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

Miriam H P van Lieshout; Alex F de Vos; Mark C Dessing; Alexander P N A de Porto; Onno J de Boer; Regina de Beer; Sanne Terpstra; Sandrine Florquin; Cornelis Van't Veer; Tom van der Poll

doi:10.1002/eji.201646554

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

Eur J Immunol. 2018 Jan;48(1):66-79. doi: 10.1002/eji.201646554. Epub 2017 Nov 3.

Authors

Miriam H P van Lieshout^{1

2}, Alex F de Vos^{1

2}, Mark C Dessing³, Alexander P N A de Porto^{1

2}, Onno J de Boer³, Regina de Beer^{1

2}, Sanne Terpstra^{1

2}, Sandrine Florquin³, Cornelis Van't Veer^{1

2}, Tom van der Poll^{1

2

4}

Affiliations

¹ Center of Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, University of Amsterdam, The Netherlands.
² Center for Experimental and Molecular Medicine, Academic Medical Center, University of Amsterdam, The Netherlands.
³ Department of Pathology, Academic Medical Center, University of Amsterdam, The Netherlands.
⁴ Division of Infectious Diseases, Academic Medical Center, University of Amsterdam, The Netherlands.

PMID: 28971472
DOI: 10.1002/eji.201646554

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.

Keywords: Bacterial infection; Inflammasome; MyD88; Pneumonia; Toll-like receptors.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
CARD Signaling Adaptor Proteins / genetics
CARD Signaling Adaptor Proteins / immunology*
Caspase 1 / immunology
Community-Acquired Infections / immunology
Community-Acquired Infections / microbiology
Immunity, Innate / genetics
Immunity, Innate / immunology
Mice
Mice, Inbred C57BL
Mice, Knockout
Myeloid Differentiation Factor 88 / genetics
NLR Family, Pyrin Domain-Containing 3 Protein / genetics
NLR Family, Pyrin Domain-Containing 3 Protein / immunology*
Pneumonia, Pneumococcal / immunology*
Pneumonia, Pneumococcal / pathology
Signal Transduction / immunology
Streptococcus pneumoniae / classification
Streptococcus pneumoniae / immunology*
Toll-Like Receptor 2 / genetics
Toll-Like Receptor 4 / genetics

Substances

CARD Signaling Adaptor Proteins
Myd88 protein, mouse
Myeloid Differentiation Factor 88
NLR Family, Pyrin Domain-Containing 3 Protein
Nlrp3 protein, mouse
Pycard protein, mouse
Tlr2 protein, mouse
Tlr4 protein, mouse
Toll-Like Receptor 2
Toll-Like Receptor 4
Caspase 1