PTX3 binds MD-2 and promotes TRIF-dependent immune protection in aspergillosis

Area of Science:

• Immunology
• Microbiology
• Molecular Biology

Background:

• The long pentraxin 3 (PTX3) is known to enhance innate immunity against Aspergillus fumigatus through complement activation and FcγR-mediated phagocytosis.
• The role of Toll-like receptors (TLRs) in modulating PTX3's antifungal resistance mechanisms remains largely unexplored.

Purpose of the Study:

• To investigate whether and how TLRs modulate PTX3-mediated antifungal resistance.
• To elucidate the specific receptor mechanism by which PTX3 confers protection against Aspergillus fumigatus.

Main Methods:

• In vitro binding assays to assess PTX3 interaction with myeloid differentiation protein 2 (MD-2).
• In vivo studies using Tlr4(-/-) and Md2(-/-) mouse models of pulmonary aspergillosis.
• Analysis of cytokine profiles, polymorphonuclear neutrophil (PMN) function, and immune protection upon PTX3 treatment or adoptive PMN transfer.
• Investigation of signaling pathways activated by PTX3-MD-2 interaction using Aspergillus conidia.

Main Results:

• PTX3 binds MD-2 in vitro and requires TLR4/MD-2 signaling for its in vivo antifungal activity.
• Md2(-/-) mice exhibit increased susceptibility to pulmonary aspergillosis, characterized by inflammation and impaired PMN function.
• PTX3 treatment failed to protect Md2(-/-) mice, but adoptive transfer of MD-2-competent PMNs restored protection.
• PTX3-mediated antifungal resistance involves TLR4/MD-2 engagement, activation of the Toll/IL-1R domain-containing adapter inducing IFN-β pathway, and convergence on IL-10 production.

Conclusions:

• PTX3 exerts its protective antifungal activity against Aspergillus fumigatus via TLR4/MD-2-mediated signaling.
• This novel mechanism involves the TLR4/MD-2/Toll/IL-1R domain-containing adapter inducing IFN-β pathway, leading to IL-10 production.
• PTX3-mediated resistance limits immunopathology during Aspergillus fumigatus infection.