01. The Role of Neutrophils in Fungal Infections
An award from the Alcon Research Institute in 2010 allowed us to travel to southern India to examine fungal and bacterial keratitis using corneal ulcer material, post-transplant corneas, and peripheral blood from patients in India (J. Infect Dis 2011, 2015. These studies showed an important role for neutrophils, and provided the basis for developing murine models of keratitis.
In addition to examining the host response to pathogenic Aspergillus and Fusarium species, we identified fungal antioxidant and iron binding pathways as novel therapeutic approaches for fungal keratitis (J. Clin Invest 2012; PLoS Path 2013). Similarly, we showed that neutrophils use calprotectin (S100A8/A9) to sequester zinc and manganese, and thereby limit hyphal growth in the cornea (J. Immunol. 2016), and that topical application of atovaquone inhibits hyphal growth in the cornea by the same mechanism (IOVS, 2018). More recently, we identified a role for CR3 rather than Dectin-1 in NETosis and hyphal killing in response to fungal pathogens, we reported an unexpected role for caspase-11 in IL-1β processing by neutrophils, and found a role for acidic mammalian chitinase (AMCase) in fungal keratitis. Most recently, we showed that neutrophil IL-1a secretion in response to fungal cell wall products is mediated by exosomes.
02. IL-1b Processing by Neutrophils
Using a murine model of Streptococcus pneumoniae keratitis, we showed that IL-1β plays an essential role in bacterial clearance, and that neutrophils were the predominant source of cleaved, bioactive IL-1β which was mediated by pneumolysin as signal 2 activation of the NLRP3 inflammasome. We also found that in contrast to macrophages, neutrophils release bioactive IL-1alpha in the absence of pyroptotic cell death. We recently reported that this process is dependent on Gasdermin D (GSDMD), and that GSDMD processing and that the mechanism of IL-1β release by neutrophils differs from that of macrophages.
03. Neutrophils as a Source of IL-17A
We reported using adoptive transfer studies that IL-17 producing neutrophils have an important role in fungal infections. We also identified a role for IL-6, IL-23 and RORyT in this process, and also found IL-17 producing neutrophils in fungal infected patients and in healthy individuals in south India. We also reported IL-17A producing neutrophils in patients with cystic fibrosis and in CFTR transgenic mice (Clin Immunol 2016, Infect Immun 2016).