Biomedical subjects
Publications and source records attributed to C J Peters.
Two Egyptian male patients with sand fly fever-Naples virus infection are presented. The virus was isolated from one patient while both patients had diagnostic rises in indirect fluorescent antibody titers to the virus. The viral isolate, SFN 85055, grows to much higher titers and plaques more efficiently than the prototype sand fly fever-Naples virus and should facilitate work with this virus.
A mutagenized clone of Rift Valley fever virus (RVFV; MV P12) used in inoculation of 3 pregnant ewes was immunogenic, nonpathogenic, and nonabortogenic. In contrast, inoculation of a matched group of 3 pregnant ewes with parent RVFV induced clinical disease and abortions. Ewes given MV P12 delivered healthy lambs that had RVFV antibody titers of less than 1:10 at birth, increasing to greater than or equal to 1:80 after ingestion of colostrum. Ewes inoculated with parent RVFV developed marked viremia, followed by RVFV antibody titers greater than or equal to 1:1,280; ewes inoculated with MV P12 developed low viremia titers and RVFV antibody titers of 1:80 to 1:320. Postpartum challenge exposure of the previously MV P12-inoculated ewes with virulent Zagazig human 501 strain RVFV indicated that the ewes were protected from clinical disease. The RVFV-susceptible female Culex pipiens that fed on the MV P12-inoculated ewes failed to transmit RVFV to hamsters; mosquitoes that fed on the parent RVFV-inoculated ewes became infected and transmitted RVFV to hamsters.
An enzyme-linked immunosorbent assay (ELISA) was developed for the rapid detection of antibodies to Rift Valley fever virus (RVFV) in ovine and bovine sera. Conditions to reduce nonspecific reactions were optimized. The ELISA results correlated with those of a plaque-reduction neutralization test, revealing 100% specificity and 90.7% sensitivity. In sera from sheep and cattle inoculated against RVFV, the hemagglutination-inhibition test in combination with the ELISA provided a better indication of response to killed RVFV vaccine than did either test alone.
Guinea pigs infected with Argentine hemorrhagic fever virus (Junin) were treated with pooled, homologous convalescent sera. Use of 15,000 or 5,000 therapeutic units of immune sera prevented all signs of illness when administered within 24 hr of infection. We could also prevent illness and death in infected guinea pigs as late as 6 days after infection if we used more antisera (30,000 therapeutic units/kg). In some treatment groups, surviving animals developed a late neurological syndrome with prominent rear-limb paralysis. Treated animals typically expressed higher viral titers in the brain than in any other organ. There appeared to be no acute exacerbation of disease by antibody administration. Our data suggest that, after replicating peripherally, Junin virus infects the brain where circulating immunoglobulins may not eliminate viable virus. Subsequent replication of virus in the brain may generate a neurological phase of the illness. Histological examination of brains from guinea pigs in treatment groups favoring the neurological phase of illness showed encephalitis, meningitis, and swollen astrocytes, suggestive of neuronal degeneration. There is likely a delicate balance among presence of virus in the brain, the amount of antibody transported into the central nervous system, and the occurrence of this late neurological aspect of experimental Argentine hemorrhagic fever. Further study of this model may elucidate factors relevant in understanding the continuing problem of the late neurological syndrome seen in some human cases of Argentine hemorrhagic fever treated with immune plasma.
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Rift Valley fever virus (RVFV), a member of the family Bunyaviridae, extended its range from sub-Saharan Africa into Egypt in 1977. Its clinical spectrum is recognized to include severe manifestations such as hemorrhagic fever and encephalitis. For these reasons, as well as the limited knowledge of specific therapy for Bunyaviridae infections, we investigated several prophylactic regimens for RVF in a mouse model. Rimantadine, thiosemicarbazone, and inosiplex were ineffective. Pretreatment with glucan was of some use, but the most encouraging results were obtained with the antiviral drug ribavirin, passive antibody, or an interferon inducer polyriboinosinic-polyribocytidylic acid complexed with poly-L-lysine and carboxymethylcellulose (poly[ICLC]). Ribavirin and poly(ICLC) were also shown to be efficacious in preventing disease in hamsters. Ribavirin (loading dose of 50 mg/kg followed by 10 mg/kg at 8-h intervals for 9 days) suppressed viremia in RVF-infected rhesus monkeys. Ribavirin also reduced virus yield in infected cell cultures; sensitivity varied markedly with cell type but not with virus strain. Immune mouse ascitic fluid, with a plaque reduction neutralization titer of 1:1024, was effective in a dose of 4 ml/kg, a volume approximately equivalent to administration of a unit of convalescent plasma to a human. Poly(ICLC) may well have functioned through interferon induction, since RVFV was shown to be sensitive to interferon in cell culture, and since another macrophage activator (glucan) was only marginally effective. These studies suggest that ribavirin, poly(ICLC), and convalescent plasma may have a role in prevention or therapy of human RVF.
Strain 13 guinea pigs inoculated subcutaneously with Pichinde virus developed fever, lost body weight, decreased water and food consumption, and died at 14 +/- 0.6 days. After FPL-55712, a leukotriene D4 antagonist, was administered beginning on PID (post-inoculation day) 3 for 18 days, the magnitude of body weight loss decreased and food intake increased, despite a persistent fever. The treated guinea pigs also survived significantly longer than infected animals receiving placebo injection (21 vs 14 days). Using guinea pig ileum bioassay and radioimmunoassay, we detected significant levels of plasma leukotrienes in Pichinde virus-infected guinea pigs on PID 11 and possibly PID 14. These findings strongly suggest that leukotrienes play a role in the pathogenesis of arenavirus infection and may account in part for the observed cardiac depression, pulmonary edema, and eventual death.
A formalin-inactivated Rift Valley fever vaccine prepared in primary monkey kidney cells has been used to protect laboratory workers from disease since 1967. A similar but improved vaccine was prepared in 1978-1979 using well characterized diploid fetal rhesus lung cells. In initial clinical trials reported here, the new vaccine elicited high levels of plaque neutralizing antibodies and caused only minimal local reactions at the injection site. Significant variability was observed in the geometric mean titre evoked by various vaccine lots. This variability had not been predicted by conventional pre-filtration or pre-inactivation virus infectivity assays, or the results of animal potency tests. These findings emphasize the need for statistically valid human potency testing and the development of accurate predictive preclinical measurements for this and other vaccines.
Spleen cells from guinea pigs infected with an attenuated strain of Junin virus (the causative agent of Argentine hemorrhagic fever) specifically lysed virus-infected syngeneic target cells in vitro. This activity was detected as early as 6 days after infection, reached a maximum on days 10-13, and persisted at lower levels, at least through day 30. Monoclonal antibody to guinea pig T cells had no effect on the activity. After B or T cell enrichment techniques, the cytolysis was found with the B cell fraction. Aggregated IgG blocked the cytolysis. These characteristics suggested lytic activity was mediated at least in part by an antibody-dependent cell-mediated cytotoxicity (ADCC) mechanism. Although some cytolysis could be detected by using exogenously added antiserum and normal spleen effector cells, such reconstruction showed less efficient killing than when spleen cells from Junin-infected guinea pigs were used. This apparent discrepancy was resolved when spleen cells from these infected animals exhibited enhanced activity in non-viral ADCC systems as well. The cytotoxic activity by spleen cells against Junin-infected targets was detected only with non-fatal Junin infections. Cytolysis could not be measured in spleen cell suspensions from guinea pigs lethally infected with Junin virus; i.e. adults infected with a virulent strain of Junin and baby guinea pigs or immunosuppressed adult animals infected with an attenuated strain. However, spleen cells from both the immunosuppressed, infected adults and the adult guinea pigs infected with a virulent strain of Junin were able to mediate cytotoxicity in a nonviral system (antibody-sensitized Vero cells). The development of spleen cell cytotoxicity by Junin-infected guinea pigs against Junin-infected target cells correlated with whether the infection was resolved or was lethal.
A comparison has been made of affinity of alpha-adrenoceptor antagonists for alpha 2 binding sites in radioligand binding assays, and functional antagonist activity at pre- and postjunctional alpha 2-adrenoceptors in various in vitro preparations. The antagonists displaced [3H]-rauwolscine from rat brain and rabbit spleen membranes but there were substantial differences in rank order and absolute potency in the two tissues. pA2 values for yohimbine, phentolamine and Wy26703 against the selective alpha 2 agonist UK-14,304 were determined in the rat left atrium, rat and rabbit vas deferens and rabbit saphenous vein preparations. The pA2 values varied substantially between the tissues, differing by two orders of magnitude in the case of Wy26703. Yohimbine was more potent in rabbit preparations while Wy26703 was markedly more potent in all the rat preparations. Yohimbine and Wy26703 were compared in the dog saphenous vein preparation where pre- and postjunctional alpha 2 antagonist activity can be compared in the same tissue. As in the rabbit preparations, yohimbine was more potent than Wy26703 at both sites but the absolute potencies were different. It is concluded that alpha 2-adrenoceptors are a heterogeneous population, different subgroups being more apparent between species rather than between tissue types or location.
Subcutaneous injections of ribavirin into guinea pigs infected intraperitoneally or intracerebrally with Junin virus significantly increased the mean time to death but did not enhance survival of the animals. We found similar results with tributylribavirin. Virus replication was delayed, but not prevented, in ribavirin-treated infected guinea pigs. The animals usually died with high virus titers in their brains and frequently were paralyzed.
To determine the accuracy of serological methods in detecting Rift Valley fever (RVF) viral antibodies, we examined serum samples obtained from 418 sheep in the Nile Delta by using five tests. The plaque reduction neutralization test (PRNT) was considered the standard serological method against which the four other tests were compared. Twenty-four serum samples had RVF viral antibodies detected by PRNT. Hemagglutination inhibition and enzyme-linked immunosorbent assay antibodies to RVF virus were also present in the same 24 serum samples. Indirect immunofluorescence was less sensitive in comparison with PRNT, and complement fixation was the least sensitive. These results extend observations made with laboratory animals to a large field-collected group of Egyptian sheep.
Rift Valley fever (RVF) surveillance was carried out in the Nile Delta by monitoring mobile and stationary sheep flocks for antibodies to RVF virus. Sheep are known to be susceptible to RVF virus infection and experienced severe morbidity in 1977 and 1978 when RVF was epidemic in Egypt. Four hundred six sheep in 32 flocks were surveyed during 1984. Twenty-four sheep from 7 flocks had antibodies to RVF virus detected by hemagglutination inhibition and plaque reduction neutralization tests. Antibodies were found primarily in sheep greater than 3 years of age, although 1- and 2-year-old sheep were included in the sample. No seroconversion was observed among 177 seronegative sheep that were bled successively for a period of 10 months. These results indicate that epizootic RVF was probably not present in the Nile Delta during 1984.
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The Hantaan virus suckling mouse model was examined to delineate virologic and histopathologic characteristics of infection at the organ level. Viral antigen and infectious virus were detected in all organs examined, with highest titers achieved in brain, lung, and kidney. A constellation of histologic lesions was identified in brain (diffuse meningoencephalitis with bilaterally symmetrical thalamic necrosis), liver (pericholangiohepatitis), lung (pneumonitis), and spleen (lymphoid hyperplasia); this tetrad is apparently unique to this model system. The chronology of clinical, virologic, serologic, and pathologic findings in Hantaan-infected newborn mice suggests an immune-mediated mechanism in disease pathogenesis.
The alpha adrenoceptors present on the saphenous vein of the dog and rabbit were characterised in vitro using the selective alpha 1 antagonist prazosin and the alpha 2 antagonists rauwolscine and yohimbine. In the dog saphenous vein, prazosin and rauwolscine competitively antagonised contractile responses to phenylephrine and UK-14,304 respectively. Noradrenaline was competitively blocked by prazosin only. In contrast, phenylephrine and methoxamine-induced responses in the rabbit saphenous vein were insensitive to prazosin and corynanthine. Rauwolscine competitively blocked responses to UK-14,304, noradrenaline and phenylephrine and pA2 values were similar against each agonist. Noradrenaline and UK-14,304 were equipotent agonists on the rabbit saphenous vein while in the dog vein noradrenaline has a lower potency than UK-14,304. These results suggest that the dog saphenous vein has a mixed population of alpha adrenoceptors, while the alpha adrenoceptors on the rabbit vein are homogeneous, with characteristics of the alpha 2 subtype.