Control of parasitemia and survival during Trypanosoma brucei brucei infection is related to strain-dependent ability to produce IL-4.

We studied non-MHC gene-dependent expression of a number of cytokines in relation to host defense and survival during Trypanosoma brucei brucei (Tbb) infection in mice. In particular, the role of IL-4 was explored with use of genomically IL-4-disrupted mice and in vivo Ab blocking. Splenocytes from MHC-identical B10.Q (relatively resistant) mice showed day 5 postinfection higher numbers of IL-4 mRNA expressing cells than C3H.Q (highly susceptible). A trypanosome-derived lymphocyte triggering factor, which is released by Tbb to polyclonally activate CD8+ T cells, stimulated naive splenocytes in vitro to a higher IL-4 response in B10.Q than in C3H.Q mice. The C3H.Q mice developed an extremely high parasitemia, showed a low Ab response against the variant surface glycoprotein (VSG), and had a mean survival time of 42 days. Conversely, B10.Q mice had lower parasitemia, mounted higher anti-VSG response, and had a mean survival time of 56 days. Deletion of the IL-4 gene had no influence on the infection in C3H.Q mice, while in B10.Q mice the deletion was associated with lower anti-VSG Ab levels and higher parasitemia. Paradoxically, B10.Q mice with disrupted IL-4 gene survived longer than the wild type. Anti-IL-4 Ab-blocking experiments in vivo displayed an enhanced parasitemia and prolonged survival in infected B10.Q mice. We conclude that 1) a non-MHC gene-related and CD8+-dependent ability to produce IL-4 partly determines the susceptibility to Tbb infection; and 2) IL-4, although involved in controlling the levels of parasitemia by its effects on immunoglobulin synthesis, also can have toxic effects on the animals.

Bakhiet M ，Jansson L ，Büscher P ，Holmdahl R ，Kristensson K ，Olsson T ... -  《JOURNAL OF IMMUNOLOGY》

Resistance to the African trypanosomes is IFN-gamma dependent.

The role of variant surface glycoprotein (VSG)-specific Th cell responses in determining resistance to the African trypanosomes was examined by comparing Th cell responses in relatively resistant and susceptible mice as well as in cytokine gene knockout mice infected with Trypanosoma brucei rhodesiense. Resistant B10.BR and C57BL/6 mice expressed Th1 cell cytokine responses to VSG stimulation during infection, while susceptible C3H mice produced weak or no Th1 cell cytokine responses. Neither resistant B10.BR and C57BL/6 mice nor susceptible C3H mice made detectable Th2 cell cytokine responses to parasite Ag. To more closely examine the potential role of IFN-gamma and other cytokines in host resistance, we determined the resistance phenotypes and Th cell responses of IFN-gamma and IL-4 knockout mice. Infected C57BL/6-IFN-gamma knockout mice were as susceptible as C57BL/6-scid mice and made an IL-2, but not an IL-4, cytokine response to VSG, while C57BL/6-IL-4 knockout mice were as resistant as the wild-type strain and exhibited both IL-2 and IFN-gamma cytokine responses. Passive transfer of spleen cells from wild-type mice to IFN-gamma knockout mice resulted in enhanced survival. Both wild-type and IFN-gamma knockout mice controlled parasitemia with VSG-specific Ab responses, although parasitemias were higher in the IFN-gamma knockout mice. Overall, this study demonstrates for the first time that relative resistance to African trypanosomes is associated with a strong Th1 cell response to parasite Ags, that IFN-gamma, but not IL-4, is linked to host resistance, and that susceptible animals do not make compensatory Th2 cell responses in the absence of Th1 cell cytokine responses.

Hertz CJ ，Filutowicz H ，Mansfield JM 《JOURNAL OF IMMUNOLOGY》

Genetics of resistance to the African trypanosomes. VI. Heredity of resistance and variable surface glycoprotein-specific immune responses.

The question of genetic linkage of parasite-specific immune responses to resistance to infection in experimental African trypanosomiasis was addressed. For this purpose, major histocompatibility complex-compatible resistant and susceptible inbred mouse strains and their F1 hybrid, F2 hybrid, and backcross offspring were infected with Trypanosoma brucei rhodesiense LouTat 1. Immunologic control of the first peak of parasitemia and survival times were the parameters measured. As we have reported previously (R. F. Levine and J. M. Mansfield, J. Immunol. 133:1564, 1984), B10.BR/SgSnJ mice are relatively resistant and controlled the growth of the infecting variant antigenic type (VAT) by mounting an antibody response to exposed epitopes of the variable surface glycoprotein (VSG). Fluctuating parasitemias resulting from sequential growth of different variable antigenic types occurred subsequently, and these mice died with a median survival time of 48 days. C3HeB/FeJ mice, relatively susceptible, did not control the infecting VAT and did not exhibit VSG-specific antibodies. These mice died with a median survival time of 22 days. The (B10.BR X C3H)F1 hybrids derived from crosses between resistant and susceptible mice all exhibited VSG-specific antibody responses and controlled the infecting VAT population. However, the median survival time of the F1 hybrids (24 days) was not significantly different from the survival time of the susceptible C3H parent. These findings demonstrate for the first time that antibody-mediated control of parasitemia is inherited as a dominant trait; that overall resistance, as measured by survival time, is inherited as a recessive trait (e.g., susceptibility is dominant); and that the two events segregate independently of one another. Further analyses of the inheritance of immunity and resistance (survival time) were made in which the F2 hybrid and backcross studies revealed that there are multiple genes controlling the VSG-specific antibody response as well as determining susceptibility. An extension of the present studies to a similar but non-major histocompatibility complex-mouse model system of resistance and susceptibility (C57BL/6J and C3H/HeJ mice, F1 hybrids, and 11 recombinant inbred B X H strains derived from them) was made in order to link the strain distribution patterns of known genetic markers with control of VSG-specific antibody responses or with control of susceptibility. Results of this study showed that resistance varied independently of the ability to control parasitemia with VSG-specific B cell responses.(ABSTRACT TRUNCATED AT 400 WORDS)

De Gee AL ，Levine RF ，Mansfield JM 《JOURNAL OF IMMUNOLOGY》

A Trypanosoma brucei bloodstream form mutant deficient in ornithine decarboxylase can protect against wild-type infection in mice.

Mutomba MC ，Li F ，Gottesdiener KM ，Wang CC ... -  《EXPERIMENTAL PARASITOLOGY》

Independent regulation of B cell responses to surface and subsurface epitopes of African trypanosome variable surface glycoproteins.

Reinitz DM ，Mansfield JM 《JOURNAL OF IMMUNOLOGY》