Cutting edge: A common polymorphism impairs cell surface trafficking and functional responses of TLR1 but protects against leprosy.
TLRs constitute an essential family of pattern recognition molecules that, through direct recognition of conserved microbial components, initiate inflammatory responses following infection. In this role, TLR1 enables host responses to a variety of bacteria, including pathogenic species of mycobacteria. In this study, we report that I602S, a common single nucleotide polymorphism within TLR1, is associated with aberrant trafficking of the receptor to the cell surface and diminished responses of blood monocytes to bacterial agonists. When expressed in heterologous systems, the TLR1 602S variant, but not the TLR1 602I variant, exhibits the expected deficiencies in trafficking and responsiveness. Among white Europeans, the 602S allele represents the most common single nucleotide polymorphism affecting TLR function identified to date. Surprisingly, the 602S allele is associated with a decreased incidence of leprosy, suggesting that Mycobacterium leprae subverts the TLR system as a mechanism of immune evasion.
Johnson
Christopher M
CM
Department of Microbiology, College of Medicine, University of Illinois, 601 South Goodwin Avenue, Urbana, IL 61801, USA.
Lyle
Elizabeth A
EA
Omueti
Katherine O
KO
Stepensky
Vitaly A
VA
Yegin
Olcay
O
Alpsoy
Erkan
E
Hamann
Lutz
L
Schumann
Ralf R
RR
Tapping
Richard I
RI
D000483:Alleles; D019943:Amino Acid Substitution; D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism*; D002478:Cells, Cultured; D005787:Gene Frequency; D006720:Homozygote; D006801:Humans; D007532:Isoleucine / Q000737:chemistry / Q000235:genetics; D007918:Leprosy / Q000235:genetics*; D009000:Monocytes / Q000276:immunology; D009166:Mycobacterium leprae / Q000276:immunology; D020641:Polymorphism, Single Nucleotide; D021381:Protein Transport; D012694:Serine / Q000737:chemistry / Q000235:genetics; D051194:Toll-Like Receptor 1 / Q000032:analysis / Q000235:genetics* / Q000378:metabolism*
D051194:Toll-Like Receptor 1; D007532:Isoleucine; D012694:Serine