Molecular Mechanism Underlying The Counter Balance Between Avoidance And Immunne Response In Caenorhabditis Elegans

Nervous system and immune system play important roles in mainteining the life of animal. A wealth of previous investigations has shown that these two systems are closely related. It has also been suggested that under some specific physiological or pathological conditions, a variety of factors, such as the different stress or psychological states, may cause the changes in nervous system, and affect immune responses. However, the limitations of clinical research, including sample sizes, control group composition, individual differences and the complexity of the mammalian brain, hinder the investigations underlying the molecular mechanisms of the relationship between nervous system and immune system.Immunity and avoidance behavior are the two major defense responses of Caenorhabditis elegans against the infection of pathogenic bateria. They have been demonstrated to be regulated by the nevous system and react coordinately during pathogenic infection. The current studies focus on the separate signal transduction pathway associated with of the immunity or avoidance. But the research about the interaction of aversion and immunity is in infancy and many questions in this area are remained unclear. For example, how do the nematodes protect themselves by the two mechanisms? Whether there is any coadjustment or inter-constraint between the two protection strategies? Is there any signalling pathway that regulates the relationship between the two systems?To understand the above problems, we here used C. elegans as a model, designed the two different conditions (after preexposure or without preexposure when pathogenic infection). Our results implied that the counterbalance existed between the immune response and avoidance behavior in C. elegans, and reveals the molecular mechanism underlying the balance.The main results were as follows:1. The counterbalance exists between two major defense strategies of immunity and avoidance.Through the assay of avoidance index and survival rates, it was showed that the survival rates in preexposure group would significantly reduce compared with the group without training, contrary to the obvious increase in avoidance index. Hence, it is determined that the immune response and escape behavior is balanced. 2. The balance between aversion and immunity is mediated by chemosensory neurons AWB and ADF.The mutants with lim-4gene disruption, AWB-killed neuron and ADF-killed neuron represented the similar survival rates and avoidance index with the group without preexposure even though they had been pre-exposed to the pathogenic bacterium, suggesting that the chemosensory neurons AWB and ADF should be involved in the regulation of counterbalance between nervous system and immunity.3. Serotonin and dopamine are the neurotransmitter to regulate the interaction between avoidance and immunity.AWB and ADF chemosensory neurons could control the synthesis of both serotonin and dopamine, and the defect of both serotonin and dopamine affected the balance between immunity and avoidance. Furthermore, the defect of either serotonin or dopamine alone had no effects on the balance of escape behavior and immune response.4. Serotonin receptors (SER-4, SER-7) and dopamine receptors (DOP-1, DOP-2, DOP-3) participate in regulating the counter balance between immunity and aversion.Serotonin receptors (SER-4, SER-7) and all dopamine receptors (DOP-1, DOP-2, DOP-3) were determined their roles in regulating the balance between immunity and avoidance, and it was found that they could differently function except for SER-1. Meanwhile, the rescue of dop-3in the lim-4mutant was sufficient to restore to the defects of the counterbalance, further confirming that AWB and ADF chemosensory neurons mediate the balance between aversion and immunity by serotonin and dopamine.5. DAF-2/DAF-16pathway enhances the avoidance behavior and suppresses the immune response after preexposure.Compared to the wild type, mutation of the signaling pathway daf-2/daf-16has significantly disturbed the balance between immunity and avoidance, suggesting the involvement of the downstream DAF-2/DAF-16pathway.Realtime PCR assay was used to further determine the expressional levels of downstream target genes transcribed by DAF-16. Our result demonstrated that those target genes of DAF-16were obviously inhibited after training. But in the mutants of Alim-4, AWB-killed neuron, ADF-killed neuron,△dop-3, and△daf-2, the mRNA levels of target genes of DAF-16were quite different from the wild type. The data suggested that the balance should be regulated by DAF-2/DAF-16pathway, which functions downstream of neural signalling.The innovations of our investigation are concluded as follows:1. It is firstly revealed that the counterbalance exists between the two main strategies of aversion and immunity when C.elegans response to pathogenic bacteria.2. It is firstly confirmed that AWB and ADF chemosensory neurons regulate the two protective strategies mediated by the functions of both serotonin and dopamine.3. DAF-2/DAF-16is the downstream signaling pathway to regulate the balance of avoidance behavior and immune response.