Staphylococcus aureus causes diseases ranging from superficial wound infections to more invasive manifestations like osteomyelitis and endocarditis. The evasion of host phagocytes recruited to the site of infection is essential to the success of S. aureus as a pathogen. A single S. aureus strain can produce up to five different bicomponent pore-forming leukotoxins that lyse immune cells by forming pores in the cellular plasma membrane. Although these leukotoxins have been considered redundant due to their cytotoxic activity toward human neutrophils, each toxin displays varied species and celltype specificities. This suggests that cellular factors may influence which cells each toxin targets. Here we describe the identification of CD11b, the α subunit of the αM/β2 integrin (CD11b/CD18), macrophage-1 antigen, or complement receptor 3, as a cellular receptor for leukocidin A/B (LukAB), an important toxin that contributes to S. aureus killing of human neutrophils. We demonstrate that CD11b renders human neutrophils susceptible to LukAB-mediated killing by purified LukAB as well as during S. aureus infection ex vivo. LukAB directly interacts with human CD11b by binding to the I domain, a property that determines the species specificity exhibited by this toxin. Identification of a LukAB cellular target has broad implications for the use of animal models to study the role of LukAB in S. aureus pathogenesis, explains the toxin's tropism toward human neutrophils and other phagocytes, and provides a cellular therapeutic target to block the effect of LukAB toward human neutrophils.toxin receptor | pore-forming cytotoxin
bMethicillin-resistant Staphylococcus aureus (MRSA) strains of the pulsed-field type USA300 are primarily responsible for the current community-associated epidemic of MRSA infections in the United States. The success of USA300 is partly attributed to the ability of the pathogen to avoid destruction by human neutrophils (polymorphonuclear leukocytes [PMNs]), which are crucial to the host immune response to S. aureus infection. In this work, we investigated the contribution of bicomponent poreforming toxins to the ability of USA300 to withstand attack from primary human PMNs. We demonstrate that in vitro growth conditions influence the expression, production, and availability of leukotoxins by USA300, which in turn impact the cytotoxic potential of this clone toward PMNs. Interestingly, we also found that upon exposure to PMNs, USA300 preferentially activates the promoter of the lukAB operon, which encodes the recently identified leukocidin AB (LukAB). LukAB elaborated by extracellular S. aureus forms pores in the plasma membrane of PMNs, leading to PMN lysis, highlighting a contribution of LukAB to USA300 virulence. We now show that LukAB also facilitates the escape of bacteria engulfed within PMNs, in turn enabling the replication and outgrowth of S. aureus. Together, these results suggest that upon encountering PMNs S. aureus induces the production of LukAB, which serves as an extra-and intracellular weapon to protect the bacterium from destruction by human PMNs.
The GTPases comprise a protein superfamily of highly conserved molecular switches adapted to many diverse functions. These proteins are found in all domains of life and often perform essential roles in fundamental cellular processes. Analysis of data from genome sequencing projects demonstrates that bacteria possess a core of 11 universally conserved GTPases (elongation factor G and Tu, initiation factor 2, LepA, Era, Obg, ThdF/TrmE, Ffh, FtsY, EngA and YchF). Investigations aimed at understanding the function of GTPases indicate that a second conserved feature of these proteins is that they elicit their function through interaction with RNA and/or ribosomes. An emerging concept suggests that the 11 universal GTPases are either necessary for ribosome function or transmitting information from the ribosome to downstream targets for the purpose of generating specific cellular responses. Furthermore, it is suggested that progenitor GTPases were early regulators of RNA function and may have existed in precursors of cellular systems driven by catalytic RNA. If this is the case, then a corollary of this hypothesis is that GTPases that do not bind RNA arose at a later time from an RNA‐binding progenitor that lost the capability to bind RNA.
Enterococcus faecalis and Enterococcus faecium infections are increasingly difficult to treat due to high levels of resistance to antibiotics. PlyV12, a bacteriophage lytic enzyme, was isolated and shown to effectively kill both E. faecalis and E. faecium (including vancomycin-resistant strains), as well as other human pathogens. We propose its development and use as an alternative therapeutic tool.Enterococcus faecalis and Enterococcus faecium are grampositive bacteria that commensally colonize the lower intestinal tract, oral cavity, and vaginal tract of humans. In healthy individuals, E. faecalis and E. faecium colonization normally has no adverse effect on the host; however, the acquisition of virulence factors and high-level antibiotic resistance by enterococci are causing these organisms to emerge as a leading source of nosocomial infections, particularly in immunocompromised patients (3,8,9,16). Common diseases caused by enterococcal infections include endocarditis, abdominal abscesses, bacteremia, and urinary tract infections.We are currently developing a novel approach to the control of pathogenic microorganisms through the action of purified bacteriophage lytic enzymes, termed lysins, produced during the natural life cycle of the bacteriophage. Lysins have evolved to rapidly break down the bacterial cell wall in order to release progeny phage (23). Structurally, lysins are commonly found as modular proteins with an amino-terminal domain that confers the enzymatic activity for a peptidoglycan bond and a carboxyterminal domain that confers binding specificity to a carbohydrate epitope in the bacterial cell wall (13)(14)(15)20). These highly evolved enzymes are normally very specific to the bacterial host of the phage from which they are derived (5, 6). When lysins are purified and applied extrinsically, their binding efficiency and catalytic activity can be harnessed to achieve targeted killing of select pathogenic bacteria with minimal effects on other commensal bacteria; this capacity is an advantage over conventional antibiotics. The efficacy of various lysins in killing Bacillus anthracis (19), Streptococcus pyogenes (a group A streptococcus) (17), and Streptococcus pneumoniae (10, 11) has been demonstrated both in vitro and in animal models of colonization and/or infection with these pathogens.In this report, we describe a lysin, PlyV12, from the enterococcal bacteriophage ⌽1 which infects the host, E. faecalis strain V12. ⌽1 (obtained from the d'Herelle collection, Laval University, Quebec, Canada) was originally isolated from sewage in 1975 and belongs to the Myoviridae family, whose members are characterized by contractile tails and icosahedral heads (2, 7). PlyV12 is a proposed amidase that exhibits a substantial lytic effect on multiple E. faecalis strains. Significantly, PlyV12 also lyses vancomycin-resistant strains of E. faecalis and strains of the closely related enterococcal pathogen E. faecium. Distinct from other reported lysins, PlyV12 was also found to be active against several disease...
SUMMARY In order for Staphylococcus aureus to thrive inside the mammalian host, the bacterium has to overcome iron scarcity. S. aureus is thought to produce toxins that lyse erythrocytes, releasing hemoglobin, the most abundant iron source in mammals. Here we identify the Duffy antigen receptor for chemokines (DARC) as the receptor for the S. aureus hemolytic leukocidins LukED and HlgAB. By assessing human erythrocytes with DARC polymorphisms, we determined that HlgAB and LukED-mediated lysis directly relates to DARC expression. DARC is required for S. aureus-mediated lysis of human erythrocytes and DARC overexpression is sufficient to render cells susceptible to toxin-mediated lysis. HlgA and LukE bind directly to DARC through different regions, and by targeting DARC, HlgAB and LukED support S. aureus growth in a hemoglobin acquisition-dependent manner. These findings elucidate how S. aureus targets and lyses erythrocytes to release one of the scarcest nutrients within the mammalian host.
The success of Staphylococcus aureus as a leading cause of deadly hospital-acquired and community-acquired infections is attributed to its high-level resistance to most antibiotics, and the multitude of virulence factors it elaborates. Most clinical isolates produce up to four bi-component pore-forming toxins capable of lysing cells of the immune system. Subtle differences in activity and target range of each leukotoxin suggest that these toxins are not redundant, but instead may have specialized functions in attacking and/or evading host defenses. In turn, the host has developed countermeasures recognizing sublytic levels of leukotoxins as signals to activate protective immune defenses. The opposing cytotoxic and immune-activating effects of leukotoxins on host cells make for a complex dynamic between S. aureus and the host.
Community-acquired infections caused by methicillin-resistant Staphylococcus aureus (MRSA) expressing the Panton-Valentine leukocidin (PVL) are rampant, but the contribution of PVL to bacterial virulence remains controversial. While PVL is usually viewed as a cytotoxin, at sublytic amounts it activates protective innate immune responses. A leukotoxic effect might predominate in high inoculum studies, whereas protective proinflammatory properties might predominate in settings with lower bacterial inocula that more closely mimic what initially occurs in humans. However, these protective effects might possibly be neutralized by antibodies to PVL, which are found in normal human sera and at increased levels following PVL + S. aureus infections. In a low-inoculum murine skin abscess model including a foreign body at the infection site, strains deleted for the pvl genes replicated more efficiently within abscesses than isogenic PVL + strains. Coinfection of mice at separate sites with isogenic PVL + and PVL -MRSA abrogated the differences in bacterial burdens, indicating a systemic effect on host innate immunity from production of PVL. Mice given antibody to PVL and then infected with seven different PVL + strains also had significantly higher bacterial counts in abscesses compared with mice given nonimmune serum. Antibody to PVL had no effect on MRSA strains that did not produce PVL. In vitro, antibody to PVL incapacitated PVL-mediated activation of PMNs, indicating that virulence of PVL + MRSA is enhanced by the interference of PVL-activated innate immune responses. Given the high rates of primary and recurring MRSA infections in humans, it appears that antibodies to PVL might contribute to host susceptibility to infection.bacterial pathogenesis | immunity | Panton-Valentine leukocidin | MRSA
We have cloned a lytic enzyme, PlyPH, with a specific lytic effect on Bacillus anthracis strains. PlyPH remains active between pH 4 and 10.5, and a single dose rescued a significant percentage of mice infected intraperitoneally with an attenuated B. anthracis strain. We propose PlyPH as a novel therapeutic agent.
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