PUBLICATION
A predicted Francisella tularensis DXD-motif glycosyltransferase blocks immune activation
- Authors
- Nau, G.J., Horzempa, J., O'Dee, D., Brown, M.J., Russo, B.C., Hernandez, A., Dillon, S.T., Cheng, J., Kane, L.P., Sanker, S., Hukriede, N.A.
- ID
- ZDB-PUB-190719-13
- Date
- 2019
- Source
- Virulence 10: 643-656 (Journal)
- Registered Authors
- Hukriede, Neil
- Keywords
- , NFκB, bacterial pathogenesis, glycosyltransferase, host-pathogen interactions, innate immunity, macrophage
- MeSH Terms
-
- Animals
- Bacterial Proteins/genetics
- Bacterial Proteins/immunology*
- Cytokines
- Female
- Francisella tularensis/enzymology*
- Francisella tularensis/genetics
- Glycosyltransferases/genetics
- Glycosyltransferases/immunology*
- Host-Pathogen Interactions*
- Humans
- Immunity, Innate
- Jurkat Cells
- Macrophages/microbiology
- Mice, Inbred C57BL
- Moths
- Mutation
- Tularemia/immunology
- Tularemia/microbiology
- Virulence
- Zebrafish
- PubMed
- 31314675 Full text @ Virulence
Citation
Nau, G.J., Horzempa, J., O'Dee, D., Brown, M.J., Russo, B.C., Hernandez, A., Dillon, S.T., Cheng, J., Kane, L.P., Sanker, S., Hukriede, N.A. (2019) A predicted Francisella tularensis DXD-motif glycosyltransferase blocks immune activation. Virulence. 10:643-656.
Abstract
Pathogens enhance their survival during infections by manipulating host defenses. Francisella tularensis evades innate immune responses, which we have found to be dependent on an understudied gene ybeX (FTL_0883/FTT_0615c). To understand the function of YbeX, we sought protein interactors in F. tularensis subsp. holarctica live vaccine strain (LVS). An unstudied Francisella protein co-immunoprecipitated with recombinant YbeX, which is a predicted glycosyltransferase with a DXD-motif. There are up to four genomic copies of this gene with identical sequence in strains of F. tularensis pathogenic to humans, despite ongoing genome decay. Disruption mutations were generated by intron insertion into all three copies of this glycosyltransferase domain containing gene in LVS, gdcA1-3. The resulting strains stimulated more cytokines from macrophages in vitro than wild-type LVS and were attenuated in two in vivo infection models. GdcA was released from LVS during culture and was sufficient to block NF-κB activation when expressed in eukaryotic cells. When co-expressed in zebrafish, GdcA and YbeX were synergistically lethal to embryo development. Glycosyltransferases with DXD-motifs are found in a variety of pathogens including NleB, an Escherichia coli type-III secretion system effector that inhibits NF-κB by antagonizing death receptor signaling. To our knowledge, GdcA is the first DXD-motif glycosyltransferase that inhibits NF-κB in immune cells. Together, these findings suggest DXD-motif glycosyltransferases may be a conserved virulence mechanism used by pathogenic bacteria to remodel host defenses.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping