Influenza Suppresses Neutrophil Recruitment to the Lung and Exacerbates Secondary Invasive Pulmonary Aspergillosis

Abstract

Aspergillus fumigatus is an environmental fungus that can cause invasive pulmonary aspergillosis when spores are inhaled into the respiratory tract and invade airway or lung tissue. Influenza is a common respiratory virus that can cause severe respiratory disease, and postinfluenza invasive pulmonary aspergillosis, which is becoming a well-recognized clinical problem, typically occurs in critically ill patients. Mice challenged with influenza A PR/8/34 H1N1 and subsequently challenged with A. fumigatus had increased fungal burden, viral burden, inflammation, and mortality compared with single infected mice. Neutrophil recruitment in the lung of superinfected mice was decreased; however, mice were not neutropenic, and there was no difference in absolute blood neutrophils between groups. Additionally, CXCL1 and CXCL2 were decreased in lungs of superinfected mice compared with controls. IFN levels were increased in mice that received influenza, and deletion of STAT1 resulted in decreased fungal burden, increased airway and lung neutrophils, and increased CXCL1 compared with wild-type mice, whereas deletion of STAT2 did not change fungal burden or airway neutrophilia compared with wild-type mice. These data demonstrate a mechanism by which influenza A-induced STAT1 signaling inhibits neutrophil recruitment and increases susceptibility to postinfluenza invasive pulmonary aspergillosis.

Early oseltamivir reduces risk for influenza-associated aspergillosis in a double-hit murine model

“…We provide a robust mouse model that corroborates our earlier retrospective data on IAPA in critically ill patients with severe influenza and confirm that IAPA develops in immunocompetent mice even without corticosteroids [1]. In line with the findings from Tobin et al (2020) [38]. In our model, immunocompetent mice showed severe body weight loss and clinical deterioration when first infected with influenza virus and superinfected 4 days later with A. fumigatus conidia, whereas single infection with influenza or Aspergillus alone generated only transient disease.…”

Mortality in critically ill patients with coronavirus disease 2019‐associated pulmonary aspergillosis: A systematic review and meta‐analysis

“…Possible mechanisms to explain the development of CAPA in patients with severe COVID‐19 are first, the pulmonary epithelial damage secondary to the release of endogenous danger molecules released from damaged or dying cells, secondly, the presence of a permissive inflammatory environment and defective IFN type I response, which favours Aspergillus invasion 52,53 . The inhibition of neutrophil recruitment by influenza A mediated signal‐transducer and activator of transcription‐1 (STAT‐1) signalling increases susceptibility IAPA 54 and such mechanisms may also be prevalent in patients with COVID‐19.…”

Neutrophils in respiratory viral infections

“…224 However, in a IAV-Aspergillus fumigatus co-infection model, mice got more severe disease and there were fewer neutrophils recruited in the superinfected mice. 225 Overall, the data so far suggest that a viral infection inhibits the neutrophil response and render the host susceptible to a subsequent bacterial or fungal infection. Interestingly, some of our recent data suggest that a signature of activated neutrophils in the nose prior to RSV challenge correlates with the development of symptomatic infection in human volunteers.…”