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PubMed2005

Crystallization of a newly discovered histidine acid phosphatase from Francisella tularensis.

Francisella tularensis is a highly infectious bacterial pathogen that is considered by the Centers for Disease Control and Prevention to be a potential bioterrorism weapon. Here, the crystallization of a 37.2 kDa phosphatase encoded by the genome of F. tularensis subsp. holarctica live vaccine strain is reported. This enzyme shares 41% amino-acid sequence identity with Legionella pneumophila major acid phosphatase and contains the RHGXRXP motif that is characteristic of the histidine acid phosphatase family. Large diffraction-quality crystals were grown in the presence of Tacsimate, HEPES and PEG 3350. The crystals belong to space group P4(1)2(1)2, with unit-cell parameters a = 61.96, c = 210.78 A. The asymmetric unit is predicted to contain one protein molecule, with a solvent content of 53%. A 1.75 A resolution native data set was recorded at beamline 4.2.2 of the Lawrence Berkeley National Laboratory Advanced Light Source. Molecular-replacement trials using the human prostatic acid phosphatase structure as the search model (28% amino-acid sequence identity) did not produce a satisfactory solution. Therefore, the structure of F. tularensis histidine acid phosphatase will be determined by multiwavelength anomalous dispersion phasing using a selenomethionyl derivative.

Acid Phosphatase↗

PubMed2006

Immunity and immunological memory following smallpox vaccination.

The smallpox vaccine consists of live vaccinia virus and is generally considered the gold standard of vaccines, since it is the only one that has led to the complete eradication of an infectious disease from the human population. Renewed fears that smallpox might be deliberately released in an act of bioterrorism have led to resurgence in the study of immunity and immunological memory to vaccinia virus and other poxviruses. Here we review our current understanding of memory T-cell, memory B-cell, and antibody responses to vaccinia and related poxviruses, both in animal models and human subjects. Of particular interest are recent advances in understanding protective immunity to poxviruses, quantifying immunological memory to the smallpox vaccine in humans, and identifying major vaccinia-specific T-cell and B-cell epitopes. In addition, potential mechanisms for maintenance of immunological memory are discussed.

Animals↗

PubMed2006

Examining the CDCynergy Event Assessment Tool: an investigation of the anthrax crisis in Boca Raton, Florida.

This paper examines the dependability of the Event Assessment Tool over time. The latter is part of a CD-ROM--Emergency Risk Communication CDCynergy--distributed primarily to public information officers in the United States by the Centers for Disease Control and Prevention. The Event Assessment Tool is designed to aid emergency professionals in identifying the magnitude of a crisis event and to suggest appropriate actions to confront such a situation. Applied twice during the 2001 anthrax bioterrorism crisis in Boca Raton, Florida, the tool functioned in a binary manner by first indicating a moderate crisis level (on 4 October) and then four days later (on 8 October) a highly intense crisis, suggesting that it is time sensitive. This anthrax event provides an opportunity for crisis and disaster managers to understand the dynamic nature of crises. Rapid changes during these types of events suggest that any metric used to predict intensity must account for this variability. Additional limitations and implications of the tool are discussed.

Anthrax↗

PubMed2006

Patient experience with, and use of, an electronic monitoring system to assess vaccination responses.

OBJECTIVE: To evaluate the user experience and acceptability of an electronic patient monitoring system. SETTING AND PARTICIPANTS: 822 Military and civilian personnel at a health clinic at a major US military headquarters used an Internet and telephone-based electronic monitoring system to report vaccination-site responses and symptoms after receiving the smallpox vaccination. Focus groups of vaccinees were conducted to help develop a survey about the experience that was distributed to 379 vaccinees (96% completion rate). RESULTS: Users of the electronic monitoring system reported that it was fast and easy to use and reported they would use a system like this again and recommend an electronic monitoring system to a friend or relative. Most users (84%) were comfortable with a physician tracking their vaccine reaction using their electronic reports, but only half (51%) were comfortable with eliminating the post-vaccination follow-up visit with their health-care provider based on their electronic reports. CONCLUSIONS: This electronic monitoring system was well received by vaccinees and allowed health-care providers to track the status of vaccinees. However, vaccinees were not comfortable replacing a physician visit with electronic monitoring, at least for the smallpox vaccination. A monitoring system like this may be useful in public health settings, such as mass vaccination or prophylaxis during a bioterrorism event, a pandemic influenza outbreak, or another public health emergency.

Adult↗

PubMed2005

Modulation of biogenesis of the Francisella tularensis subsp. novicida-containing phagosome in quiescent human macrophages and its maturation into a phagolysosome upon activation by IFN-gamma.

Francisella tularensis is a highly virulent facultative intracellular pathogen that has been categorized as a class A bioterrorism agent, and is classified into four subsp, tularensis, holarctica, mediasiatica and novicida. Although the ability of F. tularensis subsp. novicida to cause tularemia in mice is similar to the virulent subsp. tularensis and holarctica, it is attenuated in humans. It is not known whether attenuation of F. tularensis subsp. novicida in humans is resulting from a different route of trafficking within human macrophages, compared with the tularensis or holarctica subsp. Here we show that in quiescent human monocytes-derived macrophages (hMDMs), the F. tularensis subsp. novicida containing phagosome (FCP) matures into a late endosome-like stage that acquires the late endosomal marker LAMP-2 but does not fuse to lysosomes. This modulation of phagosome biogenesis by F. tularensis is followed by disruption of the phagosome at 4-12 h and subsequent bacterial escape into cytoplasm where the organism replicates. In IFN-gamma-activated hMDMs, intracellular replication of F. tularensis is completely inhibited, and is associated with failure of the organism to escape from the phagosome into the cytoplasm for up to 24 h after infection. In IFN-gamma-activated hMDMs, the FCPs acquire the lysosomal enzymes Cathepsin D, which is excluded in quiescent hMDMs. When the lysosomes of IFN-gamma-activated hMDMs are preload with Texas Red Ovalbumin or BSA-gold, the FCPs acquire both lysosomal tracers. In contrast, both lysosomal tracers are excluded from the FCPs within quiescent hMDMs. We conclude that although F. tularensis subsp. novicida is attenuated in humans, it modulates biogenesis of its phagosome into a late endosome-like compartment followed by bacterial escape into the cytoplasm within quiescent hMDMs, similar to the virulent subsp. tularensis. In IFN-gamma-activated hMDMs, the organism fails to escape into the cytoplasm and its phagosome fuses to lysosomes, similar to inert particles.

Antigens, CD↗

PubMed2007

Contribution of toxins to the pathogenesis of inhalational anthrax.

Inhalational anthrax is a life-threatening infectious disease of considerable concern, especially as a potential bioterrorism agent. Progress is gradually being made towards understanding the mechanisms used by Bacillus anthracis to escape the immune system and to induce severe septicaemia associated with toxaemia and leading to death. Recent advances in fundamental research have revealed previously unsuspected roles for toxins in various cell types. We summarize here pathological data for animal models and macroscopic histological examination data from recent clinical records, which we link to the effects of toxins. We describe three major steps in infection: (i) an invasion phase in the lung, during which toxins have short-distance effects on lung phagocytes; (ii) a phase of bacillus proliferation in the mediastinal lymph nodes, with local effects of toxins; and (iii) a terminal, diffusion phase, characterized by a high blood bacterial load and by long-distance effects of toxins, leading to host death. The pathophysiology of inhalational anthrax thus involves interactions between toxins and various cell partners, throughout the course of infection.

Animals↗

PubMed2004

Optimal use of antibiotic resistance surveillance systems.

Increasing concern about the emergence of resistance in clinically important pathogens has led to the establishment of a number of surveillance programmes to monitor the true extent of resistance at the local, regional and national levels. Although some programmes have been operating for several years, their true usefulness is only now being realised. This review describes some of the major surveillance initiatives and the way in which the data have been used in a number of different settings. In the hospital, surveillance data have been used to monitor local antibiograms and determine infection control strategies and antibiotic usage policies. In the community, surveillance data have been used to monitor public health threats, such as infectious disease outbreaks involving resistant pathogens and the effects of bioterrorism countermeasures, by following the effects of prophylactic use of different antibiotics on resistance. Initially, the pharmaceutical industry sponsored surveillance programmes to monitor the susceptibility of clinical isolates to marketed products. However, in the era of burgeoning resistance, many developers of antimicrobial agents find surveillance data useful for defining new drug discovery and development strategies, in that they assist with the identification of new medical needs, allow modelling of future resistance trends, and identify high-profile isolates for screening the activity of new agents. Many companies now conduct pre-launch surveillance of new products to benchmark activity so that changes in resistance can be monitored following clinical use. Surveillance data also represent an integral component of regulatory submissions for new agents and, together with clinical trial data, are used to determine breakpoints. It is clear that antibiotic resistance surveillance systems will continue to provide valuable data to health care providers, university researchers, pharmaceutical companies, and government and regulatory agencies.

Anti-Bacterial Agents↗

PubMed2004

Tick-borne virus diseases of human interest in Europe.

Several human diseases in Europe are caused by viruses transmitted by tick bite. These viruses belong to the genus Flavivirus, and include tick-borne encephalitis virus, Omsk haemorrhagic fever virus, louping ill virus, Powassan virus, Nairovirus (Crimean-Congo haemorrhagic fever virus) and Coltivirus (Eyach virus). All of these viruses cause more or less severe neurological diseases, and some are also responsible for haemorrhagic fever. The epidemiology, clinical picture and methods for diagnosis are detailed in this review. Most of these viral pathogens are classified as Biosafety Level 3 or 4 agents, and therefore some of them have been classified in Categories A-C of potential bioterrorism agents by the Centers for Disease Control and Prevention. Their ability to cause severe disease in man means that these viruses, as well as any clinical samples suspected of containing them, must be handled with specific and stringent precautions.

Animals↗

PubMed2005

Role of the microbiology laboratory in infectious disease surveillance, alert and response.

Surveillance is usually defined as the ongoing and systematic collection, analysis and interpretation of health data essential to the planning, implementation and evaluation of public health practice. During recent years, most of these programmes have been developed in the field of antimicrobial resistance and nosocomial infections, but efforts have also been made in other areas. Recent experiences of emerging microbial threats, including severe acute respiratory syndrome and new influenza variants affecting humans, the re-emergence of infectious disease problems and the possibility of bioterrorism have evidenced the need for implementation of infectious disease surveillance programmes. clinical microbiology laboratories play a pivotal role in these programmes. They have the first opportunity to detect these problems and should participate in the design of reporting strategies and dissemination of this information. Policies for the flow of data to national and international authorities should be established using passive surveillance strategies. However, active surveillance programmes taking advantage of new methodologies, including virtual tools and mathematical programs, should be the goal for early detection of unusual patterns of microbial pathogens, outbreaks and healthcare-associated infections. In addition, early implementation of response strategies should be designed and performed with the cooperation of microbiology laboratories, and intervention and response protocols should be defined with the participation of clinical microbiologists.

Communicable Disease Control↗

PubMed2004

Description and investigation of white particulate matter in additive solution-1 red blood cell units.

BACKGROUND: In January 2003, "white particulate matter" (WPM) was transiently observed in red blood cell (RBC) units collected predominately in the southeastern US. In this report, these events, their chronology, pertinent observations and investigations, and summaries and conclusions associated with WPM during the 2-week observation period are described. CHRONOLOGY AND INVESTIGATIONS: On January 27, 2003, WPM was first identified in RBCs; by January 31, 2003, 110 RBC units containing WPM had been identified. Elective surgeries were postponed. Approximately 400 RBC units containing WPM were inspected in the blood center and characterized into four types: I, II, III, and IV. A variety of preparations of aspirated WPM were made, including light and electron microscopic sections. RESULTS AND CONCLUSIONS: The rate of WPM-containing units was 1.67 percent (1 in 60 units), whereas the background incidence was less than 0.25 percent. Investigations revealed that WPM was composed of activated and nonactivated platelets (PLTs); no toxins, infectious agents, or agents of bioterrorism were identified. WPM correlated with certain variables studied, including PLT-rich components that had been centrifuged with a "hard spin" before leukoreduction and manufactured in one vendor's collection sets. Because the increased rate of appearance of WPM was a transient phenomenon, it is not clear whether this is a newly noticed or a new and different phenomenon from "aggregates" observed in the past.

Blood Specimen Collection↗

PubMedDate not supplied

Smallpox: what the dermatologist should know.

Despite the eradication of naturally occurring smallpox in 1977, stores of the virus have been maintained in laboratories in the United States and Russia. It is feared that certain rogue states and terrorist organizations may have illicitly acquired the virus with the intent of unleashing it as an agent of bioterrorism. The United States and other nations have begun vaccinating individuals in the military and health care workers who might become exposed. Primary care providers and dermatologists will be called upon to evaluate potential index cases and vaccination reactions. In this report, the authors review the essential clinical aspects of smallpox and potential reactions to smallpox vaccination. Special attention is given to eczema vaccinatum, which can occur in vaccinees and their family contacts with active or quiescent atopic dermatitis or a personal history of eczema.

Dermatology↗

PubMed2006

Modulation of cytokine production and enhancement of cell viability by TLR7 and TLR9 ligands during anthrax infection of macrophages.

Inhalation of Bacillus anthracis, a bioterrorism agent, results in a high mortality rate despite appropriate antibiotic therapy. Macrophages appear to be a key factor in B. anthracis pathogenesis. The burst of pro-inflammatory cytokines from macrophages could be a major cause of death in anthrax. However, preactivation of Toll-like receptors (TLRs) could modify the host response. TLR ligands stimulate the release of activating cytokines but may also down-modulate the subsequent deleterious cytokine response to pathogens. We developed a cell culture model to measure macrophage responses to B. anthracis spores and bacilli. We found that germination from spores to bacilli produced a substantial stimulus for the secretion of the cytokines IL-6, TNF-alpha, IL-10, and IL-12 p40. Our studies showed that pretreatment of mouse macrophages with the TLR9 ligand ISS-1018, or the TLR7 ligands R-848 and IT-37, results in a substantial decrease in the subsequent secretion of IL-6 and TNF-alpha in response to B. anthracis infection of macrophages. Furthermore, the TLR7 and TLR9 ligands significantly decreased anthrax-induced cytotoxicity in the macrophages. These findings suggest that TLR ligands may contribute to the enhancement of innate immunity in B. anthracis infection by suppressing potentially deleterious pro-inflammatory cytokine responses and by improving macrophage viability.

Aminoquinolines↗

PubMed1999

The role of national animal health emergency planning.

Bioterrorism is one of many contingencies that we must be better prepared to prevent from adversely impacting our food security system. Education and awareness, prevention-based training, increased monitoring and surveillance, and greater focus on coordination between government agencies at both the federal and state levels will be necessary to develop a more prevention-based national food security system. The formation of the Steering Committee on National Animal Health Emergency Management is the beginning of a profound new process. The animal industry is driving the formation of a new national animal health emergency management system. It is designed to coordinate the emergency prevention and response activities of all partners, including government (state and federal), livestock producers, and veterinary practitioners. The goal is to develop a national coordinated strategy that places primary emphasis on preventing a broader spectrum of hazards from occurring throughout the food production chain. Coordination and integration of efforts are necessary with many different stakeholders, including government agencies other than U.S. Department of Agriculture. Through a proposed National Animal Health Emergency Management Council, all stakeholders can assist in the development of a national strategic plan that can better protect our food security system.

Animal Diseases↗

PubMed2003

Pathogenic mechanisms of diseases caused by Rickettsia.

The specter of bioterrorism employing genetically engineered Rickettsia resistant to all antibiotics should reawaken the world's desire to elucidate the pathogenesis of typhus and spotted fever rickettsioses in a search for mechanisms vulnerable to interdiction. The pathogenetic sequence includes rickettsial entry into the dermis, hematogenous dissemination to vascular endothelial cells (most critically in brain and lungs), increased vascular permeability, edema, and immunity mediated by NK cells, IFN-gamma, TNF-alpha, RANTES, antibodies, and cytotoxic T lymphocytes. Silverman has demonstrated the role of reactive oxygen species (ROS) produced by R. rickettsii-infected endothelial cells in peroxidative damage to cell membranes in vitro, and Heinzen has described actin-based rickettsial intracellular mobility and intercellular spread. At this point the availability of sequences of rickettsial genomes and excellent animal models of rickettsioses have yielded insufficient progress towards the identification of rickettsial virulence factors and knowledge of the importance of injury mediated by ROS, phospholipase A(2), protease(s) or other mechanisms in vivo. Attention to the rickettsiosis-associated procoagulant state led to determination that hemostatic mechanisms largely prevent major hemorrhage without disseminated intravascular coagulation or thrombosis-mediated ischemia. Particularly lacking is knowledge of early events in vivo at the portal of entry in skin (or lung), of the effects of the inoculum medium (arthropod saliva or feces), mediators produced by infected endothelium under conditions of flow and of the contributions in vivo of immune effectors to pathology, of the role of apoptosis in rickettsial infection, and of the endothelial cell alterations that account for increased vascular permeability. The host cell receptor for the Rickettsia ligand and the mechanism of rickettsial escape from the phagosome need to be elucidated.

Chronic Disease↗

PubMed2002

Science for the common good.

A smile comes easily to the face of Anthony Fauci, Director of the National Institute of Allergy and Infectious Diseases, as he encounters visitors to his offices at the Institute. He does not, however, allow himself to be distracted from his duties for longer than it takes to nod warmly. The sense of discipline and the determination and preparedness that were instilled in him through a Jesuit course of education are apparent. He is as direct and as clear spoken in person as you've seen him on television, speaking on innumerable occasions over the past two decades about the pathology and treatment of AIDS, and more recently, delineating the public health from the national security issues precipitated by the bioterrorist events of the past year. The three office assistants who occupy his reception area have been particularly taxed in the management of Fauci's schedule since 9/11; as they pause briefly from their work to share photographs of a friend's recent wedding, Fauci is there to admonish them, semi-good-naturally, as government employees, to return to their official duties. He has been meeting with high government officials and has been courted by the media for interviews regularly since the tragedies began. Given his high profile, it is easy to forget that Fauci is, foremost, a clinical immunobiologist and physician. His dedication to science is part of his commitment to public service, also a value instilled in him by the Jesuits. Fortunately for all of us, Fauci was pursuing this combination of interests--within the venue of bioterrorism--in his official capacity at the NIAID well before the general public had awaken to the threat.

Biomedical Research↗

PubMed2003

Are we ready for pandemic influenza?

During the past year, the public has become keenly aware of the threat of emerging infectious diseases with the global spread of severe acute respiratory syndrome (SARS), the continuing threat of bioterrorism, the proliferation of West Nile virus, and the discovery of human cases of monkeypox in the United States. At the same time, an old foe has again raised its head, reminding us that our worst nightmare may not be a new one. In 2003, highly pathogenic strains of avian influenza virus, including the H5N1 and H7N7 subtypes, again crossed from birds to humans and caused fatal disease. Direct avian-to-human influenza transmission was unknown before 1997. Have we responded to these threats by better preparing for emerging disease agents, or are we continuing to act only as crises arise? Here we consider progress to date in preparedness for an influenza pandemic and review what remains to be done. We conclude by prioritizing the remaining needs and exploring the reasons for our current lack of preparedness for an influenza pandemic.

Animals↗

PubMed2002

Effect of 5-iodo-2'-deoxyuridine on vaccinia virus (orthopoxvirus) infections in mice.

There is a concern that there may be unregistered stocks of smallpox that can be used for bioterrorism or biological warfare. According to the WHO Advisory Committee on Variola Research, there is a need to develop strategies to treat smallpox infections should they reappear. It would also be important to have an effective drug at hand for the treatment of monkeypox disease in humans. We show here that 5-iodo-2'-deoxyuridine (IDU) is a potent inhibitor of vaccinia virus (VV) replication and that IDU inhibits VV DNA synthesis in a dose-dependent way. The in vivo protective effect of IDU was assessed in the VV tail lesion model in immunocompetent mice and in a lethal model for VV infection in SCID (severe combined immune deficiency) mice that had been infected either intranasally, intraperitoneally, or intravenously. Subcutaneous treatment with IDU at 150 and 100 mg/kg of body weight markedly reduced the number of tail lesions in immunocompetent NMRI mice. Untreated intranasally VV-infected SCID mice died at 20.8 +/- 3.1 days after infection (mean +/- standard deviation). Treatment with IDU (subcutaneously, 150 mg/kg/day [from day 0 to 4] and 75 mg/kg/day [from day 6 to 11]) delayed-virus induced mortality by 15 days (mean day of death +/- standard deviation, 35.8 +/- 6.7; P < 0.0001). This protective effect was associated with (i) an improvement of lung histology and (ii) a marked reduction in lung viral titers. IDU also delayed VV-induced mortality when mice had either been infected intraperitoneally or intravenously. Even when the start of treatment with IDU (in intraperitoneally VV-infected mice) was postponed until 2 or 4 days after infection, an important delay in virus-induced mortality was noted.

Animals↗

PubMed2003

Evaluation of nucleoside phosphonates and their analogs and prodrugs for inhibition of orthopoxvirus replication.

In the event of a bioterrorism attack using smallpox virus, there currently is no approved drug for the treatment of infections with this virus. We have reported previously that (S)-1-[3-hydroxy-2-(phosphonomethoxy)propyl]cytosine (HPMPC) (also known as cidofovir [CDV]) has good activity against poxvirus infections; however, a major limitation is the requirement for intravenous administration. Two related acyclic nucleoside phosphonates (ANPs), adefovir (PMEA) and tenofovir (PMPA), are active against human immunodeficiency virus or hepatitis B virus but do not have activity against the orthopoxviruses. Therefore, we have evaluated a number of analogs and potential oral prodrugs of these three compounds for their ability to inhibit the replication of vaccinia virus or cowpox virus in tissue culture cells. The most-active compounds within the CDV series were (S)-HPMPA and (butyl L-alaninyl) cyclic HPMPC, with 50% effective concentrations (EC(50)s) from 4 to 8 microM, compared with 33 to 43 microM for CDV. Although PMEA itself was not active, adefovir dipivoxil [bis[(pivaloyl)oxymethyl] PMEA] and bis(butyl L-alaninyl) PMEA were active against both viruses, and bis(butyl L-alaninyl) PME-N6-(cyclopropyl)DAP and (isopropyl L-alaninyl)phenyl PME-N6-(cyclopropyl)DAP were the most active compounds tested, with EC(50)s of 0.1 to 2.6 microM. In the PMPA series, none of the analogs tested had significantly better activity than PMPA itself. These data indicate that a number of these ANP derivatives have activity against vaccinia virus and cowpox virus in vitro and should be evaluated for their efficacies in animal models.

Adenine↗