No abstract

A primary infection of mice with Plasmodium chabaudi chabaudi (AS) is characterized by a rapid and marked inflammatory response. Typically, IL‐12, TNF‐α  and IFN‐γ  are produced in the spleen, and are transiently present in plasma. The cells involved in this early response are unknown. Here we show that dendritic cells derived from GM‐CSF‐stimulated mouse bone marrow cultures produce TNF‐α  within 30 min of exposure to P.c.chabaudi schizonts. IL‐6, IL‐12p40 and p70 follow this. The production of these cytokines was not dependent on the presence of T cells or NK cells and did not require CD40. Incubation of dendritic cells with P.c.chabaudi schizonts also resulted in up‐regulation of MHC class II, CD40 and CD86 but not CD80. In contrast to some strains of the human parasite, P. falciparum, P.c. chabaudi (AS) did not inhibit the up‐regulation of MHC class II, CD86 or CD40 induced by LPS. Therefore, the erythrocytic stages of P.c.chabaudi are able to activate dendritic cells directly. The consequences of such an interaction could be rapid activation of TH1 cells and induction of immunity, and in the event of a large response also induction of TNF‐α  associated pathology.

Cryptococcus neoformans is a pathogenic yeast and a major cause of opportunistic infection in AIDS patients. It is commonly found in an acapsular form in the environment, and infection is likely to occur by inhalation. The lung provides a suitable environment for capsule synthesis, and once encapsulated, C. neoformans becomes resistant to phagocytosis. A stable acapsular mutant of the organism is readily ingested by murine macrophages in vitro, indicating entry via constitutively competent receptors. We demonstrate in this report that this process is inhibitable by particles derived from Saccharomyces cerevisiae that are rich in mannan and ␤-glucan, as well as more purified forms of these glycans. Furthermore, ingestion of the acapsular form of C. neoformans induces a range of proinflammatory cytokines, including tumor necrosis factor alpha and granulocyte-macrophage colony-stimulating factor, which, as we have previously shown, enhance ingestion of serum-opsonized encapsulated C. neoformans in vitro. We demonstrate that ingestion of the acapsular form of the organism also enhances ingestion of the pathogenic encapsulated form. This is dependent on the production of tumor necrosis factor alpha and granulocyte-macrophage colony-stimulating factor by the macrophages, since addition of neutralizing antibodies to both cytokines inhibited the observed increase in ingestion. Together, these data demonstrate that ingestion of acapsular C. neoformans is mediated via mannose and ␤-glucan receptors on the macrophage surface and that this process activates macrophages for enhanced phagocytosis of the encapsulated form via production of macrophage-derived cytokines.