A role of sympathetic nervous system in immunomodulation of early experimental African trypanosomiasis

African trypanosomiasis or sleeping sickness is a protozoan disease prevalent in Sub-saharan Africa. It is caused by the genus Trypanosoma and occurs in humans and animals and is transmitted by infected tsetse flies. Trypanosoma brucei (T b.) rhodesiense and T b. gambiense cause human African tryponosomiasis (HAT), while T. b. brucei (T. b. b.) causes trypanosomiasis in animals.

The studies are based on a hypothesis that the first signal may be generated at the site of inoculation of T. b. b. and transmitted via the nervous system (NS) to the lymphoid organs for the rapid communication between NS and the immune cells. Spleen is considered as central control unit (CCU) and produces second signal that may trigger the innate immune reaction and develop adaptive immune response with either removal of infectious agents or further complications. Thus, the effect of sympothectomy of the spleen on immune responses in early experimental African tryponosomiasis (EAT) was investigated to determine the possible role of the autonomic NS (ANS) in very early induction of infectious mediators.

To test the hypothesis splenic sympothectomy was performed on Sprague Dawley (SD) rats and the inoculation of parasites was followed. Mononuclear cells (MNC) from spleen were prepared and checked for mRNA expression and protein production of cytokines and chemokines using Msitu hybridization and immunochemistry, respectively.

Inoculation of T. b. b. resulted in early IFN (interferon)-gammaproduction, which was recorded at 4 h post infection (p. i.) and elevated cortisone and increased splenocyte proliferation, as measured by enzymelinked immunospot assay, radioimmunoassay and thymidineincorporation assay, respectively. Splenic denervation suppressed IFN-gamma, cortisone and prostaglandin2 (PGE2) production, enhanced splenocyte proliferation, reduced parasitemia significantly and prolonged rat survival.

Cytokines mRNA expression for interleukin (IL)-4, IL-6, IL-10, IL-12,tumor necrosis factor (TNF) -alpha, TNF-beta, transforming growing factor(TGF)-beta and IFN-gamma were examined at 0 h, 4 h and 12 h p. i. aftersplenic denervation. IFN-gamma and IL-12 were preferentially expressed already at 4 h p. i. and showed more increased levels at 12 h. Splenic denervation markedly reduced mRNA expression of both IFN-gamma and IL-12. IFN-gamma production was increased at 4 h p. i. and was inhibited by denervation. Sham-operated animals exhibited similar responses to that of non-denervated controls.

The induction of 4 chemokines during early EAT was examined. mRNA and protein production of Rantes (regulated upon activation in normal T cell expressed and secreted), MCP (monocyte chemoattractant protein)-1, MIP(macrophage inflammatory protein)-1alpha and MIP-2 were detected in splenocytes at 0 h, 4 h and 12 h p. L. The gene expression and protein production of these chemokines enhanced after the challenging with T. b.b. but inhibited by splenic denervation.

Monokines IL-1beta and IL-6 produced by peritoneal macrophages (PMphi) and splenic MC cell mRNA gene expression and protein production of IL-1beta and IL-6 at 0 h, 4 h, 12 h p. i. were examined. The enhancement of mRNA gene expression and protein production of IL-1 beta and IL-6 by PMphi was registered at 4 h p. i. and mRNA gene expression and protein production were suppressed by sympothectomy of the spleen.

Our date present a suppressive effect of sympathectomy in early immunomodulation in EAT, which suggests a stimulatory role of sympathetic nervous system (SNS) in early EAT. Since the suppressive effect of sympathectomy was also found in natural immune responses in our study, we arrive at a conclusion that the effect of sympathectomy on the immune responses is not the parasite infection-specific, though it does play a role in the development and the outcome of the EAT.

List of scientific papers

I. Liu Y, Mustafa M, Li HL, Nuortio L, Mustafa A, Bakhiet M (2000). Modulation of early immune responses and suppression of Trypanosoma brucei brucei infections by surgical denervation of the spleen. Neuroimmunomodulation. 8(1): 31-8.
https://pubmed.ncbi.nlm.nih.gov/10859486

II. Liu Y, Ragaa E, Li Z, Nuortio L, Mustafa A, Bakhiet M (1999). Interferon-gamma and interleukin-12 genes are preferentially expressed during early experimental African trypanosomiasis and suppressed by denervation of the spleen. Scand J Immunol. 50(5): 485-91.
https://pubmed.ncbi.nlm.nih.gov/10564551

III. Liu Y, Li Z, Bakhiet M (1999). Upregulation of the chemokines Rantes, MCP-1, MIP-1a and MIP-2 in early infection with Trypanosoma brucei brucei and inhibition by sympathetic denervation of the spleen. Trop Med Int Health. 4(2): 85-92.
https://pubmed.ncbi.nlm.nih.gov/10206261

IV. Liu Y, Li Z, Svaren-Quiding C, Cui J, Ozenci V, Bakhiet M (2004). Splenic denervation suppresses mRNA gene expression and protein production of IL-1beta and IL-6 by peritoneal macrophages in both Trypanosoma brucei brucei-infected and non-infected rats. Neuroimmunomodulation. 11(2): 113-8.
https://pubmed.ncbi.nlm.nih.gov/14758057