Interleukin-4 causes susceptibility to invasive pulmonary aspergillosis through suppression of protective type I responses.

Aspergillus fumigatus, an opportunistic fungal pathogen, causes multiple allergic and nonallergic airway diseases. Invasive pulmonary aspergillosis (IPA) is a nonallergic, life-threatening disease of immunocompromised patients. In a murine model of IPA, interleukin (IL)-4-deficient (IL-4-/-) BALB/c mice were used to examine the role of IL-4 in lung pathology and immune responses. IL-4-/- mice were more resistant than wild-type mice to infection caused by multiple intranasal injections of viable A. fumigatus conidia. Resistance was associated with decreased lung inflammatory pathology, impaired T helper (Th)-2 responses (including lung eosinophilia), and an IL-12-dependent Th1 response. In contrast, development of host-detrimental antifungal Th2 cells occurred in IL-12-/- and interferon-gamma-/- mice and in IL-4-/- mice when subjected to IL-12 neutralization. These results demonstrate that IL-4 renders mice susceptible to infection with A. fumigatus by inhibition of protective Th1 responses. IL-4 appears to have a distinct role in the pathogenesis of allergic and nonallergic lung diseases caused by the fungus

Interleukin-4 causes susceptibility to invasive pulmonary aspergillosis through suppression of protective type I responses.

Aspergillus fumigatus, an opportunistic fungal pathogen, causes multiple allergic and nonallergic airway diseases. Invasive pulmonary aspergillosis (IPA) is a nonallergic, life-threatening disease of immunocompromised patients. In a murine model of IPA, interleukin (IL)-4-deficient (IL-4-/-) BALB/c mice were used to examine the role of IL-4 in lung pathology and immune responses. IL-4-/- mice were more resistant than wild-type mice to infection caused by multiple intranasal injections of viable A. fumigatus conidia. Resistance was associated with decreased lung inflammatory pathology, impaired T helper (Th)-2 responses (including lung eosinophilia), and an IL-12-dependent Th1 response. In contrast, development of host-detrimental antifungal Th2 cells occurred in IL-12-/- and interferon-gamma-/- mice and in IL-4-/- mice when subjected to IL-12 neutralization. These results demonstrate that IL-4 renders mice susceptible to infection with A. fumigatus by inhibition of protective Th1 responses. IL-4 appears to have a distinct role in the pathogenesis of allergic and nonallergic lung diseases caused by the fungus

Recombinant cytokines in the therapy of fungal infection

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Type 1 and Type 2 cytokines: from basic science to fungal infections

At the present time, it is clear that Th1 responses afford protection against the fungi; however, the development, maintenance and function of the protective immune responses are complex mechanisms and are influenced by multiple factors. The route of infection has been shown to affect initial cytokine production and, consequently, the induction of protective Th1 responses. The ability of different isolates of the same fungal agent to induce and sustain a protective response has also been emphasized. Protective immune responses have been shown to vary in genetically different mouse strains after infection. In addition, these protective responses, such as cellular influx and cytokine production, also vary within the same animal depending on the tissue infected. The functional dominance of certain cytokines over others in influencing development and maintenance of protective responses has been discussed. Certain cytokines may act differently in hosts lacking important components of their innate or immune repertoire. It is evident from these presentations that a more comprehensive understanding of the protective mechanisms against different fungal agents is emerging. However, there is still much to learn before cytokine modulatory therapy can be used effectively without risk in the human host

Diagnosis of aspergillosis: Role of proteomics

The expansion of the antifungal armamentarium and the implementation of imaging techniques and new nonculture-based fungal diagnostics (NCBFDs) have improved the survival of patients with invasive aspergillosis (IA). However, mortality rates still remain high, possibly influenced by several pitfalls, affecting NCBFDs and reducing the window of opportunity for earlier treatment. A large body of in vitro and in vivo studies has demonstrated that several fungal proteic components are strongly immunogenic, and both the adaptive immunity and the innate branch are heavily involved in the recognition and clearance of fungal pathogens, resulting, on occasion, in a useful tool for the treatment of IA. By evaluating these studies, this review considers the possibility of exploiting either components of the innate or adaptive immunity to support the rapid and early diagnosis of IA. Copyright © 2009 by Current Medicine Group LLC

Genes and gene pathways in Candida infection

Advances in genetic technology have promoted an explosive increase in our knowledge of genes relevant to Candida infection, and our understanding of their mode of action. Although the major influence on susceptibility to systemic infection is the presence or absence of complement C5, at least two other genes, as yet unidentified, influence the severity of tissue damage. Mice in which specific genes have been deleted (gene-knockout) mice are now readily available, and have been used both in the analysis of receptor interactions with Candida, and to study the role of T cell-derived cytokines in clearance of the infection and the development of host resistance, but results have not always been consistent. Gene profiling studies, in both humans and mice, will no doubt resolve some of the present anomalie