{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T03:22:38Z","timestamp":1760239358378,"version":"build-2065373602"},"reference-count":29,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2020,10,24]],"date-time":"2020-10-24T00:00:00Z","timestamp":1603497600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000774","name":"Defense Threat Reduction Agency","doi-asserted-by":"publisher","award":["BA06TAS022 and CBS.PHYSIO.01.SW.005."],"award-info":[{"award-number":["BA06TAS022 and CBS.PHYSIO.01.SW.005."]}],"id":[{"id":"10.13039\/100000774","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000139","name":"U.S. Environmental Protection Agency","doi-asserted-by":"publisher","award":["Interagency Agreement DW9792208901 and Contract No. EP-C-14-001 to ICF International, under Battelle contract 13KJBO0004 Task Order WAs 2-40 and 3-40."],"award-info":[{"award-number":["Interagency Agreement DW9792208901 and Contract No. EP-C-14-001 to ICF International, under Battelle contract 13KJBO0004 Task Order WAs 2-40 and 3-40."]}],"id":[{"id":"10.13039\/100000139","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pathogens"],"abstract":"<jats:p>Bacillus anthracis spores that are re-aerosolized from surface deposits after initial contamination present significant health risks for personnel involved in decontamination. To model repeated exposure to low dose B. anthracis spores, three groups of seven rabbits were challenged with multiple low-doses of B. anthracis spores 5 days a week for 3 weeks. Mortality, body temperature, heart and respiration rates, hematology, C-reactive protein, bacteremia, and serum protective antigen were monitored for 21 days post-exposure after the last of multiple doses. All rabbits exposed to a mean daily dose of 2.91 \u00d7 102 colony forming units (CFU) survived and showed minimal physiological changes attributable to exposure. One of seven rabbits receiving a mean daily dose of 1.22 \u00d7 103 CFU died and four of seven receiving a mean daily dose of 1.17 \u00d7 104 CFU died. The LD50 was calculated to be 8.1 \u00d7 103 CFU of accumulated dose. Rabbits that succumbed to the higher dose exhibited bacteremia and increases above baseline in heart rate, respiration rate, and body temperature. Two rabbits in the mean daily dose group of 1.17 \u00d7 104 CFU exhibited clinical signs of inhalation anthrax yet survived. This study provides a description of lethality, pathophysiology, and pathology in a controlled multiple low-dose inhalation exposure study of B. anthracis in the rabbit model. The data suggest that the accumulated dose is important in survival outcome and that a subset of rabbits may show clinical signs of disease but fully recover without therapeutic intervention<\/jats:p>","DOI":"10.3390\/pathogens9110877","type":"journal-article","created":{"date-parts":[[2020,10,26]],"date-time":"2020-10-26T02:34:54Z","timestamp":1603679694000},"page":"877","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Physiological Responses to Multiple Low-Doses of Bacillus anthracis Spores in the Rabbit Model of Inhalation Anthrax"],"prefix":"10.3390","volume":"9","author":[{"given":"Sarah C.","family":"Taft","sequence":"first","affiliation":[{"name":"U.S. Environmental Protection Agency, National Homeland Security Research Center, Cincinnati, OH 45224, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tonya L.","family":"Nichols","sequence":"additional","affiliation":[{"name":"U.S. Environmental Protection Agency, National Homeland Security Research Center, Cincinnati, OH 45224, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephanie A.","family":"Hines","sequence":"additional","affiliation":[{"name":"Formerly of Battelle Memorial Institute, Columbus, OH 43201, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roy E.","family":"Barnewall","sequence":"additional","affiliation":[{"name":"Battelle Memorial Institute, Columbus, OH 43201, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gregory V.","family":"Stark","sequence":"additional","affiliation":[{"name":"Formerly of Battelle Memorial Institute, Columbus, OH 43201, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jason E.","family":"Comer","sequence":"additional","affiliation":[{"name":"Institutional Office of Regulated Nonclinical Studies, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA"},{"name":"Department of Microbiology and Immunology, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA"},{"name":"Sealy Institute for Vaccine Sciences, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA"},{"name":"Center for Biodefense and Emerging Infectious Diseases, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,10,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"71","DOI":"10.3389\/fcimb.2012.00071","article-title":"Achieving Consistent Multiple Daily Low-Dose Bacillus anthracis Spore Inhalation Exposures in the Rabbit Model","volume":"2","author":"Barnewall","year":"2012","journal-title":"Front. Cell. Infect. Microbiol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2236","DOI":"10.1001\/jama.287.17.2236","article-title":"Anthrax as a Biological Weapon, 2002. Updated recommendations for management","volume":"287","author":"Inglesby","year":"2002","journal-title":"JAMA"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Taft, S.C., Nichols, T.L., Hines, S.A., Barnewall, R.E., Stark, G.V., and Comer, J.E. (2020). Physiological Responses to a Single Low-Dose of Bacillus anthracis Spores in the Rabbit Model of Inhalational Anthrax. Pathogens, 9.","DOI":"10.3390\/pathogens9060461"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1750","DOI":"10.1111\/j.1539-6924.2012.01808.x","article-title":"Benchmark Dose Analysis for Bacillus anthracis Inhalation Exposures in the Nonhuman Primate","volume":"32","author":"Taft","year":"2012","journal-title":"Risk Anal."},{"key":"ref_5","unstructured":"U.S. Environmental Protection Agency (2016). Review of Bacillus anthracis Dose-Response Data for Human Health Risk Assessment."},{"key":"ref_6","first-page":"1055","article-title":"Experimental Inhalation Anthrax in the Chimpanzee","volume":"35","author":"Albrink","year":"1959","journal-title":"Am. J. Pathol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1128\/br.30.3.646-659.1966","article-title":"Industrial inhalation Anthrax","volume":"30","author":"Brachman","year":"1966","journal-title":"Bacteriol. Rev."},{"key":"ref_8","unstructured":"Office of Research and Development National Homeland Security Research Center (2012). Technical Brief: Review of Bacillus anthracis (Anthrax) Studies for Dose-Response Modeling to Estimate Risk."},{"key":"ref_9","unstructured":"Office of Research and Development National Homeland Security Research Center (2012). Multiple Daily Low-Dose Bacillus anthracis Ames Inhalation Exposures in the Rabbit."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2031","DOI":"10.1111\/risa.12564","article-title":"Dose-Response Modeling for Inhalational Anthrax in Rabbits Following Single or Multiple Exposures","volume":"36","author":"Gutting","year":"2016","journal-title":"Risk Anal."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"943","DOI":"10.1111\/risa.12688","article-title":"Modeling Rabbit Responses to Single and Multiple Aerosol Exposures of Bacillus anthracis Spores","volume":"37","author":"Coleman","year":"2017","journal-title":"Risk Anal."},{"key":"ref_12","unstructured":"National Research Council (2011). Guide to the Care and Use of Laboratory Animals, The National Academies Press. [8th ed.]."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"4427","DOI":"10.1128\/AEM.00557-08","article-title":"Gamma Irradiation Can Be Used to Inactivate Bacillus anthracis Spores without Compromising the Sensitivity of Diagnostic Assays","volume":"74","author":"Dauphin","year":"2008","journal-title":"Appl. Environ. Microbiol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1517","DOI":"10.1128\/CVI.00292-12","article-title":"Characterization of a Therapeutic Model of Inhalational Anthrax Using an Increase in Body Temperature in New Zealand White Rabbits as a Trigger for Treatment","volume":"19","author":"Comer","year":"2012","journal-title":"Clin. Vaccine Immunol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1016","DOI":"10.1128\/CVI.00099-13","article-title":"Evaluation of Immunogenicity and Efficacy of Anthrax Vaccine Adsorbed for Postexposure Prophylaxis","volume":"20","author":"Ionin","year":"2013","journal-title":"Clin. Vaccine Immunol."},{"key":"ref_16","first-page":"982","article-title":"The pathology of experimental anthrax in rabbits exposed by inhalation and subcutaneous inoculation","volume":"122","author":"Zaucha","year":"1998","journal-title":"Arch. Pathol. Lab. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1248\/yakushi.130.841","article-title":"Hypolipidemic effect of arborium plus in experimentally induced hypercholestermic rabbits","volume":"130","author":"Murty","year":"2010","journal-title":"Yakugaku Zasshi"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1186\/1476-511X-8-39","article-title":"Effects of apple juice on risk factors of lipid profile, inflammation and coagulation, endothelial markers and atherosclerotic lesions in high cholesterolemic rabbits","volume":"8","author":"Setorki","year":"2009","journal-title":"Lipids Health Dis."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2077","DOI":"10.2174\/1568026617666170130111324","article-title":"Model Systems for Pulmonary Infectious Diseases: Paradigms of Anthrax and Tuberculosis","volume":"17","author":"Arora","year":"2017","journal-title":"Curr. Top. Med. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e01590-17","DOI":"10.1128\/AAC.01590-17","article-title":"Development of Protective Immunity in New Zealand White Rabbits Challenged with Bacillus anthracis Spores and Treated with Antibiotics and Obiltoxaximab, a Monoclonal Antibody against Protective Antigen","volume":"62","author":"Henning","year":"2018","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Lawrence, W.S., Peel, J.E., Sivasubramani, S.K., Baze, W.B., Whorton, E.B., Beasley, D.W., Comer, J.E., Hughes, D.E., Ling, L.L., and Peterson, J.W. (2020). Teixobactin Provides Protection against Inhalation Anthrax in the Rabbit Model. Pathogens, 9.","DOI":"10.3390\/pathogens9090773"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1128\/CVI.00023-06","article-title":"Detection of Anthrax Toxin in the Serum of Animals Infected with Bacillus anthracis by Using Engineered Immunoassays","volume":"13","author":"Mabry","year":"2006","journal-title":"Clin. Vaccine Immunol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"5871","DOI":"10.1128\/IAI.00792-06","article-title":"Protective Antigen as a Correlative Marker for Anthrax in Animal Models","volume":"74","author":"Kobiler","year":"2006","journal-title":"Infect. Immun."},{"key":"ref_24","first-page":"461","article-title":"Aerosolized Bacillus anthracis Infection in New Zealand White Rabbits: Natural History and Intravenous Levofloxacin Treatment","volume":"60","author":"Yee","year":"2010","journal-title":"Comp. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3432","DOI":"10.1128\/IAI.00346-09","article-title":"Kinetics of Lethal Factor and Poly-d-Glutamic Acid Antigenemia during Inhalation Anthrax in Rhesus Macaques","volume":"77","author":"Boyer","year":"2009","journal-title":"Infect. Immun."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1111\/j.1749-6632.1980.tb18910.x","article-title":"Inhalation anthrax","volume":"353","author":"Brachman","year":"1980","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2264","DOI":"10.1039\/C8AN02479K","article-title":"Accurate and selective quantification of anthrax protective antigen in plasma by immunocapture and isotope dilution mass spectrometry","volume":"144","author":"Solano","year":"2019","journal-title":"Analyst"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1765","DOI":"10.1128\/CVI.00288-12","article-title":"Development of an Inhalational Bacillus anthracis Exposure Therapeutic Model in Cynomolgus Macaques","volume":"19","author":"Henning","year":"2012","journal-title":"Clin. Vaccine Immunol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1128\/CVI.00475-10","article-title":"Antibody Responses to a Spore Carbohydrate Antigen as a Marker of Nonfatal Inhalation Anthrax in Rhesus Macaques","volume":"18","author":"Saile","year":"2011","journal-title":"Clin. Vaccine Immunol."}],"container-title":["Pathogens"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-0817\/9\/11\/877\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:27:38Z","timestamp":1760178458000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-0817\/9\/11\/877"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,10,24]]},"references-count":29,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2020,11]]}},"alternative-id":["pathogens9110877"],"URL":"https:\/\/doi.org\/10.3390\/pathogens9110877","relation":{},"ISSN":["2076-0817"],"issn-type":[{"type":"electronic","value":"2076-0817"}],"subject":[],"published":{"date-parts":[[2020,10,24]]}}}