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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    • "This finding was rather puzzling because Hla is a pore-forming toxin, which has been associated with the induction of apoptosis and cell lysis (Bhakdi and Tranum-Jensen, 1991; Bantel et al., 2001; Essmann et al., 2003). On the other hand, several studies reported the capacity of sublytic concentration of Hla to trigger signalling pathways in eukaryotic cells involved in cell proliferation (Haugwitz et al., 2006) and inflammatory responses (Rose et al., 2002; Craven et al., 2009; Hruz et al., 2009; Kebaier et al., 2012). Yet, the exact molecular mechanism underlying the effect of Hla on S. aureus-MCs interactions needs to be further investigated. "
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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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