Genomics and transcriptomics yields a system-level view of the biology of the pathogen Naegleria fowleri.
Cytoskeleton
Genome sequence
Illumina
Inter-strain diversity
Lysosomal
Metabolism
Neuropathogenic
Protease
RNA-Seq
Journal
BMC biology
ISSN: 1741-7007
Titre abrégé: BMC Biol
Pays: England
ID NLM: 101190720
Informations de publication
Date de publication:
22 07 2021
22 07 2021
Historique:
received:
16
12
2020
accepted:
24
06
2021
entrez:
23
7
2021
pubmed:
24
7
2021
medline:
1
2
2022
Statut:
epublish
Résumé
The opportunistic pathogen Naegleria fowleri establishes infection in the human brain, killing almost invariably within 2 weeks. The amoeba performs piece-meal ingestion, or trogocytosis, of brain material causing direct tissue damage and massive inflammation. The cellular basis distinguishing N. fowleri from other Naegleria species, which are all non-pathogenic, is not known. Yet, with the geographic range of N. fowleri advancing, potentially due to climate change, understanding how this pathogen invades and kills is both important and timely. Here, we report an -omics approach to understanding N. fowleri biology and infection at the system level. We sequenced two new strains of N. fowleri and performed a transcriptomic analysis of low- versus high-pathogenicity N. fowleri cultured in a mouse infection model. Comparative analysis provides an in-depth assessment of encoded protein complement between strains, finding high conservation. Molecular evolutionary analyses of multiple diverse cellular systems demonstrate that the N. fowleri genome encodes a similarly complete cellular repertoire to that found in free-living N. gruberi. From transcriptomics, neither stress responses nor traits conferred from lateral gene transfer are suggested as critical for pathogenicity. By contrast, cellular systems such as proteases, lysosomal machinery, and motility, together with metabolic reprogramming and novel N. fowleri proteins, are all implicated in facilitating pathogenicity within the host. Upregulation in mouse-passaged N. fowleri of genes associated with glutamate metabolism and ammonia transport suggests adaptation to available carbon sources in the central nervous system. In-depth analysis of Naegleria genomes and transcriptomes provides a model of cellular systems involved in opportunistic pathogenicity, uncovering new angles to understanding the biology of a rare but highly fatal pathogen.
Sections du résumé
BACKGROUND
The opportunistic pathogen Naegleria fowleri establishes infection in the human brain, killing almost invariably within 2 weeks. The amoeba performs piece-meal ingestion, or trogocytosis, of brain material causing direct tissue damage and massive inflammation. The cellular basis distinguishing N. fowleri from other Naegleria species, which are all non-pathogenic, is not known. Yet, with the geographic range of N. fowleri advancing, potentially due to climate change, understanding how this pathogen invades and kills is both important and timely.
RESULTS
Here, we report an -omics approach to understanding N. fowleri biology and infection at the system level. We sequenced two new strains of N. fowleri and performed a transcriptomic analysis of low- versus high-pathogenicity N. fowleri cultured in a mouse infection model. Comparative analysis provides an in-depth assessment of encoded protein complement between strains, finding high conservation. Molecular evolutionary analyses of multiple diverse cellular systems demonstrate that the N. fowleri genome encodes a similarly complete cellular repertoire to that found in free-living N. gruberi. From transcriptomics, neither stress responses nor traits conferred from lateral gene transfer are suggested as critical for pathogenicity. By contrast, cellular systems such as proteases, lysosomal machinery, and motility, together with metabolic reprogramming and novel N. fowleri proteins, are all implicated in facilitating pathogenicity within the host. Upregulation in mouse-passaged N. fowleri of genes associated with glutamate metabolism and ammonia transport suggests adaptation to available carbon sources in the central nervous system.
CONCLUSIONS
In-depth analysis of Naegleria genomes and transcriptomes provides a model of cellular systems involved in opportunistic pathogenicity, uncovering new angles to understanding the biology of a rare but highly fatal pathogen.
Identifiants
pubmed: 34294116
doi: 10.1186/s12915-021-01078-1
pii: 10.1186/s12915-021-01078-1
pmc: PMC8296547
doi:
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
142Informations de copyright
© 2021. The Author(s).
Références
Sci Rep. 2018 Mar 27;8(1):5239
pubmed: 29588502
Parasitol Res. 2010 Mar;106(4):917-24
pubmed: 20143092
Parasitol Res. 2004 Sep;94(1):31-6
pubmed: 15338289
Cell. 2008 Jul 11;134(1):112-23
pubmed: 18614015
J Cell Sci. 2013 Jan 1;126(Pt 1):1-7
pubmed: 23516326
Nucleic Acids Res. 2004 Jan 1;32(Database issue):D138-41
pubmed: 14681378
Exp Parasitol. 2014 Nov;145 Suppl:S2-9
pubmed: 25108159
Trends Parasitol. 2020 Jan;36(1):19-28
pubmed: 31744676
Bioinformatics. 2011 Feb 15;27(4):578-9
pubmed: 21149342
Cell. 2010 Mar 5;140(5):631-42
pubmed: 20211133
J Mol Biol. 2000 Jul 21;300(4):1005-16
pubmed: 10891285
J Biol Chem. 2002 Jun 21;277(25):22353-60
pubmed: 11948186
Nat Biotechnol. 2010 May;28(5):511-5
pubmed: 20436464
J Lipid Res. 2006 Mar;47(3):467-75
pubmed: 16401880
J Mol Evol. 2011 Oct;73(3-4):209-20
pubmed: 22057117
Mol Biol Evol. 2013 Apr;30(4):772-80
pubmed: 23329690
Environ Sci Technol. 2016 Mar 15;50(6):2890-8
pubmed: 26853055
Mol Biol Evol. 2013 Jul;30(7):1630-43
pubmed: 23603937
Infect Immun. 1992 Jun;60(6):2418-24
pubmed: 1587609
Bioinformatics. 2009 Sep 1;25(17):2286-8
pubmed: 19535536
Bioessays. 2006 Dec;28(12):1194-202
pubmed: 17120193
Genome Biol. 2000;1(5):REVIEWS3002
pubmed: 11178263
J Biol Chem. 2011 Jul 22;286(29):25756-62
pubmed: 21632547
BMC Genomics. 2014 Jun 19;15:496
pubmed: 24950717
Nucleic Acids Res. 2015 Jan;43(Database issue):D222-6
pubmed: 25414356
Bioinformatics. 2014 May 1;30(9):1236-40
pubmed: 24451626
Cell. 2010 Mar 5;140(5):606-8
pubmed: 20211127
Bioinformatics. 2011 Sep 1;27(17):2325-9
pubmed: 21697122
J Eukaryot Microbiol. 2007 Sep-Oct;54(5):411-7
pubmed: 17910685
Bioinformatics. 2014 Aug 1;30(15):2114-20
pubmed: 24695404
Bioinformatics. 2014 May 1;30(9):1312-3
pubmed: 24451623
Nat Protoc. 2012 Mar 01;7(3):562-78
pubmed: 22383036
Proc Natl Acad Sci U S A. 2009 Dec 22;106(51):21731-6
pubmed: 19995967
FASEB J. 2008 Sep;22(9):3103-10
pubmed: 18523161
J Bacteriol. 1981 Jul;147(1):217-26
pubmed: 7240093
Neuroscientist. 2008 Apr;14(2):171-81
pubmed: 17947494
Emerg Infect Dis. 2018 Jan;24(1):162-164
pubmed: 29260676
Nat Rev Mol Cell Biol. 2013 Jan;14(1):7-12
pubmed: 23212475
Genome Inform. 2009 Oct;23(1):205-11
pubmed: 20180275
J Cell Biol. 1983 Oct;97(4):1001-10
pubmed: 6619183
Int J Parasitol. 2011 Aug 1;41(9):915-24
pubmed: 21722646
Proc Int Conf Intell Syst Mol Biol. 1998;6:175-82
pubmed: 9783223
PLoS One. 2012;7(4):e34763
pubmed: 22493714
BMC Genomics. 2009 May 01;10:208
pubmed: 19409101
Eur J Biochem. 1987 Apr 15;164(2):427-34
pubmed: 3569274
Eur J Cell Biol. 2007 Feb;86(2):85-98
pubmed: 17189659
Future Microbiol. 2017 Jul;12:781-799
pubmed: 28608712
Microbiology (Reading). 2012 Mar;158(Pt 3):791-803
pubmed: 22222499
Oxf Med Case Reports. 2018 May 03;2018(5):omy010
pubmed: 29744128
PLoS Negl Trop Dis. 2017 Dec 28;11(12):e0006104
pubmed: 29284029
Clin Infect Dis. 2015 Apr 15;60(8):e36-42
pubmed: 25595746
J Eukaryot Microbiol. 2013 Mar-Apr;60(2):179-91
pubmed: 23360210
Int J Parasitol. 2011 Nov;41(13-14):1421-34
pubmed: 22079833
Science. 1996 Mar 15;271(5255):1513-8
pubmed: 8599106
Bioinformatics. 2003 Oct;19 Suppl 2:ii215-25
pubmed: 14534192
Aging Cell. 2011 Oct;10(5):879-84
pubmed: 21749634
J Cell Sci. 2012 May 15;125(Pt 10):2500-8
pubmed: 22366452
Bioinformatics. 2015 Oct 1;31(19):3210-2
pubmed: 26059717
Proc Natl Acad Sci U S A. 2003 Nov 11;100(23):13207-12
pubmed: 14576278
Environ Sci Technol. 2015 Sep 15;49(18):11125-31
pubmed: 26287820
BMJ. 2013 May 31;346:f3580
pubmed: 23729435
Cell. 2014 Sep 11;158(6):1431-1443
pubmed: 25215497
Environ Sci Technol. 2018 Mar 6;52(5):2549-2557
pubmed: 29390181
J Coll Physicians Surg Pak. 2015 Mar;25(3):159-60
pubmed: 25772952
Exp Parasitol. 1994 Mar;78(2):230-41
pubmed: 8119377
J Pathol. 1970 Apr;100(4):217-44
pubmed: 4989229
Eur J Cell Biol. 2011 Apr;90(4):342-55
pubmed: 21131095
J Cell Sci. 2010 Dec 1;123(Pt 23):4024-31
pubmed: 21045110
Mol Biol Evol. 1989 May;6(3):243-57
pubmed: 2622334
Nucleic Acids Res. 1996 Jan 1;24(1):21-5
pubmed: 8594581
J Protozool. 1974 May;21(2):239-50
pubmed: 4838474
Genome Biol Evol. 2009 Sep 10;1:364-81
pubmed: 20333205
Clin Infect Dis. 2016 Mar 15;62(6):774-6
pubmed: 26679626
Mol Biol Evol. 2009 Jul;26(7):1533-48
pubmed: 19349646
Bioinformatics. 2012 Jun 15;28(12):1647-9
pubmed: 22543367
BMC Bioinformatics. 2011 Aug 04;12:323
pubmed: 21816040
Nucleic Acids Res. 2014 Jan;42(Database issue):D222-30
pubmed: 24288371
Genome Biol. 2011;12(2):R20
pubmed: 21356102
Environ Sci Technol. 2009 Sep 1;43(17):6691-6
pubmed: 19764236
Bioinformatics. 2010 Jan 1;26(1):139-40
pubmed: 19910308
Syst Biol. 2012 May;61(3):539-42
pubmed: 22357727
Microbiology (Reading). 2017 Mar;163(3):322-332
pubmed: 28086072
Proc Natl Acad Sci U S A. 2008 Jul 22;105(29):9897-902
pubmed: 18632573
Genome Res. 2003 Sep;13(9):2178-89
pubmed: 12952885
Emerg Infect Dis. 2021 Jan;27(1):271-274
pubmed: 33350926
Clin Diagn Lab Immunol. 2005 Jul;12(7):873-6
pubmed: 16002638
Annu Rev Microbiol. 1992;46:695-729
pubmed: 1444271
FEMS Microbiol Ecol. 2017 Apr 1;93(4):
pubmed: 28334109
Nat Methods. 2012 Mar 04;9(4):357-9
pubmed: 22388286
Exp Parasitol. 2006 Nov;114(3):141-6
pubmed: 16620809
Acta Trop. 2016 Dec;164:375-394
pubmed: 27616699
Sci Rep. 2019 Nov 5;9(1):16040
pubmed: 31690847
J Cell Sci. 2005 Mar 1;118(Pt 5):843-6
pubmed: 15731001
J Intern Med. 2012 Oct;272(4):394-401
pubmed: 22443218
J Comput Biol. 2012 May;19(5):455-77
pubmed: 22506599
Trends Biochem Sci. 2016 Jun;41(6):478-490
pubmed: 27068179
Infect Immun. 1992 Jul;60(7):2784-90
pubmed: 1319405
Bioinformatics. 2011 Apr 15;27(8):1164-5
pubmed: 21335321
Plant Physiol. 2001 Dec;127(4):1711-27
pubmed: 11743115
Infect Immun. 1987 Oct;55(10):2442-7
pubmed: 3653986
J Mol Biol. 2001 Jan 19;305(3):567-80
pubmed: 11152613
J Biol Chem. 1984 Jun 10;259(11):7355-60
pubmed: 6725289
Small GTPases. 2018 Jul 4;9(4):360-364
pubmed: 27715492
Clin Infect Dis. 2012 Nov;55(9):e79-85
pubmed: 22919000
Nucleic Acids Res. 1997 Sep 1;25(17):3389-402
pubmed: 9254694
Cell Rep. 2018 Oct 16;25(3):537-543.e3
pubmed: 30332635
Exp Parasitol. 2009 Jul;122(3):212-7
pubmed: 19348803
J Parasitol. 1971 Aug;57(4):917-20
pubmed: 5568347
Genome Biol. 2013 Apr 25;14(4):R36
pubmed: 23618408
Clin Infect Dis. 2021 Jul 1;73(1):e19-e27
pubmed: 32369575
Cytoskeleton (Hoboken). 2013 Jul;70(7):360-84
pubmed: 23749648
PLoS Negl Trop Dis. 2014 Aug 14;8(8):e3017
pubmed: 25121759
Cells. 2016 Jun 14;5(2):
pubmed: 27314390
Open Biol. 2016 Jul;6(7):
pubmed: 27383626
Subcell Biochem. 2011;52:25-73
pubmed: 21557078
Nat Protoc. 2013 Aug;8(8):1494-512
pubmed: 23845962
Nat Methods. 2017 Jun;14(6):587-589
pubmed: 28481363
Nucleic Acids Res. 2007 Jul;35(Web Server issue):W585-7
pubmed: 17517783
Amino Acids. 2011 Feb;40(2):269-85
pubmed: 20512387
Chem Rev. 2014 Nov 26;114(22):11242-71
pubmed: 25337991
Small GTPases. 2011 Jan;2(1):4-16
pubmed: 21686276
J Eukaryot Microbiol. 2020 Mar;67(2):209-222
pubmed: 31705733
PLoS One. 2011 Feb 24;6(2):e17285
pubmed: 21390322
Nucleic Acids Res. 2004 Jul 1;32(Web Server issue):W309-12
pubmed: 15215400
J Protozool. 1977 Aug;24(3):437-41
pubmed: 915847
Nat Rev Mol Cell Biol. 2010 Apr;11(4):237-51
pubmed: 20237478
Mol Biol Evol. 2018 Mar 1;35(3):543-548
pubmed: 29220515
Infect Immun. 1991 Nov;59(11):4278-82
pubmed: 1937787
Water Res. 2017 Mar 1;110:15-26
pubmed: 27974249
Infect Genet Evol. 2011 Oct;11(7):1520-8
pubmed: 21843657
Clin Infect Dis. 2012 Mar;54(6):805-9
pubmed: 22238170
J Mol Biol. 1990 Oct 5;215(3):403-10
pubmed: 2231712
J Mol Biol. 2007 Nov 30;374(3):837-63
pubmed: 17959197
Syst Biol. 2010 May;59(3):307-21
pubmed: 20525638
Prog Neurobiol. 2001 Sep;65(1):1-105
pubmed: 11369436
Biochim Biophys Acta. 2001 Feb 26;1530(2-3):123-33
pubmed: 11239815
Nucleic Acids Res. 2004 Mar 19;32(5):1792-7
pubmed: 15034147
Pediatrics. 2015 Mar;135(3):e744-8
pubmed: 25667249
Biol Direct. 2008 May 29;3:21
pubmed: 18510733
Nucleic Acids Res. 2015 Jan;43(Database issue):D257-60
pubmed: 25300481
Eur J Biochem. 1996 Nov 1;241(3):779-86
pubmed: 8944766
BMC Genomics. 2008 Jun 17;9:291
pubmed: 18559084
J Med Microbiol. 1978 Aug;11(3):249-59
pubmed: 682176
J Cell Biol. 2017 Jun 5;216(6):1673-1688
pubmed: 28473602
Mol Biol Evol. 2013 May;30(5):1188-95
pubmed: 23418397
Cell. 1979 Aug;17(4):867-78
pubmed: 487433