Biofilms are sticky agglomerations comprising an assortment of bacterial cells and extracellular polysaccharide matrices and so are intrinsically resistant to antibiotics and systems of host defense [105]. of CA-MRSA Sodium Danshensu infections are soft skin and tissue infections (SSTIs) (~ 50% of total cases). However, invasive cases of CA-MRSA-related diseases, such as necrotizing pneumonia (~ 5% of total cases), are becoming increasingly more common. As a consequence, the treatment of MRSA-infections places great financial Sodium Danshensu strains on public healthcare [5]. Rabbit polyclonal to LRRC15 It is generally believed that this epidemiological success of the pulsed-field type USA300 CA-MRSA isolate, which is now pandemic in the United States, is due to a combination of high virulence, antibiotic resistance, and colonization capacity, leading to sustainable spread in the community [6]. The high number of community-associated infections with USA300 has prompted considerable research efforts aimed to develop therapeutics to combat CA-MRSA. These primarily include strategies interfering with virulence, including most notably active and passive immunization efforts directed against CA-MRSA toxins and other virulence factors (reviewed extensively in [7C10]). Here, an overview on a number of toxin families, with a focus on toxins encoded exclusively by, or showing increased expression in, CA-MRSA strains will be provided. The functions that those toxins have in pathogenesis and disease will be discussed. Finally, the rationales and caveats regarding the use of anti-toxin monoclonal antibodies (mAbs) as therapeutics for the prevention and treatment of CA-MRSA-mediated disease will be explored. 2. Toxins involved in pathogenesis produces and secretes many types of toxins with diverse functions in pathogenesis, particularly affecting immune evasion and activation of the immune response. These include alpha-hemolysin (-hemolysin, Hla), beta-toxin (-toxin), the superantigens (SAgs), the leukotoxins, and the phenol-soluble modulins (PSMs). The genes coding for -toxin, the SAgs and leukotoxins are mostly encoded by mobile genetic Sodium Danshensu elements (MGEs) [11]; therefore, toxin expression can differ greatly between different strains of toxins, such as -hemolysin and the PSMs, are genome-encoded [12, 13] and expressed by both HA- and CA-MRSA strains. However, -hemolysin and the PSMs are expressed more strongly in CA-MRSA compared to HA-MRSA strains. This suggests that differences in gene regulation may influence the epidemiological success of CA-MRSA strains such as USA300 [14, 15]. For example, it has been noted that USA300 shows increased expression of the global regulatory quorum sensing system, accessory gene regulator (locus consists of a divergent promoter, which controls the transcription of RNAII and RNAIII. The RNAII transcript contains 4 genes encoding a classical two-component quorum sensing system (mutants lacking a functional regulatory system are significantly less virulent than the corresponding wild-type strains, which has recently been exhibited specifically for USA300 [14, 17C19]. 2.1 Leukotoxins Neutrophils, or polymorphonuclear leukocytes (PMNs), are key components of the innate immune system and involved in Sodium Danshensu controlling infection [20, 21]. Possibly for that reason, produces a large variety of virulence factors that inhibit neutrophil function [22], allowing to circumvent removal by innate host defense [23]. Particularly, pore-forming, bi-component leukotoxins with cytolytic affinity towards cells of myeloid lineage, such as monocytes, macrophages and neutrophils, represent important contributors to immune evasion [24, 25]. Each leukotoxin requires one class S and one class F protein, which are individually non-toxic, to form a -barreled pore-forming structure upon oligomerization [26]. Six class S subunits (LukS-PV, HlgA, HlgC, LukE, LukM, LukH) and five class F subunits (LukF-PV, HlgB, LukD, LukF-PV, LukG) have been explained [24, 25, 27, 28]. One exception to this monogamous pairing is the -hemolysin gene cluster, which comprises three genes (([or [or [or gene cluster occurs in 99% of strains [32C34], many other leukotoxin genes are not uniformly present among isolates. The (are not found in the HA-MRSA isolate, USA200 [36] and the phage-encoded and pathogenesis remains controversial despite considerable research that has been performed on that leukotoxin [1, 15, 38, 39]. Owing to the in the beginning observed.