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Excess copper affects the growth and metabolism of plants and green algae. However, the physiological processes under Cu stress are largely unknown. In this study, we investigated Cu-induced nitric oxide (NO) generation and its relationship to proline synthesis in Chlamydomonas reinhardtii. The test alga accumulated a large amount of proline after exposure to relatively low Cu concentrations (2.5 and 5.0 microM Cu2+). A concomitant increase in the intracellular NO level was observed with increasing concentrations of Cu applied. Data analysis revealed that the endogenous NO generated was positively associated with the proline level in Cu-stressed algae. The involvement of NO in Cu-induced proline accumulation was confirmed by using an NO-specific donor, sodium nitroprusside (SNP), and an NO scavenger cPTIO [2-(4-carboxy-2-phenyl)-4,4,5,5-tetramethylinidazoline-1-oxyl-3-oxide]. Pre-treatment with 10 microM SNP increased the proline accumulation in Cu-treated cells by about 1.5-fold, while this effect could be blocked by addition of 10 microM cPTIO. We further investigated the effect of Cu and NO on the activity and transcript amount of Delta(1)-pyrroline-5-carboxylate synthetase (P5CS, EC 2.7.2.11), the key enzyme of proline biosynthesis, and observed that application of SNP was able to stimulate the P5CS activity and up-regulate the expression of P5CS in the Cu-treated algae. These results indicate that Cu-responsive proline synthesis is closely related to NO generation in C. reinhardtii, suggesting the regulatory function of NO in proline metabolism under heavy metal stress.

Polyclonal B-cell activation and hypergammaglobulinemia are prominent features of human malaria. We report here that Plasmodium falciparum-infected erythrocytes directly adhere to and activate peripheral blood B cells from nonimmune donors. The infected erythrocytes employ the cysteine-rich interdomain region 1␣ (CIDR1␣) of P. falciparum erythrocyte membrane protein 1 (PfEMP1) to interact with the B cells. Stimulation with recombinant CIDR1␣ induces proliferation, an increase in B-cell size, expression of activation molecules, and secretion of immunoglobulins (immunoglobulin M) and cytokines (tumor necrosis factor alpha and interleukin-6). Furthermore, CIDR1␣ binds to Fab and Fc fragments of human immunoglobulins and to immunoglobulins purified from the sera of different animal species. This binding pattern is similar to that of the polyclonal B-cell activator Staphylococcus aureus protein A. Our findings shed light on the understanding of the molecular basis of polyclonal B-cell activation during malaria infections. The results suggest that the var gene family encoding PfEMP1 has evolved not only to mediate the sequestration of infected erythrocytes but also to manipulate the immune system to enhance the survival of the parasite.Parasites that proliferate in restricted ecological niches such as Plasmodium spp. control the contact with their hosts in order to colonize, divide, and transmit themselves. Chronic infections with Plasmodium falciparum lead to a severely dysregulated immune system, and B cells are overactivated with the subsequent secretion of an array of different autoantibodies (2, 8), the presence of hyperglobulinemia (1), and the frequent occurrence of B-cell tumors (Burkitt's lymphoma) (17). B-cell activation has been reported in studies involving the stimulation of total peripheral lymphocytes with P. falciparum-derived products, and it has been suggested to be the result of direct and indirect mechanisms mediated by T lymphocytes and accessory cells (18,19). However, the identity of the antigens and mechanisms that lead to polyclonal activation in the course of malaria infection are currently unknown.It has previously been shown that a large proportion (83%) of fresh isolates of P. falciparum-infected erythrocytes (IE) bind nonimmune immunoglobulins (Igs) though to various degrees (25, 26). One of the domains of the P. falciparum erythrocyte membrane protein 1 (PfEMP1), the cysteine-rich interdomain region 1␣ (CIDR1␣) of FCR3S1.2 (amino acids 395 to 700), binds to CD36, PECAM-1/CD31, and nonimmune Igs (4, 5, 26). Microbial Ig binding proteins (IBPs) are produced by protozoa, viruses, parasites and both gram-positive and gramnegative bacteria (31) and play important physiological roles (20). It has been suggested that during an infectious process these IBPs may act as an evasion mechanism to divert specific antibody (Ab) responses (7, 21). The binding of CIDR1␣ to nonimmune Igs led us to investigate the interaction between human B cells and P. falciparum-IE and the involvement of CIDR1␣. The pre...

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