Arf1 and Arf6 Synergistically Maintain Survival of T Cells during Activation.

ADP-ribosylation factor (Arf) family consisting of six family members, Arf1-Arf6, belongs to Ras superfamily and orchestrates vesicle trafficking under the control of guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins. It is well established that brefeldin A, a potent inhibitor of ArfGEFs, blocks cytokine secretion from activated T cells, suggesting that the Arf pathway plays important roles in T cell functions. In this study, because Arf1 and Arf6 are the best-characterized members among Arf family, we established T lineage-specific Arf1-deficient, Arf6-deficient, and Arf1/6 double-deficient mice to understand physiological roles of the Arf pathway in the immune system. Contrary to our expectation, Arf deficiency had little or no impact on cytokine secretion from the activated T cells. In contrast, the lack of both Arf1 and Arf6, but neither Arf1 nor Arf6 deficiency alone, rendered naive T cells susceptible to apoptosis upon TCR stimulation because of imbalanced expression of Bcl-2 family members. We further demonstrate that Arf1/6 deficiency in T cells alleviates autoimmune diseases like colitis and experimental autoimmune encephalomyelitis, whereas Ab response under Th2-polarizing conditions is seemingly normal. Our findings reveal an unexpected role for the Arf pathway in the survival of T cells during TCR-induced activation and its potential as a therapeutic target in the autoimmune diseases.

Roles of OmpX, an Outer Membrane Protein, on Virulence and Flagellar Expression in Uropathogenic Escherichia coli.

Uropathogenic Escherichia coli (UPEC) is a major pathogen that causes urinary tract infection (UTI). This bacterium adheres to and internalizes within urinary tract cells, where it aggregates and subsequently forms biofilm-like multicellular colonies that protect UPEC from antimicrobial agents and the host's immune system. Here, we show that OmpX, an outer membrane protein, plays a role in the pathogenesis of UPEC in renal cells. Deletion of ompX decreased bacterial internalization and aggregation within kidney epithelial cells and also impaired the colonization of mouse urinary tracts, but the ompX mutant still adhered to the epithelial cells at a level similar to that of the parent strain. FlhD, the master regulator of flagellum-related genes, had a low expression level in the ompX mutant compared to the parent strain, and the ompX mutant exhibited defective motility due to lower flagellar production than the parent strain. The fliC mutant, which lacks flagella, exhibited lower levels of bacterial internalization and aggregation than the parent strain. Additional deletion of ompX in the fliC mutant did not further decrease bacterial internalization. These combined results suggest that OmpX contributes to flagellar production in UPEC and then sustains UPEC virulence associated with bacterial internalization and aggregation within urinary tract cells and colonization in the urinary tract.

IL-33 is essential to prevent high-fat diet-induced obesity in mice infected with an intestinal helminth.

Intestinal helminthes induce immunosuppressive responses as well as type 2 immunity. Their suppressive properties are intended to regulate inflammatory diseases such as allergies and autoimmune diseases. This study evaluated whether helminthic infections suppress obesity, a chronic inflammatory state, using an intestinal nematode, Heligmosomoides polygyrus (Hp). Infection with Hp at the same time as feeding a high-fat diet (HFD) prevented weight gain, dyslipidaemia and glucose intolerance observed in uninfected obese mice. Immunologically, Hp infection skewed M1 macrophages to M2 macrophages and induced type 2 innate lymphoid cells in adipose tissues. The expression of interleukin (IL)-33, a potent initiator of type 2 responses, was also increased in association with uncoupled protein 1 (UCP1). To further investigate the anti-obesity effects of IL-33 in mice infected with Hp, IL-33-deficient mice were fed the HFD and infected with Hp. These mutant mice rapidly gained weight compared with wild-type mice, indicating the anti-obesity effect of IL-33. In the absence of IL-33, the rapid increase in weight was not prevented, and type 2 responses and UCP1 expression were not observed even during Hp infection. These results suggested that the suppression of obesity by Hp is dependent on IL-33.

Suppression of Obesity by an Intestinal Helminth through Interactions with Intestinal Microbiota.

Obesity is increasingly causing lifestyle diseases in developed countries where helminthic infections are rarely seen. Here, we investigated whether an intestinal nematode, Heligmosomoides polygyrus, has a suppressive role in diet-induced obesity in mice. Infection with H. polygyrus suppressed weight gain in obese mice, which was associated with increased uncoupling protein 1 (UCP1) expression in adipocytes and a higher serum norepinephrine (NE) concentration. Blocking interactions of NE with its receptor on adipocytes resulted in the failure to prevent weight gain and to enhance UCP1 expression in obese mice infected with H. polygyrus, indicating that NE is responsible for the protective effects of H. polygyrus on obesity. In addition to sympathetic nerve-derived NE, the intestinal microbiota was involved in the increase in NE. Infection with H. polygyrus altered the composition of intestinal bacteria, and antibiotic treatment to reduce intestinal bacteria reversed the higher NE concentration, UCP1 expression, and prevention of the weight gain observed after H. polygyrus infection. Our data indicate that H. polygyrus exerts suppressive roles on obesity through modulation of microbiota that produce NE.

IL-23 protection against Plasmodium berghei infection in mice is partially dependent on IL-17 from macrophages.

Although IL-12 is believed to contribute to protective immune responses, the role played by IL-23 (a member of the IL-12 family) in malaria is elusive. Here, we show that IL-23 is produced during infection with Plasmodium berghei NK65. Mice deficient in IL-23 (p19KO) had higher parasitemia and died earlier than wild-type (WT) controls. Interestingly, p19KO mice had lower numbers of IL-17-producing splenic cells than their WT counterparts. Furthermore, mice deficient in IL-17 (17KO) suffered higher parasitemia than the WT controls, indicating that IL-23-mediated protection is dependent on induction of IL-17 during infection. We found that macrophages were responsible for IL-17 production in response to IL-23. We observed a striking reduction in splenic macrophages in the p19KO and 17KO mice, both of which became highly susceptible to infection. Thus, IL-17 appears to be crucial for maintenance of splenic macrophages. Adoptive transfer of macrophages into macrophage-depleted mice confirmed that macrophage-derived IL-17 is required for macrophage accumulation and parasite eradication in the recipient mice. We also found that IL-17 induces CCL2/7, which recruit macrophages. Our findings reveal a novel protective mechanism whereby IL-23, IL-17, and macrophages reduce the severity of infection with blood-stage malaria parasites.

TusDCB, a sulfur transferase complex involved in tRNA modification, contributes to UPEC pathogenicity.

tRNA modifications play a crucial role in ensuring accurate codon recognition and optimizing translation levels. While the significance of these modifications in eukaryotic cells for maintaining cellular homeostasis and physiological functions is well-established, their physiological roles in bacterial cells, particularly in pathogenesis, remain relatively unexplored. The TusDCB protein complex, conserved in γ-proteobacteria like Escherichia coli, is involved in sulfur modification of specific tRNAs. This study focused on the role of TusDCB in the virulence of uropathogenic E. coli (UPEC), a bacterium causing urinary tract infections. The findings indicate that TusDCB is essential for optimal production of UPEC's virulence factors, including type 1 fimbriae and flagellum, impacting the bacterium's ability to aggregate in bladder epithelial cells. Deletion of tusDCB resulted in decreased virulence against urinary tract infection mice. Moreover, mutant TusDCB lacking sulfur transfer activity and tusE- and mnmA mutants revealed the indispensability of TusDCB's sulfur transfer activity for UPEC pathogenicity. The study extends its relevance to highly pathogenic, multidrug-resistant strains, where tusDCB deletion reduced virulence-associated bacterial aggregation. These insights not only deepen our understanding of the interplay between tRNA sulfur modification and bacterial pathogenesis but also highlight TusDCB as a potential therapeutic target against UPEC strains resistant to conventional antimicrobial agents.

The PapB/FocB family protein TosR acts as a positive regulator of flagellar expression and is required for optimal virulence of uropathogenic Escherichia coli.

Uropathogenic Escherichia coli (UPEC) is a major causative agent of urinary tract infections. The bacteria internalize into the uroepithelial cells, where aggregate and form microcolonies. UPEC fimbriae and flagella are important for the formation of microcolonies in uroepithelial cells. PapB/FocB family proteins are small DNA-binding transcriptional regulators consisting of approximately 100 amino acids that have been reported to regulate the expression of various fimbriae, including P, F1C, and type 1 fimbriae, and adhesins. In this study, we show that TosR, a member of the PapB/FocB family is the activator of flagellar expression. The tosR mutant had similar expression levels of type 1, P and F1C fimbriae as the parent strain, but flagellar production was markedly lower than in the parent strain. Flagellin is a major component of flagella. The gene encoding flagellin, fliC, is transcriptionally activated by the sigma factor FliA. The fliA expression is induced by the flagellar master regulator FlhDC. The flhD and flhC genes form an operon. The promoter activity of fliC, fliA and flhD in the tosR mutant was significantly lower than in the parent strain. The purified recombinant TosR does not bind to fliC and fliA but to the upstream region of the flhD gene. TosR is known to bind to an AT-rich DNA sequence consisting of 29 nucleotides. The characteristic AT-rich sequence exists 550-578 bases upstream of the flhD gene. The DNA fragment lacking this sequence did not bind TosR. Furthermore, loss of the tosR gene reduced motility and the aggregation ability of UPEC in urothelial cells. These results indicate that TosR is a transcriptional activator that increases expression of the flhDC operon genes, contributing to flagellar expression and optimal virulence.

A critical role for phagocytosis in resistance to malaria in iron-deficient mice.

Both iron-deficient anemia (IDA) and malaria remain a threat to children in developing countries. Children with IDA are resistant to malaria, but the reasons for this are unknown. In this study, we addressed the mechanisms underlying the protection against malaria observed in IDA individuals using a rodent malaria parasite, Plasmodium yoelii (Py). We showed that the intra-erythrocytic proliferation and amplification of Py parasites were not suppressed in IDA erythrocytes and immune responses specific for Py parasites were not enhanced in IDA mice. We also found that parasitized IDA cells were more susceptible to engulfment by phagocytes in vitro than control cells, resulting in rapid clearance of parasitized cells and that protection of IDA mice from malaria was abrogated by inhibiting phagocytosis. One possible reason for this rapid clearance might be increased exposure of phosphatidylserine at the outer leaflet of parasitized IDA erythrocytes. The results of this study suggest that parasitized IDA erythrocytes are eliminated by phagocytic cells, which sense alterations in the membrane structure of parasitized IDA erythrocytes.

Roles of the Tol/Pal System in Bacterial Pathogenesis and Its Application to Antibacterial Therapy.

The Tol/Pal system (also written as "The Tol-Pal system") is a set of protein complexes produced by most Gram-negative bacteria. It comprises the inner membrane-associated and the outer membrane-anchored subunits composed of the TolA, TolQ, and TolR proteins and the TolB and Pal proteins, respectively. Although the Tol/Pal system was first defined as bacterial proteins involved in colicin uptake of Escherichia coli, its global roles have been characterized in several studies as mentioned in this article. Pathogenesis of many Gram-negative pathogens is sustained by the Tol/Pal system. It is also essential for cell growth and fitness in some pathogens. Therefore, the Tol/Pal system is proposed as a potential target for antimicrobial chemotherapy. Although the tol/pal mutants are low in virulence, they still have the ability to stimulate the immune system. The Pal protein is highly immunogenic and induces both adaptive and innate immune responses. Therefore, the tol/pal mutant strains and Pal proteins also have potential vaccine properties. For these reasons, the Tol/Pal system represents a promising research target in the development of antibacterial therapeutic strategies for refractory infections caused by multi-drug-resistant (MDR), Gram-negative pathogens. In this paper, we summarize studies on the Tol/Pal system associated with bacterial pathogenesis and vaccine development.

A Macroporous Magnesium Oxide-Templated Carbon Adsorbs Shiga Toxins and Type III Secretory Proteins in Enterohemorrhagic Escherichia coli, Which Attenuates Virulence.

Enterohemorrhagic Escherichia coli (EHEC) is one of the most common foodborne pathogens. However, no drug that prevents the severe complications caused by this bacterium has been approved yet. This study showed that a macroporous magnesium oxide (MgO)-templated carbon material (MgOC150) adsorbs Shiga toxins, and Type III secretory EspA/EspB proteins responsible for EHEC pathogenesis, and decreases the extracellular levels of these proteins. On the other hand, this material did not affect the growth of EHEC. Citrobacter rodentium traditionally used to estimate Type III secretion system-associated virulence in mice is highly virulent. The survival period of infected mice was prolonged when MgOC150 was administered. This adsorbent disturbed neither mammalian cells nor normal intestinal bacteria, such as Enterococcus hirae, Lactobacillus acidophilus, and Lactobacillus casei. In contrast, MgOC150 adsorbed antimicrobial agents, including ß-lactams, quinolones, tetracyclines, and trimethoprim/sulfamethoxazole. However, fosfomycin and amikacin were not adsorbed. Thus, MgOC150 can be used with fosfomycin and amikacin to treat infections. MgOC150 is used for industrial purposes, such as an electrode catalyst, a bioelectrode, and enzyme immobilization. The study proposed another potential application of MgOC150, assisting anti-EHEC chemotherapy.

Live Vaccination with Blood-Stage Plasmodium yoelii 17XNL Prevents the Development of Experimental Cerebral Malaria.

In our work, we aim to develop a malaria vaccine with cross-strain (-species) protection. C57BL/6 mice infected with the P. berghei ANKA strain (PbA) develop experimental cerebral malaria (ECM). In contrast, ECM development is inhibited in infected mice depleted of T cells. The clinical applications of immune-cell depletion are limited due to the benefits of host defense against infectious diseases. Therefore, in the present study we attempted to develop a new method for preventing ECM without immune cell depletion. We demonstrated that mice inoculated with a heterologous live-vaccine of P. yoelii 17XNL were able to prevent both ECM and lung pathology and survived longer than control mice when challenged with PbA. Live vaccination protected blood-organ barriers from PbA infection. Meanwhile, live vaccination conferred sterile protection against homologous challenge with the P. yoelii 17XL virulent strain for the long-term. Analysis of the immune response induced by live vaccination showed that cross-reactive antibodies against PbA antigens were generated. IL-10, which has an immunosuppressive effect, was strongly induced in mice challenged with PbA, unlike the pro-inflammatory cytokine IFNγ. These results suggest that the protective effect of heterologous live vaccination against ECM development results from IL-10-mediated host protection.

Roles of OmpA in Type III Secretion System-Mediated Virulence of Enterohemorrhagic Escherichia coli.

Outer membrane proteins are commonly produced by gram-negative bacteria, and they have diverse functions. A subgroup of proteins, which includes OmpA, OmpW and OmpX, is often involved in bacterial pathogenesis. Here we show that OmpA, rather than OmpW or OmpX, contributes to the virulence of enterohemorrhagic Escherichia coli (EHEC) through its type III secretion system (T3SS). Deletion of ompA decreased secretion of the T3SS proteins EspA and EspB; however, the expression level of the LEE genes that encode a set of T3SS proteins did not decrease. The ompA mutant had less abilities to form A/E lesions in host epithelial cells and lyse human red blood cells than the parent strain. Moreover, the virulence of an ompA mutant of Citrobacter rodentium (traditionally used to estimate T3SS-associated virulence in mice) was attenuated. Mice infected with the ompA mutant survived longer than those infected with the parent strain. Furthermore, mice infected with ompA developed symptoms of diarrhea more slowly than mice infected with the parent strain. Altogether, these results suggest that OmpA sustains the activity of the T3SS and is required for optimal virulence in EHEC. This work expands the roles of outer membrane proteins in bacterial pathogenesis.

Long-term acrylamide exposure exacerbates brain and lung pathology in a mouse malaria model.

The consumption of dietary acrylamide (ACR), a carcinogen, results in the dysfunction of various organs and the immune system. However, the impact of ACR exposure on the progression of infectious diseases is unknown. This study investigated the effect of ACR on the progression of malaria infection using a mouse model of malaria. C57BL/6 mice were continuously treated with ACR at a dose of 20 mg/kg bodyweight/day for six weeks (long-term exposure) or phosphate-buffered saline (PBS). Next, the mice were infected with the rodent malaria parasite, Plasmodium berghei NK65 (PbNK). Parasitemia and survival rate were analyzed in the different treatment groups. Magnetic resonance imaging (MRI) and histopathological analyses were performed to evaluate the effect of ACR exposure on the morphology of various organs. Long-term ACR exposure exacerbated PbNK-induced multiorgan dysfunction. MRI and histopathological analysis revealed signs of encephalomeningitis and acute respiratory distress syndrome in the PbNK-infected long-term ACR exposure mice, which decreased the survival rate of mice, but not in the PbNK-infected long-term PBS exposure group. These findings enhance our understanding of the impact of ACR on the progression of infectious diseases, such as malaria.

Requirement of SIRPα for protective immunity against Leishmania major.

Signal regulatory protein α (SIRPα) is a transmembrane protein that binds the protein tyrosine phosphatases SHP-1 and SHP-2 through its cytoplasmic region and is abundantly expressed on dendritic cells and macrophages. Wild-type (WT) C57BL/6 mice are known to be resistant to Leishmania major infection. We here found that C57BL/6 mice that express a mutant version of SIRPα lacking most of the cytoplasmic region manifested increased susceptibility to L. major infection, characterized by the marked infiltration of inflammatory cells in the infected lesions. The numbers of the parasites in footpads, draining lymph nodes and spleens were also markedly increased in the infected SIRPα mutant mice, compared with those for the infected WT mice. In addition, soluble leishmanial antigen-induced production of IFN-γ by splenocytes of the infected SIRPα mutant mice was markedly reduced. By contrast, the ability of macrophages of SIRPα mutant mice to produce nitric oxide in response to IFN-γ was almost equivalent to that of macrophages from WT mice. These results suggest that SIRPα is indispensable for protective immunity against L. major by the induction of Th1 response.

Development of experimental cerebral malaria is independent of IL-23 and IL-17.

Cerebral malaria (CM) is the most severe complication of Plasmodium infection. Although inappropriate immune responses to Plasmodium falciparum are reported as the major causes of CM, the precise mechanisms for development remain unclear. IL-23 and IL-17 have critical roles in the onset of autoimmunity and inflammatory diseases triggered by microbial infections. Thus, we investigated the influence of IL-23 and IL-17 on experimental CM (ECM) using Plasmodium berghei ANKA infection of C57BL/6 mice. Both IL-23 deficient mice and wild-type (WT) mice developed ECM. IL-17 deficient mice also developed ECM, while IL-17 producing cells other than CD4(+) T cells (Th17) were increased in WT mice that developed ECM. In conclusion, this study showed that IL-23 and IL-17 are not involved in ECM development.

Suppression of systemic lupus erythematosus in NZBWF1 mice infected with Hymenolepis microstoma.

Intestinal helminths induce immune suppressive responses thought to regulate inflammatory diseases including allergies and autoimmune diseases. This study was designed to evaluate whether helminthic infections suppress the natural development of systemic lupus erythematosus (SLE) in NZBWF1 mice. Infection of NZBWF1 SLE-prone mice with two nematodes failed to establish long-lasting settlement. However, the Hymenolepis microstoma (Hm) rodent tapeworm successfully established long-term parasitization of NZBWF1 mice and was used to evaluate the suppressive effects of helminth infection. Ten-month-old NZBWF1 mice developed symptoms including autoantibody generation, proteinuria, glomerular histopathology, and splenomegaly, but mice infected with Hm at 2 months of age did not show any clinical signs. Furthermore, infection with Hm reduced lymphocyte activation and increased regulatory T cells in the spleen and mesenteric lymph nodes. These results indicate that infection with Hm protects NZBWF1 mice from naturally developing SLE and suggest that pathological immunity is attenuated, presumably because of the induction of regulatory T cells.

Polyglutamine-containing microglia leads to disturbed differentiation and neurite retraction of neuron-like cells.

Expanded polyglutamine-containing proteins in neurons intrinsically contributes to neuronal dysfunctions and neuronal cell death in polyglutamine (polyQ) diseases. In addition, an expanded polyQ-containing protein in microglia also leads to apoptosis of neurons. However, detailed morphological analysis of neurons exposed to conditioned medium (CM) derived from polyQ-containing microglia has not been essentially carried out. Here, we introduced aggregated peptide with 69 glutamine repeat (69Q) into BV2 microglial cells. The 69Q-containing BV2 cells showed shorter branches. The CM from 69Q-containing microglia (69Q-CM) induced neurite retraction and fewer number of branch point of neurites of differentiated PC12 cells. Likewise, the 69Q-CM induces disturbed differentiation of PC12 cells with shorter total length of neurites and fewer number of branch point of neurites. Thus, the factor(s) released from polyQ-containing microglia affect both differentiation and degeneration of neuron-like cells.

Roles of the Tol-Pal system in the Type III secretion system and flagella-mediated virulence in enterohemorrhagic Escherichia coli.

The Tol-Pal system is a protein complex that is highly conserved in many gram-negative bacteria. We show here that the Tol-Pal system is associated with the enteric pathogenesis of enterohemorrhagic E. coli (EHEC). Deletion of tolB, which is required for the Tol-Pal system decreased motility, secretion of the Type III secretion system proteins EspA/B, and the ability of bacteria to adhere to and to form attaching and effacing (A/E) lesions in host cells, but the expression level of LEE genes, including espA/B that encode Type III secretion system proteins were not affected. The Citrobacter rodentium, tolB mutant, that is traditionally used to estimate Type III secretion system associated virulence in mice did not cause lethality in mice while it induced anti-bacterial immunity. We also found that the pal mutant, which lacks activity of the Tol-Pal system, exhibited lower motility and EspA/B secretion than the wild-type parent. These combined results indicate that the Tol-Pal system contributes to the virulence of EHEC associated with the Type III secretion system and flagellar activity for infection at enteric sites. This finding provides evidence that the Tol-Pal system may be an effective target for the treatment of infectious diseases caused by pathogenic E. coli.

Potential and Limitations of Cross-Protective Vaccine against Malaria by Blood-Stage Naturally Attenuated Parasite.

Human malaria vaccine trials have revealed vaccine efficacy but improvement is still needed. In this study, we aimed to re-evaluate vaccination with blood-stage naturally attenuated parasites, as a whole-organism vaccine model against cross-strain and cross-species malaria, to establish a better vaccination strategy. C57BL/6 mice controlled blood-stage Plasmodium yoelii 17XNL (PyNL) within 1 month of infection, while mice with a variety of immunodeficiencies demonstrated different susceptibilities to PyNL, including succumbing to hyperparasitemia. However, after recovery, survivors had complete protection against a challenge with the lethal strain PyL. Unlike cross-strain protection, PyNL-recovered mice failed to induce sterile immunity against Plasmodium berghei ANKA, although prolonged survival was observed in some vaccinated mice. Splenomegaly is a typical characteristic of malaria; the splenic structure became reorganized to prioritize extra-medullary hematopoiesis and to eliminate parasites. We also found that the peritoneal lymph node was enlarged, containing activated/memory phenotype cells that did not confer protection against PyL challenge. Hemozoins remained in the spleen several months after PyNL infection. Generation of an attenuated human blood-stage parasite expressing proteins from multiple species of malaria would greatly improve anti-malaria vaccination.

Blood-cerebrospinal fluid barrier: another site disrupted during experimental cerebral malaria caused by Plasmodium berghei ANKA.

Cerebral malaria is one of the most severe pathologies of malaria; it induces neuro-cognitive sequelae and has a high mortality rate. Although many factors involved in the development of cerebral malaria have been discovered, its pathogenic mechanisms are still not completely understood. Most studies on cerebral malaria have focused on the blood-brain barrier, despite the importance of the blood-cerebrospinal fluid barrier, which protects the brain from peripheral inflammation. Consequently, the pathological role of the blood-cerebrospinal fluid barrier in cerebral malaria is currently unknown. To examine the status of the blood-cerebrospinal fluid barrier in cerebral malaria and malaria without this pathology (non-cerebral malaria), we developed a new method for evaluating the permeabilization of the blood-cerebrospinal fluid barrier during cerebral malaria in mice, using Evans blue dye and a software-assisted image analysis. Using C57BL/6J (B6) mice infected with Plasmodium berghei ANKA strain as an experimental cerebral malaria model and B6 mice infected with P. berghei NK65 strain or Plasmodium yoelii as non-cerebral malaria models, we revealed that the permeability of the blood-cerebrospinal fluid barrier increased during experimental cerebral malaria but not during non-cerebral malaria. We observed haemorrhaging in the cerebral ventricles and hemozoin-like structures in the choroid plexus, which is a key component of the blood-cerebrospinal fluid barrier, in cerebral malaria mice. Taken together, this evidence indicates that the blood-cerebrospinal fluid barrier is disrupted in experimental cerebral malaria, whereas it remains intact in non-cerebral malaria. We also found that P. berghei ANKA parasites and CD8+ T cells are involved in the blood-cerebrospinal fluid barrier disruption in experimental cerebral malaria. An understanding of the mechanisms underlying cerebral malaria might help in the development of effective strategies to prevent and manage cerebral malaria in humans.