Search

Background Candida albicans is the single most common human fungal pathogen, and invasive candida infections carry a mortality rate of about 25%. C. albicans possesses a range of iron acquisition mechanisms that contribute to its persistence, and virulence. Patients with fungal infection have substantially increased transferrin saturation and serum iron concentrations independent of underlying hematological disorder, suggesting that host iron handling is critical to the outcome of the infection. Using a murine model of systemic iron overload, we investigated whether C.albicans-induced pathology is influenced by iron availability. Experiment Iron overloaded hepcidin knockout (Hamp−/−) and wild type (WT) litter mates were infected with C. albicans SC5314 and outcomes of infection were evaluated after 3 days. Results Compared to WT mice, Hamp−/− mice displayed increased renal fungal burden, had more renal injury, inflammation and mortality. C. albicans was in yeast form in the kidneys of WT mice but had transformed into hyphae in the iron rich renal tubular segments of Hamp−/− mice. Despite the greater pathogen burden, kidneys of Hamp−/− mice had reduced numbers of neutrophils with increased expression of p21. Conclusion Our data identify systemic iron overload as a susceptibility factor to C. albicans induced renal failure. Hepcidin deficiency was associated with increased renal iron burden and transformation of yeast into hyphae, suggesting increased virulence. Increased p21 expression in neutrophils suggests impaired NETosis and may possibly explain increased fungal burden. Our data highlight importance of dysregulated iron metabolism in disseminating candidiasis.

There are a number of diseases characterized by the presence of neutrophil elastase (NE) activity in tissues. It is generally accepted that presence of NE actively contributes to a pathological process, but the precise mechanism remains to be elucidated. We hypothesize that one NE action is activation of an inflammatory response in macrophages (Mφ). First, we show that in response to free NE exposure, Mφ release profound proteolytic activity composed of several MMPs which could contribute to extracellular matrix (ECM) degradation. Second, NE treatment also upregulated inflammatory cytokine expression, such as that of TNFα, IL-6, IL-1b, and IL-8. Therefore, Mφ activated by NE can contribute to tissue destruction on several levels, including release of proteolytic activity and by supporting chronic inflammation through expression of chemokines and cytokines. We also demonstrate that NE increases Mφ adhesion which can be attenuated by antibodies against integrin subunits. In support of our hypothesis of integrin involvement, we show an activation of the Srk kinase family in response to NE, which is a hallmark of integrin signaling pathway activation. Moreover, pretreatment of Mφ with specific Srk kinase inhibitor PP2 completely blocked cytokine production in response to NE. In summary, these data propose the mechanism of macrophage activation by NE and also suggest the inhibition of Srk can be potential therapeutic target to reduce NE-induced inflammation in lungs.