Aspergillus fumigatus conidial surface-associated proteome reveals factors for fungal evasion and host immunity modulation
Conidia are the primary infection structures in Aspergillus fumigatus, the etiologic agent of aspergillosis. Here, we characterized LipA (a lipase) and CrpA (a cysteine-rich protein), conidial surface-associated proteins important for fungal evasion and modulation of host immunity. ΔlipA and ΔcrpA conidia elicited decreased production of proinflammatory cytokines and increased production of the anti-inflammatory cytokine IL-10 from murine macrophages and in the lungs of infected mice. Murine macrophages exposed to ΔcrpA conidia produce significantly higher levels of prostaglandins PGE2 and PGD2, suggesting that deletion of CrpA modulates cytokine production through effects on eicosanoid signaling. While ΔlipA and ΔcrpA spores have lower virulence in larval zebrafish, this difference is abrogated in larvae that cannot produce prostaglandins. The CrpA protein can directly modulate PGE2 and cytokine production by macrophages, and solid-state NMR shows that ΔcrpA swollen conidia present lower β-1,3-glucan and chitin than the wild-type strain, suggesting that the effects of the ΔcrpA mutant on macrophages are due to the combinatorial effects of direct CrpA action and altered cell wall PAMP recognition. ΔlipA and ΔcrpA mutants are avirulent in an immunocompetent murine model of aspergillosis. These results highlight LipA and CrpA as key virulence factors in A. fumigatus and as promising targets for antifungal therapy.
