Reassessment of the role of splenic leukocyte oxidative activity and macrophage activation in expression of immunity to malaria

Abstract

The role of splenic leukocyte oxidative activity and macrophage activation in the development of protective immunity was examined during acute Plasmodium chabaudi adami malaria. Splenic leukocyte oxidative activity was compared in infected BALB/c and P/J mice; the latter are known to suffer from defects in macrophage function. Phorbol myristate acetate-stimulated chemiluminescence and superoxide anion production by splenic leukocytes from infected BALB/c mice were found to be increased dramatically, while the response of splenic leukocytes from infected P/J mice was elevated only minimally. Hydrogen peroxide release was slightly increased in splenic leukocytes from infected BALB/c mice but remained essentially unchanged in those from infected P/J mice. Macrophage function was assessed on the basis of measurements of tumoricidal activity. Splenic macrophages from uninfected BALB/c mice displayed significant tumoricidal activity against L929 target cells. As a result of splenomegaly during infection, tumoricidal activity, when calculated on a per-spleen basis, was increased further in infected BALB/c mice. In contrast, the tumoricidal activity of splenic macrophages from P/J mice was minimal, regardless of infection. Despite these differences, both strains of mice developed malarial infections that resolved within 16 days. Thus, while the production of reactive oxygen radicals by splenic leukocytes and the phenomenon of macrophage activation have traditionally been associated with the resolution of malarial infection, this study failed to establish a correlation between these parameters and the development of protective immunity to blood-stage infection with P. chabaudi adami.

Role of endogenous gamma interferon in host response to infection with blood-stage Plasmodium chabaudi AS

“…Anti-IFN--y MAb-treated animals exhibited a significantly higher parasitemia 1 to 2 days before the peak parasitemia as well as a significantly higher peak parasitemia. Similar to control mice, however, MAb-treated mice resolved the infection by 4 weeks, and 100% of the MAb-treated mice survived. These results suggest that early in infection control of both parasite multiplication and the level of peak parasitemia occur by IFN--y-dependent mechanisms, whereas later on in infection elimination of bloodstage P. chabaudi AS occurs by an IFN-y-independent, cell-mediated mechanism.…”

“…thesis, McGill University, 1987). Li-popolysaccharide-resistant, C57BL-derived C57BL/lOScN mice, which were found to be resistant to infection with P. chabaudi AS and to exhibit a course of infection characterized by a peak parasitemia between 30 and 40% PRBC and resolution of acute infection by 4 weeks, were treated with anti-murine IFN--y MAb. We used two different MAbs: R4-6A2, a rat anti-mouse neutralizing IgGl that was prepared against natural murine IFN-y, and DB-1, a murine anti-rat IgGl generated against recombinant rat IFN--y that can neutralize the murine molecule as well as the rat molecule (22,31).…”

“…week for 4 weeks, beginning on the day of infection; control mice were untreated. The same protocol of treatment with DB-1 has been found to impair resistance of mice to infection D with L. major (1).…”

Protective immunity against malaria after vaccination

“…The high IFN-c release that occurs during nonlethal infections (48,108) probably induces this macrophage activation, although direct activation by parasite-derived products may contribute (53). Activated macrophages with strong respiratory burst activity were also shown to be involved in the control of P. chabaudi infections in resistant C57BL/6 mice (109). Although a number of studies have shown that IFN-c is required for optimal macrophage activation (106), we recently showed that IFN-c knockout mice could still control the acute phase of a nonlethal P. yoelii infection (107) and that this was true in P. berghei NK65 infection (Couper KN, Greig R, de Souza JB & Riley EM, unpublished data).…”

Blood transfusion alters the course and outcome of Plasmodium chabaudi AS infection in mice

“…Our suggestion that the mechanism(s) which operates during crisis is mainly a nonspecific physiologic response rather than a specific immune-mediated process is consistent with experiments in mice with genetic or experimentally induced deficiencies in specific cell types or effector molecules. In murine hosts deficient in B cells and antibodies (anti-immunoglobulin M-treated mice [3] and severe combined immunodeficient [SCID] mice [7]), T cells (nude and SCID mice [7]; anti-CD4-and anti-CD8-treated mice [12]), and macrophages (silica-treated mice [17]) and in animals deficient in nitric oxide (NGmonomethyl-L-arginine-treated mice [19]) and oxidative metabolites (P/J mice [2]), there is a strikingly consistent decrease in levels of parasitemia during the period immediately following peak parasitemia. This decrease in parasitemia does not differ either in timing or in rate from that in control, immunocompetent mice.…”