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Host chitinases, chitotriosidase and acidic mammalian chitinase (AMCase), improved the antifungal activity of caspofungin (CAS) against Aspergillus fumigatus in vitro These chitinases are not constitutively expressed in the lung. Here, we investigated whether chitosan derivatives were able to induce chitinase activity in the lungs of neutropenic rats and, if so, whether these chitinases were able to prolong survival of rats with invasive pulmonary aspergillosis (IPA) or of rats with IPA and treated with CAS. An oligosaccharide-lactate chitosan (OLC) derivative was instilled in the left lung of neutropenic rats to induce chitotriosidase and AMCase activities. Rats instilled with OLC or with phosphate-buffered saline (PBS) were subsequently infected with A. fumigatus and then treated with suboptimal doses of CAS. Survival, histopathology, and galactomannan indexes were determined. Instillation of OLC resulted in chitotriosidase and AMCase activities. However, instillation of OLC did not prolong rat survival when rats were subsequently challenged with A. fumigatus In 5 of 7 rats instilled with OLC, the fungal foci in the lungs were smaller than those in rats instilled with PBS. Instillation of OLC did not significantly enhance the survival of neutropenic rats challenged with A. fumigatus and treated with a suboptimal dosage of CAS. Chitotriosidase and AMCase activities can be induced with OLC, but the presence of active chitinases in the lung did not prevent the development of IPA or significantly enhance the therapeutic outcome of CAS treatment., (Copyright © 2017 American Society for Microbiology.)

Toll-like receptor (TLR)-based signaling pathways in the host may be modulated by pathogens during the course of infection. We describe a novel immunomodulatory mechanism in which Aspergillus fumigatus conidia induce attenuation of TLR2- and TLR4-mediated interleukin (IL)-6 and IL-1beta proinflammatory responses in human mononuclear cells with suppression of IL-1beta mRNA transcription. Background TLR2 and TLR4 mRNA transcription was not influenced. A. fumigatus conidia induced TLR2 internalization and uptake into the phagosome with a resultant decrease in surface receptor expression. A. fumigatus hyphae, on the other hand, selectively downregulated the TLR4-mediated response. These novel immunosuppressive effects may facilitate the invasiveness of A. fumigatus.

The aim of the present study was to assess the influence of immunomodulation of host defense with recombinant murine granulocyte colony-stimulating factor (rmG-CSF) on intra-abdominal abscesses caused by Candida albicans. Mice received prophylaxis or therapy with 1 microg of rmG-CSF/day in the presence or absence of antifungal treatment consisting of amphotericin B (0.75 mg/kg of body weight/day) or fluconazole (50 mg/kg/day). The number of Candida CFU in abscesses was significantly reduced (P<0.05) in mice receiving rmG-CSF prophylaxis (day -1 or day -1 through 2) compared with controls on day 8 of infection. Administration of rmG-CSF therapy alone (for 5 days starting on day 4 of infection) had no influence on the number of Candida CFU in abscesses. Amphotericin B treatment was significantly more effective than fluconazole treatment (3.41 log CFU/abscesses; 95% confidence interval [CI], 3.17 log CFU/abscesses; 3.65 versus 3.90 log CFU/abscesses; 95% CI, 3.66 log CFU/abscesses, 4.16 log CFU/abscesses; P<0.05). Therapeutic administration of rmG-CSF in conjunction with an antifungal agent showed a tendency towards a further reduction of Candida CFU in abscesses than antifungal treatment only. In conclusion, in this experimental model of intra-abdominal Candida abscesses, rmG-CSF administration did not have a detrimental influence on the course of infection. Amphotericin B treatment was most effective, and additional rmG-CSF therapy did not antagonize the effect of antifungal treatment. In contrast, addition of rmG-CSF therapy to antifungal treatment might further enhance the beneficial effect of the antifungal agent.