[ODP28] 6. Host defense -b. Acquired immunity, vaccines and prevention and control of infections

[ODP-177] Francisella tularensis escapes from host immunity by metabolic reprogramming

Kensuke Shibata^1,2,3, Takashi Shimizu⁴, Masahisa Watarai⁴, Mutsunori Shirai¹ (¹Dept. Microbiol. Immunol., Yamaguchi Univ., ²Dept. Ophthal., Sch. Med., Kyushu Univ., ³Dept. Mol. Immunol., Res. Inst. Microbial Diseases, Osaka Univ., ⁴Joint Faculty of Vet. Med., Yamaguchi Univ.)

Intracellular pathogens inactivate many of metabolic pathway-related genes during evolution from free-living bacteria, yet pathogenic roles of the altered metabolic programs in host immunity are poorly understood. Here, we show that a pathogenic strain Francisella tularensis subsp. tularensis (FT) has five amino acid substitutions of ribD in the riboflavin (RF) synthetic pathway; ribD is a converting enzyme responsible for generating metabolites recognized by mucosal associated invariant T (MAIT) cells. Metabolites from a free-living strain Francisella tularensis subsp. novicida (FN) activated MAIT cells in a T cell receptor (TCR)-dependent manner, whereas introduction of FT-type ribD to the free-living strain FN attenuated the activity. Furthermore, H80C but not other substitutions of ribD in the pathogenic FT strain was responsible for the effect. Intranasal infection mouse model showed that the FT-type ribD-expressing FN impaired Th1-type MAIT cell expansion and bacterial clearance resulting in shortened survival compared to the free-living strain FN. These results demonstrate that Francisella tularensis acquires pathogenicity by alteration of metabolic programs during evolution.