Abstract

Aspergillus fumigatus is a common saprophytic fungus in the air. It can cause a severe infectious disease called invasive pulmonary aspergillosis (IPA). To establish the activation of TLRs/NF-κB signaling pathway in invasive pulmonary aspergillosis (IPA) model of wild type mouse, three groups of mouse were used in the study; the normal mice; mice infected with A. fumigatus conidia; IPA mouse infected with A. fumigatus conidia. A. fumigatus burden in lung tissue and lung pathology were detected and evaluated in IPA mouse. The levels of TLR2, TLR4 mRNA, and some inflammatory cytokines were investigated. (1) Severe inflammatory responses were found in IPA mice after nose inhalation of A. fumigatus conidia 72 h; In addition, A. fumigatus burden in IPA group was higher than that of normal mice with infection in all time. (2) Compared with normal mice with infection, IPA group displayed a low level of TLR2 mRNA in the early stage of infection, whereas it was strongly expressed in the late stage (120 h and 144 h), the expression level of TLR4 mRNA was always low during A. fumigatus infection; interestingly, the expression level of NF-κB p65 protein was quickly increased in the early stage (24 h) of infection, and then continuously declined. (3) Normal mice with A. fumigatus inoculation expressed high levels of pro-inflammatory cytokines (TNF-α, IL-1β) in the early stage of infection. The highest expression levels appeared at 48 or 72 h, and then declined to normal level. Simultaneously, anti-inflammatory cytokine IL-10 protein was elevated in the late stage of infection. However, IPA mice had a lot secretion of anti-inflammatory cytokine IL-10 protein the early stage of infection, and then displayed a significant decrease in the late stage, whereas the pro-inflammatory cytokines (TNF-α, IL-1β) was slowly secreted in low levels. The abnormal activation of TLRs/NF-κB signaling pathway induced the loss of balance between pro-inflammatory and anti-inflammatory cytokines, and eventually leads to the incidence and development of IPA.

Key words: Aspergillus fumigatus, IPA, TLRs/NF-κB, cytokine, pathogenesis.