Platelet factor 4 and Duffy antigen required for platelet killing of Plasmodium falciparum.

Platelets restrict the growth of intraerythrocytic malaria parasites by binding to parasitized cells and killing the parasite within. Here, we show that the platelet molecule platelet factor 4 (PF4 or CXCL4) and the erythrocyte Duffy-antigen receptor (Fy) are necessary for platelet-mediated killing of Plasmodium falciparum parasites. PF4 is released by platelets on contact with parasitized red cells, and the protein directly kills intraerythrocytic parasites. This function for PF4 is critically dependent on Fy, which binds PF4. Genetic disruption of Fy expression inhibits binding of PF4 to parasitized cells and concomitantly prevents parasite killing by both human platelets and recombinant human PF4. The protective function afforded by platelets during a malarial infection may therefore be compromised in Duffy-negative individuals, who do not express Fy.

Platelets kill intraerythrocytic malarial parasites and mediate survival to infection.

Platelets play a critical role in the pathogenesis of malarial infections by encouraging the sequestration of infected red blood cells within the cerebral vasculature. But platelets also have well-established roles in innate protection against microbial infections. We found that purified human platelets killed Plasmodium falciparum parasites cultured in red blood cells. Inhibition of platelet function by aspirin and other platelet inhibitors abrogated the lethal effect human platelets exert on P. falciparum parasites. Likewise, platelet-deficient and aspirin-treated mice were more susceptible to death during erythrocytic infection with Plasmodium chabaudi. Both mouse and human platelets bind malarial-infected red cells and kill the parasite within. These results indicate a protective function for platelets in the early stages of erythrocytic infection distinct from their role in cerebral malaria.

Gene expression in splenic CD4 and CD8 cells from BALB/c mice immunized with Porphyromonas gingivalis.

BACKGROUND: T cells are fundamental in the pathogenesis of periodontal disease. Suppression of cell-mediated responses is associated with disease progression together with the concomitant increase in plaque pathogens including Porphyromonas gingivalis. The aim of the present study was to examine gene expression in T cells in response to P. gingivalis in mice. METHODS: BALB/c mice were given weekly intraperitoneal injections of P. gingivalis outer-membrane antigens with Freund's incomplete adjuvant for 3 weeks, whereas control mice received phosphate buffered saline (PBS) and adjuvant only. Splenic CD4 and CD8 subpopulations were isolated by magnetic cell separation and their responses investigated using microarray analysis. RESULTS: Most genes coded for enzymes concerned with metabolic pathways. Only five and 28 genes, respectively, were upregulated in CD4 and CD8 cells extracted from P. gingivalis-immunized mice, including immunoglobulin (Ig) heavy-chain genes for IgG1 and IgG2a in CD4 cells. In contrast, 1,141 and 1,175 genes, respectively, were downregulated. A total of 60 and 65 genes, respectively, coded for immune response proteins or those relevant to periodontal disease pathogenesis. The overlap of genes in the two subsets was 21%. One of the major effects, apart from T-cell function suppression, was the shift away from Th1 responses, although there was also a downregulation of two genes and upregulation of one Th2-response gene. Genes downregulated included those encoding cytokines, proteins involved in Ig binding, antigen presentation, innate immunity, extracellular matrix, and cell adhesion molecules that could result in dysregulation in the progressive periodontal lesion. CONCLUSIONS: Early findings in humans demonstrated that periodontopathic bacteria induce immunosuppressive effects on T cells. The present study has shown that P. gingivalis had a predominant downregulatory effect on gene expression in CD4 and CD8 T cells in mice.

Role of complement C5 and T lymphocytes in pathogenesis of disseminated and mucosal candidiasis in susceptible DBA/2 mice.

The aims of the study were to compare the pathogenesis of Candida albicans infection in various organs and anatomical regions of C5-deficient (DBA/2) and C5-sufficient (BALB/c) mice, and to evaluate the importance of complement C5 and T lymphocytes as factors that determine host susceptibility or resistance. The kidneys of DBA/2 mice showed higher colonisation and more severe tissue damage than those of BALB/c, but infection at other sites, including oral and vaginal mucosa, was generally similar in the two strains. Passive transfer of C5-sufficient serum into DBA/2 mice decreased the fungal burden in the kidney, and prolonged survival of the reconstituted animals. Depletion of CD4(+) and/or CD8(+) cells did not exacerbate either systemic or mucosal infection when compared to controls, and passive transfer of splenocytes from infected donors caused only a small and transient reduction in numbers of yeasts recovered from the kidney of sub-lethally infected recipients. It is concluded that the acute susceptibility of the kidneys in this mouse strain is due to C5 deficiency expressed on a susceptible genetic background. T lymphocytes, however, appear to have minimal influence on recovery from systemic infection with this isolate of C. albicans.