Production of interleukin 10 during malaria caused by lethal and nonlethal variants of Plasmodium yoelii yoelii

Abstract

We investigated the induction of T-helper cell subsets during the course of lethal or nonlethal bloodstage Plasmodium yoelii 17X infection in C57BL/6 mice, which are relatively susceptible to these intraerythrocytic parasites. C57BL/6 mice infected with the nonlethal variant (PyNL) showed a moderate level of parasitemia and resolution of primary acute infection by week 4. Mice infected with the lethal variant (PyL) developed fulminating parasitemia and ultimately died. T-helper subset function was assessed during infection by determining the kinetics of in vitro production of the Th1-derived cytokine interferon-gamma (IFN-gamma) and the Th2-derived cytokine interleukin 10 (IL-10) by means of bioassay and enzyme-linked immunosorbent assay (ELISA), respectively. Spleen cells obtained from mice infected with PyL within the 1st week of infection produced high levels of IL-10 and IFN-gamma in response to malaria antigen. IL-10 also appeared in sera from PyL-infected mice at the same time at which the in vitro IL-10 response peaked. In contrast, spleen cells from mice infected with PyNL failed to produce IL-10 during the course of infection. CD4+ T-lymphocytes from mice infected with the lethal variant were a major source of IL-10, although non T-cells were also involved in the production of IL-10 during this malaria infection. In addition, the initial burst of IL-10 in response to malaria antigens was seen concomitantly with the production of IFN-gamma within the 1st week of infection. These results indicate that both Th1 and Th2 subsets of T-helper lymphocytes are activated during infection with the lethal variant of P. yoelii and support the contention of other investigators that a strong Th2 response early in infection is associated with the lethal outcome of malaria.

Macrophage-Mediated but Gamma Interferon-Independent Innate Immune Responses Control the Primary Wave ofPlasmodium yoeliiParasitemia

“…Despite clear evidence that anti-inflammatory cytokines and/or regulatory T cells inhibit the clearance of PyL pRBC (15,16,21,22,35,36), this study has not shown any role for T cells, NK cells, or IFN-␥ in the control of acute P. yoelii infection. However, given the absence of MHC expression on the majority of red blood cells (19), it is probable that neither T cells nor NK cells play the terminal effector role in parasite killing.…”

“…In contrast, depletion of macrophages with clodronate liposomes markedly reduced the ability of the mice to control acute PyL or PyNL infection. Taking these data together with previously published studies in which rapid induction of IL-10 or TGF-␤ and/or early activation of regulatory T cells were found to prevent control of PyL infections (15,16,22,35,36) suggests that these immunoregulatory pathways may act directly to suppress the effector functions of innately activated macrophages. Somewhat surprisingly, effector T-cell activation, expansion, and function were very similar during lethal and nonlethal P. yoelii infections.…”

“…It is clear that virulent and avirulent strains of P. yoelii differ in their ability to invade mature red blood cells (60,63), and this has recently been linked to differential copy number and expression patterns of genes putatively involved in erythrocyte invasion (1,18,41). Nevertheless, numerous studies from different laboratories have observed immunological differences between the two infections, including disparate IFN-␥ production, regulatory cytokine production, regulatory T-cell activation, and stromal cell activation (6,10,15,16,21,22,35,36,47,62), indicating that the virulence of P. yoelii parasites is not simply due to their erythrocyte invasion capacity. Significantly, our observation that clodronate liposome depletion of macrophages (58) results in more rapid growth of both PyL and PyNL parasites and more rapid onset of anemia indicates that macrophages play a major role in limiting the acute phase of P. yoelii infection.…”

Coinfection with Nonlethal Murine Malaria Parasites Suppresses Pathogenesis Caused by Plasmodium berghei NK65

“…It has been shown that mice infected with Pb NK65 develop severe parasitemia and die within 2 wk, although mice infected with Pb XAT or Py 17X cure spontaneously around 3 wk of infection (15,17). To examine whether primary infection with each of the two nonlethal parasites can induce protective immunity against Pb NK65 lethal infection, groups of C57BL/6 (B6) mice were infected with Pb XAT or Py 17X then challenged with Pb NK65 on day 30 after primary infection.…”

“…IFN-␥ and IL-10 have been shown to be associated with protection and exacerbation during P. berghei and P. yoelii malaria (17,18).…”