Differences in Patterns of Infection and Inflammation for Corticosteroid Treatment and Chemotherapy in Experimental Invasive Pulmonary Aspergillosis

Abstract

Aspergillus fumigatus causes invasive pulmonary aspergillosis (IPA). This disease is one of the most lifethreatening opportunistic infections in immunocompromised patients. The type of immunosuppressive regimen under which IPA occurs has rarely been investigated. In this study, we evaluated various parameters of the innate immune response during the progression of murine IPA induced by the intratracheal administration of A. fumigatus conidia as a function of two immunosuppressive treatments: a corticosteroid and a chemotherapeutic agent. We compared host responses various times after infection in terms of survival, pulmonary production of pro-and anti-inflammatory cytokines, cellular trafficking in the airways, lung injury, respiratory distress, and fungal development. We found that IPA pathogenesis involved predominantly fungal development in mice treated by chemotherapy and an adverse host response in mice treated with a corticosteroid. These previously unrecognized differences should be taken into account in evaluations of the pathogenesis of IPA in animal models.Aspergillus fumigatus belongs to a family of saprophytic filamentous fungi found in most environments. It sporulates abundantly, leading to the release into the atmosphere of large quantities of conidia. A. fumigatus spreads within the environment by means of airborne conidia, and the small diameter of these spores (2 to 3 m) enables them to reach the lung alveoli (19). Pulmonary host defenses against A. fumigatus are mediated by phagocytic cells of the innate immune system. Resident alveolar macrophages are thought to eliminate conidia by phagocytosis, whereas recruited polymorphonuclear neutrophils (PMN) destroy hyphae by producing reactive oxygen species (30,34).If the immune defense system of the lung is weakened, then conidia germinate and produce hyphae that invade the surrounding lung tissues (39), leading to the development of invasive pulmonary aspergillosis (IPA). This disease is one of the most life-threatening opportunistic infections in immunocompromised patients (19), and its incidence has increased in recent decades (14, 18). This increase in incidence has been associated with an increase in the number of people at risk due to solid organ transplantation, hematopoeitic stem cell transplantation, and intensive chemotherapeutic or immunosuppressive regimens (24). Furthermore, the difficulty of diagnosing IPA early and the low efficacy of treatments result in a high rate of mortality due to this disease in immunocompromised patients (10,23).Despite the increase in the number of IPA patients, the pathogenesis of this mycosis remains poorly understood. Experimental animal models of IPA have been developed for investigation of the role of innate immunity in the progression of the disease. Various infection protocols have been used and have generated conflicting data. More importantly, the type of immunosuppressive regimen in which IPA develops has received very little attention. In this study, we investigated various parameters of the innate...

Functional convergence of gliP and aspf1 in Aspergillus fumigatus pathogenicity

“…Based on this model, there is less ROS production by neutrophils in mice infected with gliotoxin-deficient mutants, which results in less fungal killing, but also reduced tissue damage and therefore delayed mortality. This model is consistent with the findings of Balloy et al, who determined that in corticosteroid-treated mice with invasive pulmonary aspergillosis, mortality is due in part to dysregulation of the host inflammatory response to the fungus [40]. …”

NAC is associated with additional alleviation of lung injury induced by invasive pulmonary aspergillosis in a neutropenic model

“…The alveolar septum was obviously widened and filled with inflammatory cells, both of which are characteristic of IPA. Moreover, hexamethylene tetramine silver staining revealed a considerable number of hyphae but few conidia in the pulmonary alveoli and interstitium at 72 h after inoculation (Figure 1), which is typical of IPA in mice with chemotherapy-induced neutropenia [31] .…”

“…TNF-α is a pro-inflammatory Th1 cytokine that is important to the host response to infectious agents, including fungal pathogens [41] . Phagocytosis of hyphae induces release of IL-10, a Th2 cytokine that regulates the inflammatory response by impairing the antifungal activity of phagocytes and secretion of proinflammatory cytokines by macrophages, T-cell, neutrophils and dendritic cells [31,35] . In this study, NAC elevated pulmonary TNF-α levels, strengthening resistance to IPA infection.…”

Methylcitrate synthase from Aspergillus fumigatus is essential for manifestation of invasive aspergillosis

“…Lungs of mice were collected from the different experiments and treated as described earlier (Balloy et al, 2005). In brief, organs were fixed in neutral buffered 3.7% formaldehyde and stored at 4°C in the dark until all organs were collected.…”