Research Project: Tolerance Mechanisms Through Innovative Population Analysis
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- Andrews-Polymenis, Helene
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Salmonella typhimurium
Overall, 32 CC lines were screened in the initial 1-week experiments. Of those 32 lines, 14 were susceptible and succumbed to infection before 7 days and 18 had >50% survival and were infected over a 3-week period. 6 of these lines displayed delayed susceptibility (succumbed to infection after 1 week but before 3 weeks), 4 were characterized as tolerant (CC002, CC017, CC043, and CC072), and 5 had resistant phenotypes (CC015, CC024, CC051, CC057, CC058). We were unable to determine the phenotype on the remaining 3 lines due to insufficient number of mice. Tolerance was defined as surviving to 3 weeks and
maintaining at least 104 CFU in spleen and liver. Resistant mice had less than 104 and/or significantly reduced the bacterial load in spleen and liver from 1 week to 3 weeks. (Figures 1-4). Resistant mice also appeared to repair tissue damage by 3 weeks while tolerant did not (Figure 5).
Tolerance appears to be heterogenous – there is not necessarily one pathway that determines tolerance across all lines. Some possible theories include preventing tissue damage (CC043) or having much more productive healthy cells in spleen and liver to make up for damaged cells (CC072). CC072 is the most interesting tolerant line because the mice significantly increase their colonization at day 21 and show a trend toward increasing tissue
damage while surviving. Each line appears to have a unique CBC and cytokines profile, which speaks to the heterogeneity of response to infection. However, this relationship needs to be probed more.
NRAMP was not a great determinant of survival as previously thought: 10/14 susceptible lines from the 1-week experiments had a wild type allele and CC045 had a mutated allele and survived to day 7. Mutated NRAMP has historically led to susceptibility before day 7 while wild type has led to resistance. Mutated NRAMP lines include CC021, CC031, CC032 (heterozygous), CC042, CC045, and CC061. Histologically, there is extraordinarily little tissue damage in the gut (ileum, cecum, colon) and most of the damage is in the systemic organs (liver and spleen). This suggests that the systemic phase of infection is what is determining if mice survive or not. The mice also do not display the typical gastrointestinal symptoms, which further supports this. There is a sex difference found in the response to infections in two of the lines. CC027 females make it to day 7, while none of the males do and CC013 females make it to day 6 while
males only make it to day 4. One line (CC013) get a head tilt after infection, which suggests there may be some salmonella in the brain, which is not a usual place for salmonella to travel There is a significant QTL peak when aspiration is put in. The CC017 is the most prone to aspiration, but only when gavaged with salmonella, never when gavaged with PBS or heavy
metals. This suggests that certain CC lines are susceptible to pulmonary Salmonella infections and/or may have reflux.
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