Early Cytokine Production Is Associated with Protection from Murine Cerebral Malaria

Abstract

Cerebral malaria (CM) is an infrequent but serious complication of Plasmodium falciparum infection in humans. Animal and human studies suggest that the pathogenesis of CM is immune mediated, but the precise mechanisms leading to cerebral pathology are unclear. In mice, infection with Plasmodium berghei ANKA results in CM on day 6 postinoculation (p.i.), while infection with the closely related strain P. berghei K173 does not result in CM. Infection with P. berghei K173 was associated with increased plasma gamma interferon (IFN-␥) at 24 h p.i. and with increased splenic and hepatic mRNAs for a range of cytokines (IFN-␥, interleukin-10 [IL-10], and IL-12) as well as the immunoregulatory enzyme indoleamine 2,3-dioxygenase. In contrast, P. berghei ANKA infection was associated with an absence of cytokine production at 24 h p.i. but a surge of IFN-␥ production at 3 to 4 days p.i. When mice were coinfected with both ANKA and K173, they produced an early cytokine response, including a burst of IFN-␥ at 24 h p.i., in a manner similar to animals infected with P. berghei K173 alone. These coinfected mice failed to develop CM. In addition, in a low-dose P. berghei K173 infection model, protection from CM was associated with early production of IFN-␥. Early IFN-␥ production was present in NK-cell-depleted, ␥␦-cell-depleted, and J␣281 ؊/؊ (NKT-cell-deficient) mice but absent from ␤2-microglobulin mice that had been infected with P. berghei K173. Taken together, the results suggest that the absence of a regulatory pathway involving IFN-␥ and CD8؉ T cells in P. berghei ANKA infection allows the development of cerebral immunopathology.

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

“…Specifically, we observed no significant differences in the T-cell response to PyL or PyNL, and despite differences in the kinetics of the IFN-␥ and NK responses to each of the two parasite strains, we found that the course of acute infection was essentially unaffected by the absence of T or B lymphocytes, NK cells, or IFN-␥. These data are somewhat unexpected, given the important roles that IFN-␥-producing NK cells and T lymphocytes play in other rodent malaria infections, such as P. berghei ANKA and P. chabaudi chabaudi (28,30,51), and highlight significant differences in the mechanisms of control of P. yoelii compared with other malaria infections. In contrast, depletion of macrophages with clodronate liposomes markedly reduced the ability of the mice to control acute PyL or PyNL infection.…”

“…7C and D). However, given the essential role of IFN-␥ in controlling nonlethal P. chabaudi infection (28,31,51,56) and in preventing cerebral malaria in P. berghei K173 infection (30), it was rather unexpected to find that during PyNL infection, the course of infection was essentially identical in WT and IFN-␥ Ϫ/Ϫ mice (Fig. 7B, C, and D).…”

“…After several days (around 5 days in mice), IFN-␥ from ␣␤ T cells begins to dominate the response. It has been reported that NK cell-derived IFN-␥ contributes to the early control of Plasmodium chabaudi, Plasmodium berghei, and Plasmodium yoelii infections (6,10,21,30,31) and that NK cell depletion enhances the virulence of nonlethal P. yoelii and P. chabaudi infections (6,20,31), although the latter finding has recently been debated (42). Conversely, ␥␦ T cells play only a minor role in the control of the acute primary wave of malaria infection, as TCR␥␦ Ϫ/Ϫ or ␥␦ T-cell-depleted mice develop comparable peak parasitemia with little or no delay in parasite clearance (24,43).…”

CNS Hypoxia Is More Pronounced in Murine Cerebral than Noncerebral Malaria and Is Reversed by Erythropoietin

“…38 -41 The inoculum number was greater for PbK because this prevents the occurrence of CM in C57BL/6 mice. 39 Age-matched BALB/c mice, housed under similar conditions, received 10 6 PbA-infected erythrocytes and served as another non-CM control group. Comparisons were made on days 7 and 8 after infection, at which time peripheral parasitemia was similarly low (mean, 4.8% to 10.4%) in all groups, thereby ruling out any confounding factors caused by global hypoxia secondary to anemia.…”

Erythroferrone contributes to hepcidin repression in a mouse model of malarial anemia

“…Mice injected with PbK-parasitized RBCs develop high parasitemia and severe anemia and die without cerebral symptoms 18-22 days post-infection. 31 We then infected Erfedeficient mice and examined the impact of Erfe deletion on hepcidin expression, parasitemia and RBC indices. By highlighting the contribution of ERFE in hepcidin regulation in malaria, this study may suggest new therapeutic strategies to combat malaria.…”