Possible importance of macrophage-derived mediators in acute malaria

Abstract

Tumor necrosis factor, lymphocyte-activating factor, and enhanced levels of type I interferon were found in serum samples taken 2 h after mice infected with Plasmodium vinckei subsp. petteri received a small intravenous injection of endotoxin. These three mediators are among those released when mice receive an endotoxin injection 2 weeks after Mycobacterium bovis BCG or Corynebacterium parvum have been administered. There is indirect evidence that this wider range of mediators is also released in P. vinckei subsp. petteri-infected mice given parenteral endotoxin. A recent report that endotoxin is detectable in the plasma of malaria-infected mice and children implies that these mediators may also be released in the acute phase of the natural infection. We propose that these macrophage-derived mediators may be important in the glucocorticoid antagonism, bone marrow depression, fever, hypergammaglobulinemia, splenomegaly, elevation of serum amyloid A, consumptive coagulopathy, and shock syndrome with associated organ damage which can accompany malaria. The intraerythrocytic parasite death seen at crisis in some malarias, as well as the subsequent development of specific protective immunity, may also depend on these mediators.

Pathogenesis of Malaria and Clinically Similar Conditions

“…A collaboration with the original laboratory studying TNF showed that TNF-rich serum fractions would indeed inhibit malaria parasite growth in vivo (99), that malaria infection would replace BCG as a primer for TNF production (99), and that the ability of a priming agent in our system paralleled its effectiveness, at the same dose, to prime for TNF generation (E. A. Carswell, personal communication). In addition, interleukin-1 (IL-1) (then called lymphocyte-activating factor) was present in the TNF-rich fractions, and roles for it in malaria were proposed (99). Thus developed the argument that TNF and similar mediators were involved in the host response to malaria parasites, a field previously the province of antibody-based mechanisms.…”

“…Moreover, the ability of these agents to protect against hemoprotozoa could be predicted by how well they sensitized mice to LPS (81). A collaboration with the original laboratory studying TNF showed that TNF-rich serum fractions would indeed inhibit malaria parasite growth in vivo (99), that malaria infection would replace BCG as a primer for TNF production (99), and that the ability of a priming agent in our system paralleled its effectiveness, at the same dose, to prime for TNF generation (E. A. Carswell, personal communication). In addition, interleukin-1 (IL-1) (then called lymphocyte-activating factor) was present in the TNF-rich fractions, and roles for it in malaria were proposed (99).…”

“…A few years later, the idea of the effects of LPS in mammals being mediated by soluble factors generated by host cells had become a widely accepted principle (273). Thus, it was reasoned that this group of cyto-kines would explain much of the illness and pathology of malaria, the Jarisch-Herxheimer syndrome (discussed below), and the clinical similarity between malaria and typhoid (99). This seemed inevitable for this disease and other infections caused by gram-negative bacteria, since in the 1970s the Sloan-Kettering group had often used Salmonella infection instead of BCG, and LPS from Salmonella strains instead of Escherichia coli, to generate TNF (Carswell, personal communication).…”

“…Thus, the pursuit of the LPS-inducible soluble factors (later called cytokines) appeared to be the best way to understand disease pathogenesis in malaria and babesiosis. Since individuals recently recovered from malaria withstand high doses of both malaria parasites and LPS (186,341), it was reasoned (79,83,99) that this approach to innate malarial tolerance in different host species offered insight, in terms of reduced levels of TNF and related cytokines, into understanding the acquired malarial tolerance seen in children in malarial areas.…”

Using Complementary and Alternative Medicines to Target the Host Response during Severe Influenza

“…Instead, the pathogen induces host cells to generate excessive amounts of pro-inflammatory cytokines, the prototypic example being tumor necrosis factor (TNF), that alter organ function and host metabolism, thus generating the disease we observe (1,2). This general concept, originally proposed to describe the severe disease caused by malaria infection (3), then sepsis (4) and influenza (5), has taken root in the mainstream, and is now often referred to as the 'cytokine storm' (6).…”