α‐Toxin Facilitates the Generation of CXC Chemokine Gradients and Stimulates Neutrophil Homing in<i>Staphylococcus aureus</i>Pneumonia

Bartlett, Allison H.; Foster, Timothy J.; Hayashida, Atsuko; Park, Pyong Woo

doi:10.1086/592758

Cited by 90 publications

(89 citation statements)

References 47 publications

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“…Lung histopathology showed that wild-type strains (12 lungs scored) and Δpvl strains (11 lungs scored) induced lung injury (Table S1), a finding consistent with the capacity of PVLnegative S. aureus to elaborate other virulence determinants, such as staphylococcal protein A and α-hemolysin, which also contribute to acute lung injury (13,26,27). However, compared with the Δpvl strain, the wild-type strain caused significantly more extensive necrosis with disruption of pulmonary architecture, hemorrhagic infiltration, exudate/fibrin deposition, alveolar and interstitial edema, and PMN infiltration and destruction (Table S1).…”

supporting

confidence: 60%

Polymorphonuclear leukocytes mediate Staphylococcus aureus Panton-Valentine leukocidin-induced lung inflammation and injury

Diep

Chan

Tattevin

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

305

333

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Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) is epidemic in the United States, even rivaling HIV/AIDS in its public health impact. The pandemic clone USA300, like other CA-MRSA strains, expresses Panton-Valentine leukocidin (PVL), a pore-forming toxin that targets polymorphonuclear leukocytes (PMNs). PVL is thought to play a key role in the pathogenesis of necrotizing pneumonia, but data from rodent infection models are inconclusive. Rodent PMNs are less susceptible than human PMNs to PVL-induced cytolysis, whereas rabbit PMNs, like those of humans, are highly susceptible to PVL-induced cytolysis. This difference in target cell susceptibility could affect results of experimental models. Therefore, we developed a rabbit model of necrotizing pneumonia to compare the virulence of a USA300 wild-type strain with that of isogenic PVL-deletion mutant and -complemented strains. PVL enhanced the capacity of USA300 to cause severe lung necrosis, pulmonary edema, alveolar hemorrhage, hemoptysis, and death, hallmark clinical features of fatal human necrotizing pneumonia. Purified PVL instilled directly into the lung caused lung inflammation and injury by recruiting and lysing PMNs, which damage the lung by releasing cytotoxic granule contents. These findings provide insights into the mechanism of PVL-induced lung injury and inflammation and demonstrate the utility of the rabbit for studying PVL-mediated pathogenesis.

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supporting

confidence: 60%

Polymorphonuclear leukocytes mediate Staphylococcus aureus Panton-Valentine leukocidin-induced lung inflammation and injury

Diep

Chan

Tattevin

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

305

333

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“…McLoughlin et al (26) recently found that IFN-␥ correlated with increased CXC chemokine levels that, in turn, directly recruited neutrophils during S. aureus infection. Our data are compatible with this, but in the McLoughlin et al paper, as well as in the paper by Bartlett et al (5), increased chemokines and neutrophils were associated with worse outcomes. We found that increased levels of IFN-␥, chemokines, and neutrophils in S. aureus-infected lungs from Pilrb Ϫ/Ϫ mice were associated with a significantly better outcome.…”

Section: Discussionsupporting

confidence: 92%

Modulation of Paired Immunoglobulin-Like Type 2 Receptor Signaling Alters the Host Response toStaphylococcus aureus-Induced Pneumonia

Banerjee¹,

Stevenaert²,

Pande³

et al. 2010

Infect Immun

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Paired immunoglobulin-like type 2 receptors (PILRs) inhibitory PILR␣ and activating PILR␤ are predominantly expressed on myeloid cells. Their functions in host defense and inflammation are largely unknown, and in this study, we evaluated their roles in an acute Staphylococcus aureus pneumonia model. Compared to their respective controls, Pilrb ؊/؊ mice or mice in which PILR␣ was activated with an agonistic antibody showed improved clearance of pulmonary staphylococci and improved survival. These mice had reduced serum or bronchoalveolar lavage fluid levels of interleukin-1␤ (IL-1␤), tumor necrosis factor alpha (TNF-␣), and IL-6 and elevated levels of gamma interferon (IFN-␥), IL-12, and IL-10. In contrast, mice in which PILR␤ was activated had increased lung bacterial burdens and higher mortality coupled with an intense proinflammatory response with highly elevated levels of IL-1␤, TNF-␣, and IL-6. Treatment groups with reduced bacterial burdens had higher levels of Keratinocyte-derived chemokine (KC), macrophage inflammatory protein 2 (MIP-2), and MIP-1␣ in bronchoalveolar lavage fluid and an increased influx of neutrophils and macrophages to the lungs. Consistent with our in vivo findings, bone marrow-derived macrophages from Pilrb ؊/؊ mice released significantly less IL-1␤ and TNF-␣ and more IFN-␥ and IL-12 than did the wild-type macrophages when directly stimulated with heat-killed S. aureus. To our knowledge, this is the first evidence that S. aureus directly interacts with PILR␤. It provides a mechanism by which manipulating the balance in favor of an inhibitory PILR signal, by activation of PILR␣ or deletion of PILR␤, helps to control acute S. aureus-mediated pneumonia and attenuate the inflammatory response. These results highlight the importance of PILRs in innate immunity and the control of inflammation.

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“…Space during MrSa Pneumonia MRSA pneumonia is characterized by a massive influx of neutrophils into the lungs (26,27 Figure 4A). We wondered whether this enhanced neutrophil recruitment was related to elevated BALF levels of neutrophil attracting CXC chemokines.…”

Section: Tlr9 Deficiency Results In Increased Neutrophils Numbers In mentioning

confidence: 99%

Toll-Like Receptor 9 Enhances Bacterial Clearance and Limits Lung Consolidation in Murine Pneumonia Caused by Methicillin-Resistant Staphylococcus aureus

Meer

Achouiti

Ende

et al. 2016

Mol Med

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α‐Toxin Facilitates the Generation of CXC Chemokine Gradients and Stimulates Neutrophil Homing inStaphylococcus aureusPneumonia

Abstract: These data suggest that alpha-toxin enhances virulence by facilitating the generation of CXC chemokine gradients and stimulating chemokine-induced neutrophil influx in S. aureus pneumonia.

Cited by 90 publications

References 47 publications

Polymorphonuclear leukocytes mediate Staphylococcus aureus Panton-Valentine leukocidin-induced lung inflammation and injury

Polymorphonuclear leukocytes mediate Staphylococcus aureus Panton-Valentine leukocidin-induced lung inflammation and injury

Modulation of Paired Immunoglobulin-Like Type 2 Receptor Signaling Alters the Host Response toStaphylococcus aureus-Induced Pneumonia

Toll-Like Receptor 9 Enhances Bacterial Clearance and Limits Lung Consolidation in Murine Pneumonia Caused by Methicillin-Resistant Staphylococcus aureus

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