Immune responses of goats persistently infected with caprine arthritis-encephalitis virus.

Eight cesarean-derived goat kids were inoculated with caprine arthritis-encephalitis virus (CAEV), and proliferative responses of their peripheral blood mononuclear cells to mitogens and CAEV antigen were monitored for 9 months. Antibody specific for CAEV was measured by an enzyme-linked immunosorbent assay. Five cesarean-derived noninfected goats were tested simultaneously. Significant differences between the infected and control mononuclear cell proliferation reactions to CAEV began 14 days post-inoculation and continued in a fluctuant manner until 134 days post-inoculation. The magnitude of the proliferative reaction steadily increased in infected goats until the end of the experiment at 271 days post-inoculation. Responses to mitogens were not significantly different between infected and control goats. Virus-inoculated goats produced CAEV-specific antibody that reached a maximum level between 49 and 77 days post-inoculation and then declined to lower levels through 271 days post-inoculation. The virus-inoculated goats developed mild but characteristic clinical evidence of caprine arthritis-encephalitis, and CAEV was reisolated from four goats at 286 days post-inoculation. The five control goats developed neither an anti-CAEV immune response nor clinical disease, and CAEV could not be reisolated from them.     

Epitope-specific humoral immunity to Plasmodium vivax Duffy binding protein

Erythrocyte invasion by Plasmodium vivax is completely dependent on binding to the Duffy blood group antigen by the parasite Duffy binding protein (DBP). The receptor-binding domain of this protein lies within a cysteine-rich region referred to as region II (DBPII). To examine whether antibody responses to DBP correlate with age-acquired immunity to P. vivax, antibodies to recombinant DBP (rDBP) were measured in 551 individuals residing in a village endemic for P. vivax in Papua New Guinea, and linear epitopes mapped in the critical binding region of DBPII. Antibody levels to rDBP(II) increased with age. Four dominant linear epitopes were identified, and the number of linear epitopes recognized by semi-immune individuals increased with age, suggesting greater recognition with repeated infection. Some individuals had antibodies to rDBP(II) but not to the linear epitopes, indicating the presence of conformational epitopes. This occurred in younger individuals or subjects acutely infected for the first time with P. vivax, indicating that repeated infection is required for recognition of linear epitopes. All four dominant B-cell epitopes contained polymorphic residues, three of which showed variant-specific serologic responses in over 10% of subjects examined. In conclusion, these results demonstrate age-dependent and variant-specific antibody responses to DBPII and implicate this molecule in partial acquired immunity to P. vivax in populations in endemic areas.     

SspA is required for lethal Salmonella enterica serovar Typhimurium infections in calves but is not essential for diarrhea

Salmonella pathogenicity island 1 (SPI-1) encodes virulence determinants, which are important for enteropathogenicity in calves. To determine whether the Salmonella enterica serovar Typhimurium SPI-1 effector proteins SspA and SptP are important for enteropathogenicity, strains lacking these proteins were tested during oral infection of calves. Calves infected with a sptP mutant or its isogenic parent developed diarrhea and lethal morbidity. In contrast, calves infected with an sspA mutant developed diarrhea, which resolved within 10 days but did not result in mortality. The sspA mutant was recovered from bovine intestinal tissues at numbers similar to those obtained for its isogenic parent and caused marked intestinal lesions. Thus, the severity of pathological changes caused by serovar Typhimurium strains or their ability to cause diarrhea were not predictive of their ability to cause lethal morbidity in calves. We conclude that factors other than or in addition to bacterial colonization, intestinal lesions, or electrolyte loss contribute to lethal morbidity in calves infected with serovar Typhimurium.     

Massive haemorrhagic necrosis of the liver after liver transplantation.

Six of the first 85 patients who received the first 100 liver transplantations carried out in Birmingham developed a syndrome of fulminant liver failure with distinctive clinical and pathological features. The typical clinical presentation was of an uneventual initial postoperative period, followed by a sudden deterioration in graft function, progressing rapidly to graft failure. All six patients died. The characteristic pathological changes were those of massive haemorrhage and hepatocyte necrosis with only mild inflammation and without occlusive lesions in large arteries or veins. These distinctive features differed from other recognised patterns of graft damage and seemed to comprise a specific post-transplant syndrome. The pathogenesis was not clear and in the absence of any definite aetiology it is suggested that the term "massive haemorrhagic necrosis" be used to describe these cases. Additional findings seen in five of the six cases were venoocclusive lesions (n = 4) and a combination of ductopenia and foam cell arteriopathy (n = 2). The presence of these associated lesions suggests that there may be an overlap with other types of graft damage.     

Polyglutamine-expanded androgen receptors form aggregates that sequester heat shock proteins, proteasome components and SRC-1, and are suppressed by the HDJ-2 chaperone

Spinal bulbar muscular atrophy is a neurodegenerative disorder caused by a polyglutamine expansion in the androgen receptor (AR). We show in transiently transfected HeLa cells that an AR containing 48 glutamines (ARQ48) accumulates in a hormone-dependent manner in both cytoplasmic and nuclear aggregates. Electron microscopy reveals both types of aggregates to have a similar ultrastructure. ARQ48 aggregates sequester mitochondria and steroid receptor coactivator 1 and stain positively for NEDD8, Hsp70, Hsp90 and HDJ-2/HSDJ. Co-expression of HDJ-2/HSDJ significantly represses aggregate formation. ARQ48 aggregates also label with antibodies recognizing the PA700 proteasome caps but not 20S core particles. These results suggest that ARQ48 accumulates due to protein misfolding and a breakdown in proteolytic processing. Furthermore, the homeostatic disturbances associated with aggregate formation may affect normal cell function.     

Administration of bacterial lipopolysaccharide elicits circulating tumor necrosis factor-alpha in neonatal calves.

The presence of tumor necrosis factor-alpha (TNF-alpha) during endotoxemia in ruminants has not been reported previously. In this study, we detected the in vivo release of bovine TNF-alpha by using WEHI-164 murine fibrosarcoma cells as targets in an 18-h cytotoxicity assay. Treatment of the WEHI-164 cells with 1 microgram of actinomycin D (dactinomycin) enhanced approximately twofold the susceptibility of the cells to TNF-alpha activity. TNF-alpha activity in sera from neonatal calves injected intravenously with 2.7 micrograms of Escherichia coli lipopolysaccharide (LPS) increased rapidly within the first 2 h postinjection and then declined until it was undetectable by 4 h postinjection. Sera taken before LPS administration had no TNF-alpha activity. LPS (10 micrograms/ml) and fetal, newborn, and pooled adult bovine sera alone and in combination had no direct cytotoxic effects on WEHI-164 cells. TNF-alpha cytotoxic activity is probably not due to the presence of interleukin-1 (IL-1), alpha interferon, or gamma interferon in the sera since recombinant human IL-1, natural bovine IL-1, and recombinant bovine alpha and gamma interferons had no direct cytotoxic effects on WEHI-164 cells. A monoclonal antibody that neutralizes recombinant human TNF-alpha significantly reduced the cytotoxic activity of sera from LPS-injected calves.     

Pathogen-related oral spirochetes from dental plaque are invasive.

Spirochetes that share pathogen-restricted antigens with Treponema pallidum subsp. pallidum have been identified in dental plaque and diseased gingival tissues, but it is not known whether these spirochetes possess virulence characteristics. In this study, plaque spirochetes were able to transmigrate a tissue barrier in vitro and were identified on the other side by using monoclonal antibodies specific for pathogen-restricted determinants from T. pallidum subsp. pallidum. This invasive capability is shared with T. pallidum subsp. pallidum, but cultured oral and intestinal treponemes did not perforate the tissue barrier. Cocultures indicated that invasive treponemes do not create opportunities for cultivable oral treponemes to cross the barrier. These findings indicate that gingival tissues may be a port of entry for previously unrecognized invasive spirochetes in humans.