The complement system in <i>Aspergillus fumigatus</i> infections and its crosstalk with pentraxins

Parente, Raffaella; Doni, Andrea; Bottazzi, Barbara; Garlanda, Cecilia; Inforzato, Antonio

doi:10.1002/1873-3468.13744

Cited by 25 publications

(26 citation statements)

References 184 publications

(251 reference statements)

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“…This finding is consistent with the fact that GAG is a polysaccharide and therefore a natural target for the lectin pathway specialized on the recognition of microbial carbohydrates. The relevance of the lectin pathway for GAG-stimulated complement activation might also partly explain why MBL-deficient mice showed an improved survival in a mouse model of systemic aspergillosis, as reviewed elsewhere ( 29 ).…”

Section: Discussionmentioning

confidence: 98%

Aspergillus-Derived Galactosaminogalactan Triggers Complement Activation on Human Platelets

et al. 2020

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Invasive fungal infections caused by Aspergillus ( A .) and Mucorales species still represent life-threatening diseases in immunocompromised individuals, and deeper knowledge about fungal interactions with elements of innate immunity, such as complement and platelets, appears essential for optimized therapy. Previous studies showed that galactosaminogalactan secreted by A. fumigatus and A. flavus is deposited on platelets, thereby inducing their activation. Since the altered platelet surface is a putative trigger for complement activation, we aimed to study the interplay of platelets with complement in the presence of fungal GAG. Culture supernatants (SN) of A. fumigatus and A. flavus both induced not only GAG deposition but also subsequent deposition of complement C3 fragments on the platelet surface. The SN of a Δ uge3 mutant of A. fumigatus , which is unable to synthesize GAG, did not induce complement deposition on platelets, nor did the SN of other Aspergillus species and all tested Mucorales. Detailed analysis revealed that GAG deposition itself triggered the complement cascade rather than the GAG-induced phosphatidylserine exposure. The lectin pathway of complement could be shown to be crucially involved in this process. GAG-induced complement activation on the platelet surface was revealed to trigger processes that might contribute to the pathogenesis of invasive aspergillosis by A. fumigatus or A. flavus . Both pro-inflammatory anaphylatoxins C3a and C5a arose when platelets were incubated with SN of these fungal species; these processes might favor excessive inflammation after fungal infection. Furthermore, platelets were stimulated to shed microparticles, which are also known to harbor pro-inflammatory and pro-coagulant properties. Not only did early processes of the complement cascade proceed on platelets, but also the formation of the terminal complement C5b-9 complex was detected on platelets after incubation with fungal SN. Subsequently, reduced viability of the platelets could be shown, which might contribute to the lowered platelet numbers found in infected patients. In summary, fungal GAG initiates an interplay between complement and platelets that can be supposed to contribute to excessive inflammation, thrombocytopenia, and thrombosis, which are important hallmarks of fatal invasive mycoses.

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Section: Discussionmentioning

confidence: 98%

Aspergillus-Derived Galactosaminogalactan Triggers Complement Activation on Human Platelets

et al. 2020

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“…In the present study, A. fumigatus was the sole Ascomycota expressing α-Gal. Aspergillus fumigatus conidia is susceptible to ACP activation [53]. Therefore, the synthesis of α-Gal and binding of anti-α-Gal Abs on the surface of A. fumigatus may be an ultimate fungal strategy for ACP evasion in animals lacking endogenous α-Gal and capable of producing inhibitory natural anti-α-Gal Abs.…”

Section: Discussionmentioning

confidence: 99%

Gut Microbiota Abrogates Anti-α-Gal IgA Response in Lungs and Protects against Experimental Aspergillus Infection in Poultry

et al. 2020

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Naturally occurring human antibodies (Abs) of the isotypes IgM and IgG and reactive to the galactose-α-1,3-galactose (α-Gal) epitope are associated with protection against infectious diseases, caused by pathogens expressing the glycan. Gut microbiota bacteria expressing α-Gal regulate the immune response to this glycan in animals lacking endogenous α-Gal. Here, we asked whether the production of anti-α-Gal Abs in response to microbiota stimulation in birds, confers protection against infection by Aspergillus fumigatus, a major fungal pathogen that expresses α-Gal in its surface. We demonstrated that the oral administration of Escherichia coli O86:B7 strain, a bacterium with high α-Gal content, reduces the occurrence of granulomas in lungs and protects turkeys from developing acute aspergillosis. Surprisingly, the protective effect of E. coli O86:B7 was not associated with an increase in circulating anti-α-Gal IgY levels, but with a striking reduction of anti-α-Gal IgA in the lungs of infected turkeys. Subcutaneous immunization against α-Gal did not induce a significant reduction of lung anti-α-Gal IgA and failed to protect against an infectious challenge with A. fumigatus. Oral administration of E. coli O86:B7 was not associated with the upregulation of lung cytokines upon A. fumigatus infection. We concluded that the oral administration of bacteria expressing high levels of α-Gal decreases the levels of lung anti-α-Gal IgA, which are mediators of inflammation and lung damage during acute aspergillosis.

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“…PTX3 binds several complement proteins, including C1q, mannose binding lectin, ficolin-1 and -2, and activates the classical and lectin pathways (Bottazzi et al, 2010;Bally et al, 2019;Parente et al, 2020). In addition to activators, PTX3 interacts with complement inhibitors like FH and C4BP (Deban et al, 2008;Braunschweig and Jozsi, 2011).…”

Section: Discussionmentioning

confidence: 99%

“…One of the ligands of FH is the long pentraxin 3 (PTX3) (Deban et al, 2008), a multimeric glycoprotein with a distinctive quaternary structure (Bottazzi et al, 1997;Inforzato et al, 2008;Inforzato et al, 2010;Inforzato et al, 2012) that is produced by a number of somatic and immune cells, and plays key roles in innate immunity, tissue remodeling, and inflammation (Doni et al, 2019;Parente et al, 2019;Parente et al, 2020). Current evidence indicates that PTX3 is locally made by the RPE in the presence of pro-inflammatory cytokines (Woo et al, 2013), and in conditions of oxidative stress (Wang et al, 2016;Hwang et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Control of Complement Activation by the Long Pentraxin PTX3: Implications in Age-Related Macular Degeneration

et al. 2020

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Dysregulation of the complement system is central to age-related macular degeneration (AMD), the leading cause of blindness in the developed world. Most of the genetic variation associated with AMD resides in complement genes, with the greatest risk associated with polymorphisms in the complement factor H (CFH) gene; factor H (FH) is the major inhibitor of the alternative pathway (AP) of complement that specifically targets C3b and the AP C3 convertase. Long pentraxin 3 (PTX3) is a soluble pattern recognition molecule that has been proposed to inhibit AP activation via recruitment of FH. Although present in the human retina, if and how PTX3 plays a role in AMD is still unclear. In this work we demonstrated the presence of PTX3 in the human vitreous and studied the PTX3-FH-C3b crosstalk and its effects on complement activation in a model of retinal pigment epithelium (RPE). RPE cells cultured in inflammatory AMD-like conditions overexpressed the PTX3 protein, and up-regulated AP activating genes. PTX3 bound RPE cells in a physiological setting, however this interaction was reduced in inflammatory conditions, whereby PTX3 had no complement-inhibiting activity on inflamed RPE. However, on non-cellular surfaces, PTX3 formed a stable ternary complex with FH and C3b that acted as a “hot spot” for complement inhibition. Our findings suggest a protective role for PTX3 in response to complement dysregulation in AMD and point to a novel mechanism of complement regulation by this pentraxin with potential implications in pathology and pharmacology of AMD.

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The complement system in Aspergillus fumigatus infections and its crosstalk with pentraxins

Cited by 25 publications

References 184 publications

Aspergillus-Derived Galactosaminogalactan Triggers Complement Activation on Human Platelets

Aspergillus-Derived Galactosaminogalactan Triggers Complement Activation on Human Platelets

Gut Microbiota Abrogates Anti-α-Gal IgA Response in Lungs and Protects against Experimental Aspergillus Infection in Poultry

Control of Complement Activation by the Long Pentraxin PTX3: Implications in Age-Related Macular Degeneration

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