Exogenous l-Valine Promotes Phagocytosis to Kill Multidrug-Resistant Bacterial Pathogens.
The emergence of multidrug-resistant bacteria presents a severe threat to public health and causes extensive losses in livestock husbandry and aquaculture. Effective strategies to control such infections are in high demand. Enhancing host immunity is an ideal strategy with fewer side effects than antibiotics. To explore metabolite candidates, we applied a metabolomics approach to investigate the metabolic profiles of mice afterKlebsiella pneumoniaeinfection. Compared with the mice that died fromK. pneumoniaeinfection, mice that survived the infection displayed elevated levels of l-valine. Our analysis showed that l-valine increased macrophage phagocytosis, thereby reducing the load of pathogens; this effect was not only limited toK. pneumoniaebut also includedEscherichia coliclinical isolates in infected tissues. Two mechanisms are involved in this process: l-valine activating the PI3K/Akt1 pathway and promoting NO production through the inhibition of arginase activity. The NO precursor l-arginine is necessary for l-valine-stimulated macrophage phagocytosis. The valine-arginine combination therapy effectively killedK. pneumoniaeand exerted similar effects in other Gram-negative (E. coliandPseudomonas aeruginosa) and Gram-positive (Staphylococcus aureus) bacteria. Our study extends the role of metabolism in innate immunity and develops the possibility of employing the metabolic modulator-mediated innate immunity as a therapy for bacterial infections.
Center for Proteomics, State Key Laboratory of Bio-Control, School of Life Sciences, Guangdong Province Key Laboratory for Pharmaceutical Functional Genes, Sun Yat-sen University , Guangzhou , China.
Xin-Hai
XH
Chen
Center for Proteomics, State Key Laboratory of Bio-Control, School of Life Sciences, Guangdong Province Key Laboratory for Pharmaceutical Functional Genes, Sun Yat-sen University , Guangzhou , China.
Shi-Rao
SR
Liu
Center for Proteomics, State Key Laboratory of Bio-Control, School of Life Sciences, Guangdong Province Key Laboratory for Pharmaceutical Functional Genes, Sun Yat-sen University , Guangzhou , China.
Bo
B
Peng
Center for Proteomics, State Key Laboratory of Bio-Control, School of Life Sciences, Guangdong Province Key Laboratory for Pharmaceutical Functional Genes, Sun Yat-sen University , Guangzhou , China.
Dan
D
Li
Center for Proteomics, State Key Laboratory of Bio-Control, School of Life Sciences, Guangdong Province Key Laboratory for Pharmaceutical Functional Genes, Sun Yat-sen University , Guangzhou , China.
Zhi-Xue
ZX
Cheng
Third Affiliated Hospital of Sun Yat-sen University , Guangzhou , China.
Jia-Xin
JX
Zhu
Center for Proteomics, State Key Laboratory of Bio-Control, School of Life Sciences, Guangdong Province Key Laboratory for Pharmaceutical Functional Genes, Sun Yat-sen University , Guangzhou , China.
Song
S
Zhang
Center for Proteomics, State Key Laboratory of Bio-Control, School of Life Sciences, Guangdong Province Key Laboratory for Pharmaceutical Functional Genes, Sun Yat-sen University , Guangzhou , China.
Yu-Ming
YM
Peng
Center for Proteomics, State Key Laboratory of Bio-Control, School of Life Sciences, Guangdong Province Key Laboratory for Pharmaceutical Functional Genes, Sun Yat-sen University , Guangzhou , China.
Hui
H
Li
Third Affiliated Hospital of Sun Yat-sen University , Guangzhou , China.
Tian-Tuo
TT
Zhang
Center for Proteomics, State Key Laboratory of Bio-Control, School of Life Sciences, Guangdong Province Key Laboratory for Pharmaceutical Functional Genes, Sun Yat-sen University , Guangzhou , China.
Xuan-Xian
XX
Peng
bacterial infections; l-arginine; l-valine; nitric oxide; phagocytosis