by S. aureus in a skin infection model. Furthermore, active immunization reduced acute lung injury in a lung infection model. Moreover, active or passive immunization significantly reduced S. aureus colonization in a nasal colonization model. Finally, anti-SasX IgG enhanced the susceptibility of S. aureus to killing by human neutrophils. We conclude that SasX is a potential target for therapeutics or vaccines designed to moderate colonization and infection by sasX-positive epidemic strains of S. aureus. Staphylococcus aureus is a major global source of morbidity and mortality (1), causing more than 11,000 deaths per year in the United States alone (2). It is particularly notorious as a dangerous hospital-associated pathogen. Treatment of S. aureus infections is severely complicated by antibiotic resistance (3). In particular, resistance to methicillin in methicillin-resistant S. aureus (MRSA), which in many countries occurs in more than half of infectious S. aureus isolates, is a major health care concern. In addition, many S. aureus strains are resistant to a wide variety of other antibiotics, leaving only very limited options for treatment. In an era that has seen a broad withdrawal of pharmaceutical companies from the much-needed development of novel antibiotics, researchers in companies and academia are again beginning to attempt vaccine development against S. aureus. A working vaccine against S. aureus infections is not available, and multiple reasons have been discussed for why an anti-S. aureus vaccine is difficult to find (4, 5). These include first and foremost the large arsenal of immune evasion factors of S. aureus, which target both acquired and innate immune defenses (6). However, there is promising evidence indicating that passive and active vaccination against S. aureus should in principle be possible, notwithstanding the fact that we still do not completely understand the mechanisms the immune system uses for protective immunity against S. aureus (4).Infective S. aureus and MRSA isolates are very diverse regarding geographical origin and time of isolation. Over the years, specific predominant MRSA clones arose and were thereafter replaced by others, in a scenario of epidemic waves (7). Furthermore, infections in different geographic areas are characterized by a divergent and often endemic composition of prevalent S. aureus and MRSA lineages. This situation ...

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide and has an extremely poor prognosis. Surgical resection is always inapplicable to HCC patients diagnosed at an advanced tumor stage. The mechanisms underlying HCC cell proliferation remain obscure. In the present study, SWItch/sucrose nonfermentable catalytic subunit SNF2 (SNF2H) expression was tested in HCC tissues and Wnt/β-catenin pathway activation upon overexpression of SNF2H or knockdown of SNF2H expression was investigated in cultured HCC cells. It was demonstrated that SNF2H is a vital factor for HCC growth. The SNF2H expression level is increased in HCC tissues compared with paratumoral liver tissues. SNF2H promotes HCC cell proliferation and colony formation ability in vitro. SNF2H may increase the protein level of β-catenin and enhance its nuclear accumulation in HCC cells, thereby leading to the activation of the Wnt/β-catenin signaling pathway. In conclusion, the present results indicate that SNF2H plays a vital role in HCC cell growth, suggesting that SNF2H may be a promising therapeutic target for HCC treatment.

During 2005–2014, community-associated methicillin-resistant Staphylococcus aureus infections increased in Shanghai, China. Most infections were caused by sequence type 59 S. aureus that lacked Panton-Valentine leukocidin. This finding challenges the notion that Panton-Valentine leukocidin is necessary for epidemiologic success of community-associated methicillin-resistant S. aureus.

Improving the Sensitivity and Robustness of Bioreporter for Copper wastewater, and drinking water. Since whole-cell bioreporters are relatively inexpensive and easy to operate, the combination of this method with other physicochemical techniques will in turn provide more specific information on the degree of toxicity in water environments.