Inhibition of Host Neuraminidase Increases Susceptibility to Invasive Pulmonary Aspergillosis

Frank Van De Veerdonk, Jr, MD, PhD,1 Intan Dewi, MD,2 Christina Cunha, PhD,3 Lore vanderBeeke, MD,4 Martin Jaeger, PhD,2 Mark Gresnigt, PhD,2 Agustin Resendiz, PhD,5 Katrien Lagrou, MD,6 Greetje Van De Velde, PhD,7 Joost Wauters, MD,7 and Agostinho Carvalho, PhD3

Author address: 

1Radboud University, Nijmegen, Netherlands 2Radboudumc, Nijmegen, Netherlands 3Braga University, Braga, Portugal 4University of Leuven, Leuven, Belgium 5UZ Leuven, Leuven, Netherlands 6Department of Laboratory Medicine and National Reference Center for Mycosis, Excellence Center for Medical Mycology (ECMM), University Hospitals Leuven, Leuven, Belgium 7UZ Leuven, Leuven, Belgium

Abstract: 

Background

Influenza-associated aspergillosis (IAA) is an emerging fungal infection with high mortality and morbidity and the pathogenesis of this disease is not well understood. Interestingly, the number of IAA case reports has increased since the widespread use of neuraminidase inhibitors, such as oseltamivir in 2009. We set out to determine whether oseltamivir could contribute to the pathogenesis of IAA by modulating host responses.

Methods

First, peripheral blood mononuclear cells (PBMCs) and neutrophils from healthy donors were stimulated with neuraminidase (NA)-treated A. fumigatus or were pre-exposed to NA prior to stimulation with Aspergillus conidia. In addition, PBMCs and neutrophils were pretreated with oseltamivir carboxylate prior to stimulation. Cytokines were measured from supernatants after 24 hours of incubation at 37°C. C57BL/6 and BALB/c mice were treated with oseltamivir prior to intranasal challenge with A. fumigatus. Immunosuppression was induced by corticosteroid or cyclophosphamide.

Results

We demonstrate that Aspergillus treated with NA induced an enhanced immune response. Moreover, PBMCs and neutrophils treated with NA produced increased cytokine responses. Blocking NA in vitro with oseltamivir reduced Aspergillus-induced cytokine responses. Next we investigated the effects of blocking neuraminidase activity with oseltamivir in vivo. Immunocompetent mice and mice treated with corticosteroids showed increased mortality, lung fungal burden, and decreased cytokine production when treated with oseltamivir. These effects were not observed in cyclophosphamide-treated mice, suggesting that the effects of NA activity in anti-Aspergillus host defense acts mainly via myeloid cells.

Conclusion

Our results provide evidence that host neuraminidase activity is important for protective anti-Aspergillus immune responses. Treatment with oseltamivir, thus blocking host NA activity, in a setting of corticosteroid use might therefore 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.

2018

abstract No: 

967

Full conference title: 

ID week 2018
    • ID Week 2018