Bioterrorism Event Research Articles

Screen of FDA-approved drug library identifies maprotiline, an antibiofilm and antivirulence compound with QseC sensor-kinase dependent activity in Francisella novicida

Development of new therapeutics against Select Agents such as Francisella is critical preparation in the event of bioterrorism. Testing FDA-approved drugs for this purpose may yield new activities unrelated to their intended purpose and may hasten the discovery of new therapeutics. A library of 420 FDA-approved drugs was screened for antibiofilm activity against a model organism for human tularemia, Francisella (F.) novicida, excluding drugs that significantly inhibited growth. The initial screen was based on the 2-component system (TCS) dependent biofilm effect, thus, the QseC dependence of maprotiline anti-biofilm action was demonstrated. By comparing their FDA-approved uses, chemical structures, and other properties of active drugs, toremifene and polycyclic antidepressants maprotiline and chlorpromazine were identified as being highly active against F. novicida biofilm formation. Further down-selection excluded toremifene for its membrane active activity and chlorpromazine for its high antimicrobial activity. The mode of action of maprotiline against F. novicida was sought. It was demonstrated that maprotiline was able to significantly down-regulate the expression of the virulence factor IglC, encoded on the Francisella Pathogenicity Island (FPI), suggesting that maprotiline is exerting an effect on bacterial virulence. Further studies showed that maprotiline significantly rescued F. novicida infected wax worm larvae. In vivo studies demonstrated that maprotiline treatment could prolong time to disease onset and survival in F. novicida infected mice. These results suggest that an FDA-approved drug such as maprotiline has the potential to combat Francisella infection as an antivirulence agent, and may have utility in combination with antibiotics.

General procedures in response to suspected attacks with highly contagious and pathogenic agents

The discovery of undefined powders that are content of letters or parcels with or without threats in writing addressed to institutions, groups or persons, often raises the suspicion of an attack involving biological agents such as anthrax. Subsequent investigations and analyses by local authorities often aim at excluding anthrax or anthrax spores. Suspicion and actions are then mistakenly justified by referring to the 2001 anthrax letter attacks in the USA, which now lie more than 10 years in the past. In Germany to date there has never been a terrorist attack involving dangerous biological agents, neither in letters nor in any other possible form. In addition, it cannot be assumed that anthrax bacteria or spores will be used again in a bioterrorist event. In the case of a valid suspicion of a threatening letter, neither analyses to exclude only a certain group of substances (e.g. biological, chemical or radiological) nor analyses to exclude only one biological agent (e.g. anthrax) in particular would provide sufficient information for decision makers to conduct further actions in coping with the given situation. Moreover, a sequence of procedures such as consultation, exclusion, and analyses should be followed in order to systematically exclude all relevant threats. Therefore, and in respect to the current CBRNE threat assessment for Germany, the following article provides recommendations of actions to be taken for coping with a valid suspicion of an intentional release of biological agents utilizing powder letters as an example.

Military Real-time Syndromic Surveillance System for Biosurveillance Portal in Korea

As a part of the Korea-US joint Biosurveillance Portal project, we have developed the military syndromic surveillance system with electronic medical records from military hospitals for early identification of bio-terror related events among Armed Forces in Korea. Respiratory, Gastrointestinal, Botulism, Dermatologic, Neurologic, Hemorrhagic and Fever syndromes were defined by different ICD-10 codes and their alert thresholds were developed based on the characteristics of time series derived using daily counts of ICD-10 codes for each syndrome.

Characterization of the interaction of staphylococcal enterotoxin B with CD1d expressed in human renal proximal tubule epithelial cells.

BackgroundParticipation of renal cells in the pathogenesis of staphylococcal enterotoxin B (SEB) is critical for late cleansing and sequestration of the antigens facilitated by CD1d mediated antigen sensing and recognition. This is a noted deviation from the typical antigen recognition process that recruits the major histocompatibility complex class II (MHC II) molecules. The immunological importance of CD1d is underscored by its influences on the performances of natural killer T-cells and thereby mediates the innate and adaptive immune systems.ResultsUsing diffraction-based dotReady™ immunoassays, the present study showed that SEB directly and specifically conjugated to CD1d. The specificity of the conjugation between SEB and CD1d expressed on human renal proximal tubule epithelial cells (RPTEC) was further established by selective inhibition of CD1d prior to its exposure to SEB. We found that SEB induced the expression of CD1d on the cell surface prompting a rapid conjugation between them. The mRNA transcripts encoding CD1d remained elevated potentially after completing the antigen cleansing process.ConclusionMolecular targets associated with the delayed pathogenic response have essential therapeutic values. Particularly in the event of bioterrorism, the caregivers are typically able to intervene much later than the toxic exposures. Given circumstances mandate a paradigm shift from the conventional therapeutic strategy that counts on targeting the host markers responding to the early assault of pathogens. We demonstrated the role of CD1d in the late stage of pathogen recognition and cleansing, and thereby underscored its clinical potential in treating bioweaponizable antigens, such as Staphylococcal enterotoxin B (SEB).Electronic supplementary materialThe online version of this article (doi:10.1186/s12866-015-0344-5) contains supplementary material, which is available to authorized users.

Potential biodefense model applications for portable chlorine dioxide gas production.

Development of decontamination methods and strategies to address potential infectious disease outbreaks and bioterrorism events are pertinent to this nation's biodefense strategies and general biosecurity. Chlorine dioxide (ClO2) gas has a history of use as a decontamination agent in response to an act of bioterrorism. However, the more widespread use of ClO2 gas to meet current and unforeseen decontamination needs has been hampered because the gas is too unstable for shipment and must be prepared at the application site. Newer technology allows for easy, onsite gas generation without the need for dedicated equipment, electricity, water, or personnel with advanced training. In a laboratory model system, 2 unique applications (personal protective equipment [PPE] and animal skin) were investigated in the context of potential development of decontamination protocols. Such protocols could serve to reduce human exposure to bacteria in a decontamination response effort. Chlorine dioxide gas was capable of reducing (2-7 logs of vegetative and spore-forming bacteria), and in some instances eliminating, culturable bacteria from difficult to clean areas on PPE facepieces. The gas was effective in eliminating naturally occurring bacteria on animal skin and also on skin inoculated with Bacillus spores. The culturable bacteria, including Bacillus spores, were eliminated in a time- and dose-dependent manner. Results of these studies suggested portable, easily used ClO2 gas generation systems have excellent potential for protocol development to contribute to biodefense strategies and decontamination responses to infectious disease outbreaks or other biothreat events.

Immunogenicity and safety of four different dosing regimens of anthrax vaccine adsorbed for post-exposure prophylaxis for anthrax in adults

BackgroundStrategies to implement post exposure prophylaxis (PEP) in case of an anthrax bioterror event are needed. To increase the number of doses of vaccine available we evaluated reducing the amount of vaccine administered at each of the vaccinations, and reducing the number of doses administered. MethodsHealthy male and non-pregnant female subjects between the ages of 18 and 65 were enrolled and randomized 1:1:1:1 to one of four study arms to receive 0.5mL (standard dose) of vaccine subcutaneously (SQ) at: (A) days 0, 14; (B) days 0 and 28; (C) days 0, 14, and 28; or (D) 0.25mL at days 0, 14, and 28. A booster was provided on day 180. Safety was assessed after each dose. Blood was obtained on days 0, 7, 14, 21, 28, 35, 42, 49, 56, 63, 70, 84, 100, 180, and 201 and both Toxin Neutralizing antibody and anti-PA IgG antibody measured. ResultsAlmost all subjects developed some local reactions with 46–64% reported to be of moderate severity and 3.3% severe during the primary series. Vaccine groups that included a day 14 dose induced a ≥4 fold antibody rise in more subjects on days 21, 28, and 35 than the arm without a day 14 dose. However, schedules with a full day 28 dose induced higher peak levels of antibody that persisted longer. The half dose regimen did not induce antibody as well as the full dose study arms. ConclusionDepending on the extent of the outbreak, effectiveness of antibiotics and availability of vaccine, the full dose 0, 28 or 0, 14, 28 schedules may have advantages.

How the Current West African Ebola Virus Disease Epidemic Is Altering Views on the Need for Vaccines and Is Galvanizing a Global Effort to Field-Test Leading Candidate Vaccines

Since it first appeared as a clinical syndrome in Central Africa in the mid1970s, accompanied by isolation of the causative virus, Ebola virus disease has fascinated infectious disease clinicians, virologists, and epidemiologists because of the striking clinical syndrome exhibited by patients (which culminates in a hemorrhagic diathesis in approximately 35% of infected individuals) [1], high case-fatality rate (50%–90%), and facile transmissibility of the virus among close contacts [2], including caregivers [3]. Heretofore, its limited geographic distribution (Central and East Africa) and modest overall burden of disease, manifested as occasional small outbreaks ultimately interrupted by institution of stringent infection control methods, combined to make this an uncommon exotic tropical infectious disease [4]. After the 11 September 2001 attacks and subsequent anthrax bioterrorism episodes in the United States, there was concern in the United States and Europe over the potential use of certain pathogens as bioterrorism agents. Ebolavirus, with its high case-fatality rate and potential for enhanced transmissibility, is ranked by the Centers for Disease Control and Prevention as a category A bioterrorism agent (highest priority). This prompted virologists to study the pathogenesis of ebolavirus infection and vaccine developers to design strategies to generate vaccine candidates. During the next decade, impressive progress was made in Ebola vaccine research. However, the population targets for use of such vaccines were limited and included civilian populations in defined geographic areas, for whom reactive immunization would be performed following a deliberate release during a bioterrorism event, and laboratory scientists working with the virus.

Willingness of the local health department workforce to respond to infectious disease events: empirical, ethical, and legal considerations.

According to the Institute of Medicine, the local health department workforce is at the hub of the public health emergency preparedness system. A growing body of research has pointed to troubling attitudinal gaps among local health department workers, a vital response cohort, regarding willingness to respond to emergent infectious disease threats, ranging from naturally occurring pandemics to bioterrorism events. A summary of relevant literature on the empirical evidence, ethical norms, and legal standards applicable to the willingness of public health professionals to respond to an infectious disease emergency is presented. Recommendations are proposed for future work to be done to bring the relevant empirical, ethical, and legal considerations together to develop practical guidance for the local response to infectious disease emergencies.

Biological threat detection in the air and on the surface: how to define the risk.

The improvements in the existing methods of rapid detection and biological pathogen surveillance are still needed. The new spectroscopic methods that rely on the unique structural features and intrinsic fluorescence of microorganisms are well fitted for monitoring the spread of airborne biological agents or their reagentless detection in the air, and these methods may bring a new quality to bioaerosols remote detection. This review describes the problem of the confidence in the environmental testing results that may affect clearance standard, sampling techniques, and the estimation of risk of human exposure to the low concentrations of harmful microorganisms during bioterrorist event or naturally occurring outbreaks. Higher recovery efficiency of dangerous biological agents from the air and contaminated surfaces would enable more reliable environmental human risk exposure assessment.

Evaluation of the relationship between the Adenosine Triphosphate (ATP) bioluminescence assay and the presence of Bacillus anthracis spores and vegetative cells.

Background: The Adenosine triphosphate (ATP) bioluminescence assay was utilized in laboratory evaluations to determine the presence and concentration of vegetative and spore forms of Bacillus anthracis Sterne 34F2. Methods: Seventeen surfaces from the healthcare environment were selected for evaluation. Surfaces were inoculated with 50 µL of organism suspensions at three concentrations of 104, 106, 108 colony forming units per surface (CFU/surface) of B. anthracis. Culture-based methods and ATP based methods were utilized to determine concentrations. Results: When all concentrations were evaluated together, a positive correlation between log-adjusted CFU and Relative Light Units (RLU) for endospores and vegetative cells was established. When concentrations were evaluated separately, a significant correlation was not demonstrated. Conclusions: This study demonstrated a positive correlation for ATP and culture-based methods for the vegetative cells of B. anthracis. When evaluating the endospores and combining both metabolic states, the ATP measurements and CFU recovered did not correspond to the initial concentrations on the evaluated surfaces. The results of our study show that the low ATP signal which does not correlate well to the CFU results would not make the ATP measuring devises effective in confirming contamination residual from a bioterrorist event.

Pediatric anthrax clinical management: executive summary.

* Abbreviations: AVA — : anthrax vaccine adsorbed CDC — : Centers for Disease Control and Prevention PEP — : postexposure prophylaxis The use of Bacillus anthracis as a biological weapon is considered a potential national security threat by the US government. B anthracis has the ability to be used as a biological weapon and to cause anthrax, which can rapidly progress to systemic disease with high mortality in those who are untreated. Therefore, clear plans for managing children after a B anthracis bioterror exposure event must be in place before any intentional release of the agent. This document provides a summary of the guidance contained in the clinical report (appendices cited in this executive summary refer to those in the clinical report) for diagnosis and management of anthrax, including antimicrobial treatment and postexposure prophylaxis (PEP), use of antitoxin, and recommendations for use of anthrax vaccine in neonates, infants, children, adolescents, and young adults up to the age of 21 years (referred to as “children”). Key considerations in a mass B anthracis exposure scenario include the following: 1. Public health authorities will determine the presence and extent of a bioterror event. Information of importance to health care providers and the public will be made available as soon as possible by the Centers for Disease Control and Prevention (CDC), including information posted on the CDC Anthrax Web site: www.cdc.gov/anthrax. 2. Within 48 hours of exposure to B anthracis spores, public health authorities plan to provide a 10-day course of antimicrobial prophylaxis to the local population, including children likely to have been exposed to spores (Appendix 1). Public health officials will provide information about points of dispensing locations that will distribute antibiotic agents. 3. Within 10 days of exposure, public health authorities plan to further define those who have had a clear and significant exposure and will require an additional 50 days of antimicrobial PEP, …

Designing an effective microbial forensics program for law enforcement and national security purposes.

Forensic capabilities that provide lead information, and investigative, intelligence, prosecution and policy decision support can be invaluable for responding to and resolving bioterrorism events. Attributing biological attacks through scientific and other resources and processes is an important goal, for which science can be instrumental. Some even believe that having effective microbial forensics capabilities along with others can even deter adversaries from using biological weapons. For those nations that do not have such or wish to integrate or upgrade capabilities, thoughtful analysis and consideration of certain design principles will increase the likelihood that success will be attained.

Forensic Microbiology

The field of forensic science has obtained notoriety due, in part, to several sensational court cases, such as the murder trial of O. J. Simpson and the involuntary manslaughter conviction trial of Michael Jackson's physician, Conrad Murray, which captured national attention. In addition, although their roles are not always adequately portrayed, several modern television programs have brought to life the roles forensic scientists play in the criminal justice system. Forensic science encompasses many different areas. Most people are aware of DNA analysis, toxicology, fingerprint comparison, and ballistics, to mention a few. A newer area of forensic science is forensic microbiology. A landmark event in U.S. history, the Bacillus anthracis bioterrorism event in 2001, brought this field of science to the forefront. Forensic microbiology had been practiced before the anthrax event, and forensic microbiology involves more than just bioterror. This article discusses some of the roles that microbiology plays in forensic science.

Bioterrorism: a Laboratory Who Does It?

In October 2001, the first disseminated biological warfare attack was perpetrated on American soil. Initially, a few clinical microbiology laboratories were testing specimens from acutely ill patients and also being asked to test nasal swabs from the potentially exposed. Soon after, a significant number of clinical microbiology and public health laboratories received similar requests to test the worried well or evaluate potentially contaminated mail or environmental materials, sometimes from their own break rooms. The role of the clinical and public health microbiology laboratory in response to a select agent event or act of bioterrorism is reviewed.

Special Considerations for Prophylaxis for and Treatment of Anthrax in Pregnant and Postpartum Women

In August 2012, the Centers for Disease Control and Prevention, in partnership with the Association of Maternal and Child Health Programs, convened a meeting of national subject matter experts to review key clinical elements of anthrax prevention and treatment for pregnant, postpartum, and lactating (P/PP/L) women. National experts in infectious disease, obstetrics, maternal fetal medicine, neonatology, pediatrics, and pharmacy attended the meeting, as did representatives from professional organizations and national, federal, state, and local agencies. The meeting addressed general principles of prevention and treatment for P/PP/L women, vaccines, antimicrobial prophylaxis and treatment, clinical considerations and critical care issues, antitoxin, delivery concerns, infection control measures, and communication. The purpose of this meeting summary is to provide updated clinical information to health care providers and public health professionals caring for P/PP/L women in the setting of a bioterrorist event involving anthrax.

Validation of high throughput sequencing and microbial forensics applications.

High throughput sequencing (HTS) generates large amounts of high quality sequence data for microbial genomics. The value of HTS for microbial forensics is the speed at which evidence can be collected and the power to characterize microbial-related evidence to solve biocrimes and bioterrorist events. As HTS technologies continue to improve, they provide increasingly powerful sets of tools to support the entire field of microbial forensics. Accurate, credible results allow analysis and interpretation, significantly influencing the course and/or focus of an investigation, and can impact the response of the government to an attack having individual, political, economic or military consequences. Interpretation of the results of microbial forensic analyses relies on understanding the performance and limitations of HTS methods, including analytical processes, assays and data interpretation. The utility of HTS must be defined carefully within established operating conditions and tolerances. Validation is essential in the development and implementation of microbial forensics methods used for formulating investigative leads attribution. HTS strategies vary, requiring guiding principles for HTS system validation. Three initial aspects of HTS, irrespective of chemistry, instrumentation or software are: 1) sample preparation, 2) sequencing, and 3) data analysis. Criteria that should be considered for HTS validation for microbial forensics are presented here. Validation should be defined in terms of specific application and the criteria described here comprise a foundation for investigators to establish, validate and implement HTS as a tool in microbial forensics, enhancing public safety and national security.

Teaching Bioterrorism Preparedness with Simulation - The Pneumonic Plague Example

Future bioterrorism acts are an unfortunate possibility for which healthcare providers and medical systems must prepare. Plague, caused by Yersinia pestis, is a potential bioterrorism agent which healthcare providers in the developed world have only a low familiarity. This article provides a teaching strategy using medical simulation to assist healthcare professionals and institutions in preparing for bioterrorism events.

Challenges for forensic science: new demands in today’s world

In their 2009 report entitled ‘Strengthening forensic science in the United States: a path forward,’ the National Research Council (NRC) provided an assessment of the past, present, and future state of forensic science – especially related to impression evidence. The NRC described the need for further advances in some forensic science disciplines in order to improve criminal investigations, reduce the possibility of wrongful convictions, and to enhance national security. Recent events in international and domestic terrorism and the identification of dozens of wrongful convictions have further demonstrated the need for forensic science to address new challenges. From the bioterrorism events within the United States related to the anthrax mailings, to the seemingly endless stream of improvised explosive devices in the Iraq/Afghanistan wars, forensic science has new demands and an increasingly important opportunity to play a vital role in the world’s major events. With this demand comes a requirement to enhance the very foundations on which many disciplines in forensic science rest. The need for objective, scientifically-based criteria for determining identifications has never been more important and it will take researchers and practitioners working together to move forensic science in the proper direction.

Field epidemiological study on news reports that related to public health emergencies

All news reports (NR) that were related to public health emergency (PHE) were collected from the Southern Metropolis Daily (SMD) to explore the characteristics of epidemiology in the fields. Based on the theory of communication that including both case and text analysis, qualitative analysis on all the NR regarding PHE published in SMD from the years of 2008 to 2012, was carried out and input to database using the EpiData. Numbers of articles as indicators were compared to show the yearly change of different types of events. Various features of the NR including coverage, source of information, location of the incident, style and size of news, with or without editorials etc. were statistically analyzed by SPSS version 18.0. Among all the 998 reports related to PHE, higher proportion was found in the events of Infectious diseases (35.3%) and food safety (34.1%)respectively. Events on vaccines and drugs used for disease prevention and control (8.9%), environmental pollution caused incidents (8.0%)appeared to be less frequent. Events related to occupational disease, poisoning, bioterrorism and biochemical events were rare. Looking at the monthly distribution of reports, we noticed that the peaks occurred in 2008 and in 2009, which were caused by the Melamine-contamination events and the 2009 H1N1 pandemic. Between 2010 and 2012, figures of monthly reports were smooth, including some critical events from the interests of the media. Most events took place in Guangdong province (34.3%) and other provinces (50.9%), with some were from Hong Kong, Macao and Taiwan regions (9.5%). However, international events (5.2%)were less seen. Extensive coverage accounted for 17.6% of all of reports, and 11.5% allotted the editorials or other forms of in-depth reports. Most of the source of reports on infectious diseases and food safety were from the official release, however. The main sources of occupational diseases and poisoning, vaccines and drug incidents, environmental pollution related incidents were reported by active journalists through interview. Reports on hand, foot and mouth disease, influenza, milk safety, AIDS and lead pollution showed continued concern in the past five years by SMD. NR on public health emergencies by SM had encompassed all 10 categories-related events formulated by the Ministry of Health. Sustained and in-depth coverage were more commonly seen. Field-epidemiologists should learn interdisciplinary sciences on the theory and methodology of communication. They also need to interact with media people during the whole processes of public health emergency preparedness and responses.

Bacillus cereus Sensu Lato Genomes: Basis for Identifying Anthrax Disease Strain Sources

Why would one want to sequence the genomes of 94 additional, mostly soil and water isolates of Bacillus cereus sensu lato (1)? The answer is of course to be able to make a rapid analysis during a bioterrorism event, to develop a portable kit for the rapid identification of anthrax spores (by proteomic analysis), and to determine their precise origin (by means of DNA genomic polymorphisms). The draft genome sequences of 94 environmental Bacillus cereus sensu lato strains were deposited in GenBank (1) to facilitate the identification of the closely related subspecies B. cereus, Bacillus anthracis, Bacillus mycoides, and Bacillus thuringiensis and toxicity determinants. Strains of this species often harbor pathogenicity plasmids and show different envirotypes and pathotypes.