GENETIC BACKGROUND IMPACTS HOST RESPONSE TO BACTERIAL TOXINS CHALLENGE IN COLLABORATIVE CROSS MICE

Background: Sepsis and septic shock are the main cause of death in intensive care units, with mortality rates between 30-70%. Bacterial Toxins released from both gram-negative and gram-positive bacteria is considered as potent microbial mediators implicated in the pathogenesis of sepsis and septic shock. Previous investigations have shown different response to toxins among various inbred mouse strains, indicating that there is a genetic contribution in the response to these toxins. However, genes underlying these mapped loci remain unknown.

Aims: To examine the phenotypic response to bacterial toxins [lipopolysaccharide (LPS), Lipoteichoic acid (LTA) and Toxic Shock Syndrome Toxin -1 (TSST-1)] challenge in Collaborative Cross (CC) lines population which have high genetic diversity and are extremely powerful for high resolution mapping QTL.

Methods: In this study, we have used a unique genetic recourse population namely the Collaborative Cross (CC) mouse model. Total 176 mice of 15 CC lines were challenged with high dose (15 mg kg^-1) of LPS.in addition, 84 mice of 13 CC lines were challenged with high dose 50 (mg kg^-1) of LTA . After injecting mice were monitored for Mean survival time (MST), body weight loss (BWL) and rectal body temperature (RBT) at the following time points: 0, 2, 4, 6, 24, 30, 48, 54, 72 hours post LPS injection and 0,2, 4, 6, 24, 30, 48, 54, 72,96,120,144,168 hours post LTA injection .

Results: All mice challenged with the LPS showed shock symptoms, however One-way analysis of variation (ANOVA) was significant (P<0.05) for BWL, RBT and MST between the CC lines. Moreover, Sex effect was observed in MST as survival time was longer among females than males (p<0.05). Despite the high dose of LTA injected, no deaths during the challenge were recorded. However, ANOVA results indicate significant variability in response between the different CC lines both in body temperature and body weight

Conclusions: Our results together with heritability calculation suggest that there is a genetic effect on the susceptibility to septic shock and sepsis. In addition, females seem to be more resistant for septic shock.