Adaptive iron utilization compensates for the lack of an inducible uptake system inNaegleria fowleriand represents a potential target for therapeutic intervention

AbstractWarm fresh water is a natural habitat for many single-celled organisms, including protozoan parasites such as the infamous brain-eating amoeba,Naegleria fowleri,which can become pathogenic for mammals, including humans. The condition caused byN. fowleriis known as primary amoebic meningoencephalitis, which is a generic and usually fatal infection of the brain with rapid onset. One of the important factors influencing a wide spectrum of pathogens, includingN. fowleri, is the bioavailability of iron in the environment. The strategy of withholding iron evolved in mammalian hosts, and the different strategies of pathogens to obtain it are an important part of host-parasite interactions.In the present study, we employ different biochemical and analytical methods to explore the effect of decreased iron availability on the cellular processes ofN. fowleri. We show that under iron starvation, nonessential, iron-dependent, mostly cytosolic pathways inN. fowleriare downregulated, while the metal is utilized in the mitochondria to maintain vital respiratory processes. Surprisingly,N. fowlerifails to respond to acute shortages of iron by the induction of a reductive iron uptake system that seems to be the main iron-obtaining strategy of the parasite. Our work aims to demonstrate the importance of mitochondrial iron in the biology ofN. fowleriand to explore the plausibility of exploiting it as a potential target for therapeutic interference.Author SummaryNaegleria fowleriis undoubtedly one of the deadliest parasites of humans, hence the name “brain-eating amoeba”. Being dangerous, but rare, it may be regarded as a highly understudied pathogen of humans. Unfortunately, the symptoms of primary amoebic meningoencephalitis may be confused with much more common bacterial meningoencephalitis; therefore, it is quite probable that many infections caused byN. fowlerihave been misdiagnosed as bacterial infections without further inquiry. In many cases, fast diagnosis is vital for commencing the correct therapy, and even then, complete success of the treatment is very rare. Our laboratory focuses on the uptake and intracellular metabolism of metals in unicellular eukaryotes, so we decided to explore the biology ofN. fowlerifrom this aspect. Changes in the proteome, as a direct effect of iron-deficient conditions, were described, and these data were used to further explore the ways in whichN. fowleriresponds to these conditions on a cellular level and how its biology changes. Based on these findings, we propose that the struggle ofN. fowlerito obtain iron from its host could be exploited for therapeutic interference purposes in primary amoebic meningoencephalitis patients.