Lack of a Major Role of Staphylococcus aureus Panton-Valentine Leukocidin in Lower Respiratory Tract Infection in Nonhuman Primates

Olsen, Randall J.; Kobayashi, Scott D.; Ayeras, Ara A.; Ashraf, Mohammad; Graves, Shawna F.; Ragasa, Willie; Humbird, Tammy; Greaver, Jamieson; Cantu, Constance; Swain, Jody; Jenkins, Leslie; Blasdel, Terry L.; Cagle, Philip T.; Gardner, Donald J.; DeLeo, Frank R.; Musser, James M.

doi:10.2353/ajpath.2010.090960

Cited by 43 publications

(43 citation statements)

References 48 publications

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“…In contrast, PVL may contribute to S. aureus persistence in a model of osteomyelitis (Table 1) (215). Additional studies in primates were unable to uncover a role for PVL in a pneumonia model (216). The discrepancy in virulence characteristics associated with pneumonia in rabbits and primates likely stems from the fact that primate PMNs are also relatively insensitive to the lytic functions of the toxin (200).…”

Section: Luksf-pv (Pvl)mentioning

confidence: 89%

The Bicomponent Pore-Forming Leucocidins of Staphylococcus aureus

Alonzo

Torres

2014

Microbiol Mol Biol Rev

239

290

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SUMMARY The ability to produce water-soluble proteins with the capacity to oligomerize and form pores within cellular lipid bilayers is a trait conserved among nearly all forms of life, including humans, single-celled eukaryotes, and numerous bacterial species. In bacteria, some of the most notable pore-forming molecules are protein toxins that interact with mammalian cell membranes to promote lysis, deliver effectors, and modulate cellular homeostasis. Of the bacterial species capable of producing pore-forming toxic molecules, the Gram-positive pathogen Staphylococcus aureus is one of the most notorious. S. aureus can produce seven different pore-forming protein toxins, all of which are believed to play a unique role in promoting the ability of the organism to cause disease in humans and other mammals. The most diverse of these pore-forming toxins, in terms of both functional activity and global representation within S. aureus clinical isolates, are the bicomponent leucocidins. From the first description of their activity on host immune cells over 100 years ago to the detailed investigations of their biochemical function today, the leucocidins remain at the forefront of S. aureus pathogenesis research initiatives. Study of their mode of action is of immediate interest in the realm of therapeutic agent design as well as for studies of bacterial pathogenesis. This review provides an updated perspective on our understanding of the S. aureus leucocidins and their function, specificity, and potential as therapeutic targets.

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Section: Luksf-pv (Pvl)mentioning

confidence: 89%

The Bicomponent Pore-Forming Leucocidins of Staphylococcus aureus

Alonzo

Torres

2014

Microbiol Mol Biol Rev

239

290

View full text Add to dashboard Cite

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“…A recent study performed vaccination experiments using LukS and/or LukF before infection with USA300 and disclosed improved survival in vaccinated mice, suggesting that PVL significantly contributes to S. aureus pathogenesis (58). Arguing that mouse models might not be ideal to study the in vivo role of PVL, Olsen et al (59) infected nonhuman primates with USA300 and isogenic PVL deletion-mutant strains and ultimately did not identify a major role for PVL in aggravating pneumonia in vivo. Nevertheless, no previous report studied the precise innate immune mechanisms associated with PVL.…”

Section: Discussionmentioning

confidence: 99%

TLR 2 and CD14 Mediate Innate Immunity and Lung Inflammation to Staphylococcal Panton–Valentine Leukocidin In Vivo

Zivkovic

Sharif

Stich

et al. 2011

The Journal of Immunology

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The pore-forming toxin Panton–Valentine leukocidin (PVL) is carried by community-acquired methicillin-resistant Staphylococcus aureus and associated with necrotizing pneumonia together with poor prognosis of infected patients. Although the cell-death–inducing properties of PVL have previously been examined, the pulmonary immune response to PVL is largely unknown. Using an unbiased transcriptional profiling approach, we show that PVL induces only 29 genes in mouse alveolar macrophages, which are associated with TLR signaling. Further studies indicate that PVL directly binds to TLR2 and induces immune responses via NF-κB in a TLR2, CD14, MyD88, IL-1R–associated kinase 1, and TNFR-associated factor 6-dependent manner. PVL-mediated inflammation is independent of pore formation but strongly depends on the LukS subunit and is suppressed in CD14/TLR2−/− cells. In vivo PVL or LukS induced a robust inflammatory response in lungs, which was diminished in CD14/TLR2−/− mice. These results highlight the proinflammatory properties of PVL and identify CD14/TLR2 as an essential receptor complex for PVL-induced lung inflammation.

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“…Introduction of PVL into a laboratory S. aureus strain changed the expression of other virulence factors (143), but deletion of PVL from the USA300 and USA400 clinical isolates had no influence on global gene expression (147). Experiments on mice and rabbits have usually confirmed a role for PVL in virulence (143,(145)(146)(147)(148)(149)469), whereas studies using rats and primates, and occasionally mice and rabbits, have not identified a role for PVL in infection (155,345,470,471). Given the relative insensitivity of mouse and rat PMNs to PVL, rabbits appear to be a better model for studying the effects of PVL, as their PMNs are more sensitive to PVL, more closely resembling the human situation (145).…”

Section: Cautionary Notesmentioning

confidence: 99%

Role of Pore-Forming Toxins in Bacterial Infectious Diseases

Los

Randis

Aroian

et al. 2013

Microbiol Mol Biol Rev

350

351

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SUMMARY Pore-forming toxins (PFTs) are the most common bacterial cytotoxic proteins and are required for virulence in a large number of important pathogens, including Streptococcus pneumoniae , group A and B streptococci, Staphylococcus aureus , Escherichia coli , and Mycobacterium tuberculosis . PFTs generally disrupt host cell membranes, but they can have additional effects independent of pore formation. Substantial effort has been devoted to understanding the molecular mechanisms underlying the functions of certain model PFTs. Likewise, specific host pathways mediating survival and immune responses in the face of toxin-mediated cellular damage have been delineated. However, less is known about the overall functions of PFTs during infection in vivo . This review focuses on common themes in the area of PFT biology, with an emphasis on studies addressing the roles of PFTs in in vivo and ex vivo models of colonization or infection. Common functions of PFTs include disruption of epithelial barrier function and evasion of host immune responses, which contribute to bacterial growth and spreading. The widespread nature of PFTs make this group of toxins an attractive target for the development of new virulence-targeted therapies that may have broad activity against human pathogens.

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Lack of a Major Role of Staphylococcus aureus Panton-Valentine Leukocidin in Lower Respiratory Tract Infection in Nonhuman Primates

Cited by 43 publications

References 48 publications

The Bicomponent Pore-Forming Leucocidins of Staphylococcus aureus

The Bicomponent Pore-Forming Leucocidins of Staphylococcus aureus

TLR 2 and CD14 Mediate Innate Immunity and Lung Inflammation to Staphylococcal Panton–Valentine Leukocidin In Vivo

Role of Pore-Forming Toxins in Bacterial Infectious Diseases

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