Role of complement and Fcγ receptors in the protective activity of the long pentraxin PTX3 against Aspergillus fumigatus

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Ficolins and pentraxins are soluble oligomeric pattern-recognition molecules that sense danger signals from pathogens and altered self-cells and might act synergistically in innate immune defense and maintenance of immune tolerance. The interaction of M-ficolin with the long pentraxin pentraxin 3 (PTX3) has been characterized using surface plasmon resonance spectroscopy and electron microscopy. M-ficolin was shown to bind PTX3 with high affinity in the presence of calcium ions. The interaction was abolished in the presence of EDTA and inhibited by N-acetyl-D-glucosamine, indicating involvement of the fibrinogen-like domain of M-ficolin. Removal of sialic acid from the single N-linked carbohydrate of the C-terminal domain of PTX3 abolished the interaction. Likewise, an M-ficolin mutant with impaired sialic acid-binding ability did not interact with PTX3. Interaction was also impaired when using the isolated recognition domain of M-ficolin or the monomeric C-terminal domain of PTX3, indicating requirement for oligomerization of both proteins. Electron microscopy analysis of the M-ficolin–PTX3 complexes revealed that the M-ficolin tetramer bound up to four PTX3 molecules. From a functional point of view, immobilized PTX3 was able to trigger M-ficolin–dependent activation of the lectin complement pathway. These data indicate that interaction of M-ficolin with PTX3 arises from its ability to bind sialylated ligands and thus differs from the binding to the short pentraxin C-reactive protein and from the binding of L-ficolin to PTX3. The M-ficolin–PTX3 interaction described in this study represents a novel case of cross-talk between soluble pattern-recognition molecules, lending further credit to the integrated view of humoral innate immunity that emerged recently.

Section: Discussionmentioning

confidence: 99%

M-Ficolin Interacts with the Long Pentraxin PTX3: A Novel Case of Cross-Talk between Soluble Pattern-Recognition Molecules

Gout

Moriscot

Doni

et al. 2011

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“…Among these, the long pentraxin 3 (PTX3) has been found to have a nonredundant protective role in the immune response to A. fumigatus (21). PTX3 modulates different effector pathways involved in innate resistance to A. fumigatus, including complement activation, promotion of phagocytosis, and regulation of inflammation (22)(23)(24)(25)(26). The molecular mechanisms underlying the opsonic activity of PTX3 and increased phagocytosis of conidia by neutrophils involved FcgRII-, CD11b-, and complementdependent mechanisms (26).…”

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confidence: 99%

PTX3 Binds MD-2 and Promotes TRIF-Dependent Immune Protection in Aspergillosis

Bozza

Campo

Arseni

et al. 2014

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The long pentraxin 3 (PTX3) modulates different effector pathways involved in innate resistance to Aspergillus fumigatus, including complement activation or promotion of phagocytosis by interacting with FcγRs. However, whether and how TLRs modulate PTX3 mediates antifungal resistance is not known. In this study, we demonstrate that PTX3 binds myeloid differentiation protein 2 (MD-2) in vitro and exerts its protective antifungal activity in vivo through TLR4/MD-2–mediated signaling. Similar to Tlr4−/− mice, Md2−/− mice displayed high susceptibility to pulmonary aspergillosis, a phenotype associated with a proinflammatory cytokine profile and impaired antifungal activity of polymorphonuclear neutrophils. Treating Md2−/− mice with PTX3 failed to confer immune protection against the fungus, whereas adoptive transfer of MD-2–competent polymorphonuclear neutrophils restored it. Mechanistically, engagement of MD-2 by PTX3-opsonized Aspergillus conidia activated the TLR4/Toll/IL-1R domain-containing adapter inducing IFN-β–dependent signaling pathway converging on IL-10. Thus, we have identified a novel receptor mechanism, involving the TLR4/MD-2/Toll/IL-1R domain-containing adapter inducing IFN-β–mediated signaling, whereby PTX3 elicits antifungal resistance with limited immunopathology in A. fumigatus infection.

“…In vivo studies have underlined the pivotal role played by PTX3 in the protection against selected bacteria, fungi, and viruses (28,32,33). Therefore, we evaluated the ability of orally administered PTX3 to protect neonate mice against P. aeruginosa, which is responsible for a wide variety of clinical symptoms from mild infection (e.g., pneumonia) to sepsis or death among infants in neonatal intensive care (57).…”

Section: Discussionmentioning

confidence: 99%

“…The pivotal role of PTX3 in innate immunity has been evidenced in Ptx3 2/2 mice, which are susceptible to selected fungal, bacterial, and viral infections (32,33). This susceptibility has been related to a deficient activation of the phagocytic cup and an inability to a mount a protective Th1 response (28,29,32). Given the central role played by PTX3 in the protection against selected pathogens and the high susceptibility of newborns to microbial infections, we evaluated the expression levels of PTX3 in neonates and assessed whether maternal milk may compensate for a potential defect.…”

mentioning

confidence: 99%

“…PTX3 is also stored in specific granules of neutrophils, which serve as a reservoir of preformed PTX3 suitable for a rapid release (27). PTX3 binds specific pathogens (e.g., Aspergillus fumigatus, Pseudomonas aeruginosa) and promotes their phagocytosis and clearance by phagocytes (27)(28)(29). PTX3 has also been involved in complement activation (30) and regulation of inflammatory response (31).…”

mentioning

confidence: 99%

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Prototypic Long Pentraxin PTX3 Is Present in Breast Milk, Spreads in Tissues, and Protects Neonate Mice from Pseudomonas aeruginosa Lung Infection

Jaillon

Mancuso

Hamon

et al. 2013

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Newborns and infants present a higher susceptibility to infection than adults, a vulnerability associated with deficiencies in both the innate and adaptive immune systems. Innate immune receptors are sensors involved in the recognition and elimination of microbes that play a pivotal role at the interface between innate and adaptive immunity. Pentraxin 3 (PTX3), the prototypic long pentraxin, is a soluble pattern recognition receptor involved in the initiation of protective responses against selected pathogens. Because neonates are generally resistant to these pathogens, we suspected that PTX3 may be provided by a maternal source during the early life times. We observed that human colostrum contains high levels of PTX3, and that mammary epithelial cell and CD11b+ milk cells constitutively produce PTX3. Interestingly, PTX3 given orally to neonate mice was rapidly distributed in different organs, and PTX3 ingested during lactation was detected in neonates. Finally, we observed that orally administered PTX3 provided protection against Pseudomonas aeruginosa lung infection in neonate mice. Therefore, breastfeeding constitutes, during the early life times, an important source of PTX3, which actively participates in the protection of neonates against infections. In addition, these results suggest that PTX3 might represent a therapeutic tool for treating neonatal infections and support the view that breastfeeding has beneficial effects on the neonates’ health.