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2018 Agenda and Abstracts | < Previous Next >

2018 OMIG Abstract

Understanding Fungal Virulence In Keratitis Through A Reverse-Translational Approach

Kevin K. Fuller1, Robert A. Cramer2, Jay C. Dunlap2, Kathryn J. Ray3,Thomas Lietman3, Kuppamuthu Dharmalingam4, and Michael E. Zegans2
1University of Oklahoma Health Sciences Center, OK, USA; 2Geisel School of Medicine at Dartmouth, NH, USA; 3University of California San Francisco, CA, USA; 4Aravind Medical Research Foundation, India


Purpose: Fusarium species are a significant cause of fungal keratitis worldwide. Fusaria are resistant to many of the current antifungals, and this may contribute to the high treatment failure rate in fungal keratitis patients overall. Accordingly, a better understanding of fungal factors that drive infection in the eye is required to develop novel antifungal strategies. The overarching aim of this project is to identify such fungal virulence factors in a clinically-informed manner.

Methods: The NEI-funded Mycotic Ulcer Treatment Trial (MUTT) enrolled 323 patients across South India to compare topical voriconazole and natamycin monotherapies. 128 isolates (40%) were identified as Fusarium in the clinic and were analyzed further in this work. Species-level identification was performed at Dartmouth and OUHSC by sequencing the internal- transcribed spacer (ITS) and translation elongation factor-1 (tef-1) loci. Phenotypic analyses were also performed at Dartmouth and OUHSC by spot inoculating microconidia onto glucose minimal medium agar and analyzing colony diameters under various growth conditions. Statistical comparisons of the phenotypic and patient data sets were performed at UCSF.

Results: Molecular genotypingrevealed that the majority of Fusarium isolates (80%) belong to the Fusariumsolani species complex (FSSC). Not only were the FSSC organisms most prevalent, they were statistically correlated with worst baseline scar size compared to the non-FSSC organisms (p=.031). These isolates displayed marked variability in growth rate at 30oC and 37oC, but only growth at the latter temperature was correlated with patient outcome; specifically, increased growth rate was predictive of longer re-epithelization time.

Conclusion: Our data implicate FSSC species as the most common and most severe agents in Fusarium keratitis during the MUTT. The phenotypic analyses so far suggest that growth at physiological temperature is variable across FSSC isolates, and those that grow faster at this temperature are associated with worse infection. This serves as a proof-of-principle for our study design, and continued analyses should inform our understanding of (1) microbial factors that influence patient outcome, and (2) fungal pathways that can serve as targets for novel therapeutics.

Disclosure: N

Support: NIH/NEI grant R21EYE28677-01 awarded to MEZ and KKF (MPIs)


2018 Agenda and Abstracts | < Previous Next >