Protective role of host complement system in Aspergillus fumigatus infection

Abstract

Invasive aspergillosis (IA) is a life-threatening fungal infection for immunocompromised hosts. It is, therefore, necessary to understand the immune pathways that control this infection. Although the primary infection site is the lungs, aspergillosis can disseminate to other organs through unknown mechanisms. Herein we have examined the in vivo role of various complement pathways as well as the complement receptors C3aR and C5aR1 during experimental systemic infection by Aspergillus fumigatus, the main species responsible for IA. We show that C3 knockout (C3-/-) mice are highly susceptible to systemic infection of A. fumigatus. Intriguingly, C4-/- and factor B (FB)-/- mice showed susceptibility similar to the wild-type mice, suggesting that either the complement pathways display functional redundancy during infection (i.e., one pathway compensates for the loss of the other), or complement is activated non-canonically by A. fumigatus protease. Our in vitro study substantiates the presence of C3 and C5 cleaving proteases in A. fumigatus. Examination of the importance of the terminal complement pathway employing C5-/- and C5aR1-/- mice reveals that it plays a vital role in the conidial clearance. This, in part, is due to the increased conidial uptake by phagocytes. Together, our data suggest that the complement deficiency enhances the susceptibility to systemic infection by A. fumigatus.

Development of a murine model to study the cerebral pathogenesis of Aspergillus fumigatus

“…3D ). These results are consistent with previous reports of induction of complement upon exposure to A. fumigatus ( 32 , 42 , 43 ). Furthermore, human cerebral spinal fluid from CA patients shows an increase in C1q, C3, C3a, and C5 ( 44 , 45 ), and people with defects in complement activation or who are taking the anti-C5 monoclonal antibody therapy, eculizumab, are at risk for invasive aspergillosis ( 46 , 47 ).…”

Humoral Immunity Against Aspergillus fumigatus

“…Amplifies complement cascade. Increases phagocytosis and modulates immune response [ 15 , 20 , 21 ] C5a Complement system NA NA Recruits neutrophils at the site of infection [ 24 , 25 ] Cathelicidin (LL-37) AMP NA ↑ in BAL Discrepant results in the literature [ 41 , 56 , 64 , 65 ] CRP APP NA ↓ in BAL Promotes conidia phagocytosis by neutrophils [ 41 , 72 ] Defensin (α-) AMP NA NA Fungicidal effect on swollen conidia and hyphae [ 58 , 61 ] Defensin (ß-) AMP NA NA Inhibition of germination [ 56 ] Ficolin-1 Collectin Chitin β-1,3-glucan ↑ in BAL Opsonizes hyphae increase IL-8 secretion by lung epithelial cells [ 40 , 41 ] Ficolin-2 Collectin GlcNAc GalNAc ↓ or ↑ in BAL Opsonizes conidia and decrease pro-inflammatory cy...…”

“…C5a and C5b are generated via the cleavage of C5 by C5 convertase at a common checkpoint to all complement pathways. While C5b takes part in MAC, unlikely to harm A. fumigatus , C5a acts as an anaphylotoxin, able to recruit immune cells, particularly neutrophils.Thus, C5 −/− mice resulted in a significant higher mortality in a systemic intravenous mice model of aspergillosis [ 24 ]. Interestingly, C5 cleavage could also result from a non-canonical pathway triggered by A. fumigatus swollen conidia or hyphae [ 25 ], or by a fungal-associated metalloprotease [ 23 ].…”

“…Interestingly, C5 cleavage could also result from a non-canonical pathway triggered by A. fumigatus swollen conidia or hyphae [ 25 ], or by a fungal-associated metalloprotease [ 23 ]. C5a-receptor was found to be required to mount a protective immune response against systemic aspergillosis [ 24 ]. Of note, vilobelimab, an anti-C5a monoclonal antibody, has been shown to be beneficial in mechanically ventilated patients with COVID-19 patients [ 26 ].…”

“…Regarding NAbs, a recent study suggests that complement C3 enhances NAbs pool contributing to innate defense against aspergillosis delaying mortality in a mouse model [ 24 ]. Furthermore, an essential axis was identified between innate B1a lymphocytes, A. fumigatus binding NAbs and lung neutrophils explaining the increased susceptibility to IPA of non-neutropenic patients with severe viral pneumonia [ 85 ].…”