ABSTRACT
Murine Typhus is a zoonosis caused by the organism Rickettsia typhi and is transmitted to humans by fleas. It is endemic in several areas of Texas, California and Hawaii where the vector is supported predominantly by rodents in addition to opossums, domestic and feral cats and domestic dogs. We present a typical case in an adult from Corpus Christi, located in one of the four endemic areas in Texas. Included is an overview of the organism's pathogenicity and our host responses, both influencing the milder clinical course seen with this species of Rickettsia.
Subject(s)
Ectoparasitic Infestations/epidemiology , Endemic Diseases , Insect Vectors , Rickettsia typhi/pathogenicity , Typhus, Endemic Flea-Borne/epidemiology , Animals , Ceftriaxone/therapeutic use , Disease Reservoirs , Doxycycline/therapeutic use , Drug Therapy, Combination , Ectoparasitic Infestations/diagnosis , Ectoparasitic Infestations/drug therapy , Humans , Male , Middle Aged , Prednisone/therapeutic use , Siphonaptera/microbiology , Texas/epidemiology , Typhus, Endemic Flea-Borne/diagnosis , Typhus, Endemic Flea-Borne/drug therapyABSTRACT
The Rrm2b gene encodes p53R2, a catalytic subunit of ribonucleotide reductase that is required for DNA repair. Embryonic stem (ES) cells containing a retroviral insertion in the Rrm2b locus were used to generate mutant mice. Analysis of kidney RNA from Rrm2b (-/-) mice showed that the retroviral insertion disrupted expression of Rrm2b transcripts. Rrm2b (-/-) pups were represented at the expected Mendelian ratios at 10-12 days of age and grew normally past weaning. Mice failed to thrive after 6 weeks of age and began to die by 8 weeks of age. Phenotyping revealed that Rrm2b (-/-) mice died from a severe glomerular lesion that led to nephrotic syndrome and chronic renal failure. In kidneys of Rrm2b (-/-) mice, podocytes were enlarged and there was evidence of foot process effacement by 6 weeks of age. By 8 weeks of age, progressive podocyte hypertrophy and loss of foot processes was accompanied by hypertrophy of glomerular capillary endothelial cells that was extensive enough to restrict capillary blood flow. Collapsing glomerulopathy with avascular glomeruli was widespread in mice surviving beyond 9 weeks of age. Additional abnormalities in other organ systems were minor or consistent with secondary effects of renal failure. These findings suggest that lack of p53R2, the protein encoded by Rrm2b, has early and relatively selective detrimental effects on the kidney glomerulus that lead to rapid death from progressive renal failure.
Subject(s)
Cell Cycle Proteins/genetics , Kidney Glomerulus/pathology , Renal Insufficiency/genetics , Renal Insufficiency/pathology , Ribonucleotide Reductases/genetics , Animals , Female , Male , Mice , Microscopy, Electron , Time FactorsABSTRACT
The availability of both the mouse and human genome sequences allows for the systematic discovery of human gene function through the use of the mouse as a model system. To accelerate the genetic determination of gene function, we have developed a sequence-tagged gene-trap library of >270,000 mouse embryonic stem cell clones representing mutations in approximately 60% of mammalian genes. Through the generation and phenotypic analysis of knockout mice from this resource, we are undertaking a functional screen to identify genes regulating physiological parameters such as blood pressure. As part of this screen, mice deficient for the Wnk1 kinase gene were generated and analyzed. Genetic studies in humans have shown that large intronic deletions in WNK1 lead to its overexpression and are responsible for pseudohypoaldosteronism type II, an autosomal dominant disorder characterized by hypertension, increased renal salt reabsorption, and impaired K+ and H+ excretion. Consistent with the human genetic studies, Wnk1 heterozygous mice displayed a significant decrease in blood pressure. Mice homozygous for the Wnk1 mutation died during embryonic development before day 13 of gestation. These results demonstrate that Wnk1 is a regulator of blood pressure critical for development and illustrate the utility of a functional screen driven by a sequence-based mutagenesis approach.
Subject(s)
Blood Pressure/physiology , Protein Serine-Threonine Kinases/deficiency , Animals , Base Sequence , Blood Pressure/genetics , DNA, Complementary/genetics , Gene Library , Genetic Techniques , Heterozygote , Humans , Hypertension/therapy , Intracellular Signaling Peptides and Proteins , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Minor Histocompatibility Antigens , Molecular Sequence Data , Mutagenesis, Insertional/methods , Phenotype , Protein Serine-Threonine Kinases/genetics , Protein Serine-Threonine Kinases/physiology , Sequence Tagged Sites , WNK Lysine-Deficient Protein Kinase 1ABSTRACT
Normal sensory transduction requires the efficient disposal of acid (H+) generated by neuronal and sensory receptor activity. Multiple highly sensitive transport mechanisms have evolved in prokaryotic and eukaryotic organisms to maintain acidity within strict limits. It is currently assumed that the multiplicity of these processes provides a biological robustness. Here we report that the visual and auditory systems have a specific requirement for H+ disposal mediated by the sodium bicarbonate cotransporter NBC3 (refs. 7,8). Mice lacking NBC3 develop blindness and auditory impairment because of degeneration of sensory receptors in the eye and inner ear as in Usher syndrome. Our results indicate that in certain sensory organs, in which the requirement to transduce specific environmental signals with speed, sensitivity and reliability is paramount, the choice of the H+ disposal mechanism used is limited.
