Molecular Mechanisms For Tyramine Signals In The Regulation Of Avoidance Response To Candida Albicans In Caenorhabditis Elegans

Microbes profoundly influence the immune and metabolic physiology of host organisms.The nematode Caenorhabditis elegans,an experimental host,is helpful to dissect the molecular basis of interactions between host species and microorganisms.C.elegans exhibits diverse behaviors in response to bacteria,a nutrient source,and pathogens by activating conserved innate immune pathways and/or by aversive behaviors.Recognizing and distinguishing among pathogens or developing an avoidance behavior response have dramatic effects on survival of animals.So far,studies on aversive behavior to pathogens are mainly focused on Gram-positive or Gram-negative bacteria,and the model of the aversive behavior to pathogenic fungi has not been established in nematodes.The neurotransmitter tyramine plays a key role in the regulation of various behaviors in animals.However,the potential role of tyramine in regulating the aversive behavior to pathogenic fungi is still largely unclear.Thus,the aim for this thesis is to investigate the possible functions and the underlying molecular mechanisms for the involvement of tyrosine decarboxylase of TDC-1 and tyramine receptor(s)in the regulation of the aversive behavior response to fungal infection in C.elegans.Mutation of tdc-1 caused severe defect in the aversive behavior response to C.albicans SC5314 infection.Meanwhile,exogenous tyramine significantly enhanced the aversive behavior.After TDC-1::GFP transgenic nematode were infected for 4 hours to 24 hours,the expression of TDC-1:: GFP was dramatically up-regulated.Tissue-specific rescue assay showed that TDC-1 could play a key role in the aversive behavior in RIM interneurons.During the aversive behavior response to C.albicans,GLR-1(a AMPA ionotropic glutamate receptor)acted upsteam of a transcription factor LIM-4 to regulate the function of TDC-1 in RIM neurons,which formed a signaling cascade of GLR-1-LIM-4-TDC-1 for the control of aversive behavior.TDC-1 further acted upstream of NKAT-1,a kynurenine aminotransferase III,and a neuropeptide FLP-18 to regulate the aversive behavior.The released neuropeptide FLP-18 might further activate NPR-1,a G protein-coupled receptor,in SAA interneurons to regulate the aversive behavior.Therefore,the signaling cascade of TDC-1-NKAT-1-FLP-18-NPR-1 was identified for the function of tyramine signal in the regulation of aversive behavior response to C.albicans SC5314.Tyramine signals normally function by activating the corresponding receptors.Among the known 3 tyramine receptors,deletion mutation of ser-2 caused the defect in aversive behavior to C.albicans SC5314.After C.albicans infection for 12 hours,the expression level of SER-2::GFP was significantly up-regulated in AIY interneurons.Tissue-specific rescue assay showed that SER-2 could function in AIY interneurons.The downstream target of SER-2 was identified as FAX-1,a conserved nuclear receptor,during the control of the aversive behavior response to fungal infection.FAX-1 further acted upsteam of NCS-1,a neuronal calcium sensing protein,to regulate the aversive behavior to C.albicans.In conclusion,the evidence presented in this study demonstrate the importance of tyramine signals in the regulation of aversive behavior response to fungal infection.On one hand,our results revealed that tyrosine decarboxylase TDC-1 and its receptor SER-2 play a key role in the control of aversive behavior to C.albicans.Meanwhile,we also identified a signaling cascade of GLR-1-LIM-4-TDC-1-NKAT-1-FLP-18-NPR-1,which suggests that tyramine may modulate the aversive behavior to fungal infection by activating neuropeptide FLP-18 in the RIM-SAA neuronal circuit.Our results will deepen our understanding the molecular mechanisms and neuronal circuit of aversive response to fungal infection.Our data will provide a new perspective for the role of tyramine signals in the regulation of host-microbe interactions.