A comparative ‘omics approach to candidate pathogenicity factor discovery in the brain-eating amoeba<i>Naegleria fowleri</i>

Ek, Herman; Greninger, Alex; Giezen, Mark van der; Ml, Ginger; Ramírez-Macías, Inmaculada; Hc, Miller; Mj, Morgan; Tsaousis, Anastasios D.; Vargová, Romana; S, Rodrigo Najle; Macintyre, Georgina; Müller, Norbert; Wittwer, Matthias; Dc, Zysset-Burri; Eliáš, Marek; Slamovits, Claudio H.; Weirauch, Matthew T.; Fritz‐Laylin, Lillian K.; Marciano‐Cabral, Francine; Puzon, Geoffrey J.; Walsh, Tom; Chiu, Charles Y.; Dacks, Joel B.

doi:10.1101/2020.01.16.908186

Cited by 13 publications

(12 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The current treatment regimen using miltefosine (MIL) and amphotericin B (AMB) was confirmed to be effective at inhibiting growth in vitro , which is in agreement with previous reports ( 20 – 23 ) and validates our assays performed to detect compounds that inhibit growth of Naegleria . The importance of fatty acid oxidation for N. fowleri was demonstrated in a recent in vivo study, as Herman et al observed upregulation of genes of N. fowleri involved in FAO after mouse passage ( 24 ). Our results now show that FAO inhibition is a valid target for new PAM therapy options, as etomoxir (ETO), perhexiline (PHX), and thioridazine (TDZ) showed total growth inhibition of N. fowleri .…”

Section: Discussionmentioning

confidence: 95%

Inhibition of Fatty Acid Oxidation as a New Target To Treat Primary Amoebic Meningoencephalitis

Sarink

Tielens

Verbon

et al. 2020

Antimicrob Agents Chemother

View full text Add to dashboard Cite

Primary amoebic meningoencephalitis (PAM) is a rapidly fatal infection caused by the free-living amoeba Naegleria fowleri. The amoeba migrates along the olfactory nerve to the brain, resulting in seizures, coma, and, eventually, death. Previous research has shown that Naegleria gruberi, a close relative of N. fowleri, prefers lipids over glucose as an energy source. Therefore, we tested several already-approved inhibitors of fatty acid oxidation alongside the currently used drugs amphotericin B and miltefosine. Our data demonstrate that etomoxir, orlistat, perhexiline, thioridazine, and valproic acid inhibited growth of N. gruberi. We then tested these compounds on N. fowleri and found etomoxir, perhexiline, and thioridazine to be effective growth inhibitors. Hence, not only are lipids the preferred food source for N. gruberi, but also oxidation of fatty acids seems to be essential for growth of N. fowleri. Inhibition of fatty acid oxidation could result in new treatment options, as thioridazine inhibits N. fowleri growth in concentrations that can be reached at the site of infection. It could also potentiate currently used therapy, as checkerboard assays revealed synergy between miltefosine and etomoxir. Animal testing should be performed to confirm the added value of these inhibitors. Although the development of new drugs and randomized controlled trials for this rare disease are nearly impossible, inhibition of fatty acid oxidation seems a promising strategy as we showed effectivity of several drugs that are or have been in use and that thus could be repurposed to treat PAM in the future.

show abstract

Section: Discussionmentioning

confidence: 95%

Inhibition of Fatty Acid Oxidation as a New Target To Treat Primary Amoebic Meningoencephalitis

Sarink

Tielens

Verbon

et al. 2020

Antimicrob Agents Chemother

View full text Add to dashboard Cite

show abstract

“…While reviewing the adaptations of Naegleria in the various environments, we cannot avoid discussing the potential role of AOX in the pathogenesis of N. fowleri . A recently published ‘omics approach investigating the potential genes that could be driving the pathogenicity of N. fowleri demonstrated up-regulation of mitochondrial energy conversion genes including those involved in ubiquinone biosynthesis, isocitrate dehydrogenase (TCA cycle), complex I and complex III of oxidative phosphorylation (Herman et al ., 2020). While the authors have demonstrated up-regulation of enzymes indirectly involved in oxidative stress pathway (e.g.…”

Section: Discussionmentioning

confidence: 99%

“…While the authors have demonstrated up-regulation of enzymes indirectly involved in oxidative stress pathway (e.g. agmatine deiminase), they were not able to demonstrate any significant change in the expression levels of any of the N. fowleri AOX homologs (Herman et al ., 2020). Based on these observations, it would be interesting to investigate the expression levels of AOX from the amoebas collected directly from the brain, either through transcriptomics and /or proteomics, as well as investigate whether this protein is essential for the survival of N. fowleri in such a complicated and variable environment.…”

Section: Discussionmentioning

confidence: 99%

Localization and Functional Characterization of the Alternative Oxidase inNaegleria

Cantoni

Osborne

Taïb

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

The Alternative oxidase (AOX) is a protein involved in maintaining the Krebs cycle in instances where the respiratory chain has been inhibited, while allowing for the maintenance of cell growth and necessary metabolic processes for survival. Among eukaryotes, alternative oxidases have disperse distribution and are found in plants, fungi and a few protists, including Naegleria ssp. Naegleria species are free-living unicellular amoeboflagellates, and include the pathogenic species of N. fowleri, the so-called brain eating amoeba. Using a multidisciplinary approach, we aimed to understand the evolution, localization and function of AOX and the role that plays in Naegleria’s biology. Our analyses suggest that the protein was present in last common ancestor of the genus and structure prediction showed that all functional residues are also present in Naegleria species. Using a combination of cellular and biochemical techniques, we also functionally characterize N. gruberi’s AOX in its mitochondria and we demonstrate that its inactivation affects its proliferation. Consequently, we discuss the benefits of the presence of this protein in Naegleria species, along with its potential pathogenicity role in N. fowleri. We predict that our findings will spearhead new explorations to understand the cell biology, metabolism and evolution of Naegleria and other free-living relatives.

show abstract

“…Finally, with this genome, a phylogenomic analysis was carried out among the reported genomes of the genus Naegleria , placing the ATCC 30863 strain as the closest, followed by N. lovaniensis , while N. gruberi was found to be phylogenomically more distant [ 47 ]. In addition to the genomes described above, the sequences of N. fowleri strains “986” and “V212” were published in 2020, which will be described later [ 34 ].…”

Section: Omics Applications In Free-living Amoebaementioning

confidence: 99%

“…Although there is a possibility that some ORFs are poorly predicted, according to a recent study, they are more likely to be N. fowleri specific ORFs and emphasizes the importance of conducting molecular tests on them. Returning to the ORFs with identified homologs, it was observed that six of these encode functional proteins and that the rest contain recognizable conserved domains [ 34 ].…”

Section: Omics Applications In Free-living Amoebaementioning

confidence: 99%

Application of the omics sciences to the study of Naegleria fowleri, Acanthamoeba spp., and Balamuthia mandrillaris: current status and future projections

et al. 2021

View full text Add to dashboard Cite

In this review, we focus on the sequenced genomes of the pathogens Naegleria fowleri, Acanthamoeba spp. and Balamuthia mandrillaris, and the remarkable discoveries regarding the pathogenicity and genetic information of these organisms, using techniques related to the various omics branches like genomics, transcriptomics, and proteomics. Currently, novel data produced through comparative genomics analyses and both differential gene and protein expression in these free-living amoebas have allowed for breakthroughs to identify genes unique to N. fowleri, genes with active transcriptional activity, and their differential expression in conditions of modified virulence. Furthermore, orthologous genes of the various nuclear genomes within the Naegleria and Acanthamoeba genera have been clustered. The proteome of B. mandrillaris has been reconstructed through transcriptome data, and its mitochondrial genome structure has been thoroughly described with a unique characteristic that has come to light: a type I intron with the capacity of interrupting genes through its self-splicing ribozymes activity. With the integration of data derived from the diverse omic sciences, there is a potential approximation that reflects the molecular complexity required for the identification of virulence factors, as well as crucial information regarding the comprehension of the molecular mechanisms with which these interact. Altogether, these breakthroughs could contribute to radical advances in both the fields of therapy design and medical diagnosis in the foreseeable future.

show abstract

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

Abstract: 3Red-Enfermedades Cardiovasculares (CIBERCV) 2 4 8= CSIRO Land and Water 2 5 9= CSIRO Land and Water, Black Mountain Laboratories 2 6

Cited by 13 publications

References 49 publications

Inhibition of Fatty Acid Oxidation as a New Target To Treat Primary Amoebic Meningoencephalitis

Inhibition of Fatty Acid Oxidation as a New Target To Treat Primary Amoebic Meningoencephalitis

Localization and Functional Characterization of the Alternative Oxidase inNaegleria

Application of the omics sciences to the study of Naegleria fowleri, Acanthamoeba spp., and Balamuthia mandrillaris: current status and future projections

Contact Info

Product

Resources

About