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Klebsiella pneumoniae hijacks the Toll-IL-1R protein SARM1 in a type I IFN-dependent manner to antagonize host immunity

Summary Many bacterial pathogens antagonize host defense responses by translocating effector proteins into cells. It remains an open question how those pathogens not encoding effectors counteract anti-bacterial immunity. Here, we show that Klebsiella pneumoniae exploits the evolutionary conserved innate protein SARM1 to regulate negatively MyD88- and TRIF-governed inflammation, and the activation of the MAP kinases ERK and JNK. SARM1 is required for Klebsiella induction of interleukin-10 (IL-10) by fine-tuning the p38-type I interferon (IFN) axis. SARM1 inhibits the activation of Klebsiella-induced absent in melanoma 2 inflammasome to limit IL-1β production, suppressing further inflammation. Klebsiella exploits type I IFNs to induce SARM1 in a capsule and lipopolysaccharide O-polysaccharide-dependent manner via the TLR4-TRAM-TRIF-IRF3-IFNAR1 pathway. Absence of SARM1 reduces the intracellular survival of K. pneumoniae in macrophages, whereas sarm1-deficient mice control the infection. Altogether, our results illustrate an anti-immunology strategy deployed by a human pathogen. SARM1 inhibition will show a beneficial effect to treat Klebsiella infections.

E. Immunoblot analysis of phosphorylated p38 (P-p38), and tubulin levels in lysates of wild-type (WT) and tlr4 -/macrophages non-infected (NI) or infected with Kp52145 for the indicated time points.
F. Immunoblot analysis of phosphorylated p38 (P-p38), and tubulin levels in lysates of wild-type (WT) and tram -/trif -/macrophages non-infected (NI) or infected with Kp52145 for the indicated time points.
In all infections, after 1 h contact, the medium was replaced with medium containing gentamicin (100 µg/ml) to kill extracellular bacteria.
In panels A, B and G, values are presented as the mean ± SD of three independent experiments measured in duplicate. In panel C, values are presented as the mean ± SD of two independent experiments measured in duplicate. In panels D, E and F the images are representative of three independent experiments. In panel A and C, ****P ≤ 0.0001; * P≤ 0.05 for the indicated comparisons using one way-ANOVA with Bonferroni contrast for multiple comparisons test. In panel B, **P≤ 0.01 using unpaired t test. In panel G, ****P ≤ 0.0001 for the comparison between infected knockout and wild-type cells for 6 h; # P ≤ 0.0001 for the comparison between infected knock-out and wildtype cells for 16 h using one way-ANOVA with Bonferroni contrast for multiple comparisons test. In all infections, after 1 h contact, the medium was replaced with medium containing gentamicin (100 µg/ml) to kill extracellular bacteria.
In panels A, C and D values are presented as the mean ± SD of three independent experiments measured in duplicate. ****P ≤ 0.0001; ns, P > 0.05 for the indicated comparisons using one way-ANOVA with Bonferroni contrast for multiple comparisons test. In panel G, values are presented as the mean ± SD of three independent experiments measured in duplicate. **P≤ 0.01 using unpaired t test. In panels B, E and F, images are representative of three independent experiments. In all infections, after 1 h contact, the medium was replaced with medium containing gentamicin (100 µg/ml) to kill extracellular bacteria.
Values are presented as the mean ± SD of three independent experiments measured in triplicate.

macrophages.
A. Adhesion in wild-type (WT) and sarm1 -/macrophages. Cells were infected with Kp52145 for 30 min, wells were washed and bacteria were quantified by lysis, serial dilution and viable counting on LB agar plates.
B. Phagocytosis of Kp52145 by wild-type (WT) and sarm1 -/macrophages. Cells were infected for 30 min, wells were washed, and it was added medium containing gentamicin (100 µg/ml) to kill extracellular bacteria. After 30 min, cells were washed and bacteria were quantified by lysis, serial dilution and viable counting on LB agar plates.