Raymond S. Weinstein

Effective antiprotease-antibiotic treatment of experimental anthrax

BackgroundInhalation anthrax is characterized by a systemic spread of the challenge agent, Bacillus anthracis. It causes severe damage, including multiple hemorrhagic lesions, to host tissues and organs. It is widely believed that anthrax lethal toxin secreted by proliferating bacteria is a major cause of death, however, the pathology of intoxication in experimental animals is drastically different from that found during the infectious process. In order to close a gap between our understanding of anthrax molecular pathology and the most prominent clinical features of the infectious process we undertook bioinformatic and experimental analyses of potential proteolytic virulence factors of B. anthracis distinct from lethal toxin.MethodsSecreted proteins (other than lethal and edema toxins) produced by B. anthracis were tested for tissue-damaging activity and toxicity in mice. Chemical protease inhibitors and rabbit immune sera raised against B. anthracis proteases were used to treat mice challenged with B. anthracis (Sterne) spores.ResultsB. anthracis strain delta Ames (pXO1-, pXO2-) producing no lethal and edema toxins secrets a number of metalloprotease virulence factors upon cultivation under aerobic conditions, including those with hemorrhagic, caseinolytic and collagenolytic activities, belonging to M4 and M9 thermolysin and bacterial collagenase families, respectively.These factors are directly toxic to DBA/2 mice upon intratracheal administration at 0.5 mg/kg and higher doses. Chemical protease inhibitors (phosphoramidon and 1, 10-phenanthroline), as well as immune sera against M4 and M9 proteases of B. anthracis, were used to treat mice challenged with B. anthracis (Sterne) spores. These substances demonstrate a substantial protective efficacy in combination with ciprofloxacin therapy initiated as late as 48 h post spore challenge, compared to the antibiotic alone.ConclusionSecreted proteolytic enzymes are important pathogenic factors of B. anthrasis, which can be considered as effective therapeutic targets in the development of anthrax treatment and prophylactic approaches complementing anti-lethal toxin therapy.

Biological and chemical terrorism : a guide for healthcare providers and first responders

A Quick Reference for Potential Biological Weapons (tear out sheet) Preface How to Use This Book Introduction Basic Bioterrorism (Section I) What is Bioterrorism? Flu-Like Illness What Makes an Effective Weapon Personal Precautions: Table 1 (Comparison of Symptoms of Potential Biological Weapons to Influenza) Table 2 (Signs that Suggest an Attack with a Biological Weapon) Syndromic Cross References (Section 2) Fever with Prominent Arthralgias Acute Hepatic Syndrome Hemorrhagic Diathesis Hilar Adenopathy or Widened Mediastinum Fever with Petechiae Cutaneuos Lesions of Ulcertations Acute Respiratory Syndrome With Fever Acute Respiratory Syndrome Without Fever Flu-Like Illness with Rash Fever with Lymphadenopathy Acute Neurologic Syndrome with Fever Acute Neurologic Syndrome without Fever Acute GI Syndrome with Fever Acute GI Syndrome without Fever Individual Biologic Weapon Detalied Quick Reference (Section 3) Aflatoxins Anthrax (Inhalational & gastrointestinal) Anthrax (Cutaneous) Blastomucosis Botulism (Botulism Toxins) Brucellosis Crimean-Congo Hemorrhagic Fever Chikungunya Cholera Dengue Fever (Dengue Hemorrhagic Fever) Domoic Acid (Amnesic Shellfish Poisining) Ebola and Marburg Viral Hemorrhagic Fevers Encephalis, Viral (Venezuelan, Eastern, Western, St. Louis, Japanese, and West Nile Virus) Imfluenza Glanders Hantavirus Kyansunur Forest Disease Lassa Virus and the South American Viral Hemorrhagic Fevers Legionellosis Leptospirosis Melioidosis Nipah Virus Omsk Hemorrhagic Fever Plague Psittacosis Q Fever Ricin and Abrin Rocky Mountain Spotted Fever Rift Valley Fever Salmonellosis (Typhoid, parathypoid and Non-Typhoidal) Saxitoxin (Paralytic Shellfish Poisoning) Staphylococcal Enterotoxin B Shigellosis Smallpox (information sheet) Smallpox (Color Atlas and Visual Guide) Trichothescene (T-2) Mycotoxins Tetrodotoxin Tularemia Typhus (Epedemic, Murine and Scrub) Yellow Fever Basic Chemical Terrorism (Section 4) What is Chemical Terrorism Physical Properties of Chemical Weapons Protecting Yourself Chemical Weapon Syndriomic Cross References (Section 5) Prominent Skin Rash, Blistering, and/or Burns Prominent Pulmonary Symptoms Seizures and/or Sudde Coma Acute Hemolytic Anemia Individual Chemical Weapon Detailed Quick References (Section 6) Nerve Agents Cyanides (Blood Agents) Hydrogen Sulfide Pulmonary Agents Mustard Lewisite hosgene Oxime (CX) Anhydrous Ammonia, Sulfur Dioxide, and Hydrogen Chloride Hydrogen Flouride Arsine Lacrimators (Tear Gas) References Resources on the Internet Glossary Index

Significantly reduced CCR5-tropic HIV-1 replication in vitro in cells from subjects previously immunized with Vaccinia Virus

BackgroundAt present, the relatively sudden appearance and explosive spread of HIV throughout Africa and around the world beginning in the 1950s has never been adequately explained. Theorizing that this phenomenon may be somehow related to the eradication of smallpox followed by the cessation of vaccinia immunization, we undertook a comparison of HIV-1 susceptibility in the peripheral blood mononuclear cells from subjects immunized with the vaccinia virus to those from vaccinia naive donors.ResultsVaccinia immunization in the preceding 3-6 months resulted in an up to 5-fold reduction in CCR5-tropic but not in CXCR4-tropic HIV-1 replication in the cells from vaccinated subjects. The addition of autologous serum to the cell cultures resulted in enhanced R5 HIV-1 replication in the cells from unvaccinated, but not vaccinated subjects. There were no significant differences in the concentrations of MIP-1α, MIP-1β and RANTES between the cell cultures derived from vaccinated and unvaccinated subjects when measured in culture medium on days 2 and 5 following R5 HIV-1 challenge.DiscussionSince primary HIV-1 infections are caused almost exclusively by the CCR5-tropic HIV-1 strains, our results suggest that prior immunization with vaccinia virus might provide an individual with some degree of protection to subsequent HIV infection and/or progression. The duration of such protection remains to be determined. A differential elaboration of MIP-1α, MIP-1β and RANTES between vaccinated and unvaccinated subjects, following infection, does not appear to be a mechanism in the noted protection.