Immunity against Moraxella catarrhalis requires guanylate-binding proteins and caspase-11-NLRP3 inflammasomes

Area of Science:

• Immunology
• Microbiology
• Cell Biology

Background:

• Moraxella catarrhalis is a significant respiratory pathogen causing otitis media and COPD.
• Toll-like receptors are involved but do not fully explain the immune response complexity.
• Host immune responses to M. catarrhalis involve both membrane-bound and cytosolic pattern-recognition receptors.

Purpose of the Study:

• To investigate the host immune response pathways activated by M. catarrhalis.
• To identify cytosolic innate immune sensors involved in M. catarrhalis recognition.
• To determine the role of inflammasomes and guanylate-binding proteins (GBPs) in host defense.

Main Methods:

• Global transcriptomic and targeted cytokine analyses of primary mouse bone marrow-derived macrophages.
• Stimulation of macrophages with M. catarrhalis, outer membrane vesicles, or lipooligosaccharide (LOS).
• Assays to detect caspase-4/11 activation, gasdermin-D-dependent pyroptosis, and NLRP3 inflammasome activity.

Main Results:

• M. catarrhalis, its outer membrane vesicles, and LOS activate caspase-4/11, gasdermin-D-dependent pyroptosis, and the NLRP3 inflammasome in macrophages.
• This activation is initiated by type I interferon signaling and guanylate-binding proteins (GBPs).
• Inflammasomes and GBPs, especially GBP2, are essential for host defense against M. catarrhalis in vivo.

Conclusions:

• The interferon-inflammasome axis plays a critical role in cytosolic recognition and immunity against M. catarrhalis.
• This pathway provides novel molecular targets for mitigating pathological inflammation caused by M. catarrhalis.
• Understanding these innate immune mechanisms is key to developing new therapeutic strategies.