Journal article
Systematic Genetic Interaction Analysis Identifies a Transcription Factor Circuit Required for Oropharyngeal Candidiasis
mBio, Vol.13(1), pp.e0344721-e0344721
02/22/2022
DOI: 10.1128/mbio.03447-21
PMCID: PMC8749425
PMID: 35012341
Abstract
The pathology of oral candidiasis has features of biofilm formation, a well-studied process
in vitro
. Based on that analogy, we hypothesized that the network of transcription factors that regulates
in vitro
biofilm formation has similarities and differences during oral infection.
ABSTRACT
Oropharyngeal candidiasis (OPC) is a common infection that complicates a wide range of medical conditions and can cause either mild or severe disease depending on the patient. The pathobiology of OPC shares many features with candidal biofilms of abiotic surfaces. The transcriptional regulation of
C. albicans
biofilm formation on abiotic surfaces has been extensively characterized and involves six key transcription factors (Efg1, Ndt80, Rob1, Bcr1, Brg1, and Tec1). To determine if the
in vitro
biofilm transcriptional regulatory network also plays a role in OPC, we carried out a systematic genetic interaction analysis in a mouse model of
C. albicans
OPC. Whereas each of the six transcription factors are required for
in vitro
biofilm formation, only three homozygous deletion mutants (
tec1
ΔΔ,
bcr1
ΔΔ, and
rob1
ΔΔ) and one heterozygous mutant (
tec1
Δ/
TEC1
) have reduced infectivity in the mouse model of OPC. Although single mutants (heterozygous or homozygous) of
BRG1
and
EFG1
have no effect on fungal burden, double heterozygous and homozygous mutants have dramatically reduced infectivity, indicating a critical genetic interaction between these two transcription factors during OPC. Using epistasis analysis, we have formulated a genetic circuit, [
EFG1
+
BRG1
]→
TEC1
→
BCR1
, that is required for OPC infectivity and oral epithelial cell endocytosis. Surprisingly, we also found transcription factor mutants with
in vitro
defects in filamentation, such as
efg1
ΔΔ,
rob1
ΔΔ, and
brg1
ΔΔ filament, during oral infection and that reduced filamentation does not correlate with infectivity. Taken together, these data indicate that key
in vitro
biofilm transcription factors are involved in OPC but that the network characteristics and functional connections during infection are distinct from those observed
in vivo
.
IMPORTANCE
The pathology of oral candidiasis has features of biofilm formation, a well-studied process
in vitro
. Based on that analogy, we hypothesized that the network of transcription factors that regulates
in vitro
biofilm formation has similarities and differences during oral infection. To test this, we employed the first systematic genetic interaction analysis of
C. albicans
in a mouse model of oropharyngeal infection. This revealed that the six regulators involved in
in vitro
biofilm formation played roles
in vivo
but that the functional connections between factors were quite distinct. Surprisingly, we also found that while many of the factors are required for filamentation
in vitro
, none of the transcription factor deletion mutants was deficient for this key virulence trait
in vivo
. These observations clearly demonstrate that
C. albicans
regulates key aspects of its biology differently
in vitro
and
in vivo
.
Details
- Title: Subtitle
- Systematic Genetic Interaction Analysis Identifies a Transcription Factor Circuit Required for Oropharyngeal Candidiasis
- Creators
- Norma V. Solis - UCLA Medical CenterRohan S. Wakade - University of IowaVirginia E. Glazier - Niagara UniversityTomye L. Ollinger - University of IowaMelanie Wellington - University of IowaAaron P. Mitchell - University of GeorgiaScott G. Filler - University of California, Los AngelesDamian J. Krysan - Roy J. and Lucille A. Carver College of Medicine
- Contributors
- Deborah A. Hogan (Editor)
- Resource Type
- Journal article
- Publication Details
- mBio, Vol.13(1), pp.e0344721-e0344721
- DOI
- 10.1128/mbio.03447-21
- PMID
- 35012341
- PMCID
- PMC8749425
- NLM abbreviation
- mBio
- ISSN
- 2150-7511
- eISSN
- 2150-7511
- Grant note
- DOI: 10.13039/100000060, name: HHS | NIH | National Institute of Allergy and Infectious Diseases, award: 5R01AI133409; DOI: 10.13039/100000060, name: HHS | NIH | National Institute of Allergy and Infectious Diseases, award: 5R01DE026600
- Language
- English
- Date published
- 02/22/2022
- Academic Unit
- Microbiology and Immunology; Stead Family Department of Pediatrics; Infectious Disease (Pediatrics)
- Record Identifier
- 9984297324602771
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