Bacillus anthracis

About: Bacillus anthracis is a research topic. Over the lifetime, 3994 publications have been published within this topic receiving 128122 citations.

Immunologic studies of anthrax. IV. Evaluation of the immunogenicity of three components of anthrax toxin.

Abstract: Summary Three components of anthrax toxin (edema factor, protective antigen and lethal factor) were separated and tested singly at three dose levels and in factorial combination (27 treatments) to determine their efficacy as immunogens in a resistant host (rat) and in a susceptible host (guinea pig). Each treatment was evaluated as an immunogen by five criteria: ( 1 ) protection of the host against challenge, ( 2 ) influence on the number of bacilli/milliliter of blood at death, ( 3 ) change in the units of toxin/milliliter of blood at death, ( 4 ) a development of antibody titer (Ouchterlony) and ( 5 ) units of toxin neutralized/milliliter of blood. These evaluations showed that ( 1 ) the LF component was highly immunogenic in rats against either toxin or spore challenge and in guinea pigs against spore challenge; ( 2 ) the PA component was immunogenic against spore challenge in rats and guinea pigs, but completely ineffective against toxin challenge in rats; ( 3 ) the EF component alone was nonimmunogenic; ( 4 ) the effects of LF and PA combinations interacted significantly with LF to increase resistance in the rat, but was not additive in resistance in the guinea pig. The number of organisms/milliliter of terminal blood decreased as resistance to establishment of disease increased. The units of toxin/milliliter of terminal blood were closely related to the number of bacilli/milliliter of blood at death. Only 17% of the prechallenge serum of guinea pigs, principally among the LF treatments, produced antigen antibody precipitin lines on Ouchterlony plates. The rat sera were all negative in this test. The antigen used to immunize man and animals should contain all the toxin components for maximum efficiency.

Lung epithelial injury by B. anthracis lethal toxin is caused by MKK-dependent loss of cytoskeletal integrity.

Abstract: Bacillus anthracis lethal toxin (LT) is a key virulence factor of anthrax and contributes significantly to the in vivo pathology. The enzymatically active component is a Zn(2+)-dependent metalloprotease that cleaves most isoforms of mitogen-activated protein kinase kinases (MKKs). Using ex vivo differentiated human lung epithelium we report that LT destroys lung epithelial barrier function and wound healing responses by immobilizing the actin and microtubule network. Long-term exposure to the toxin generated a unique cellular phenotype characterized by increased actin filament assembly, microtubule stabilization, and changes in junction complexes and focal adhesions. LT-exposed cells displayed randomly oriented, highly dynamic protrusions, polarization defects and impaired cell migration. Reconstitution of MAPK pathways revealed that this LT-induced phenotype was primarily dependent on the coordinated loss of MKK1 and MKK2 signaling. Thus, MKKs control fundamental aspects of cytoskeletal dynamics and cell motility. Even though LT disabled repair mechanisms, agents such as keratinocyte growth factor or dexamethasone improved epithelial barrier integrity by reducing cell death. These results suggest that co-administration of anti-cytotoxic drugs may be of benefit when treating inhalational anthrax.

Human Lung Innate Immune Response to Bacillus anthracis Spore Infection

Abstract: Bacillus anthracis, the causative agent of inhalational anthrax, enters a host through the pulmonary system before dissemination. We have previously shown that human alveolar macrophages participate in the initial innate immune response to B. anthracis spores through cell signal-mediated cytokine release. We proposed that the lung epithelia also participate in the innate immune response to this pathogen, and we have developed a human lung slice model to study this process. Exposure of our model to B. anthracis (Sterne) spores rapidly activated the mitogen-activated protein kinase signaling pathways ERK, p38, and JNK. In addition, an RNase protection assay showed induction of mRNA of several cytokines and chemokines. This finding was reflected at the translational level by protein peak increases of 3-, 25-, 9-, 34-, and 5-fold for interleukin-6 (IL-6), tumor necrosis factor alpha, IL-8, macrophage inflammatory protein 1α/β, and monocyte chemoattractant protein 1, respectively, as determined by an enzyme-linked immunosorbent assay. Inhibition of individual pathways by UO126, SP600125, and SB0203580 decreased induction of chemokines and cytokines by spores, but this depended on the pathways inhibited and the cytokines and chemokines induced. Combining all three inhibitors reduced induction of all cytokines and chemokines tested to background levels. An immunohistochemistry analysis of IL-6 and IL-8 revealed that alveolar epithelial cells and macrophages and a few interstitial cells are the source of the cytokines and chemokines. Taken together, these data showed the activation of the pulmonary epithelium in response to B. anthracis spore exposure. Thus, the lung epithelia actively participate in the innate immune response to B. anthracis infection through cell signal-mediated elaboration of cytokines and chemokines.