Transforming Growth Factor β-Induced Failure of Resistance to Infection with Blood-Stage Plasmodium chabaudi in Mice

The role of transforming growth factor β (TGF-β) in infection with Plasmodium chabaudi was investigated with resistant and susceptible mouse models. C57BL/10 mice produced gamma interferon (IFN-γ) and nitric oxide (NO) shortly after infection and cleared the parasite spontaneously. In contrast, BALB/c mice showed a transient enhancement of TGF-β production, followed by a relative lack of IFN-γ and NO production, and succumbed to the infection. However, there was no correlation between levels of serum TGF-β and splenic TGF-β mRNA in both mouse strains before and after infection. Administration of recombinant TGF-β (rTGF-β) rendered resistant mice susceptible because of suppression of subsequent production of IFN-γ and NO. Administration of anti-TGF-β antibody to the infected BALB/c mice resulted in remarkable increases in serum IFN-γ and NO, and the mice resisted the infection. Splenic CD4(+) T and CD11b(+) cells of C57BL/10 mice were significantly activated after infection, but this was completely abrogated by administration of rTGF-β. These results suggested that, in the P. chabaudi-susceptible but not resistant mice, production of TGF-β was promoted, and subsequent failure of IFN-γ- and NO-dependent resistance to the parasite was induced. This study is the first to indicate that TGF-β production was the key event in failure of resistance to mouse malaria.