Role of cytokines against invasive aspergillosis: evidence from preclinical studies

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Aspergillus fumigatus is the most frequent causative agent of invasive aspergillosis, a predominant life-threatening opportunistic infection in immunocompromised individuals. A. fumigatus conidia reach the alveoli via inhalation, where the pulmonary alveolar macrophages (PAM) ingest and destroy them intracellularly by non-oxidative anti-fungal mechanisms. Circulating phagocytes (i.e., neutrophils and monocytes) can destroy hyphae that germinate from conidia, which escape phagocytosis by PAM, by both oxidative and non-oxidative mechanisms. In addition, other immune cells such as natural killer lymphocytes, tissue macrophages and platelets play an important role in host defence against A. fumigatus. Given that the vulnerability of immunocompromised patients is due mainly to qualitative and quantitative phagocytic deficiencies, the ability of cytokines to regulate the function of host defence cells is of great importance for the management of infections caused by A. fumigatus. Cytokines can augment or suppress the anti-fungal phagocyte function by altering oxidative burst, cell-mediated hyphal damage, phagocytosis, restoration of corticosteroid treatment effects, and secretion of other cytokines. The hemopoietic growth factors granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor as well as macrophage colony-stimulating factor, and the Th1 pattern cytokines interferon-γ, interleukin-12 and tumour necrosis factor-α augment phagocyte function against A. fumigatus, while interleukin-4, interleukin-10 and transforming growth factor-β suppress it. Furthermore, other cytokines such as interleukin-8, -13, -15, -18 and -25 may exhibit anti-Aspergillus effects. Finally, besides the direct immunomodulatory properties of cytokines, the latter may collaborate with anti-fungal drugs enhancing even more the inhibition of fungal growth by phagocytes. Therefore, combination of immunotherapy and anti-fungal chemotherapy might be an alternative therapeutic approach for controlling A. fumigatus infections successfully.

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