Alteration of Fermentative Metabolism Enhances Mucor Circinelloides Virulence

Overview

Journal Infect Immun

Publisher American Society for Microbiology

Specialty Allergy & Immunology

Date 2019 Nov 6

PMID 31685547

Citations 11

Authors

Sharel P Diaz-Perez

J Alberto Patino-Medina

Marco I Valle-Maldonado

Adolfo Lopez-Torres

Irvin E Jacome-Galarza

Veronica Anaya-Martinez

Veronica Gomez-Ruiz

Jesus Campos-Garcia

Rosa E Nunez-Anita

Rafael Ortiz-Alvarado

Martha I Ramirez-Diaz

J Felix Gutierrez-Corona

Victor Meza-Carmen

Affiliations

Soon will be listed here.

Abstract

The fungus undergoes yeast-mold dimorphism, a developmental process associated with its capability as a human opportunistic pathogen. Dimorphism is strongly influenced by carbon metabolism, and hence the type of metabolism likely affects fungus virulence. We investigated the role of ethanol metabolism in virulence. A mutant in the gene (M5 strain) exhibited higher virulence than the wild-type (R7B) and the complemented (M5/pEUKA-) strains, which were nonvirulent when tested in a mouse infection model. Cell-free culture supernatant (SS) from the M5 mutant showed increased toxic effect on nematodes compared to that from R7B and M5/pEUKA- strains. The concentration of acetaldehyde excreted by strain M5 in the SS was higher than that from R7B, which correlated with the acute toxic effect on nematodes. Remarkably, strain M5 showed higher resistance to HO, resistance to phagocytosis, and invasiveness in mouse tissues and induced an enhanced systemic inflammatory response compared with R7B. The mice infected with strain M5 under disulfiram treatment exhibited only half the life expectancy of those infected with M5 alone, suggesting that acetaldehyde produced by contributes to the toxic effect in mice. These results demonstrate that the failure in fermentative metabolism, in the step of the production of ethanol in , contributes to its virulence, inducing a more severe tissue burden and inflammatory response in mice as a consequence of acetaldehyde overproduction.

Citing Articles

a novel dimorphic species resembling in a clinical sample: questions on ecological strategy.

Li N, Bowling J, de Hoog S, Aneke C, Youn J, Shahegh S mBio. 2024; 15(8):e0014424.

PMID: 38953355 PMC: 11323738. DOI: 10.1128/mbio.00144-24.

Molecular mechanisms that govern infection and antifungal resistance in Mucorales.

Lax C, Nicolas F, Navarro E, Garre V Microbiol Mol Biol Rev. 2024; 88(1):e0018822.

PMID: 38445820 PMC: 10966947. DOI: 10.1128/mmbr.00188-22.

Alternative models of mucormycosis.

Scheler J, Binder U Front Cell Infect Microbiol. 2024; 14:1343834.

PMID: 38362495 PMC: 10867140. DOI: 10.3389/fcimb.2024.1343834.

Blood Serum Stimulates the Virulence Potential of Mucorales through Enhancement in Mitochondrial Oxidative Metabolism and Rhizoferrin Production.

Patino-Medina J, Alejandre-Castaneda V, Valle-Maldonado M, Martinez-Pacheco M, Ruiz-Herrera L, Ramirez-Emiliano J J Fungi (Basel). 2023; 9(12).

PMID: 38132728 PMC: 10744254. DOI: 10.3390/jof9121127.

Transcription Factors Tec1 and Tec2 Play Key Roles in the Hyphal Growth and Virulence of Mucor lusitanicus Through Increased Mitochondrial Oxidative Metabolism.

Alejandre-Castaneda V, Patino-Medina J, Valle-Maldonado M, Garcia A, Ortiz-Alvarado R, Ruiz-Herrera L J Microbiol. 2023; 61(12):1043-1062.

PMID: 38114662 DOI: 10.1007/s12275-023-00096-8.

References

Patino-Medina J, Valle-Maldonado M, Maldonado-Herrera G, Perez-Arques C, Jacome-Galarza I, Diaz-Perez C . Role of Arf-like proteins (Arl1 and Arl2) of Mucor circinelloides in virulence and antifungal susceptibility. Fungal Genet Biol. 2019; 129:40-51. DOI: 10.1016/j.fgb.2019.04.011. View

Kim J . Human fungal pathogens: Why should we learn?. J Microbiol. 2016; 54(3):145-8. DOI: 10.1007/s12275-016-0647-8. View

Brenner S . The genetics of Caenorhabditis elegans. Genetics. 1974; 77(1):71-94. PMC: 1213120. DOI: 10.1093/genetics/77.1.71. View

Pfaffl M . A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res. 2001; 29(9):e45. PMC: 55695. DOI: 10.1093/nar/29.9.e45. View

Setshedi M, Wands J, de la Monte S . Acetaldehyde adducts in alcoholic liver disease. Oxid Med Cell Longev. 2010; 3(3):178-85. PMC: 2952076. DOI: 10.4161/oxim.3.3.12288. View

Schopf R, Trompeter M, Bork K, MORSCHES B . Effects of ethanol and acetaldehyde on phagocytic functions. Arch Dermatol Res. 1985; 277(2):131-7. DOI: 10.1007/BF00414111. View

BARTNICKI GARCIA S . SYMPOSIUM ON BIOCHEMICAL BASES OF MORPHOGENESIS IN FUNGI. III. MOLD-YEAST DIMORPHISM OF MUCOR. Bacteriol Rev. 1963; 27:293-304. PMC: 441189. DOI: 10.1128/br.27.3.293-304.1963. View

Petrikkos G, Skiada A, Lortholary O, Roilides E, Walsh T, Kontoyiannis D . Epidemiology and clinical manifestations of mucormycosis. Clin Infect Dis. 2012; 54 Suppl 1:S23-34. DOI: 10.1093/cid/cir866. View

Grahl N, Puttikamonkul S, Macdonald J, Gamcsik M, Ngo L, Hohl T . In vivo hypoxia and a fungal alcohol dehydrogenase influence the pathogenesis of invasive pulmonary aspergillosis. PLoS Pathog. 2011; 7(7):e1002145. PMC: 3141044. DOI: 10.1371/journal.ppat.1002145. View

10.

Torres-Guzman J, Martinez-Cadena G . Genetic evidence for independence between fermentative metabolism (ethanol accumulation) and yeast-cell development in the dimorphic fungus Mucor rouxii. Curr Genet. 1994; 26(2):166-71. DOI: 10.1007/BF00313806. View

11.

Binder U, Maurer E, Lass-Florl C . Mucormycosis--from the pathogens to the disease. Clin Microbiol Infect. 2014; 20 Suppl 6:60-6. DOI: 10.1111/1469-0691.12566. View

12.

Henao-Mejia J, Elinav E, Strowig T, Flavell R . Inflammasomes: far beyond inflammation. Nat Immunol. 2012; 13(4):321-4. DOI: 10.1038/ni.2257. View

13.

Matthaiou D, Christodoulopoulou T, Dimopoulos G . How to treat fungal infections in ICU patients. BMC Infect Dis. 2015; 15:205. PMC: 4419464. DOI: 10.1186/s12879-015-0934-8. View

14.

Chayakulkeeree M, Ghannoum M, Perfect J . Zygomycosis: the re-emerging fungal infection. Eur J Clin Microbiol Infect Dis. 2006; 25(4):215-29. DOI: 10.1007/s10096-006-0107-1. View

15.

Ocampo J, Fernandez Nunez L, Silva F, Pereyra E, Moreno S, Garre V . A subunit of protein kinase a regulates growth and differentiation in the fungus Mucor circinelloides. Eukaryot Cell. 2009; 8(7):933-44. PMC: 2708453. DOI: 10.1128/EC.00026-09. View

16.

Sypherd P, Borgia P, Paznokas J . Biochemistry of dimorphism in the fungus Mucor. Adv Microb Physiol. 1978; 18:67-104. DOI: 10.1016/s0065-2911(08)60415-4. View

17.

Muller M, Mentel M, van Hellemond J, Henze K, Woehle C, Gould S . Biochemistry and evolution of anaerobic energy metabolism in eukaryotes. Microbiol Mol Biol Rev. 2012; 76(2):444-95. PMC: 3372258. DOI: 10.1128/MMBR.05024-11. View

18.

Aranda A, del Olmo Ml M . Response to acetaldehyde stress in the yeast Saccharomyces cerevisiae involves a strain-dependent regulation of several ALD genes and is mediated by the general stress response pathway. Yeast. 2003; 20(8):747-59. DOI: 10.1002/yea.991. View

19.

Ramage G, Mowat E, Jones B, Williams C, Lopez-Ribot J . Our current understanding of fungal biofilms. Crit Rev Microbiol. 2009; 35(4):340-55. DOI: 10.3109/10408410903241436. View

20.

McIntyre M, Breum J, Arnau J, Nielsen J . Growth physiology and dimorphism of Mucor circinelloides (syn. racemosus) during submerged batch cultivation. Appl Microbiol Biotechnol. 2002; 58(4):495-502. DOI: 10.1007/s00253-001-0916-1. View