Wild-derived allele of Tmem173 potentiates an alternate signaling response to cytosolic DNA.
Abstract: The cellular
recognition of cytosolic DNA is critical for maintaining homeostasis and to signal
warnings to prevent the spread of pathogens such as HSV1 or Listeria. Inborn mutations
in the human population determine the susceptibility or ability to clear infection.
Mouse models of infectious disease are an invaluable resource for the study of these
mechanisms of disease progression... read more. However, classical laboratory mouse strains do not
always recapitulate the diversity in immune responses found in the human population.
Wild derived mice are an excellent source of genomic and phenotype diversity in the lab.
Herein, we report and characterize phenotype variations in the wild-derived mouse strain
MOLF/Ei and classical lab mouse strain in interferon stimulated gene induction to
cytosolic DNA species. Using forward genetic analysis, we identified multiple loci that
confer attenuated IFNβ production in MOLF/Ei macrophages to pathogen derived
cytosolic di-nucleotides. Fine mapping of a major locus of linkage revealed a novel
polymorphic allele of Tmem173 (STING). The MOLF allele of Tmem173 produces a protein
with multiple amino acid changes, and an internal 6 amino acid deletion. Most of these
amino acid changes are confined to the understudied N-terminus. These polymorphisms in
MOLF STING altogether confer a lack of induction of the IFNβ promoter in an
overexpression assay that seems to be attributed to the most N-terminal proximal
mutations. The loss-of-function of MOLF STING is inherited in macrophages of C57Bl/6
mice congenic for the MOLF Tmem173 allele. C57Bl/6 macrophages congenic for MOLF STING
display a shifted interferon signal profile in response to different c-di-nucleotides
when compared to wild-type C57Bl/6. Furthermore, expression of MOLF STING in STING-/-
MEFs show attenuated trafficking of MOLF STING after c-di-nucleotide activation compared
to B6 STING. Several, human alleles of STING confer a loss-of-function or
gain-of-function phenotype that may dramatically affect immunity. The study of this
novel allele in mice will aid in the mechanistic study the STING pathway that has
recently garnered much attention as being central to the response to cytosolic
Thesis (Ph.D.)--Tufts University, 2016.
Submitted to the Dept. of Immunology.
Advisor: Alexander Poltorak.
Committee: Brigitte Huber, Ralph Isberg, Joan Mecsas, Cheleste Thorpe, and Ann Marshak-Rothstein.
Keyword: Immunology.read less