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PubMed1979

Mucosal defenses against Salmonella infection in the mouse.

Specific pathogen-free ICR (Institute of Cancer Research) mice were challenged with Salmonella orally, aerogenically, or parentally 24 hr after they received sublethal whole-body irradiation. The early growth for the sublethal inoculum was identical in irradiated and control mice. In the irradiated group, Salmonella multiplied in the liver and spleen until death of the host. Increasing the dose of irradiation reduced the size of the mean lethal dose for the intravenous, intraperitoneal, and aerogenic challenges. However, in the orally challenged mice, the 50% lethal dose dropped only 100-fold when the radiation was increased from 0 to 400 rad, with little further decrease even when the dose was increased to 800 rad. Presumably, the local gut defenses were responsible for this considerable disparity in the lethal effects of an oral vs. parenteral challenge. No evidence was found for enhanced local infection of the gut or increased involvement of the gut-associated lymphoid organs in the irradiated host. The increased mortality seen in the irradiated group seemed to be associated with a continued unrestricted growth of Salmonella in the liver and spleen when the number of peripheral blood leukocytes was at a minimum. Resistance to the sublethal salmonella challenge was eventually restored as the total counts of white blood cells returned to normal.

Administration, Oral↗

PubMed1978

Requirement for macrophages for interferon to be effective against encephalomyocarditis virus infection of mice.

Suppression of macrophages in mice by treatments with silica or auro-thiomalate (Myocrisin) reduced production of serum interferon by polyriboinosinic acid:polyribocytidylic acid by 85 to 90%, indicating that this double-stranded polynucleotide caused interferon production primarily in macrophages. Suppression of macrophages in mice by silica or Myocrisin treatment did not significantly affect the susceptibility of mice to encephalomyocarditis virus, although at virus doses around 20 times the 50% lethal dose they died about 48 h earlier. Macrophage interferon protected mice from encephalomyocarditis virus infection at much lower doses than fibroblast interferon, and treatment of mice with silica or Myocrisin abolished the protection conferred by macrophage interferon, whereas these treatments had a much smaller effect on the protection afforded by fibroblast interferon. The requirement for macrophages for interferon to be effective in mice can explain why macrophage suppression can cause normally nonlethal viruses to kill adult mice.

Animals↗

PubMed1978

Relationship between gentamicin susceptiblity criteria and therapeutic serum levels for Pseudomonas aeruginosa in mouse infection model.

In this study estimations of in vivo and in vitro gentamicin susceptibility for a series of strains of Pseudomonas aeruginosa were compared. The series included an extremely susceptible strain, typically susceptible strains by current susceptibility criteria, and strains with enzymatic and permeability-mediated resistance. In vivo testing was done by using a mice protection test involving six 1-h doses of gentamicin and an inoculum of 50 50% lethal doses of P. aeruginosa. Both normal mice and cyclophosphamide-treated mice were used. It was found that peak serum levels and serum levels of gentamicin obtained just prior to the sixth dose (fifth dose trough levels) required for protection were much higher than minimal inhibitory concentrations (MICs) or minimal bactericidal concentrations (MBCs) obtained in high-cation medium. However, first dose trough levels were similar to MICs or MBCs. Only an extremely susceptible strain, 280, could be treated at antibiotic dosages and serum levels which are considered likely to be safe in humans. A distinct inoculum effect was found in the mice tests, with a 10-fold increase in inoculum producing a 4-fold increase in the amount of gentamicin required, but no inoculum effect was found for MICs. These results suggest that current susceptibility criteria in use for gentamicin and P. aeruginosa overestimate gentamicin susceptibility, particularly when low-cation growth medium is used for susceptibility testing and when treating disseminated infection.

Animals↗

PubMed1977

Immunization with Shigella dysenteriae type 1: evaluation of antitoxic immunity in prevention of experimental disease in rhesus monkeys (Macaca mulatta).

The role of serum antitoxic antibody in protection against the dysentery caused by Shigella dysenteriae type 1 (Shiga's bacillus) was studied in monkeys fed 10(10) virulent organisms after parenteral immunization with a formalin-inactivated Shiga toxoid preparation standardized in mice. Two 125-microgram doses of toxoid adsorbed on aluminum hydroxide adjuvant and given 14 days apart provided mice with a 54-fold increase in resistance to parenteral toxin. In rhesus monkeys (Macaca mulatta), the same regimen of toxoid permitted the safe parenteral administration of toxin in incremental doses ranging from 100 to 1,000 mouse 50% lethal doses and resulted in correspondingly high titers of antitoxin in serum. Nevertheless, the immunized monkeys responded to orally administered Shiga bacilli by development of diarrhea and dysentery that was as severe as (or more severe than) the response of unimmunized controls. The failure of extraordinarily high levels of circulating antibody to protect against experimental shigellosis suggests that the intestinal mucosal sites of toxinmediated response are beyond the reach of systemic antitoxin.

Animals↗

PubMed1977

Immunity in plague: protection of the vervet (Cercopithecus aethips) against pneumonic plague by the oral administration of live attenuated Yersinia pestis.

Protection against pneumonic plague by the oral administration of a live, attenuated Yersinia pestis vaccine, EV76 (Paris) F, was evaluated in the vervet (Cercopithecus aethips). Six animals were vaccinated with a dose of 1.175 X 10(9) colony-forming units (cfu); all tolerated the dose and developed antibodies to Fraction I of Y. pestis. Three immunized animals were challenged with an inhaled dose of 3.2 X 10(6) cfu (160 LD50 [50% lethal dose]) of virulent Y. pestis strain 195/P and two survived; the other three received a challenge dose of 4.9 X 10(6) cfu (245 LD50) and one survived. The three surviving monkeys had high titers of antibody to Fraction I. At necropsy of the animals that succumbed to the challenge infection, almost complete consolidation of the lungs was apparent, and sizable effusions were present in the thoracic cavities. Indeed, the striking pathology indicated the severest form of pneumonic plague. Since it can be assumed that the animal surviving challenge with the larger inoculum would have survived the smaller dose, we conclude that the immunization procedure protected half of the vervets that were exposed to challenge.

Administration, Oral↗

PubMed1978

Listeria monocytogenes cell walls induce decreased resistance to infection.

A significant decrease in murine resistance to Listeria monocytogenes was induced by using crude Listeria cell wall fraction (LCWF) and purified Listeria cell walls (PF). When equal amounts of these materials were injected, PF was more effective than LCWF in decreasing resistance. The PF effect was dose dependent when measured either as a decrease in 50% lethal dose of the Listeria challenge or as a decrease in survival time of the infected mice. PF apparently does not act directly on the Listeria since it (i) did not cause a change in in vitro growth of Listeria and (ii) did not increase the virulence of Listeria passaged in vivo or in vitro. The greatest decrease in resistance was observed when both PF and the Listeria challenge were injected intraperitoneally, which may suggest a localized effect. A decrease in resistance was seen when PF was given as early as 3 days before challenge. There was little or no decrease in resistance when PF was given 2 days after the Listeria challenge. Mice previously immunized with live Listeria were immune to Listeria challenge. However, after PF injection the immune mice showed a decreased resistance which was of the same order of magnitude as that seen in unimmunized mice. The effect of PF seems to be at least partially nonspecific, since a decrease in resistance to Salmonella typhimurium could also be demonstrated in PF-treated mice. Phagocytosis of Listeria both in vivo and in vitro did not appear to be inhibited by PF, although the ability of PF-treated mice to kill Listeria in the peritoneal cavity was inhibited.

Animals↗

PubMed1978

Role of nonagglutinating antibody in the protracted immunity of vaccinated mice to Pseudomonas aeruginosa infection.

Effective immunization against infection with Pseudomonas aeruginosa is difficult to evaluate because agglutinin levels decline rapidly. Because fractionation of hyperimmune sera often yields more specific antibody than can be accounted for by direct agglutination tests, an immunoglobulin-specific assay based on antiglobulin augmentation was used to characterize antibody responses of C3H/HeJ mice vaccinated with P. aeruginosa type 2 lipopolysaccharide. Nonagglutinating antibodies, initially detected at 2 weeks post-primary vaccination, were predominantly immunoglobulin G after 5 weeks, and they remained elevated at levels usually 32-fold higher than the direct titer throughout the 4-month study period. The sequential production of immunoglobulin M, then immunoglobulin G, followed that found in orthodox immunological responses. Sera that contained nonagglutinating antibodies but not direct agglutinins (14 to 16 weeks) enhanced phagocytosis of P. aeruginosa type 2 by macrophages from unimmunized mice and passively immunized mice against lethal challenge doses; bactericidal activity of these sera was not demonstrated in the presence or absence of complement. When challenged with 1, 10, and 100 50% lethal doses at 16 weeks, survival rates of actively immunized mice were significantly higher than those of unvaccinated mice (P < 0.001). Thus, at a time when no direct agglutinins were detectable, the augmented system detected nonagglutinating antibodies that could confer protracted resistance in vaccinated mice to pseudomonas infection.

Agglutinins↗

PubMed1978

O antigen as virulence factor in mouse typhoid: effect of B-cell suppression.

Immunosuppression by cyclophosphamide was used to make mice incapable of B-lymphocyte responses; they could not make an antibody response to NIP-Ficoll. These mice, as well as untreated mice, were challenged intraperitoneally with graded doses of isogenic O-4,12 or O-6,7 Salmonella typhimurium derivatives. The 50% lethal dose of the O-6,7 strains was 35- to 70-fold higher than that of the O-4,12 strains, both in the normal and the immunosuppressed animals, although the latter were approximately 1,000-fold more susceptible to the infection by either challenge organism. We conclude that the O-antigen-dependent difference in the mouse virulence of these sister strains is not mediated through differences in their capacity to evoke B-lymphocyte-mediated immune responses.

Animals↗

PubMed1978

Comparative efficacy and toxicity of a ribosomal vaccine, acetone-killed cells, lipopolysaccharide, and a live cell vaccine prepared from Salmonella typhhimurium.

The protective and toxic properties of a ribosomal vaccine prepared from Salmonella typhimurium W118-2 were systematicaly compared with those of an acetone-killed whole cell vaccine, purified lipopolysaccharide, and living cells in CD-1 mice. Tests of graded immunizing doses of each vaccine against several challenge doses of live strain W118-2 showed that, although the protection given by ribosomes approached the levels of protection conferred by living organisms, acetone-killed cells administered in appropriate dosages provided levels of protection comparable to that of ribosomes. Lipopolysaccharide was found to be significantly less protective than the other vaccines. On a dry-weight basis, ribosomes were the least toxic with a 50% toxic dose (TD50) of 5,000 microgram; acetone-killed cells had an intermediate TD50 of 1,400 microgram; and lipolysaccharide was the most toxic, with a TD50 of 320 microgram. The dose of each vaccine that protected 50% of the mice against a challenge of 1,00 times the 50% lethal dose was determined and divided by the TD50 to give the therapeutic index. This ratio also indicated that the ribosomes and acetone-killed cells were equally effective, whereas lipopolysaccharide was markedly inferior.

Acetone↗

PubMed1979

Experimental plague in the California ground squirrel.

In experiments to determine the current susceptibility to plague, it was demonstrated that 256 Yersinia pestis (a local strain of high virulence) were required to produce a 50% infectious dose (ID50) in California ground squirrels (Spermophilus beecheyi) that had been collected in southeastern Monterey County, California; 6,070 Y. pestis were required to produce a 50% lethal dose (LD50). (The LD50 was about 24 times the ID50.) The frequency of serologic response to the specific fraction 1 antigen of Y. pestis and mortality were dose-related. Approximately half of the squirrels inoculated with six to 6,070 Y. pestis survived without seroconversion, whereas antibody to specific fraction 1 antigen was always observed in squirrels that survived challenges of greater than or equal to 60,700 Y. pestis. However, titers never exceeded 1:64. The implications of these data for enzootic and epizootic transmission of plague in resistant squirrel populations are examined.

Animals↗

PubMed1977

Biological and biochemical properties of 1-(2-chloroethyl)-3-(beta-D-glucopyranosyl)-1-nitrosourea (NSC D 254157), a nitrosourea with reduced bone marrow toxicity.

1-(2-Chloroethyl)-3-(beta-D-glucopyranosyl)-1-nitrosourea (GANU), a water-soluble nitrosourea, differs from 2-[3-(2-chloroethyl)-3-nitrosoureido]-D-glucopyranose (chlorozotocin) by the placement of the cytotoxic group on C-1 of glucose. Its biological and biochemical properties are compared with those of chlorozotocin. At a 10% lethal dose (10 mg/kg i.p.), GANU demonstrates minimal myelosuppression. This dose failed to depress normal bone marrow DNA synthesis, in contrast to a 96% inhibition in L1210 DNA synthesis. In L1210 cell suspension, equimolar doses of GANU and chlorozotocin produced equivalent degrees of inhibition in DNA synthesis. GANU has significant L1210 activity in BALB/c X DBA/2 F1 mice treated on Day 2 of tumor growth. A 117% increased life-span and 15% 45-day survivors are atained with 15 mg/kg i.p., a 50% lethal dose. However, in concurrent studies using randomly selected littermate groups of mice, GANU proved less active than chlorozotocin which produced a 306% increased life-span (15 mg/kg i.p.). GANU and chlorozotocin have similar in vitro alkylating activity but the in vitro carbamoylating activity of GANU is sevenfold that of chlorozotocin. On a molar basis, the lethal toxicity of GANU is twice that of chlorozotocin. The significant carbamoylating activity of GANU may contribute to its greater toxicity and therefore limit the mumoles of alkylating agent that can be administered to the tumor. These structure-activity studies further confirm that the addition of a glucose carrier to a cytotoxic nitrosourea moiety can selectively reduce bone marrow toxicity while retaining antitumor activity.

Animals↗

PubMed1978

Infectious agents in immunodeficient murine models: pathogenicity of Nocardia asteroides in congenitally athymic (nude) and hereditarily asplenic (Dh/+) mice.

Congenitally athymic (Nu/Nu), hereditarily asplenic (Dh/+), and littermate control mice were given intravenous injections of homogeneous cell suspensions of the virulent Nocardia asteroides GUH-2. Kill curve, 50% lethal dose, and kidney clearance data were obtained over a period of 3 months postinfection. N. asteroides initiated both an acute infectious process and a chronic, progressive disease in these animals when given intravenously. The heterozygous (Nu/+) mice appeared to be slightly more susceptible to the acute phase of infection than their nude littermates. In contrast, nude mice were at least 50 times more susceptible to chronic nocardial infection than were the heterozygous (Nu/+) controls. Swiss Webster specific pathogen-free mice were similar to heterozygous (Nu/+) mice in their susceptibility to N. asteroides. The hereditarily asplenic (Dh/+) mice were not as susceptible to lethal infection as were nude mice. However, asplenic mice demonstrated an inability to eliminate nocardia from infected kidneys, whereas their littermate control (+/+) mice were able to mount an effective response and destroy most of the organisms within the kidneys. Similar observations were noted when nude and heterozygous (Nu/+) littermate mice were infected in the footpad. The nude mice developed a systemic infection and died within 4 weeks with little inflammation of the footpad and no macroscopic lesions. In contrast, heterozygous (Nu/+) mice developed extensive local abscesses in the foot that persisted for at least 4 weeks. There was no animal death and no evidence of dissemination. The data presented herein indicate that T cells are essential for adequate host response against infection with a virulent strain of N. asteroides.

Animals↗

PubMed1977

Protective effects of passively transferred immune T- or B-lymphocytes in mice infected with Salmonella typhimurium.

Purified populations of bone marrow-derived (B-) lymphocytes and thymus-derived (T-) lymphocytes were obtained from C3D2F1 hybrid mice shown to be immune to Salmonella typhimurium. These subpopulations of lymphocytes were injected into normal mice; four days later the animals were challenged with 50 50% lethal doses of S. typhimurium, and viable bacteria in livers, spleens, and blood were counted at various intervals after challenge. On day 8 after challenge, the mice supplemented with B-lymphocytes showed a significant decrease in the number of organisms recovered from all three sites, compared with that seen in recipients of T-lymphocytes and in controls. The mice given B-lymphocytes showed a better rate of survival (65%) than mice that received only T-lymphocytes (21%) or T-lymphocyte fractions contaminated 10%-30% with B-lymphocytes (49%). These data indicate that, although the humoral response is not totally protective, it does play an important role in the suppression of the infection during its early stages.

Animals↗

PubMed1977

Adjuvant protection against bacterial infection in granulocytopenic mice.

The hypothesis that the induction of nonspecific resistance to infection by immunostimulation prior to drug-induced granulocytopenia would afford increased protection to subsequent bacterial challenge was tested in a murine model of infection with Pseudomonas aeruginosa or Staphylococcus aureus in mice rendered granulocytopenic with cyclophosphamide. Prior intraperitoneal immunostimulation of mice with complete Freund's adjuvant (CFA) or Mycobacterium bovis (Bacille Calmette-Guèrin; BCG) increased the 50% lethal dose in mice challenged subcutaneously with P. aeruginosa, but only CFA protected against challenge with S. aureus. The degree of protection was 1-2 log 10. Corynebacterium parvum provided no protection against infection with P. aeruginosa. The protective effect observed with CFA and BCG substantiates our hypothesis and indicates that nonspecific immunostimulation may be of value in protection of granulocytopenic patients from opportunistic infections.

Adjuvants, Immunologic↗

PubMed1977

A polyvalent human gamma-globulin immune to Pseudomonas aeruginosa: passive protection of mice against lethal infection.

As a means to development of guidelines for therapeutic application to human disease, preparations of human polyvalent gamma-globulin immune to Pseudomonas aeruginosa (PG) were studied in acute infections in mice. PG was highly effective in controlling lethal infections induced in mice by the major immunotypes of P. aeruginosa; greater than or equal to 10 microgram of of gamma-globulin per mouse protected against challenge with less than or equal to 10(6) 50% lethal doses of P. aeruginosa. PG was less than or equal to 57 times more effective than normal human gamma-globulin. The active antibody component is specific for each immunotype; it is of the IgG type and undoubltedly is directed against the O-antigen. PG was was not protective against challenge with Escherichia coli, Enterobacter cloacae, Proteus mirabilis, or Klebsiella pneumoniae; a low degree of cross-protection was seen against Serratia marcescens. In a model infection involving mice in a terminal stage of advanced P. aeruginosa infection, human plasma immune to P. aeruginosa proved ineffective, but the gamma-globulin component showed moderate activity. The apparent irreversibility of this late-stage infection is not clearly ascribable to a toxin. It is postulated that the successful treatment of advanced P. aeruginosa infections in humans would require multiple therapeutic approaches, including passive immunization with a high-potency, specifically immune globulin.

Animals↗

PubMed1978

Characterization of lipopolysaccharide of Haemophilus influenzae.

Lipopolysaccharide from strains of Haemophilus influenzae was extracted and isolated by the hot phenol-water procedure. The preparations were relatively insoluble in water but could be solubilized with surface-active agents. The preparations contained carbohydrate (30%), fatty acid (29%), and phosphate (4.7%); protein content was less than 1%. Thin-layer chromatography, gas-liquid chromatography, and colorimetric assays detected glucose, galactose, glucosamine, heptose, and a 2-keto-3-deoxy-octonate-like molecule (less than 1%). Neither methylpentose nor dideoxyhexose was detected. The lipid portion was composed of fatty acids common to lipopolysaccharide of Salmonella. The preparations provoked positive dermal Shwartzman reactions and biphasic febrile responses in rabbits, responses typical of endotoxic activity. The 50% lethal dose for mice was decreased from 16.5 microgram/g to 0.015 microgram/g by concomitant administration of actinomycin D. The preparations were shown to be polyclonal activators of bone marrow-derived (B) cells. Limulus lysate gelation was seen with 8.0 ng of lipopolysaccharide. Preliminary hemagglutination data suggested at least three different antigenic factors associated with the lipopolysaccharide of H. influenzae type b. The H. influenzae lipopolysaccharide appeared biologically similar to that of enterobacteria but chemically different.

Animals↗

PubMed1979

Chlamydia psittaci: growth characteristics and enumeration of serotypes 1 and 2 in cultured cells.

The growth characteristics of Chlamydia psittaci serotypes 1 and 2 (ovine and bovine origin) were studed in mouse L cells. Formation of inclusions and yield of infectious progeny for serotype 1 were maximal when host cells were treated with cycloheximide and the pH in the cell culture medium was 7.2-7.4. The number of cells that contained inclusions and the infectivity yield for serotype 2 were maximal when the pH was 6.6-7.0. Treatments with diethylaminoethyl dextran and cycloheximide increased inclusion formation in serotype 2 but decreased the yield per infected cell. For both serotypes, centrifugation of the chlamydiae onto monolayers infected 50-1,200 times the number of cells infected with use of stationary adsorption. An enumeration method for L-cell infectious units was developed that gave higher titers than the chicken embryo 50% lethal dose after yolk sac inoculation.

Animals↗

PubMed1976

Difference in response to mouse hepatitis virus among susceptible mouse strains.

After intraperitoneal inoculation with a high-virulent mouse hepatitis virus (MHV) a significant difference was seen in survival time between DDD and CDF1 (BALB/c X DDD) mice, while 50% lethal doses were not significantly different. With 3 X 10(3) PFU of the virus CDF1 and DDD mice died in 45 and 120 hr, respectively, on the average. This difference of susceptibility between DDD and CDF1 mice was first demonstrable at the age of 1 week and was more pronounced at the age of 4 weeks but showed no dependence of the sex. Virus titers ran 2 to 3 log higher in the liver and blood of CDF1 than in those of DDD mice, while being only 1 log higher in the spleen. At an early stage of infection viral antigen was demonstrable by immunofluorescence in sinusoidal lining cells of the liver more prominently in VDF1 than in DDD mice. Interferon production occurring in parallel with virus growth was significantly higher in CDF1 than in DDD mice. In DDD mice, liver lesions were rather focal with some accumulation of round cells, while they were confluent with poor cellular response in CDF1 mice. Viral growth in cultured peritoneal macrophages from CDF1 mice was 1 log higher than in those from DDD mice. The results suggest that the divergence in response to MHV among susceptible mice greatly depends upon the susceptibility of macrophages and reticuloendothelial cells which constitute primary targets of the virus.

Animals↗