Abstract
Prions are unusual disease agents that lack nucleic acids. Instead their infectious potential is due to a protein that is identical in sequence to a normal mammalian protein (PrPC) but that has an altered conformation (PrPSc), rendering it protease–resistant. The immune system appears to promote rather than protect from prion disease. However, with proper immunization, mice can mount a protective immune response against recombinant PrP. Mice were immunized once every two weeks for 14 weeks by subcutaneous injection of PrP mixed with Freund's adjuvant. They were challenged with a brain homogenate of mouse-adapted scrapie either before or following vaccination. Immunization delayed the onset of disease and the delay of disease onset was correlated with antibody levels. Symptoms of disease were delayed longer in mice vaccinated before challenge than in mice vaccinated after challenge. It is hoped that this approach may hold promise for immunization of other species against prion disease.
Sigurdsson EM, Brown DR, Daniels M, Kascsak RJ, Kascsak R, Carp R, Meeker HC, Frangione B, Wisniewski T. Immunization delays the onset of prion disease in mice. Am J Pathol 161:13–17, 2002
Bovine leukemia virus, a deltaretrovirus, infects ruminants and causes B lymphocyte proliferative disease. It is unclear whether lymphocytosis is due to enhanced proliferation or reduced apoptosis. In an effort to determine which of these two processes was actually responsible for increasing lymphocytes counts, European investigators examined the lymphocytes of experimentally infected sheep, using a combination of in vivo 5-bromodeoxyuridine injection, ex vivo techniques, and mathematical modeling. Based on these studies, the investigators concluded that lymphocytosis in infected animals was due to accelerated lymphocyte proliferation rather than to decreased lymphocyte apoptosis. Furthermore, there appeared to be very efficient removal in vivo of retrovirus-infected cells expressing viral proteins. Thus the resistance to apoptosis apparent in vitro does not appear to play an important role in disease evolution in vivo.
Debaq C, Asquith B, Kerkhofs P, Portetelle D, Burny A, Kettmann R, Willems L. Increased cell proliferation, but not reduced cell death, induces lymphocytosis in bovine leukemia virus-infected sheep. Proc Natl Acad Sci 99:10048–10053, 2002
It has long been known that caloric restriction dramatically prolongs life in rodents. More recent studies in primates indicate that caloric restriction attenuates age-related changes in plasma triglycerides, melatonin, oxidative damage, and glucose tolerance and suggest that caloric restriction enhances life span. Important markers of caloric restriction in primates include reduced body temperature, reduced plasma insulin, and maintenance of youthful levels of the adrenal steroid dehydroepiandrosterone sulfate (DHEAS). Recent studies from the National Institute on Aging demonstrated that men with lower temperature and insulin levels and higher DHEAS levels lived longer than others in their cohort. While these findings do not provide definitive evidence that changes in the longer-surviving men are due to calorie restriction, they suggest a possible relationship.
Roth GS, Lane MA, Ingram DK, Mattison JA, Elahi D, Tobin JD, Muller D, Metter EJ. Biomarkers of caloric restriction may predict longevity in humans. Science 297:811, 2002
Lentiviruses include those that cause peripheral immune deficiency, such as human immunodeficiency (HIV), and those that cause immune activation, like equine infectious anemia. However, both of these groups of retroviruses cause inflammation and neuronal injury in the central nervous system. A recent review in the Journal of Virology compared the neuropathogenic mechanisms of eight different lentiviruses with regard to viral characteristics, including neuroinvasion, neurotropism, neurovirulence, and host factors, including genetic susceptibility and immune response. The authors concluded that, despite differences between nonhuman lentiviruses and HIV, simian immunodeficiency and feline immunodeficiency viruses have many features in common with HIV and allow the performance of valuable in vivo studies.
Patrick MK, Johnston JB, Power C. Lentiviral neuropathogenesis: comparative neurotropism, neurovirulence, and host neurosusceptibility. J Virol 76:7923–7931, 2002
A recent multi-national effort has resulted in a physical map of the mouse genome based on analysis of bacterial artificial chromosomes (BAC) clones. Overlapping BAC clones were used to construct contigs and these were then compared to the human genome sequence. Coverage of the mouse genome was essentially complete. A total of 97% of mouse map could be aligned with the human genome sequence, covering approximately 88% of the human genome. A total of 288 “conserved segments” (identity and order of genes conserved) were identified within 167 regions of “conserved synteny” (identity of genes conserved, but not order) in the two species. The pattern of sequence conservation suggested that multiple interchromosomal rearrangements and intrachromosomal inversions have occurred since the human and mouse genomes diverged from that of a common ancestor. This new information will facilitate identification of mouse homologues of human genes.
Gregory SG, Sekhon M, Schein J, Zhao S, Osoegawa K, Scott CE, Evans RS, Burridge PW, Cox TV, Fox CA, Hutton RD, Mullenger IR, Phillips KJ, Smith J, Stalker J, Threadgold GJ, Birney E, Wylie K, Chinwalla A, Wallis J, Hillier L, Carter J, Gaige T, Jaeger S, Kremitzki C, Layman D, Maas J, McGrane R, Mead K, Walker R, Jones S, Smith M, Asano J, Bosdet I, Chan S, Chittaranjan S, Chiu R, Fjell C, Fuhrmann D, Girn N, Gray C, Guin R, Hsiao L, Krzywinski M, Kutsche R, Lee SS, Mathewson C, McLeavy C, Messervier S, Ness S, Pandoh P, Prabhu AL, Saeedi P, Smailus D, Spence L, Stott J, Taylor S, Terpstra W, Tsai M, Vardy J, Wye N, Yang G, Shatsman S, Ayodeji B, Geer K, Tsegaye G, Shvartsbeyn A, Gebregeorgis E, Krol M, Russell D, Overton L, Malek JA, Holmes M, Heaney M, Shetty J, Feldblyum T, Nierman WC, Catanese JJ, Hubbard T, Waterston RH, Rogers J, De Jong PJ, Fraser CM, Marra M, McPherson JD, Bentley DR. A physical map of the mouse genome. Nature 418:743–750, 2002