Pathogenic Inflammation in Fungal Infections: the Contribution of the Th17 Pathway

Teresa Zelante, Antonella De Luca, Carmen D' Angelo, Silvia Bozza, Silvia Moretti, Pierluigi Bonifazi, Lucia Pitzurra, Francesca Fallarino, Paolo Puccetti, Luigina Romani

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Pathogenic Inflammation in Fungal Infections: the Contribution of the Th17 Pathway


Background: The inflammatory response to fungi may serve to limit infection but an overzealous or heightened inflammatory response may contribute to pathogenicity, as documented by the occurrence of intractable fungal infections in patients with immunoreconstitution disease or primary immunodeficiencies associated with heightened immune reactivity. IL-12, by initiating and maintaining Th1 responses, was thought to be responsible for overreacting immune and autoimmune disorders. The newly described Th17 pathway is now thought to contribute to immune pathogenesis previously attributed to the Th1 lineage. Objective: This study examined the role of Th17 in inflammation and immunity to Candida albicans or Aspergillus fumigatus in experimental models of infections. Methods: Mice with selected genetic deficiencies (i.e, IL-23, IL-12 or both or TLR-deficient) were exposed to C. albicans or A. fumigatus and assessed for susceptibility to infection, gut or airway inflammation, and parameters of innate and adaptive immunity. Results: The Th17 pathway and not the uncontrolled Th1 response was associated with defective pathogen clearance, failure to resolve inflammation and initiate protective immune responses. Conditions of high-threat inflammation predisposed to Th17 activation, whereby the unrestricted fungal growth resulted from the activation of not only pathogenic Th17 cells but also Th2 cells, whose activation is strictly dependent on fungal burden. Blockade of IL-17/IL-23 prevented pathogenic inflammatory responses, ameliorated infections and restored protective Th1 antifungal resistance, thus causally linking pathogenic inflammation to Th17 development. Conclusion and clinical implications: The above findings provide a molecular connection between the failure to resolve inflammation and lack of antifungal immune resistance and point to strategies for immune therapy of fungal infections that attempt to limit inflammation to stimulate an effective immune response. Inhibition of the Th17 pathway may potentially represent a novel strategy for the prevention of inflammatory immunity and allergy in fungal diseases.

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15th International Symposium on Infections in the Immunocompromised Host