Host Defense and Pathogenesis in Staphylococcus aureus Infections

“with pattern recognition receptors expressed on the neutrophil cell surface, including TLRs.(30) Neutrophil TLRs activate signal transduction pathways that prolong cell survival;(31) promote or enhance adhesion, phagocytosis, release of cytokines, chemokines, and ROS;(31,32) and trigger granule exocytosis,(33) thereby…”

“Recently, novel cytolytic peptides have been found in S aureus, the a-type PSMs, which are encoded in an operon on the genomes of all sequenced S aureus strains.26 The a-helical and amphipathic a-type PSMs have pronounced in vitro and in vivo leukocidal activity, in addition to proinflammatory and chemotactic activiti…”

“Historically, CA S aureus infections almost always were caused by methicillin-susceptible S aureus (MSSA) rather than MRSA,(4) but this distribution has changed dramatically in the United States over the past 10 years.(6) Two reports in the late 1990s marked the beginning of a new era in MRSA epidemiology.”

“These secondarily-derived products, including hypochlorous acid, hydroxyl radical, chloramines, and singlet oxygen, are effective microbicidal compounds [40-43].”

“These toxins include the TSST, exfoliative toxins involved in staphylococcal scalded skin syndrome, and the staphylococcal enterotoxins (SEs).(78) Toxic shock syndrome (TSS) is a severe acute disease and may be of menstrual or nonmenstrual origin.”

“Nonetheless, the emergence of multi-drug resistant isolates of USA300 with resistance to clindamycin [13,98], and the potential to acquire even more antibiotic resistance, present a further complication in staphylococcal disease management.”

“To that end, normal turnover of aging neutrophils occurs by spontaneous apoptosis and in the absence of an activating agent.(52) On the other hand, neutrophil apoptosis is accelerated significantly following phagocytosis,(53,54) and this phenomenon appears critical to the resolution of the inflammatory response (see F…”

“the PVL genes (lukS-PV and lukF-PV, abbreviated as lukS/F-PV) and fatal necrotizing pneumonia renewed and intensified interest in understanding the biological role of this bicomponent cytolytic toxin.(83) Epidemiologic data alone, however, are insufficient to establish whether PVL directly contributes to widespread di…”

“A high percentage of hospital infections are caused by methicillin-resistant S aureus (MRSA).(4) Notably, there is”

“Two reports in the late 1990s marked the beginning of a new era in MRSA epidemiology.(7,8) Isolates”

“classified as pulsed-field gel electrophoresis type USA400 emerged as the prototype CA-MRSA genotype.(9,10) A complete genome sequence is available for MW2, a representative USA400 clinical isolate that caused fatal septicemia in 1998.”

“From 1997 to 1999, S aureus was reported as the most abundant cause of bloodstream, skin and soft tissue, and lower respiratory tract infections in the United States, Canada, Europe, Latin America, and the Western Pacific.1 The pathogen is the leading cause of hospital-associated infections in the United States,2 and…”

“Notably, CA-MRSA lineages differ markedly in genotypic and phenotypic characters from traditional hospital-associated MRSA lineages.(10,13,81)”

“the abundance of mechanisms that the bacterium uses to evade killing by phagocytes (see Table 1).(57)”

“1).(45,46) Neutrophil a-defensins comprise up to 50% of the protein in azurophilic granules and have potent antimicrobial activity.”

“As anexample of the importance of the TLRs inhost defense, mice deficient inTLR2 are more susceptible to S aureus infection compared with wild-type mice.(34)”

“NOD2 senses muramyl dipeptide derived from S aureus PGN and ultimately promotes transcription of NF-kB target genes in the nucleus.(37) Phagocytosis also is facilitated by host pattern recognition molecules known as collectins, such as mannose-binding lectin, and these molecules are reviewed elsewhere.”

“S aureus also produces molecules that directly recruit PMNs (eg, phenol soluble modulin-like peptides, PSMs).(26) Although the pathogen elicits a robust”

“ing binding of cationic AMPs, and they are encoded by the dlt operon and the mprF locus, respectively.(71,72) Furthermore, expression of the VraFG transporter is increased upon AMP exposure.”

“with components of the specific granules, such as lactoferrin, further augmenting antimicrobial potential.(48)”

“Polysaccharide intercellular adhesion (PIA) is a biofilmrelated extracellular matrix substance [60], predominantly characterized in S.”

“Notably, CA-MRSA lineages differ markedly in genotypic and phenotypic characters from traditional hospital-associated MRSA lineages.(10,13,81)”

“aureus growth by sequestering nutrient Mn2+ and Zn2+ within abscesses [50].”

“These secondarily-derived products, including hypochlorous acid, hydroxyl radical, chloramines, and singlet oxygen, are effective microbicidal compounds [40-43].”

“toxins is accomplished by cross-linking the T-cell receptor with the major histocompatibility complex (MHC) class 2.(77) These toxins include the TSST, exfoliative toxins involved in staphylococcal scalded skin syndrome, and the staphylococcal enterotoxins (SEs).”

“ing binding of cationic AMPs, and they are encoded by the dlt operon and the mprF locus, respectively.(71,72) Furthermore, expression of the VraFG transporter is increased upon AMP exposure.”

“Although USA400 remained a significant cause of CA-MRSA infections through 2005 [11,12], it has been replaced almost completely by a genotype known as USA300 [6,13], which is now epidemic in the United States.”

“ROS also trigger a broad response of S aureus to circumvent innate host defense mechanisms, which includes production of many toxins and mechanisms involved in the uptake of iron.66 In addition, the characteristic yellow pigment of S aureus, a carotenoid pigment called staphyloxanthin, recently has been shown to play…”

“Many strains are encapsulated by a polysaccharide capsule that has strain-specific chemical composition and protects from phagocytosis.59 Polysaccharide intercellular adhesion (PIA) is a biofilm-related extracellular matrix substance,60 predominantly characterized in S epidermidis but produced by most S aureus strains…”

“Phagocytosis also is facilitated by host pattern recognition molecules known as collectins, such as mannose-binding lectin, and these molecules are reviewed elsewhere.(38)”

“Polysaccharide intercellular adhesion (PIA) is a biofilm-related extracellular matrix substance,(60) predominantly characterized in S epidermidis but produced by most S aureus strains, whose most important and unique feature is a positive net charge.(61) It has been shown to protect from neutrophil phagocytosis and AM…”

“Many strains are encapsulated by a polysaccharide capsule that has strain-specific chemical composition and protects from phagocytosis.(59) Polysaccharide intercellular adhesion (PIA) is a biofilm-related extracellular matrix substance,(60) predominantly characterized in S epidermidis but produced by most S aureus str…”

“First, relatively nonspecific proteases are released to digest any protein-based antimicrobial effector.(68) In addition, S aureus senses the presence of AMPs and reacts by up-regulation of mech-”

“of USA300 and USA400 to circumvent killing by human polymorphonuclear leukocytes (PMNs) and cause rapid destruction of these host cells.(16,17)”

“Menstrual TSS is caused by S aureus colonization of tampons.(79) Nonmenstrual TSS also may be caused by enterotoxins, which, however have a more notorious role as the cause for S aureus food poisoning.”

“antimicrobial mechanisms, which likely account for noted postphagocytosis survival.(17,58) Finally, they often produce toxins that lyse phagocytes, thus using the same kind of weapon that neutrophils use to kill bacteria.”

“The C3 convertase blocker SCIN (staphylococcal complement inhibitor) is but one of a series of S aureus factors with the task of inhibiting complement function.(64) In fact, complement inhibition”

“As such, it is reasonable to propose that clindamycin or linezolid could be beneficial in inhibiting protein synthesis and thus toxin production in CA-MRSA infections.(95) Nonetheless, the”

“a rabbit bacteremia model, providing evidence that ACME contributes to pathogenesis.(82) Two gene clusters identified in ACME, arc and opp-3, may function as virulence determinants.”

“Epidemiologic data alone, however, are insufficient to establish whether PVL directly contributes to widespread dissemination of CA-MRSA clones.(84,85) It is of interest that early studies led Woodin to conclude that PVL alone is not a very toxic substance,(86) as intravenous injection of PVL in rabbits resulted in gr…”

“Protein A also has a more specific role in the pathogenesis of airway infections by interacting with the tumor necrosis factor a receptor on airway epithelia.(76)”

“Immunization with inactivated a-toxin or passive transfer of anti-a-toxin antibodies also protected mice from lethal pneumonia.(90) Taken together, these studies indicate that a-toxin plays an essential role in pneumonia.”

“have recurrent bacterial and fungal infections, especially infections caused by S aureus.(44)”

“The current CA-MRSA epidemic is due to clonal emergence of USA300 isolates that have enhanced virulence or a “hypervirulence” phenotype [14,15].”

“Menstrual TSS is caused by S aureus colonization of tampons.79 Nonmenstrual TSS also may be caused by enterotoxins, which, however have a more notorious role as the cause for S aureus food poisoning.80 COMMUNITY-ASSOCIATEDMETHICILLIN-RESISTANT STAPHYLOCOCCUS AUREUS VIRULENCE Hospital-Associated Versus Community-Associ…”

“α-toxin (α-hemolysin, Hla)—α-toxin is a well-characterized pore forming cytolytic toxin that is similar in sequence and function to the leukocidins [95], albeit it does not lyse neutrophils [96].”

“Concomitant with the production of ROS, neutrophil cytoplasmic granules fuse with bacteria-containing phagosomes, a process called degranulation.(45) Fusion of azuro-”

“Priming includes mobilization of secretory vesicles (and thus up-regulation of specific cell surface receptors, eg, CD11b/CD18) and secretion of cytokines, but fails to trigger release of azurophilic granules or elicit production of superoxide.(29) Importantly, chemotactic/ priming agents ultimately promote efficient…”

“anisms to interfere specifically with the activity of cationic AMPs, using a dedicated three-component AMP sensing system.(69,70) The regulated resistance mechanisms”

“Furthermore, expression of the VraFG transporter is increased upon AMP exposure.(70) VraFG has a demonstrated role in AMP resistance(69) and the”

“Although USA400 remained a significant cause of CA-MRSA infections through 2005 [11,12], it has been replaced almost completely by a genotype known as USA300 [6,13], which is now epidemic in the United States.”

“Indeed, bacterial pathogens have devised mechanisms to alter apoptosis and promote pathogenesis.(55,56) For example, USA300 and USA400 cause rapid PMN lysis and/or accelerate bacteria-induced apoptosis to the point of secondary lysis.”

“emergence of USA300 isolates that have enhanced virulence or a hypervirulence phenotype.(14,15) Hypervirulence, defined here as the ability of CA-MRSA to cause widespread infections in otherwise healthy individuals, likely is related in part to the ability”

“aureus strain Newman, no significant contribution of PVL to lethal pneumonia was found [88,89].”

“is an excellent example of the functional redundancy of S aureus molecules interfering with the same immune defense mechanism (see Table 1).(65)”

“On the other hand, neutrophil apoptosis is accelerated significantly following phagocytosis [53,54] and this phenomenon appears critical to the resolution of the inflammatory response (Fig.”

“Indeed, bacterial pathogens have devised mechanisms to alter apoptosis and promote pathogenesis [55,56].”

“at substimulatory concentration, to enhance superoxide production elicited by a second stimulus.(27) Neutrophils can be primed for enhanced adhesion, phagocytosis, production of reactive oxygen species (ROS), cytokine secretion, leukotriene synthesis, degranulation, and bactericidal activity.”

“and there is strong expression of the agr regulatory molecule RNAIII in CA-MRSA strains, there may be a key role of this virulence regulator in CA-MRSA disease that remains to be investigated.(100)”

“Peptidoglycan recognition protein (PGRP) is a secreted host protein that contributes to intracellular killing of gram-positive bacteria by neutrophils.(35) There are four”

“5 billion in 2003.(3) A high percentage of hospital infections are caused by methicillin-resistant S aureus (MRSA).”

“cently, the failure to replicate the regulatory effects of PVL in USA300 and USA400 indicated that PVL does not contribute to CA-MRSA virulence by means of a gene regulatory mechanism.(92)”

“dase that generates high levels of superoxide, a process traditionally called respiratory burst.(39) Superoxide anion is short-lived and dismutates rapidly to hydrogen peroxide and forms other secondary reactive products.”

“Epidemiological data alone, however, is insufficient to establish whether PVL directly contributes to widespread dissemination of CA-MRSA clones [84,85].”

“Neutrophil TLRs activate signal transduction pathways that prolong cell survival [31], promote and/or enhance adhesion, phagocytosis, release of cytokines, chemokines and ROS [31,32], and trigger granule exocytosis [33], thereby contributing to microbicidal activity.”

“aureus to circumvent innate host defense mechanisms, which includes production of many toxins and mechanisms involved in the uptake of iron [66].”

“studies have demonstrated that stimulation of CD41 T-cells by S aureus capsular polysaccharide leads to production of chemokines that recruit neutrophils to the site of infection.(23,24) Further, S aureus cell surface components, primarily peptidoglycan (PGN), long have been known to elicit production of C5a,(25) a po…”

“A first step in the eradication of invading microorganisms is active recruitment of PMNs to the site of infection by chemotaxis.(18) This is a multistep process whereby neutrophils are mobilized from peripheral blood or bone marrow in response to”

“a-toxin is a well-characterized pore forming cytolytic toxin that is similar in sequence and function to the leukocidins,(97) albeit it does not lyse neutrophils.(98) Recently, it was shown to be an essential virulence factor during S aureus pneumonia.”

“studies have demonstrated that stimulation of CD41 T-cells by S aureus capsular polysaccharide leads to production of chemokines that recruit neutrophils to the site of infection.(23,24) Further, S aureus cell surface components, primarily peptidoglycan (PGN), long have been known to elicit production of C5a,(25) a po…”

“These secondarily-derived products, including hypochlorous acid, hydroxyl radical, chloramines, and singlet oxygen, are effective microbicidal compounds [40-43].”

“From 1997 to 1999, S aureus was reported as the most abundant cause of bloodstream, skin and soft tissue, and lower respiratory tract infections in the United States, Canada, Europe, Latin America, and the Western Pacific.1 The pathogen is the leading cause of hospital-associated infections in the United States,2 and…”

“aureus lipoteichoic acid (LTA) and capsular polysaccharide induce production of IL-8 by peripheral blood monocytes [19] and epithelial and endothelial cells [20], respectively.”

“From 1997 to 1999, S aureus was reported as the most abundant cause of bloodstream, skin and soft tissue, and lower respiratory tract infections in the United States, Canada, Europe, Latin America, and the Western Pacific.1 The pathogen is the leading cause of hospital-associated infections in the United States,2 and…”

“sequester nonspecific antibodies on its surface, which protects efficiently from attacks by the innate and acquired immune systems.(75) Protein A also has a more specific role in the pathogenesis of airway infections by interacting with the tumor necrosis factor a receptor on airway epithelia.”

“S aureus-activated endothelial cells produce IL-8 that promotes transmigration of neutrophils.(21) Freely secreted virulence molecules of S aureus, including toxic shock syndrome toxin-1 (TSST1), enterotoxin A (SEA), or enterotoxin B (SEB), also elicit production of IL-8 by human monocytic cells.”

“For instance, group IIA phospholipase A2 (gIIA-PLA2), a small (approximately 14 kDa) cationic antimicrobial protein found in extracellular fluids, synergizes with the neutrophil NADPH oxidase to promote digestion of S aureus phospholipids.(49) More recently, studies by Corbin and colleagues(50) found that neutrophil c…”

“There is Table 1 Staphylococcus aureus molecules that contribute to immune evasion or alter host immune function Gene(s) Protein orMolecule Function/Effect on Immune System mprF Multiple peptide resistance factor, MprF Promotes resistance to cationic AMPs psm Phenol-soluble modulinlike peptides, PSMs Cause leukocyte l…”

“Woodin to conclude that PVL alone is not a very toxic substance [86], as intravenous injection of PVL in rabbits resulted in granulocytopenia followed by a marked granulocytosis, and was not lethal.”

“The b-barrel structured leukocidins form pores almost exclusively in leukocytes, by means of a mechanism similar to that used by a-toxin.(73) Although the biochemical function of leukocidins—that is, lysis of leukocytes—has been clearly established, their role in S aureus virulence and the biological reason for the pr…”

“aureus, including toxic shock syndrome toxin-1 (TSST1), enterotoxin A (SEA), or enterotoxin B (SEB), also elicit production of IL-8 by human monocytic cells [22].”

“aureus produces many other molecules that promote host colonization, facilitate evasion of the innate immune system and alter immune response”

“Further on, it has been shown that phagocytosis significantly accelerates neutrophils apoptosis, which appears to contribute to the resolution of the inflammatory response [21,22].”