Staphylococcus aureus -Hemolysin Mediates Virulence in a Murine Model of Severe Pneumonia Through Activation of the NLRP3 Inflammasome

Department of Medicine, Division of Infectious Diseases, University of North Carolina, Chapel Hill, USA.
The Journal of Infectious Diseases (Impact Factor: 6). 03/2012; 205(5):807-17. DOI: 10.1093/infdis/jir846
Source: PubMed


Staphylococcus aureus is a dangerous pathogen that can cause necrotizing infections characterized by massive inflammatory responses and tissue destruction. Staphylococcal α-hemolysin is an essential virulence factor in severe S. aureus pneumonia. It activates the nucleotide-binding domain and leucine-rich repeat containing gene family, pyrin domain containing 3 (NLRP3) inflammasome to induce production of interleukin-1β and programmed necrotic cell death. We sought to determine the role of α-hemolysin-mediated activation of NLRP3 in the pathogenesis of S. aureus pneumonia. We show that α-hemolysin activates the NLRP3 inflammasome during S. aureus pneumonia, inducing necrotic pulmonary injury. Moreover, Nlrp3(-/-) mice have less-severe pneumonia. Pulmonary injury induced by isolated α-hemolysin or live S. aureus is independent of interleukin-1β signaling, implicating NLRP3-induced necrosis in the pathogenesis of severe infection. This work demonstrates the exploitation of host inflammatory signaling by S. aureus and suggests the NLRP3 inflammasome as a potential target for pharmacologic interventions in severe S. aureus infections.

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Available from: Irving Coy Allen, Oct 05, 2015
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    • "Although not as abundantly colonized with microbes as the intestinal tract, the surface of the lung, particularly in the upper airways, is continuously exposed to a wide variety of commensal and pathogenic bacteria, viruses, and fungi. As in the intestine , several different inflammasomes have been shown to detect invading bacteria in the lung: the NLRP3 inflammasome senses infection with Klebsiella pneumoniae, Chlamydia pneumoniae, Haemophilus influenzae, Streptococcus pneumoniae , and Staphylococcus aureus, the latter two through the detection of pore-forming toxins (Willingham et al. 2009; He et al. 2010; McNeela et al. 2010; Kebaier et al. 2012; Rotta Detto Loria et al. 2013); the NLRC4 inflammasome responds to a number of flagellated bacteria including Legionella pneumoniae and Burkholderia pseudomallei (Case et al. 2009; Ceballos- Olvera et al. 2011); the NLRP1b inflammasome is activated by secreted toxins from B. anthracis (Kovarova et al. 2012); and both the NLRP3 and AIM2 inflammasomes are proposed to play a role during Mycobacterium tuberculosis infection (Dorhoi et al. 2012; Saiga et al. 2012). Despite the induction of potent proinflammatory immune responses, which might not always be desirable in the lung, the majority of inflammasome activation helps to fight and resolve bacterial lung infections through pyroptosis, IL-1b and IL-18 secretion. "
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    ABSTRACT: Inflammasomes are large cytosolic multiprotein complexes that assemble in response to detection of infection- or stress-associated stimuli and lead to the activation of caspase-1-mediated inflammatory responses, including cleavage and unconventional secretion of the leaderless proinflammatory cytokines IL-1β and IL-18, and initiation of an inflammatory form of cell death referred to as pyroptosis. Inflammasome activation can be induced by a wide variety of microbial pathogens and generally mediates host defense through activation of rapid inflammatory responses and restriction of pathogen replication. In addition to its role in defense against pathogens, recent studies have suggested that the inflammasome is also a critical regulator of the commensal microbiota in the intestine. Finally, inflammasomes have been widely implicated in the development and progression of various chronic diseases, such as gout, atherosclerosis, and metabolic syndrome. In this perspective, we discuss the role of inflammasomes in infectious and noninfectious inflammation and highlight areas of interest for future studies of inflammasomes in host defense and chronic disease.
    Cold Spring Harbor perspectives in biology 10/2014; 6(12). DOI:10.1101/cshperspect.a016287 · 8.68 Impact Factor
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    • "Infectious mastitis is defined as the inflammatory response initiated when microorganisms enter the mammary gland challenging the host defense [1]. This common disease has either clinical or asymptomatic (subclinical) characteristics and is generally perceived as a significant burden for the well-being of mammals and especially dairy animals [2]. "
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    ABSTRACT: Infection of the mammary gland with live bacteria elicits a pathogen-specific host inflammatory response. To study these host-pathogen interactions wild type mice, NF-kappaB reporter mice as well as caspase-1 and IL-1beta knockout mice were intramammarily challenged with Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus). The murine mastitis model allowed to compare the kinetics of the induced cytokine protein profiles and their underlying pathways. In vivo and ex vivo imaging showed that E. coli rapidly induced NF-kappaB inflammatory signaling concomitant with high mammary levels of TNF-alpha, IL-1 alpha and MCP-1 as determined by multiplex analysis. In contrast, an equal number of S. aureus bacteria induced a low NF-kappaB activity concomitant with high mammary levels of the classical IL-1beta fragment. These quantitative and qualitative differences in local inflammatory mediators resulted in an earlier neutrophil influx and in a more extensive alveolar damage post-infection with E. coli compared to S. aureus. Western blot analysis revealed that the inactive proIL-1beta precursor was processed into pathogen-specific IL-1beta fragmentation patterns as confirmed with IL-1beta knockout animals. Additionally, caspase-1 knockout animals allowed to investigate whether IL-1beta maturation depended on the conventional inflammasome pathway. The lack of caspase-1 did not prevent extensive proIL-1beta fragmentation by either of S. aureus or E. coli. These non-classical IL-1beta patterns were likely caused by different proteases and suggest a sentinel function of IL-1beta during mammary gland infection. Thus, a key signaling nodule can be defined in the differential host innate immune defense upon E. coli versus S. aureus mammary gland infection, which is independent of caspase-1.
    PLoS ONE 08/2014; 9(8):e105680. DOI:10.1371/journal.pone.0105680 · 3.23 Impact Factor
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    • "24 hours after bleomycin aspiration, mice were given daily intraperitoneal injections of 50 μg human SAP in 20 mM sodium phosphate buffer or an equal volume of buffer, as described previously [23]–[25], [29], [53]. Arterial oxygen saturation, heart rate, and pulse distention (which measures the local blood flow at the sensor location, and is an indirect indicator of blood flow and blood pressure), were measured using the Mouse Ox vital signs monitor (STARR Life Sciences, Pittsburgh, PA), as described previously [24], [55]. Mice were sedated for 60 seconds with 4% isoflurane in oxygen, removed to room air, and then parameters monitored until the mice were active. "
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    ABSTRACT: Fibrosing diseases, such as pulmonary fibrosis, cardiac fibrosis, myelofibrosis, liver fibrosis, and renal fibrosis are chronic and debilitating conditions and are an increasing burden for the healthcare system. Fibrosis involves the accumulation and differentiation of many immune cells, including macrophages and fibroblast-like cells called fibrocytes. The plasma protein serum amyloid P component (SAP; also known as pentraxin-2, PTX2) inhibits fibrocyte differentiation in vitro, and injections of SAP inhibit fibrosis in vivo. SAP also promotes the formation of immuno-regulatory Mreg macrophages. To elucidate the endogenous function of SAP, we used bleomycin aspiration to induce pulmonary inflammation and fibrosis in mice lacking SAP. Compared to wildtype C57BL/6 mice, we find that in Apcs-/- "SAP knock-out" mice, bleomycin induces a more persistent inflammatory response and increased fibrosis. In both C57BL/6 and Apcs-/- mice, injections of exogenous SAP reduce the accumulation of inflammatory macrophages and prevent fibrosis. The types of inflammatory cells present in the lungs following bleomycin-aspiration appear similar between C57BL/6 and Apcs-/- mice, suggesting that the initial immune response is normal in the Apcs-/- mice, and that a key endogenous function of SAP is to promote the resolution of inflammation and fibrosis.
    PLoS ONE 04/2014; 9(4):e93730. DOI:10.1371/journal.pone.0093730 · 3.23 Impact Factor
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