Anthrax vaccine recipients lack antibody against the loop neutralizing determinant: A protective neutralizing epitope from Bacillus anthracis protective antigen

Oscherwitz, Jon; Quinn, Conrad P.; Cease, Kemp B.

doi:10.1016/j.vaccine.2015.03.037

Cited by 9 publications

(5 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Thus, those host populations with lower mortality (kudu in ENP and zebra in KNP) are more likely to be exposed to sublethal amounts of the pathogen based on their foraging behavior and the relative risk of that behavior in the two landscapes ( 43 , 44 , 51 ), yet show greater toxin neutralization than their counterparts in the other park. A previous study showed that animals that were immunized with antigens of spore origin conferred protection against B. anthracis through the production of antibodies that reduced spore germination ( 83 ). This type of sublethal natural “immunization” may have induced anti-spore antibodies and reduced germination in zebra in KNP and kudu in ENP ( 84 ), but this hypothesis would need further investigation.…”

Section: Discussionmentioning

confidence: 99%

Immunological Evidence of Variation in Exposure and Immune Response to Bacillus anthracis in Herbivores of Kruger and Etosha National Parks

et al. 2022

View full text Add to dashboard Cite

Exposure and immunity to generalist pathogens differ among host species and vary across spatial scales. Anthrax, caused by a multi-host bacterial pathogen, Bacillus anthracis, is enzootic in Kruger National Park (KNP), South Africa and Etosha National Park (ENP), Namibia. These parks share many of the same potential host species, yet the main anthrax host in one (greater kudu (Tragelaphus strepsiceros) in KNP and plains zebra (Equus quagga) in ENP) is only a minor host in the other. We investigated species and spatial patterns in anthrax mortalities, B. anthracis exposure, and the ability to neutralize the anthrax lethal toxin to determine if observed host mortality differences between locations could be attributed to population-level variation in pathogen exposure and/or immune response. Using serum collected from zebra and kudu in high and low incidence areas of each park (18- 20 samples/species/area), we estimated pathogen exposure from anti-protective antigen (PA) antibody response using enzyme-linked immunosorbent assay (ELISA) and lethal toxin neutralization with a toxin neutralization assay (TNA). Serological evidence of pathogen exposure followed mortality patterns within each system (kudus: 95% positive in KNP versus 40% in ENP; zebras: 83% positive in ENP versus 63% in KNP). Animals in the high-incidence area of KNP had higher anti-PA responses than those in the low-incidence area, but there were no significant differences in exposure by area within ENP. Toxin neutralizing ability was higher for host populations with lower exposure prevalence, i.e., higher in ENP kudus and KNP zebras than their conspecifics in the other park. These results indicate that host species differ in their exposure to and adaptive immunity against B. anthracis in the two parks. These patterns may be due to environmental differences such as vegetation, rainfall patterns, landscape or forage availability between these systems and their interplay with host behavior (foraging or other risky behaviors), resulting in differences in exposure frequency and dose, and hence immune response.

show abstract

Section: Discussionmentioning

confidence: 99%

Immunological Evidence of Variation in Exposure and Immune Response to Bacillus anthracis in Herbivores of Kruger and Etosha National Parks

et al. 2022

View full text Add to dashboard Cite

show abstract

“…Taken together, cAb29 stabilizes an exposed conformation that is sampled by the D2L2 loop without the antibody. Consequently, our results provide a mechanistic basis for using the D2L2 as a target for developing anthrax vaccinations aimed at eliciting the formation of effective neutralizing antibodies [14,28,29].…”

Section: Discussionmentioning

confidence: 83%

Neutralization of the anthrax toxin by antibody-mediated stapling of its membrane penetrating loop

Hoelzgen

Zalk

Alcalay

et al. 2021

Preprint

View full text Add to dashboard Cite

Anthrax infection is associated with severe illness and high mortality. Protective antigen (PA) is the central component of the anthrax toxin, which is the main virulent factor of anthrax. Upon endocytosis, PA opens a pore in the membranes of endosomes, through which the toxin's cytotoxic enzymes are extruded. The PA pore is formed by a cooperative conformational change where PA's membrane-penetrating loops associate, forming a hydrophobic rim that pierces the membrane. Due to its crucial role in anthrax progression, PA is an important target of monoclonal antibodies-based therapy. cAb29 is a highly effective neutralizing antibody against PA. We determined the cryo-EM structure of PA in complex with the Fab portion of cAb29. We found that cAb29 neutralizes the toxin by clamping the membrane-penetrating loop of PA to a static region on PA's surface, thereby preventing pore formation. Therefore, our results provide the structural basis for the antibody-based neutralization of PA and bring to focus the membrane-penetrating loop of PA as a target for the development of better anti-anthrax vaccines.

show abstract

“…Taken together, cAb29 stabilizes an exposed conformation that is sampled by the D2L2 loop without the antibody. Consequently, our results provide a mechanistic basis for using D2L2 as a target for the development of anthrax vaccines aimed at eliciting the formation of effective neutralizing antibodies (Oscherwitz et al, 2015;McComb & Martchenko, 2016;Yin et al, 2008).…”

Section: Discussionmentioning

confidence: 85%

Neutralization of the anthrax toxin by antibody-mediated stapling of its membrane-penetrating loop

Hoelzgen¹,

Zalk²,

Alcalay³

et al. 2021

Acta Cryst Sect D Struct Biol

View full text Add to dashboard Cite

Anthrax infection is associated with severe illness and high mortality. Protective antigen (PA) is the central component of the anthrax toxin, which is one of two major virulence factors of Bacillus anthracis, the causative agent of anthrax disease. Upon endocytosis, PA opens a pore in the membranes of endosomes, through which the cytotoxic enzymes of the toxin are extruded. The PA pore is formed by a cooperative conformational change in which the membrane-penetrating loops of PA associate, forming a hydrophobic rim that pierces the membrane. Due to its crucial role in anthrax progression, PA is an important target for monoclonal antibody-based therapy. cAb29 is a highly effective neutralizing antibody against PA. Here, the cryo-EM structure of PA in complex with the Fab portion of cAb29 was determined. It was found that cAb29 neutralizes the toxin by clamping the membrane-penetrating loop of PA to the static surface-exposed loop of the D3 domain of the same subunit, thereby preventing pore formation. These results provide the structural basis for the antibody-based neutralization of PA and bring into focus the membrane-penetrating loop of PA as a target for the development of better anti-anthrax vaccines.

show abstract

Anthrax vaccine recipients lack antibody against the loop neutralizing determinant: A protective neutralizing epitope from Bacillus anthracis protective antigen

Cited by 9 publications

References 20 publications

Immunological Evidence of Variation in Exposure and Immune Response to Bacillus anthracis in Herbivores of Kruger and Etosha National Parks

Immunological Evidence of Variation in Exposure and Immune Response to Bacillus anthracis in Herbivores of Kruger and Etosha National Parks

Neutralization of the anthrax toxin by antibody-mediated stapling of its membrane penetrating loop

Neutralization of the anthrax toxin by antibody-mediated stapling of its membrane-penetrating loop

Contact Info

Product

Resources

About