Boosted TCA cycle enhances survival of zebrafish to Vibrio alginolyticus infection

Abstract

Vibrio alginolyticus is a waterborne pathogen that infects a wide variety of hosts including fish and human, and the outbreak of this pathogen can cause a huge economic loss in aquaculture. Thus, enhancing host's capability to survive from V. alginolyticus infection is key to fighting infection and this remains still unexplored. In the present study, we established a V. alginolyticus-zebrafish interaction model by which we explored how zebrafish survived from V. alginolyticus infection. We used GC-MS based metabolomic approaches to characterize differential metabolomes between survival and dying zebrafish upon infection. Pattern recognition analysis identified the TCA cycle as the most impacted pathway. The metabolites in the TCA cycle were decreased in the dying host, whereas the metabolites were increased in the survival host. Furthermore, the enzymatic activities of the TCA cycle including pyruvate dehydrogenase (PDH), α-ketoglutaric dehydrogenase (KGDH) and succinate dehydrogenase (SDH) also supported this conclusion. Among the increased metabolites in the TCA cycle, malic acid was the most crucial biomarker for fish survival. Indeed, exogenous malate promoted zebrafish survival in a dose-dependent manner. The corresponding activities of KGDH and SDH were also increased. These results indicate that the TCA cycle is a key pathway responsible for the survival or death in response to infection caused by V. alginolyticus, and highlight the way on development of metabolic modulation to control the infection.

Reduced redox‐dependent mechanism and glucose‐mediated reversal in gentamicin‐resistant Vibrio alginolyticus

“…Vaccines stimulate the host's active immunity against bacterial pathogens (Guo et al ., ; Cheng et al ., ; Peng et al ., ). Metabolome‐reprogramming molecules reprogram host's anti‐infective metabolome that enhances innate immune responses (Yang et al ., ; Cheng et al ., ; Jiang et al ., ). Phage therapy and antibacterial peptides attack bacterial cells directly (Pires et al ., ; Zhang et al ., ).…”

Malate enhances survival of zebrafish against Vibrio alginolyticus infection in the same manner as taurine

“…These include the specific killing of pathogenic bacteria (bacteriophages and inhibition of chromosome II replication in vibrios), growth inhibition (short-chain fatty acids and polyhydroxyalkanoates), inhibition of virulence gene expression (interfering with the regulation of virulence factor expression and specifically inhibiting a certain virulence factor), and reprogramming of the antibioticresistant metabolome (reverting bacterial antibiotic resistance to uptake antibiotics) [35,37,38]. Recently, we have developed reprogramming metabolomics to modulate the host metabolome against bacterial infection without the use of antibiotics [19,20], where malate is identified as a crucial reprogramming molecule [28]. Malate boosts the TCA cycle to enhance the survival of zebrafish to V. alginolyticus infection [28] but the underlying mechanism is unknown.…”

“…Recently, we have developed reprogramming metabolomics to modulate the host metabolome against bacterial infection without the use of antibiotics [19,20], where malate is identified as a crucial reprogramming molecule [28]. Malate boosts the TCA cycle to enhance the survival of zebrafish to V. alginolyticus infection [28] but the underlying mechanism is unknown. The present study explores the mechanisms by which malate reprograms the fish's metabolome to fight against V. alginolyticus infection.…”

“…These results indicate that the elevated taurine was attributed to the metabolic transformation from the activated TCA cycle. Then, we tested whether taurine provides protection against infection caused by V. alginolyticus in zebrafish as malate did [28]. Thus, 12.5 μg, 25 μg, 50 μg, 100 μg, 300 μg, or 600 μg taurine was injected into zebrafish followed by V. alginolyticus challenge.…”

“…The metabolite was identified as the most crucial biomarker that differentiates the infective metabolome from the antiinfective metabolome. Exogenous malate potentiated zebrafish to combat the bacterium and thereby elevated zebrafish survival [28]. However, how malate reprograms the infective metabolome and the relationship between the reprogramming and innate immune response are unknown.…”