Hereditary resistance to anthrax and sensitivity to the anthrax toxin in mice

The degree of the hereditary susceptibility of mice to anthrax caused by noncapsular and capsule-forming Bacillus anthracis strains has been found to be directly related to the sensitivity of the animals to the edematogenic and immunosuppressing action of anthrax toxin. The genetic analysis indicates that resistance to anthrax is probably controlled by a dominant gene, not linked with histocompatibility complex H-2 and, probably, unrelated to the presence of hemolytic activity in mouse sera, determined by component C5 of the complement.     

Recent progress in the development of anthrax vaccines

Bacillus anthracis is the etiological agent of anthrax. Although anthrax is primarily an epizootic disease; humans are at risk for contracting anthrax. The potential use of B. anthracis spores as biowarfare agent has led to immense attention. Prolonged vaccination schedule of current anthrax vaccine and variable protection conferred; often leading to failure of therapy. This highlights the need for alternative anthrax countermeasures. A number of approaches are being investigated to substitute or supplement the existing anthrax vaccines. These relied on expression of Protective antigen (PA), the key protective immunogen; in bacterial or plant systems; or utilization of attenuated strains of B. anthracis for immunization. Few studies have established potential of domain IV of PA for immunization. Other targets including the spore, capsule, S-layer and anthrax toxin components have been investigated for imparting protective immunity. It has been shown that co-immunization of PA with domain I of lethal factor that binds PA resulted in higher antibody responses. Of the epitope based vaccines, the loop neutralizing determinant, in particular; elicited robust neutralizing antibody response and conferred 97% protection upon challenge. DNA vaccination resulted in varying degree of protection and seems a promising approach. Additionally, the applicability of monoclonal and therapeutic antibodies in the treatment of anthrax has also been demonstrated. The recent progress in the direction of anthrax prophylaxis has been evaluated in this review.     

Heme catabolism in the causative agent of anthrax

A challenge common to all bacterial pathogens is to acquire nutrients from hostile host environments. Iron is an important cofactor required for essential cellular processes such as DNA repair, energy production and redox balance. Within a mammalian host, most iron is sequestered within heme, which in turn is predominantly bound by hemoglobin. While little is understood about the mechanisms by which bacterial hemophores attain heme from host‐hemoglobin, even less is known about intracellular heme processing. Bacillus anthracis, the causative agent of anthrax, displays a remarkable ability to grow in mammalian hosts. Hypothesizing this pathogen harbors robust ways to catabolize heme, we characterize two new intracellular heme‐binding proteins that are distinct from the previously described IsdG heme monooxygenase. The first of these, HmoA, binds and degrades heme, is necessary for heme detoxification and facilitates growth on heme iron sources. The second protein, HmoB, binds and degrades heme too, but is not necessary for heme utilization or virulence. The loss of both HmoA and IsdG renders B. anthracis incapable of causing anthrax disease. The additional loss of HmoB in this background increases clearance of bacilli in lungs, which is consistent with this protein being important for survival in alveolar macrophages.     

Challenges in disposing of anthrax waste

Disasters often create large amounts of waste that must be managed as part of both immediate response and long-term recovery. While many federal, state, and local agencies have debris management plans, these plans often do not address chemical, biological, and radiological contamination. The Interagency Biological Restoration Demonstration's (IBRD) purpose was to holistically assess all aspects of an anthrax incident and assist in the development of a plan for long-term recovery. In the case of wide-area anthrax contamination and the follow-on response and recovery activities, a significant amount of material would require decontamination and disposal. Accordingly, IBRD facilitated the development of debris management plans to address contaminated waste through a series of interviews and workshops with local, state, and federal representatives. The outcome of these discussions was the identification of 3 primary topical areas that must be addressed: planning, unresolved research questions, and resolving regulatory issues.     

Implications of autophagy in anthrax pathogenicity

The etiological agent for anthrax is Bacillus anthracis, which produces lethal toxin (LT) that exerts a myriad of effects on many immune cells. In our previous study, it was demonstrated that LT and protective antigen (PA) induce autophagy in mammalian cells. Preliminary results suggest that autophagy may function as a cellular defense mechanism against LT-mediated toxemia. This degradation pathway may also be relevant to other aspects of the immune response in both innate and adaptive immunity. Understanding the role of autophagy in response to anthrax infection and the possibility of modulating this degradation pathway as potential countermeasures are subjects for further investigation.     

Specific intoxication in anthrax infection

The pathomorphological picture of experimental B. anthracis infection in white rats (strain Fisher-344) essentially corresponds to experimental anthracic intoxication with very moderately pronounced morphological manifestation of B. anthracis invasion. This indicates that specific anthracic intoxication is an essential component of the pathological process in B. anthracis infection.     

Crystallographic studies of the anthrax lethal toxin

Anthrax lethal toxin comprises two proteins: protective antigen (PA; MW 83 kDa) and lethal factor (LF; MW 87 kDa). We have recently determined the crystal structure of the 735-residue PA in its monomeric and heptameric forms ( Petosa et al . 1997 ). It bears no resemblance to other bacterial toxins of known three-dimensional structure, and defines a new structural class which includes homologous toxins from other Gram-positive bacteria. We have proposed a model of membrane insertion in which the water-soluble heptamer undergoes a substantial pH-induced conformational change involving the creation of a 14-stranded β-barrel. Recent work by Collier's group ( Benson et al . 1998 ) lends strong support to our model of membrane insertion. 'Lethal factor' is the catalytic component of anthrax lethal toxin. It binds to the surface of the cell-bound PA heptamer and, following endocytosis and acidification of the endosome, translocates to the cytosol. We have made substantial progress towards an atomic resolution crystal structure of LF. Progress towards a structure of the 7:7 translocation complex between the PA heptamer and LF will also be discussed.