Susceptibility to anthrax lethal toxin is controlled by three linked quantitative trait loci.
Anthrax lethal toxin (LT) is the principal virulence factor associated with lethal pathologies following infection with Bacillus anthracis. Macrophages are the primary effector cells mediating lethality since macrophage-depleted mice are resistant to LT challenge. Recently, Ltxs1, the gene controlling differential susceptibility of murine macrophages to cytolysis following in vitro exposure to LT, was identified as Kif1c. To directly assess the in vivo role of Kif1c alleles in mortality, we studied a panel of interval-specific recombinant congenic lines carrying various segments of central chromosome 11 derived from LT-resistant DBA/2 mice on the LT-susceptible BALB/c background. The results of this study reveal that mortality is controlled by three linked quantitative trait loci (QTL): Ltxs1/Kif1c (42-43 cM), Ltxs2 (35-37 cM), and Ltxs3 (45-47 cM). The Ltxs3 interval encompasses Nos2, which is an attractive candidate gene for Ltxs3. In this regard, we demonstrate that selective, pharmacologically based inhibition of Nos2 activity in vivo partially overrides genetic resistance to LT and that Nos2 expression as determined by reverse transcription-polymerase chain reaction differs significantly between DBA/2 and BALB/c macrophages. Additionally, to recapitulate dominant resistance to mortality as seen in (BALB/c x DBA/2) F(1) hybrids, DBA/2 alleles are required at all three QTL.
Department of Microbiology, University of Illinois, Urbana, IL, USA.
Ryan D
RD
McAllister
Yogendra
Y
Singh
Wendy D
WD
du Bois
Michael
M
Potter
Thomas
T
Boehm
Nathan D
ND
Meeker
Parley D
PD
Fillmore
Lisa M
LM
Anderson
Matthew E
ME
Poynter
Cory
C
Teuscher
D000818:Animals; D000942:Antigens, Bacterial; D001427:Bacterial Toxins / Q000235:genetics* / Q000494:pharmacology; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D016547:Kinesins / Q000235:genetics; D008297:Male; D051379:Mice; D020297:Mice, Congenic; D019001:Nitric Oxide Synthase / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D040641:Quantitative Trait Loci / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013045:Species Specificity
D000942:Antigens, Bacterial; D001427:Bacterial Toxins; C485246:Kif1c protein, mouse; C030325:anthrax toxin; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D016547:Kinesins