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© The Rockefeller University Press, 0022-1007/1998/7/39/ $5.00
The Journal of Experimental Medicine, Volume 188, Number 1, July 1, 1998 39-48

Articles

Transforming Growth Factor β Production Is Inversely Correlated with Severity of Murine Malaria Infection

Fakhereldin M. Omer and Eleanor M. Riley

From the Institute of Cell, Animal and Population Biology, University of Edinburgh, Edinburgh, EH9 3JT United Kingdom

We have examined the role of the immunomodulatory cytokine transforming growth factor (TGF)-β in the resolution and pathology of malaria in BALB/c mice. Circulating levels of TGF-β, and production of bioactive TGF-β by splenocytes, were found to be low in lethal infections with Plasmodium berghei. In contrast, resolving infections with P. chabaudi chabaudi or P. yoelii were accompanied by significant TGF-β production. A causal association between the failure to produce TGF-β and the severity of malaria infection was demonstrated by treatment of infected mice with neutralizing antibody to TGF-β, which exacerbated the virulence of P. berghei and transformed a resolving P. chabaudi chabaudi infection into a lethal infection, but had little effect on the course of P. yoelii infection. Parasitemia increased more rapidly in anti–TGF-β–treated mice but this did not seem to be the explanation for the increased pathology of infection as peak parasitemias were unchanged. Treatment of P. berghei–infected mice with recombinant TGF-β (rTGF-β) slowed the rate of parasite proliferation and prolonged their survival from 15 to up to 35 d. rTGF-β treatment was accompanied by a significant decrease in serum tumor necrosis factor {alpha} and an increase in interleukin 10. Finally, we present evidence that differences in TGF-β responses in different malaria infections are due to intrinsic differences between species of malaria parasites in their ability to induce production of TGF-β. Thus, TGF-β seems to induce protective immune responses, leading to slower parasite growth, early in infection, and, subsequently, appears to downregulate pathogenic responses late in infection. This duality of effect makes TGF-β a prime candidate for a major immunomodulatory cytokine associated with successful control of malaria infection.

Key Words: transforming growth factor β • malaria • tumor necrosis factor {alpha} • interleukin 10 • immunomodulation

Address correspondence to Eleanor M. Riley, Institute of Cell, Animal and Population Biology, University of Edinburgh, West Mains Rd., Edinburgh, EH9 3JT, UK. Phone: 44-131-650-5540; Fax: 44-131-667-3210; E-mail: e.riley{at}ed.ac.uk


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