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Abstract. The clinical signs, hematologic changes, serum and fecal virus titers, specific antibody production and the occurrence of histologic lesions were studied in 22 nine-week-old seronegative beagle dogs inoculated by the oral and intravenous route with canine parvovirus. Approximately 30% of the dogs had clinical signs of pyrexia, depression, vomiting, and diarrhea irrespective of the route of inoculation. Events in the dogs inoculated intravenously preceded those in dogs inoculated orally by approximately two days. Only one dog died. Lymphopenia was the most consistent hematologic change. Viremia always preceded the initiation of fecal virus shedding. Viral titers in the serum and feces were significantly greater in symptomatic dogs compared to asymptomatic dogs. Termination of the plasma viremia coincided with the onset of the humoral immune response, but viremia persisted one day longer in symptomatic dogs. The severity of lymphoid tissue and intestinal infection, assessed by tissue immunofluorescence and histology, was also greater in symptomatic dogs. The severity of intestinal disease was highly correlated with the magnitude and duration of viremia.The clinical signs, clinicopathologic and pathologic changes in fatal cases of naturally occurring canine parvovirus enteritis have been well-do~umented.~~~.Fatal cases are characterized by leukopenia and extensive necrosis of intestinal gland epithelium and lymphoid tissues. Although subclinical infection with canine parvovirus is less wellcharacterized, serologic evidence and limited epidemiologic s t~d i e s '~. ' ' ,~~ suggest that canine parvovirus infection more frequently results in subclinical than fatal disease. Similarly, experimental canine parvovirus enteritis infrequently results in severe clinical disease. Severe illness has been experimentally produced by intravenod5 and by oronasal and intraga~tric'.~~ inoculation of puppies. In the later clinical signs occurred only in dogs vaccinated with a mixed vaccine five days prior to canine parvovirus inoculation. Factors associated with the variation in the severity of the enteric disease in both the experimental and the natural setting have not been identified.This study was undertaken to determine the pathogenesis of experimental canine parvovirus enteritis and to identify factors associated with its variable severity. Materials and MethodsEighteen conventional and ten specific pathogen free seronegative nine-week-old beagle dogs were housed in individual 10. 13. 14. 16. 18.21.23.25.26.28.30.32.39.4l cages within isolation units, fed commercial dry dog food, and provided water ad libitum.Following a 12-hour fast, seven conventional and four specific pathogen free dogs were inoculated orally, and an equal number intravenously with I O5 tissue culture infective doses (TCID5,J of canine parvovirus. Four conventional and two specific pathogen free dogs were uninoculated controls. Rectal temperatures and clinical signs were recorded daily.Blood and fecal samples were collected daily for three days ...

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Intracellular phosphorylations polymorphonuclear neutrophils are mediated by kinases, including mitogen activated-protein (MAP) kinases and phosphatidylinositol 3-kinase. In the present study we demonstrate their effector functions upon both ligation of cell-surface seven-transmembrane-spanning receptors by bacterial peptide formylmethionyl-leucylphenylalanine as well as in the process of destruction of Staphylococcus aureus. To regulate neutrophil MAP kinases p38 and p44/42, specifically, we made use of their specific inhibitors 10 microM SK&F 86002 (for p38) and PD 098059 (for activating kinase of p44/42). SK&F 86002 was a potent inhibitor (by 70%) of induced antimicrobial oxygen-radical generation compared with PD 098059 (by 20%). SK&F 86002 and PD 098059 inhibited mobilization of a dominant neutrophil adhesion molecule, beta2 integrin, from cytoplasmic granules to the plasma membrane by 40 and 10% respectively, and the combination of the two drugs resulted in a 90% effect. The combined effect of both drugs was moderate inhibition of bacterial destruction, despite the fact that neither compound had detectable effect on bactericidal activity if applied individually. Bacterial destruction was also inhibited by wortmannin (0.1 microM), the specific inhibitor of phosphatidylinositol 3-kinase, which had previously been described to target various other activations of the neutrophil, including oxygen-radical generation. Although the relative contribution of p38 and p44/42 MAP kinases varied, the marked effects of the combined inhibition of the kinases revealed their concerted actions to be critical for normal neutrophil function.