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Forty eight hours after the immunization with vaccines containing antigenic complexes of typhoid-paratyphoid and dysentery bacteria (0.65--1 mg of the antigens per vaccination dose) some of the persons vaccinated displayed an increase in the leukocyte count chiefly on account of the neutrophil forms and monocytes, a moderate elevation of bilirubin, asaraginamino-transferase and glutamic dehydrogenase in the serum; there was also some reduction of serum cholesterol, the appearance of cylinders and of protein traces in the urine, as well as ECG changes. The noted changes were of short duration and were not recorded in later examinations. The persons vaccinated presented no complains 24 hours, 2, 3, and 9 days after the vaccination and completely retained their working capacity.
The enhancement by exogenous ferric iron, both systemic and local, of the infectivity of 120 strains of bacteria, representing 17 genera, was measured in the skin of guinea-pigs. Systemic iron enhanced only 23% of 115 strains, and local iron 49% of 71 strains. Systemic iron, by an apparently anti-inflammatory action, depressed the size of lesions produced by 27 of the non-enhanced strains from nine of the genera tested. For most strains, the degree of enhancement was small, ranging from 2- to 8-fold, and often evident only with the more effective local iron; among these were some near-saprophytes like Mycobacterium phlei, M. smegmatis, Bacillus cereus and Clostridium bifermentans. Substantial enhancement, from 14- to 50-fold, was observed with the more pathogenic among the strains tested: namely BCG, Corynebacterium ovis, C. murium, Listeria monocytogenes, Erysipelothrix rhusiopathiae, Cl. perfringens, Cl. septicum, Cl. oedematiens, and some strains of Klebsiella spp., Proteus spp. and Aeromonas hydrophila. The enhancement of BCG by a single dose of iron given locally with the inoculum was only feebly manifest after 7 days, but substantial after 14--19 days, indicating the decisive effect of interference with an early humoral defence on the establishment of chronic infection some time later. Insofar as guinea-pigs whose antibacterial defences are lowered by substantial amounts of exogenous iron in the circulation represent human subjects at risk of infection because of clinical states characterised by excess of available iron, the results of the survey suggest that only a minority among the environmental bacteria can take advantage of the decreased resistance associated with such states; but that this minority is likely to include the more virulent strains in the environment.
Sera from rabbits immunized with sonicates of Mycobacterium bovis BCG were passed through an immunoadsorbent made of a soluble BCG extract to make partially purified antibodies to BCG. These antibodies were in turn used to prepare an immunoadsorbent through which the BCG extract was passed. The partially purified antigenic material was radiolabeled and subjected to electrophoresis in acrylamide gels. One of the radiolabeled fractions isolated (BCG-C) was found to bind to antibodies to BCG and H37Rv, but not to antibodies in sera from rabbits immunized with other mycobacterial species or Nocardia asteroides. The reaction between BCG-C and the partially purified antibodies to BCG was inhibited by small amounts of different BCG antigens. Cultures obtained from 25 patients with tuberculous diseases, other bacterial cultures, and various bacterial extracts were tested for their capacity to inhibit this reaction. Each of 13 mycobacteria identified as M. tuberculosis inhibited this reaction. Equivalent numbers of 12 strains of mycobacteria other than M. tuberculosis and high concentrations of other bacterial extracts did not inhibit, indicating that determinants of BCG present in M. tuberculosis were not detected in the other mycobacteria or in non-acid-fast bacteria. The use of sequential purification procedures could be of potential clinical value in quickly differentiating between M. tuberculosis and a variety of other mycobacteria.
Resistance and susceptibility to mycobacterial infection in the Biozzi high and low lines of mice which were genetically selected for their responses to heterologous erythrocytes have been found to be related to the innate ability of nonimmune macrophages to kill or inhibit the growth of the organisms during the first two weeks after infection and to their ability to mount specific and nonspecific immune responses. High antibody-producer mice were more capable of expressing cell-mediated immune parameters than low antibody-producer mice. A direct relationship was observed between the ability of bacteria (BCG vaccine) to multiply inside the reticuloendothelial system and the development of cell-mediated immunity, as measured by the delayed local reaction at the injection site, the lymphoproliferative response in the draining nodes, the tuberculin delayed-type hypersensitivity, the acquired resistance, and the adjuvant effect after BCG inoculation. In high line mice, apart from the inability of their macrophages to inhibit the early growth of bacteria, their lymphocytes in spleen and thymus were more capable of being stimulated in vitro by varying concentrations of living BCG. The data presented in this report are compatible with the hypothesis that a group of genes segregated in each line during the selective breeding controls the innate microbicidal activity.
Gram-positive bacteria or their constituents influence the immune response in various ways. For instance: Listeria monocytogenes cellwall fraction acts as B-cell mitogen, in this way enhancing a humoral immune response. Corynebacterium parvum acts as a macrophage stimulant evoking maximum macrophage activation. BCG, among other things, leads to an enhancement of a T-cell response to unrelated antigens. The hypothetical therapeutic consequences are discussed.
Bacterial growth within 72 hr after an intravenous inoculation with Listeria monocytogenes was enhanced strikingly in the liver of mice, when viable cells of sarcoma-180 were injected subcutaneously into ddN, C3H/He, and BALB/c mice 5 hr before the inoculation. Such an enhanced bacterial growth appears to be attributable to a depressed ability of macrophages to digest engulfed bacteria. Pretreatments with zymosan, killed BCG, or viable BCG prevented such depression in tumor-bearing mice and increased the bactericidal activity in the liver of normal and tumor-bearing mice above the level of non-treated normal mice. Such adjuvants may be useful not only for augmentation of antitumor activity but also for augmentation of antimicrobial activity in tumor-bearing hosts.
BACKGROUND: Acinetobacter baumannii is a critical global health threat due to multidrug resistance and high mortality. Although antimicrobial resistance mechanisms are well characterised, the virulence determinants that drive severe infections remain poorly understood. METHODS: We screened 89 carbapenem-resistant clinical isolates of A. baumannii for virulence in animal infection models and combined comparative genomics with functional assays to identify virulence factors. An immunoglobulin-binding protein from A. baumannii (ImbA) encoded on the type D plasmid was selected and characterised. Protein-immunoglobulin interactions were analysed by pull-down and biolayer interferometry. Additional ImbA inhibition of IgG-Fcγ receptor binding by flow cytometry were tested. Protective efficacy was evaluated in mice using vaccination or anti-ImbA antibodies. FINDINGS: A type D plasmid was consistently linked to high virulence in clinical isolates. The deletion of plasmid-encoded ImbA attenuated virulence. ImbA bound murine IgA and IgG with high affinity. The binding to the Fc region of IgG disrupted IgG-Fcγ receptor interactions. Vaccination with recombinant ImbA improved survival and reduced bacterial dissemination in female mice with anti-ImbA antibodies partially protecting against lethal infection. Bacterial burdens in the blood were reduced in treated groups. INTERPRETATION: Our study demonstrates ImbA as an unrecognised plasmid-encoded virulence factor in A. baumannii. By intercepting host immunoglobulins, ImbA drives immune evasion and hypervirulence. Blocking ImbA by vaccination and antibody therapy restored host defence and improved outcomes in female mice, highlighting ImbA as a non-antibiotic therapeutic target with potential against multidrug-resistant A. baumannii. FUNDING: Bio&Medical Technology Development Program of the National Research Foundation (NRF), funded by the Korean government (MSIT) (No. RS-2023-00219213); Korea Research Institute of Bioscience and Biotechnology (KRIBB) Research Initiative Program.
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Structural components of microorganisms have been studied for immunopotentiating effect with the aid of transplantable (line 10) tumors in syngeneic guinea pigs. Microbial components were associated with oil droplets, suspended in Tween-saline, and injected intralesionally. BCG cell walls, given in this way, produced regression and cure of 50-60% of established tumors, as did viable BCG. Lipid extraction markedly reduced the tumor-regressing potency of cell walls, but P3, a trehalose mycolate present in the extract, restored full activity to the cell wall residue. P3 alone was nonsensitizing and had no antitumor activity, but it enhanced the latter property of various other microbial products. For example, the cure rates produced by cell walls of M. tuberculosis, M. bovis, M. phlei, or M. smegmatis were enhanced from 20-60% to as much as 90% by addition of P3. P3 also conferred antitumor activity on products from unrelated microbes, such as cell walls of E. coli, and in combination with endotoxins from rough Re mutant salmonellae, it produced cure rates of up to 93%. These results suggest that P3 is essential to the immunopotentiating activity of mycobacteria and that it may be broadly applicable in immunotherapy of cancer with microbial agents.
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Tuberactinamine N, the cyclic peptide moiety of tuberactinomycin N, was obtained in a crystalline state through liberation of gamma-hydroxy-beta-lysine from tuberactinomycin N by acid treatment. Tuberactinamine N possesses an intramolecular hydrogen bond in its molecule and showed antibacterial activities comparable to those of the original antibiotics. Conversion of tuberactinomycin N to O was achieved through coupling of diacyl-beta-lysine with tuberactinamine N followed by removal of the protecting groups.
The fate of virulent and avirulent strains of Salmonella typhimurium in untreated and iron-injected mice and in transferrin-containing media demonstrated a direct relationship between bacterial virulence and the ability of bacteria to acquire transferrin-bound iron. Effects of injected iron on the development of infections with virulent and avirulent bacterial strains were determined in normal and immune mice by determinations of bacterial numbers in tissue homogenates and the mortality of infected animals. Results showed that infected and iron-injected mice died much more rapidly and frequently from overwhelming infections than infected and saline-injected mice. The infection-promoting effect of iron varied with the degree of bacterial virulence; the more virulent the bacteria, the more helpful was iron for the development of lethal infections. Siderophores promoted lethal infections in mice infected with virulent but not with avirulent bacteria. Experiments with vaccinated animals showed that iron exerted a deleterious effect on acquired immunity. Immune mice infected with virulent bacteria and injected with iron developed lethal infections as rapidly and nearly as frequently as similarly treated normal mice. Siderophores did not promote the development of lethal infections in immune mice. The effectiveness of iron, but not of siderophores, to promote bacterial infections in vaccinated mice revealed that acquired immunity is dependent upon the activity of an iron-neutralizable antibacterial system.
Serological studies of passive immunity in experimentally induced bovine colibacillosis was studied in a 41-cow university herd. Pregnant dams were antigenized prepartum with two injections administered by the subcutaneous and intrammamary routes with one of four vaccine preparations (killed bacteria, live bacteria, culture supernatant, or heart infusion broth [control]). The data indicate that 77% of the neonates born to vaccinated dams were strongly protected against oral challenge with Escherichia coli strain B-44. Bacterial agglutinin and passive hemagglutination titers of colostral whey directly reflected the efficacy of the vaccines. A notable decrease in the whey titers to somatic and capsular antigens occurred after heat treatment at 56 C for 30 min. Complicity of heat-liable immune factor(s) in protection from scouring was suggested. The nature of the protective antigen is not clearly defined by these studies but there is some evidence that the K antigen may play a vital role in this regard.
A review of recent knowledges of the specific determinants of Escherichia coli pathogenicity allows the development of new effective immunisation against the colibacillosis of the pig. Especially experimental and field trials provide promising results by oral or parenteral vaccinations, with attenuated bacteria neutralising the effect of enterotoxins or with partially purified protein surface antigen preventing bacterial attachment to the intestinal wall. However it is necessary to bear in mind the necessity of not neglecting sanitary management.