title: Sequence variations and protein expression levels of the two immune evasion proteins Gpm1 and Pra1 influence virulence of clinical Candida albicans isolates.
abstract: Candida albicans, the important human fungal pathogen uses multiple evasion strategies to control, modulate and inhibit host complement and innate immune attack. Clinical C. albicans strains vary in pathogenicity and in serum resistance, in this work we analyzed sequence polymorphisms and variations in the expression levels of two central fungal complement evasion proteins, Gpm1 (phosphoglycerate mutase 1) and Pra1 (pH-regulated antigen 1) in thirteen clinical C. albicans isolates. Four nucleotide (nt) exchanges, all representing synonymous exchanges, were identified within the 747-nt long GPM1 gene. For the 900-nt long PRA1 gene, sixteen nucleotide exchanges were identified, which represented synonymous, as well as non-synonymous exchanges. All thirteen clinical isolates had a homozygous exchange (A to G) at position 73 of the PRA1 gene. Surface levels of Gpm1 varied by 8.2, and Pra1 levels by 3.3 fold in thirteen tested isolates and these differences influenced fungal immune fitness. The high Gpm1/Pra1 expressing candida strains bound the three human immune regulators more efficiently, than the low expression strains. The difference was 44% for Factor H binding, 51% for C4BP binding and 23% for plasminogen binding. This higher Gpm1/Pra1 expressing strains result in enhanced survival upon challenge with complement active, Factor H depleted human serum (difference 40%). In addition adhesion to and infection of human endothelial cells was increased (difference 60%), and C3b surface deposition was less effective (difference 27%). Thus, variable expression levels of central immune evasion protein influences immune fitness of the human fungal pathogen C. albicans and thus contribute to fungal virulence.
authors.affiliation: Department of Infection Biology, Leibniz-Institute for Natural Product Research and Infection Biology, Hans-Knöll-Institute, Jena, Germany.
authors.forename: Shanshan
authors.initials: S
authors.lastname: Luo
authors.affiliation: Friedrich-Schiller-University Hospital, Clinic of Dermatology and Allergology, Jena, Germany.
authors.forename: Uta-Christina
authors.initials: UC
authors.lastname: Hipler
authors.affiliation: Department of Infection Biology, Leibniz-Institute for Natural Product Research and Infection Biology, Hans-Knöll-Institute, Jena, Germany.
authors.forename: Christin
authors.initials: C
authors.lastname: Münzberg
authors.affiliation: Department of Infection Biology, Leibniz-Institute for Natural Product Research and Infection Biology, Hans-Knöll-Institute, Jena, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Skerka
authors.affiliation: Department of Infection Biology, Leibniz-Institute for Natural Product Research and Infection Biology, Hans-Knöll-Institute, Jena, Germany; Friedrich-Schiller-University, Jena, Germany.
authors.forename: Peter F
authors.initials: PF
authors.lastname: Zipfel
mesh_terms: D019943:Amino Acid Substitution; D002176:Candida albicans / Q000235:genetics* / Q000276:immunology* / Q000302:isolation & purification / Q000472:pathogenicity; D002177:Candidiasis / Q000276:immunology* / Q000382:microbiology*; D003179:Complement C3b / Q000378:metabolism; D050716:Complement C4b-Binding Protein / Q000378:metabolism; D017242:Complement Factor H / Q000378:metabolism; D005656:Fungal Proteins / Q000235:genetics*; D014644:Genetic Variation; D006801:Humans; D057131:Immune Evasion / Q000235:genetics*; D050296:Microbial Viability / Q000235:genetics / Q000276:immunology; D010736:Phosphoglycerate Mutase / Q000235:genetics*; D010958:Plasminogen / Q000378:metabolism; D011485:Protein Binding / Q000276:immunology; D017422:Sequence Analysis, DNA; D014774:Virulence / Q000235:genetics; D037521:Virulence Factors / Q000235:genetics*
chemical_list: D050716:Complement C4b-Binding Protein; D005656:Fungal Proteins; C088491:PRA1 protein, Candida albicans; D037521:Virulence Factors; D003179:Complement C3b; D017242:Complement Factor H; D010958:Plasminogen; C526914:Gpm1 protein, Candida albicans; D010736:Phosphoglycerate Mutase