No abstract

Naegleria fowleri is a single-cell organism living in warm freshwater that can become a deadly human pathogen known as a brain-eating amoeba. The condition caused by N. fowleri, primary amoebic meningoencephalitis, is usually a fatal infection of the brain with rapid and severe onset. Iron is a common element on earth and a crucial cofactor for all living organisms. However, its bioavailable form can be scarce in certain niches, where it becomes a factor that limits growth. To obtain iron, many pathogens use different machineries to exploit an iron-withholding strategy that has evolved in mammals and is important to host-parasite interactions. The present study demonstrates the importance of iron in the biology of N. fowleri and explores the plausibility of exploiting iron as a potential target for therapeutic intervention. We used different biochemical and analytical methods to explore the effect of decreased iron availability on the cellular processes of the amoeba. We show that, under iron starvation, nonessential, iron-dependent, mostly cytosolic pathways in N. fowleri are downregulated, while the metal is utilized in the mitochondria to maintain vital respiratory processes. Surprisingly, N. fowleri fails to respond to acute shortages of iron by inducing the reductive iron uptake system that seems to be the main iron-obtaining strategy of the parasite. Our findings suggest that iron restriction may be used to slow the progression of infection, which may make the difference between life and death for patients.

Many of the currently available anti-parasitic and anti-fungal frontline drugs have severe limitations, including adverse side effects, complex administration, and increasing occurrence of resistance. The discovery and development of new therapeutic agents is a costly and lengthy process.

Primary amoebic meningoencephalitis is a rare but fatal central nervous system (CNS) disease caused by the “brain-eating amoeba” Naegleria fowleri . A major obstacle is the requirement for drugs with the ability to cross the blood-brain barrier, which are used in extremely high doses, cause severe side effects, and are usually ineffective.

Warm 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 by N. fowleri is 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, including N. 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 of N. fowleri. We show that under iron starvation, nonessential, iron-dependent, mostly cytosolic pathways in N. fowleri are downregulated, while the metal is utilized in the mitochondria to maintain vital respiratory processes. Surprisingly, N. fowleri fails 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 of N. fowleri and to explore the plausibility of exploiting it as a potential target for therapeutic interference.Author SummaryNaegleria fowleri is 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 by N. fowleri have 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 of N. fowleri from 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 which N. fowleri responds to these conditions on a cellular level and how its biology changes. Based on these findings, we propose that the struggle of N. fowleri to obtain iron from its host could be exploited for therapeutic interference purposes in primary amoebic meningoencephalitis patients.