A comparative ‘omics approach to candidate pathogenicity factor discovery in the brain-eating amoebaNaegleria fowleri

Of the 40 describedNaegleriaspecies, onlyN. fowlerican establish infection in humans, killing almost invariably within two weeks. In the brain, the amoeba performs piece-meal ingestion, or trogocytosis, of brain material causing massive inflammation. Conversely, its close relativeNaegleria gruberi, which is used as a laboratory model organism, is non-pathogenic. The exact pathogenicity factors distinguishingN. fowlerifrom its harmless relatives are unclear. We have here taken an -omics approach to understandingN. fowleribiology and infection at the system level. We provide the first analysis of genomic diversity between strains, finding little conservation in synteny but high conservation in protein complement. We also demonstrate that theN. fowlerigenome encodes a similarly complete cellular repertoire to that found inN. gruberi. Our comparative genomic analysis, together with a transcriptomic analysis of low versus high pathogenicityN. fowlericultured in a mouse infection model, allowed us to construct a model of cellular systems involved in pathogenicity and furthermore provides ~500 novel candidate pathogenicity factors in this currently rare but highly fatal pathogen.