Pentraxin 3 protects from MCMV infection and reactivation through TLR sensing pathways leading to IRF3 activation

Area of Science:

• Immunology
• Virology
• Microbiology

Background:

• Reactivation of human cytomegalovirus (HCMV) post-transplantation causes significant morbidity and mortality.
• HCMV reactivation increases susceptibility to opportunistic infections like Aspergillus species (spp).
• Antimicrobial polypeptides can inhibit viral fusion by targeting cell surface sugars.

Purpose of the Study:

• To investigate if Pentraxin 3 (PTX3) binds HCMV and MCMV.
• To determine the impact of PTX3 on viral infectivity and superinfection in vivo.
• To elucidate the molecular mechanisms underlying PTX3's antiviral and antifungal effects.

Main Methods:

• Binding assays to assess PTX3 interaction with HCMV and MCMV.
• In vitro studies to evaluate PTX3's effect on viral entry and infectivity.
• In vivo experiments in transplantation models to assess protection against MCMV infection, reactivation, and Aspergillus superinfection.
• Analysis of immune pathways, including interferon regulatory factor 3 (IRF3), Toll-like receptor 9 (TLR9), Myeloid differentiation primary response 88 (MyD88), interleukin-12 (IL-12), and interferon-gamma (IFN-gamma).

Main Results:

• PTX3 demonstrated binding to both HCMV and MCMV.
• PTX3 significantly reduced viral entry and infectivity in vitro.
• PTX3 provided protection against MCMV primary infection, reactivation, and Aspergillus superinfection in vivo.
• PTX3 activated IRF3 in dendritic cells via a TLR9/MyD88-independent pathway.
• PTX3 promoted the IL-12/IFN-gamma-dependent effector pathway.

Conclusions:

• PTX3 exhibits broad antiviral and antifungal properties relevant to post-transplant complications.
• PTX3 functions by modulating innate immune sensing and effector pathways.
• PTX3 represents a potential therapeutic host-defense protein against HCMV and associated superinfections.