Antibodies specific for heat shock proteins in human and murine malaria

Heat shock proteins (HSPs) are immunodominant antigens recognized by the host immune system in various infectious diseases. We analyzed HSP-specific antibodies, including immunoglobulin G (IgG), IgM and IgA, in sera from malaria patients in Thailand by using an enzyme-linked immunosorbent assay. All of the antibodies to HSP90 were remarkably increased in the patients compared with those in controls, while only IgM to HSP70 or IgA to HSP65 was significantly elevated. Further experiments showed that anti-HSP IgG was significantly increased in C57BL/6 mice infected with a non-lethal strain of Plasmodium yoelii, with anti-HSP90 IgG being the most elevated. These results suggest that the antigenic potential of HSP90 is higher than those of HSP70 and HSP65 in malaria infection.     

Neuropathogenesis of AIDS

Neurological disease directly attributable to HIV-1 infection (HIV dementia) is one of the most frequent disorders in persons with AIDS. HIV-1 dementia is associated with neuronal loss, but occurs in the absence of direct viral infection of neurons, suggesting that neurological damage occurs by an indirect mechanism. Recent studies have identified a number of candidate HIV-1 neurotoxins that may cause neuronal damage through common pathways involving the induction of oxidative stress and excitotoxicity. These findings suggest new therapeutic approaches to the prevention and treatment of HIV-1-induced neurological disease.     

Neuropathogenesis of chimeric simian human immunodeficiency virus infection in rhesus macaques

Comparative studies were performed to determine the neuropathogenesis of infection in macaques with simian human immunodeficiency virus (SHIV)89.6P and SHIV(KU). Both viruses utilize the CD4 receptor and CXCR4 co-receptor. However, in addition, SHIV89.6P uses the CCR5 co-receptor. Both agents are dual tropic for CD4+ T cells and blood-derived macrophages of rhesus macaques. Following inoculation into macaques, both caused rapid elimination of CD4+ T cells but they varied greatly in mechanisms of neuropathogenesis. Two animals infected with SHIV89.6P developed typical lentiviral encephalitis in which multinucleated giant cell formation, nodular accumulations of microglial cells, activated macrophages and astrocytes, and perivascular accumulations of mononuclear cells were present in the brain. Many of the macrophages in these lesions contained viral RNA. Three macaques infected with SHIV(KU) and killed on days 6, 11 and 18, respectively, developed a slowly progressive infection in the CNS but macrophages were not productively infected and there were no pathological changes in the brain. Two other animals infected with this virus and killed several months later showed minimal infection in the brain even though one of the two developed encephalitis of unknown etiology. The basic difference in the mechanisms of neuropathogenesis by the two viruses may be related to co-receptor usage. SHIV89.6P, in utilizing the CCR5 co-receptor, caused neuropathogenic effects that are similar to other neurovirulent primate lentiviruses.     

Neuropathogenesis of chimeric simian human immunodeficiency virus infection in rhesus macaques

Comparative studies were performed to determine the neuropathogenesis of infection in macaques with simian human immunodeficiency virus (SHIV)89.6P and SHIV_KU. Both viruses utilize the CD4 receptor and CXCR4 co-receptor. However, in addition, SHIV89.6P uses the CCR5 co-receptor. Both agents are dual tropic for CD4⁺ T cells and blood-derived macrophages of rhesus macaques. Following inoculation into macaques, both caused rapid elimination of CD4⁺ T cells but they varied greatly in mechanisms of neuropathogenesis. Two animals infected with SHIV89.6P developed typical lentiviral encephalitis in which multinucleated giant cell formation, nodular accumulations of microglial cells, activated macrophages and astrocytes, and perivascular accumulations of mononuclear cells were present in the brain. Many of the macrophages in these lesions contained viral RNA. Three macaques infected with SHIV_KU and killed on days 6, 11 and 18, respectively, developed a slowly progressive infection in the CNS but macrophages were not productively infected and there were no pathological changes in the brain. Two other animals infected with this virus and killed several months later showed minimal infection in the brain even though one of the two developed encephalitis of unknown etiology. The basic difference in the mechanisms of neuropathogenesis by the two viruses may be related to co-receptor usage. SHIV89.6P, in utilizing the CCR5 co-receptor, caused neuropathogenic effects that are similar to other neurovirulent primate lentiviruses.     

Genetic control of resistance to murine malaria

Strain variation in the level of resistance to malaria was investigated in inbred mice after infection with Plasmodium chabaudi. Following intraperitoneal infection with the typing dose of parasitized erythrocytes, mice of 11 inbred strains could be separated using survival time as the criterium into resistant and susceptible groups. Genetic analysis of F₁ hybrid and backcross progeny derived from one of the most resistant (B10.A) and from the most susceptible (A/J) strains as parents suggested that host resistance in this strain combination was genetically controlled by a dominant, non-H-2-linked, autosomal gene or closely linked genes. Analysis of the mechanisms of resistance to P chabaudi showed (1) phenotypic expression of the resistance gene was apparent within 6 days of infection as a significant difference between resistant and susceptible mice in the level of parasitemia; (2) the level of host NK cell activity was not related to the level of host resistance to malaria; (3) compared with susceptible A/J mice, resistant B1O.A hosts had an augmented erythropoietic response during the course of malaria as well as during phenylhydrazine-induced anemia and (4) treatment with BCG or P acnes resulted in an equal degree of protection, measured by parasitemia and survival, in both resistant and susceptible mice.     

Filaria-induced IL-10 suppresses murine cerebral malaria

Filarial nematodes achieve long survival in their hosts due to their capacity to modulate immune responses. Therefore, immunomodulation by filarial nematodes may alter responses to concomitant infections such as malaria. Cerebral malaria (CM), a severe complication of Plasmodium falciparum infections, is triggered as a consequence of the immune response developed against malaria parasites. The question arises whether prior infection with helminth parasites is beneficial against CM. In the present work a murine model for subsequent has been used to assess this hypothesis. C57BL/6 mice were infected with the rodent filarial parasite Litomosoides sigmodontis and the murine model parasite for CM, Plasmodium berghei ANKA. Previously filaria-infected C57BL/6 mice showed significantly reduced CM rates. CD8⁺ T cell recruitment to the brain, a hallmark for CM development, was reduced in protected mice. Furthermore, in contrast to P. berghei single-infected animals, filaria-infected mice had significantly higher levels of circulating IL-10. The requirement for IL-10 in CM protection was demonstrated by the lack of protection in IL-10 KO mice. This suggests that the anti-inflammatory IL-10 elicited by filarial nematodes is able to suppress the overwhelming inflammatory reaction otherwise triggered against malaria parasites in C57BL/6 mice, preventing full progress to CM.     

Glycosylphosphatidyl-inositols in murine malaria: Plasmodium yoelii yoelii

Glycosylphosphatidyl-inositols (GPIs) are vital major glycoconjugates in intraerythrocytic stages of Plasmodium. Here, we report on the biosynthesis and the characterization of GPIs synthesized by the murine malarial parasite P. yoelii yoelii YM. Parasitized erythrocytes were labeled in vivo and in vitro with either radioactive nucleotide sugar precursors, ethanolamine or glucosamine. The pathway leading to the formation of GPI precursors was found to resemble that described for P. falciparum; however, in P. yoelii, the formation of an additional hydrophilic precursor containing an acid-labile modification was detected. The data suggest that this modification is linked to the fourth mannose attached to the trimannosyl backbone in an alpha1-2 linkage. The modification was susceptible to hydrofluoric acid (HF), but not to nitrous acid (HNO(2)). Data obtained from size-exclusion chromatography on Bio-Gel P4, and Mono Q analysis of the fragments generated by HNO(2) deamination suggest that the modification is due to the presence of an additional ethanolamine linked to the fourth mannose via a phosphodiester bond.     

Circulating and tissue-bound immune complex formation in murine malaria.

Immune complex formation during Plasmodium berghei infection of OF1 mice was investigated. Circulating immune complexes (CIC) were detected by the Clg-binding assay and the conglutinin-binding solid-phase assay in lethal or drug-limited infections. CIC appeared on day 9 of infection, peaked on day 11, and disappeared only after complete cure of the infection. Analysis of the immune complexes detected by the Clq-binding assay revealed the following characteristics: sedimentation coefficients of 13S to 21S, resistance to DNAse, and selective removal by filtration through protein A bound to Sepharose. Glomerular deposits of IgM preceded the appearance of CIC, whereas deposits of IgG and C3 were concomitant with the appearance of CIC. Tissue-bound immunoglobulins were also found in the choroid plexus. The appearance of anti-malarial antibodies and malarial antigens in the serum was closely associated with a depression of C3 levels and the presence of CIC. Drug treatment was followed by normalization of C3 levels, and clearance of both CIC and malarial antigens.     

Neuropathogenesis of influenza virus infection in mice

The neurovirulent WSN strain of influenza A virus, introduced into the olfactory bulb of C57BL/6 mice, selectively attacks several brain nuclei which are highly implicated in the pathogenesis of neuropsychiatric disturbances. The virus-infected neurons are eradicated through apoptotic neurodegeneration. On the other hand, activated microglia serve the neuroprotection against virus infection.     

Fas and perforin contribute to the pathogenesis of murine cerebral malaria

Abstract

Malaria is a serious health, social and economic problem for over 40% of the world's population living in endemic regions. Of the half-billion people infected with malaria each year, some 2.5 million will develop cerebral complications. Even with expedient treatment with anti-malarials, the prognosis for an individual displaying symptoms of cerebral malaria remains poor, with an estimated 25%of cases resulting in death. There is, as yet, no direct treatment for cerebral malaria, and the exact mechanism by which it causes death is still undetermined.