ASC and NLRP3 impair host defense during lethal pneumonia caused by serotype 3 Streptococcus pneumoniae in mice
Miriam H P van Lieshout1,2, Alex F de Vos1,2, Mark C Dessing3
1Center of Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, University of Amsterdam, The Netherlands.
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.
Insights
The NLRP3 inflammasome impairs host defense against Streptococcus pneumoniae pneumonia. Mice lacking NLRP3 inflammasome components showed improved survival and reduced bacterial burden, challenging existing immune response paradigms.
Area of Science:
- Immunology
- Microbiology
- Infectious Diseases
Background:
- Streptococcus pneumoniae causes community-acquired pneumonia.
- The Nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome is implicated in protective immunity against high-dose S. pneumoniae serotype 2.
- The role of NLRP3 inflammasome in low-dose serotype 3 S. pneumoniae infection is unclear.
Purpose of the Study:
- To investigate the role of the NLRP3 inflammasome in host defense during lethal airway infection with low-dose serotype 3 S. pneumoniae.
- To determine if Toll-like receptor signaling pathways influence host defense in this model.
Main Methods:
- Mice lacking NLRP3 inflammasome components (Nlrp3-/- and Asc-/-) were infected with low-dose serotype 3 S. pneumoniae.
- Survival studies and analysis of bacterial load were performed.
- Mice deficient in Toll-like receptor signaling (Tlr2-/-/Tlr4-/- and Myd88-/-) were also studied.
Main Results:
- Nlrp3-/- and Asc-/- mice exhibited significantly reduced mortality rates compared to wild-type controls.
- These mice also showed diminished bacterial growth and dissemination.
- Host defense was not altered in Tlr2-/-/Tlr4-/- and Myd88-/- mice, indicating Toll-like receptor independence.
Conclusions:
- The NLRP3 inflammasome impairs host defense during lethal pneumonia caused by serotype 3 S. pneumoniae.
- These findings challenge the paradigm that proximal innate immune detection systems are essential for effective bacterial host defense.
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