ASC and NLRP3 impair host defense during lethal pneumonia caused by serotype 3 Streptococcus pneumoniae in mice

Abstract

Streptococcus (S.) pneumoniae is the most common cause of community-acquired pneumonia. The Nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, consisting of NLRP3, ASC (the adaptor apoptosis-associated speck-like protein containing a CARD) and caspase-1, has been implicated in protective immunity during pneumonia induced by high doses of S. pneumoniae serotype 2. Here we investigated the role of the NLRP3 inflammasome in the host response during lethal airway infection with a low dose of serotype 3 S. pneumoniae. Mice were euthanized at predefined endpoints for analysis or observed in survival studies. In additional studies, Tlr2 −/− /Tlr4 −/− mice and Myd88 −/− mice incapable of Toll-like receptor signaling were studied. In stark contrast with existing literature, both Nlrp3 −/− and Asc −/− mice showed a strongly improved host defense, as reflected by a markedly reduced mortality rate accompanied by diminished bacterial growth and dissemination. Host defense was unaltered in Tlr2 −/− /Tlr4 −/− mice and Myd88 −/− mice. These results show that the NLRP3 inflammasome impairs host defense during lethal pneumonia caused by serotype 3 S. pneumoniae. Our findings challenge the current paradigm that proximal innate detection systems are indispensable for an adequate host immune response against bacteria.

The TLR4-MyD88 Signaling Axis Regulates Lung Monocyte Differentiation Pathways in Response to Streptococcus pneumoniae

“…Consistent with these previous studies (54,57), we show here that TLR4 −/− and MyD88 −/− infected mice have a higher bacterial load than their corresponding WT counterparts. Interestingly, lungs from infected MyD88 −/− mice had fewer bacterial CFUs than TLR4 −/− mice, which may indicate that the TRIF-dependent TLR4-signaling cascade plays an important role in bacterial clearance (Figures 6B,C).…”

“…The local IIR in the lung is important to combat S. pneumoniae, which involves the coordination of multiple cell populations and the activation of effector functions like phagocytosis, cytokine release, the complement cascade and antigen-presentation. Indeed, the IIR against S. pneumoniae is initiated through the recognition of PAMPs by TLRs, whose role and that of TLR-adaptor proteins and inflammasome complexes, has been studied using mouse models of infection (54)(55)(56)(57). MyD88 and TLR4 are involved in local and systemic bacterial control, as well as in the recruitment of polymorphonuclear Figure 4.…”

Pulmonary Innate Immune Response Determines the Outcome of Inflammation During Pneumonia and Sepsis-Associated Acute Lung Injury

“…Of note, during lethal pneumonia caused by a low dose of serotype 3 S. pneumoniae , NLRP3 increases the incidence of ALI and mortality due to the bacterial dissemination and the development of the sepsis ( 94 ). Also, during S. aureus -induced pneumonia, NLRP3 deficiency prevents the onset of severe necrotic pneumonia via promoting bacterial clearance ( 95 ).…”

Competitive Cell Death Interactions in Pulmonary Infection: Host Modulation Versus Pathogen Manipulation

“…Many independent research groups have demonstrated the induction of regulated membrane-permeabilizing cell death via pyroptotic or necroptotic signaling to be detrimental to the host response to pneumococcal pneumonia, primarily due to the hyper-inflammatory response these modes of cell death promote. For instance, recent work demonstrated that nucleotide-binding domain, leucine-rich repeat-containing, and pyrin domain-containing 3 (NLRP3) and apoptosisassociated speck-like protein containing a caspase recruitment domain (ASC) knockout mice had improved host defense in a lethal infection model with S. pneumoniae (89). The inhibition of pyroptosis is thought to improve host defense to pneumococcal pneumoniae by suppressing hyper-inflammation that is detrimental to pulmonary barrier integrity without inhibiting bacterial clearance by phagocytes.…”