Abstract
The opportunistic fungal pathogen Aspergillus fumigatus can cause life-threatening infections, particularly in immunocompromised patients. Most pathogenic microbes control host innate immune responses at the earliest time, already before infiltrating host immune cells arrive at the site of infection. Here, we identify Aspf2 as the first A. fumigatus Factor H-binding protein. Aspf2 recruits several human plasma regulators, Factor H, factor-H-like protein 1 (FHL-1), FHR1, and plasminogen. Factor H contacts Aspf2 via two regions located in SCRs6–7 and SCR20. FHL-1 binds via SCRs6–7, and FHR1 via SCRs3–5. Factor H and FHL-1 attached to Aspf2-maintained cofactor activity and assisted in C3b inactivation. A Δaspf2 knockout strain was generated which bound Factor H with 28% and FHL-1 with 42% lower intensity. In agreement with less immune regulator acquisition, when challenged with complement-active normal human serum, Δaspf2 conidia had substantially more C3b (>57%) deposited on their surface. Consequently, Δaspf2 conidia were more efficiently phagocytosed (>20%) and killed (44%) by human neutrophils as wild-type conidia. Furthermore, Aspf2 recruited human plasminogen and, when activated by tissue-type plasminogen activator, newly generated plasmin cleaved the chromogenic substrate S2251 and degraded fibrinogen. Furthermore, plasmin attached to conidia damaged human lung epithelial cells, induced cell retraction, and caused matrix exposure. Thus, Aspf2 is a central immune evasion protein and plasminogen ligand of A. fumigatus. By blocking host innate immune attack and by disrupting human lung epithelial cell layers, Aspf2 assists in early steps of fungal infection and likely allows tissue penetration.
Highlights
Aspergillus species, as ubiquitous saprophytes, are optimally adjusted to living in a variety of environmental niches
To demonstrate the cofactor activity of Factor H or Factor-H-like protein 1 (FHL-1) bound to Aspf2, the human regulators were bound to immobilized Aspf2 (2 μg/100 μl)
Both Factor H and FHL-1 bound to Aspf2, and binding was dose dependent (Figure S1A in Supplementary Material, upper panel lanes 1–4, FHL1: lower panel lanes 1–4)
Summary
Aspergillus species, as ubiquitous saprophytes, are optimally adjusted to living in a variety of environmental niches. Aspergillus fumigatus is an opportunistic fungal pathogen that can cause a broad spectrum of diseases, such as hypersensitivity pneumonitis, allergic asthma [1], and allergic bronchopulmonary aspergillosis (ABPA), in immune-compromised individuals. A. fumigatus can cause invasive aspergillosis, which has a high rate of morbidity and mortality [2]. Immune crosstalk between A. fumigatus and the host immediately starts upon infection, when the pathogen reaches the lung tissue. This crosstalk includes control of innate immune attack by the host, blockade of the complement system, and damage of epithelial cells that line up the lung tissue at sites of infection. Individuals with polymorphisms in MBL or pentraxin 3 genes are susceptible to chronic necrotizing pulmonary aspergillosis [8, 9]. Mice deficient in the complement protein C5 show increased mortality when challenged with A. fumigatus [10, 11]
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