Macrophage cytokines as correlate of differential resistance to African trypanosomiasis
BALB/c mice are susceptible to 'T. congolense' infection as they succumb within 8.4 ± 0.5 days while C57Bl/6 mice are relatively resistant as they survive up to 163 ± 12 days. Evidence suggests that macrophages play a central role in resistance to trypanosomiasis. The expression of mRNA and/or production of cytokines (IL-6, IL-10, TNF-α, TGF-β1 and IL-12) and nitric oxide (NO) by macrophages from C57Bl/6 and BALB/c mice in response to 'T. congolense' or 'T. brucei' were studied. The bone marrow-derived macrophage cell line (BALB.BM) and bone marrow-derived macrophages (BMDM) of BALB/c mice produced significantly more IL-6 and IL-10 and less TNF-α or TNF-α mRNA and IL-12 than the C57Bl/6 macrophage cell line (ANA-1) and BMDM following phagocytosis of 'T. congolense ' or upon challenge with 'T. congolense' or ' T. brucei' whole cell extracts (WCE). Preincubation or simultaneous stimulation of cells with IFN-ɣ further upregulated the IL-10 production in BALB.BM and BALB/c BMDM but not in ANA-1 and C57Bl/6 BMDM.A higher ratio of IL-6: IL-12 secretion by macrophages in response to trypanosomal WCE positively correlated with genetic susceptibility to experimental African trypanosomiasis as well as the virulence of the strains of trypanosomes. No significant differences in the expression of TGF-β1 mRNA were observed in BALB.BM and ANA-1 cells following phagocytosis of 'T. congolense' and in 'T. congolense'-infected BALB/c and C57Bl/6 mice. C57Bl/6 macrophages produced significantly more NO than BALB/c macrophages upon stimulation with 'T. congolense' WCE or following phagocytosis of 'T. congolense'. Phagocytosis of 'T. congolense' mediated by antibodies to variant surface glycoprotein (VSG) of IgG2a isotype induced several fold higher NO than phagocytosis mediated by IgM antibodies. NO had a trypanostatic effect on 'T. congolense in vitro' but an influence on the infectivity of the parasites 'in vivo' could not be demonstrated. IL-4, IL-10 and IFN-ɣ did not show any growth enhancing or inhibitory effects on 'T. congolense in vitro'. I suggest that a lower production of IL-6 and IL-10 and a higher production of TNF-α, IL-12 and NO by a particular animal's macrophages might be a suitable indicator for the animal's genetic resistance to African trypanosomiasis.
Doctor of Philosophy (Ph.D.)