Introduction
Influenza-associated aspergillosis (IAA) is an emerging fungal infection with high mortality and morbidity due to a debilitating respiratory failure that can even occur in immunocompetent individuals. The pathogenesis of this disease has not been understood completely. One of our study aims to determine whether exposure to neuraminidase, which is naturally present on the surface of influenza, could affect host response against A. fumigatus. Previous studies have identified the presence of sialic acid residues on Aspergillus conidial surface, which are important for the interaction between the fungus and pulmonary epithelial cells. Moreover, peripheral blood mononuclear cells (PBMCs) also express receptors that contain sialic acids. Furthermore, most patients who are infected with influenza receive neuraminidase-inhibitors (NAI) during the course of the disease. We therefore also investigated whether NAI could modulate host cytokine response upon stimulation with A. fumigatus.
Methods
PBMC and polymorphonuclear cells (PMNs) were stimulated with neuraminidase (NA)-treated A.  fumigatus conidia or were pre-exposed to NA prior to stimulation with conidia. In a different set of experiments, cells were pre-treated with Oseltamivir carboxylate prior to stimulation. TNFα, IL-1β, IL-6, and IL-1RA were measured from supernatants after 24 hours of incubation at 37˚C. In vivo experiments were performed in corticosteroid-treated C57BL/6J mice and cyclophosphamide-treated BALBc mice. Survival rate, lung fungal burden, and histopathology were assessed subsequently.
Results
Our findings showed that the presence of neuraminidase modulates sialic acid residues on both Aspergillus conidial and host immune cell surface, resulting in increased cytokine production. We did not observe a difference in cytokine production in oseltamivir-treated cells compared to controls in-vitro, which suggests that in our in vitro system endogenous neuraminidase does not play a role in modulation of host-Aspergillus interaction. This was in contrast to experiments performed in vivo where corticosteroid-treated mice pre-treated with oseltamivir exhibited a higher mortality, increased lung fungal burden, and decreased cytokine production. However this effect were not observed in cyclophosphamide-treatment, possibly suggesting an important role of neutrophils in regards to neuraminidase activity.
Conclusion
Overall, our current results indicate that neuraminidase activity might influence host-Aspergillus interactions and that treatment of oseltamivir in a setting of corticosteroid use might increase susceptibility to Aspergillus infection. These results warrant further study on the role of neuraminidase and the effects of oseltamivir on susceptibility to invasive pulmonary aspergillosis during active influenza infection.

The role of oseltamivir in the host response against aspergillosis