Abstract

Despite Aspergillus being the leading cause of exogenous fungal endophthalmitis following traumatic injury to the eye, its pathogenesis is not fully understood. In the current study, we developed a murine model of Aspergillus fumigatus (AF) endophthalmitis and investigated the disease pathobiology. Endophthalmitis was induced by intravitreal injection of Aspergillus spores in immunocompetent and immunocompromised (neutropenic) C57BL/6 mice, and disease severity was assessed by eye exam, fungal burden estimation, and histological examination. Our data showed that AF infection caused a time-dependent increase in corneal haze, opacity, and hypopyon beginning at two days post-infection (DPI). The fungal burden in infected eyes of immunocompetent mice peaked at 2 DPI and declined over 9 DPI. AF-infected neuroretina exhibited induction of innate immune response via upregulation of Toll-like receptors (TLRs) and inflammatory mediators (TNFα, IL-1β, and IL6), and increased polymorphonuclear neutrophil (PMN) infiltration. Histological analysis revealed heavy cellular infiltrates in the vitreous cavity as well as disruption of normal retinal architecture and increased retinal cell death. Neutropenic mice exhibited severe disease pathology with the prolonged fungal burden and increased inflammatory mediators. Our study described the first immunocompetent murine model of exogenous AF endophthalmitis and demonstrated an important role of neutrophils in innate defense against fungal endophthalmitis.

Highlights

  • Endophthalmitis is a detrimental ocular infection leaving one-third of those infected nearly blind [1]

  • We found that intravitreal injections of 15,000 spores/eye resulted in reproducible fungal endophthalmitis in B6 mice as evidenced by a time-dependent increase in corneal opacity, hypopyon, angiogenesis, and intraocular inflammation (Figure 1A)

  • To further assess the disease severity, histological analysis was performed which demonstrated a time-dependent increase in cellular infiltration, retinal folding as well as disorganization of the retinal architecture; 5 days post-infection (DPI) onwards the Aspergillus fumigatus (AF)-infected retina was totally disintegrated (Figure 1B). These findings coincided with increased retinal cell death, as indicated by a greater number of transferase dUTP nick end labeling (TUNEL) positive cells in the infected eyes (Figure 1C). These results indicate that AF causes endophthalmitis and results in severe retinal tissue damage in mouse eyes

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Summary

Introduction

Endophthalmitis is a detrimental ocular infection leaving one-third of those infected nearly blind [1]. Severe vision loss is a result of retinal damage caused by both pathogen virulence factors and an uncontrolled host inflammatory response [2,3,4]. After bacterial pathogens [5], fungi are the leading cause of both exogenous and endogenous endophthalmitis [6]. The exogenous fungal endophthalmitis is more common following penetrating ocular trauma, whereas endogenous fungal endophthalmitis results from hematogenous spread of organisms to the eye mainly in immunocompromised individuals [7,8,9]. Fungal endophthalmitis accounts for 8.6 to 18.6% of culture-positive endophthalmitis where Candida and Aspergillus spp. are the most common causative agents [10,11]. The prognosis of fungal endophthalmitis is poor, depending on the virulence of the pathogen, timing, and mode of intervention

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