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1.  Anthrax of the Gastrointestinal Tract 
Emerging Infectious Diseases  2002;8(7):649-651.
When swallowed, anthrax spores may cause lesions from the oral cavity to the cecum. Gastrointestinal anthrax is greatly underreported in rural disease-endemic areas of the world. The apparent paucity of this form of anthrax reflects the lack of facilities able to make the diagnosis in these areas. The spectrum of disease, ranging from subclinical infection to death, has not been fully recognized. In some community-based studies, cases of gastrointestinal anthrax outnumbered those of cutaneous anthrax. The oropharyngeal variant, in particular, is unfamiliar to most physicians. The clinical features of oropharyngeal anthrax include fever and toxemia, inflammatory lesion(s) in the oral cavity or oropharynx, enlargement of cervical lymph nodes associated with edema of the soft tissue of the cervical area, and a high case-fatality rate. Awareness of gastrointestinal anthrax in a differential diagnosis remains important in anthrax-endemic areas but now also in settings of possible bioterrorism.
doi:10.3201/eid0807.020062
PMCID: PMC2730335  PMID: 12095428
anthrax; anthrax classification; anthrax epidemiology; anthrax diagnosis; bioterrorism
2.  Risk practices for animal and human anthrax in Bangladesh: an exploratory study 
Infection Ecology & Epidemiology  2013;3:10.3402/iee.v3i0.21356.
Introduction
From August 2009 to October 2010, International Centre for Diarrheal Disease Research, Bangladesh and the Institute of Epidemiology, Disease Control and Research together investigated 14 outbreaks of anthrax which included 140 animal and 273 human cases in 14 anthrax-affected villages. Our investigation objectives were to explore the context in which these outbreaks occurred, including livestock rearing practices, human handling of sick and dead animals, and the anthrax vaccination program.
Methods
Field anthropologists used qualitative data-collection tools, including 15 hours of unstructured observations, 11 key informant interviews, 32 open-ended interviews, and 6 group discussions in 5 anthrax-affected villages.
Results
Each cattle owner in the affected communities raised a median of six ruminants on their household premises. The ruminants were often grazed in pastures and fed supplementary rice straw, green grass, water hyacinth, rice husk, wheat bran, and oil cake; lactating cows were given dicalcium phosphate. Cattle represented a major financial investment. Since Islamic law forbids eating animals that die from natural causes, when anthrax-infected cattle were moribund, farmers often slaughtered them on the household premises while they were still alive so that the meat could be eaten. Farmers ate the meat and sold it to neighbors. Skinners removed and sold the hides from discarded carcasses. Farmers discarded the carcasses and slaughtering waste into ditches, bodies of water, or open fields. Cattle in the affected communities did not receive routine anthrax vaccine due to low production, poor distribution, and limited staffing for vaccination.
Conclusion
Slaughtering anthrax-infected animals and disposing of butchering waste and carcasses in environments where ruminants live and graze, combined with limited vaccination, provided a context that permitted repeated anthrax outbreaks in animals and humans. Because of strong financial incentives, slaughtering moribund animals and discarding carcasses and waste products will likely continue. Long-term vaccination coverage for at-risk animal populations may reduce anthrax infection.
doi:10.3402/iee.v3i0.21356
PMCID: PMC3843109  PMID: 24298326
anthrax; Bangladesh; ruminants; vulture; qualitative
3.  Coxiella burnetii Seroprevalence in Small Ruminants in The Gambia 
PLoS ONE  2014;9(1):e85424.
Background
Q fever is a zoonosis caused by Coxiella burnetii, a Gram negative bacterium present worldwide. Small ruminants are considered the main reservoirs for infection of humans. This study aimed to estimate the extent of C. burnetii infection among sheep and goats in part of The Gambia.
Methodology/Principal Findings
This survey was carried out from March to May 2012 at two areas in The Gambia. The first area comprised a cluster of seven rural villages situated 5–15 km west of Farafenni as well as the local abattoir. A second sampling was done at the central abattoir in Abuko (30 km from the capital, Banjul) in the Western Region. Serum samples were obtained from 490 goats and 398 sheep. In addition, 67 milk samples were obtained from lactating dams. Sera were tested with a Q fever ELISA kit. C. burnetii DNA was extracted from milk samples and then detected using a specific quantitative multiplex PCR assay, targeting the IS1111a element. A multivariable mixed logistic regression model was used to examine the relationship between seropositivity and explanatory variables. An overall seroprevalence of 21.6% was found. Goats had a significantly higher seroprevalence than sheep, respectively 24.2% and 18.5%. Seropositive animals were significantly older than seronegative animals. Animals from the villages had a significantly lower seroprevalence than animals from the central abattoir (15.1% versus 29.1%). C. burnetii DNA was detected in 2 out of 67 milk samples, whereas 8 samples gave a doubtful result.
Conclusion/Significance
A substantial C. burnetii seroprevalence in sheep and goats in The Gambia was demonstrated. People living in close proximity to small ruminants are exposed to C. burnetii. Q fever should be considered as a possible cause of acute febrile illness in humans in The Gambia. Future studies should include a simultaneous assessment of veterinary and human serology, and include aetiology of febrile illness in local clinics.
doi:10.1371/journal.pone.0085424
PMCID: PMC3893215  PMID: 24454863
4.  Tick-Borne Rickettsioses, Neglected Emerging Diseases in Rural Senegal 
Background
Rickettsioses are one of the most important causes of systemic febrile illness among travelers from developed countries, but little is known about their incidence in indigenous populations, especially in West Africa.
Methodology/Principal Findings
Overall seroprevalence evaluated by immunofluorescence using six rickettsial antigens (spotted fever and typhus group) in rural populations of two villages of the Sine-Saloum region of Senegal was found to be 21.4% and 51% for spotted fever group rickettsiae for Dielmo and Ndiop villages, respectively. We investigated the role of tick-borne rickettsiae as the cause of acute non-malarial febrile diseases in the same villages. The incidence of rickettsial DNA in 204 blood samples from 134 (62M and 72F) febrile patients negative for malaria was studied. DNA extracted from whole blood was tested by two qPCR systems. Rickettsial DNA was found in nine patients, eight with Rickettsia felis (separately reported). For the first time in West Africa, Rickettsia conorii was diagnosed in one patient. We also tested 2,767 Ixodid ticks collected in two regions of Senegal (Niakhar and Sine-Saloum) from domestic animals (cows, sheep, goats, donkeys and horses) by qPCR and identified five different pathogenic rickettsiae. We found the following: Rickettsia aeschlimannii in Hyalomma marginatum rufipes (51.3% and 44.8% in Niakhar and Sine-Saloum region, respectively), in Hyalomma truncatum (6% and 6.8%) and in Rhipicephalus evertsi evertsi (0.5%, only in Niakhar); R. c. conorii in Rh. e. evertsi (0.4%, only in Sine-Saloum); Rickettsia massiliae in Rhipicephalus guilhoni (22.4%, only in Niakhar); Rickettsia sibirica mongolitimonae in Hyalomma truncatum (13.5%, only in Sine-Saloum); and Rickettsia africae in Rhipicephalus evertsi evertsi (0.7% and 0.4% in Niakhar and Sine-Saloum region, respectively) as well as in Rhipicephalus annulatus (20%, only in Sine-Saloum). We isolated two rickettsial strains from H. truncatum: R. s. mongolitimonae and R. aeschlimannii.
Conclusions/Significance
We believe that together with our previous data on the high prevalence of R. africae in Amblyomma ticks and R. felis infection in patients, the presented results on the distribution of pathogenic rickettsiae in ticks and the first R. conorii case in West Africa show that the rural population of Senegal is at risk for other tick-borne rickettsioses, which are significant causes of febrile disease in this area.
Author Summary
Spotted fever rickettsioses are endemic diseases known since the beginning of the 21st century. They may be severe, like Rocky Mountain Spotted fever in the Americas, and are always transmitted by the tick bite. In Africa, little is known about the prevalence of these diseases; most available data is from the travelers who felt ill after coming back to Europe and USA. We have studied the distribution of bacteria causing different spotted fevers (rickettsiae) in rural Senegal, as well as the role of these bacteria in human pathology among indigenous population. We have found that up to half of tested villagers have serological evidence of contact with rickettsiae and in some cases these bacteria may be found in the blood of feverish patients. From the other side, almost all species of ticks that may be collected in the villages on domestic animals also harbor the pathogenic bacteria. In total, six different species of rickettsiae were identified in ticks. We believe that our data cast light on the problem of unexplained fevers in West Africa.
doi:10.1371/journal.pntd.0000821
PMCID: PMC2939048  PMID: 20856858
5.  Evaluation of the House Fly Musca domestica as a Mechanical Vector for an Anthrax 
PLoS ONE  2010;5(8):e12219.
Anthrax is a disease of human beings and animals caused by the encapsulated, spore-forming, Bacillus anthracis. The potential role of insects in the spread of B. anthracis to humans and domestic animals during an anthrax outbreak has been confirmed by many studies. Among insect vectors, the house fly Musca domestica is considered a potential agent for disease transmission. In this study, laboratory-bred specimens of Musca domestica were infected by feeding on anthrax-infected rabbit carcass or anthrax contaminated blood, and the presence of anthrax spores in their spots (faeces and vomitus) was microbiologically monitored. It was also evaluated if the anthrax spores were able to germinate and replicate in the gut content of insects. These results confirmed the role of insects in spreading anthrax infection. This role, although not major, given the huge size of fly populations often associated with anthrax epidemics in domestic animals, cannot be neglected from an epidemiological point of view and suggest that fly control should be considered as part of anthrax control programs.
doi:10.1371/journal.pone.0012219
PMCID: PMC2923185  PMID: 20808920
6.  Anthrax Lethal Toxin-Mediated Killing of Human and Murine Dendritic Cells Impairs the Adaptive Immune Response 
PLoS Pathogens  2005;1(2):e19.
Many pathogens have acquired strategies to combat the immune response. Bacillus anthracis interferes with host defenses by releasing anthrax lethal toxin (LT), which inactivates mitogen-activated protein kinase pathways, rendering dendritic cells (DCs) and T lymphocytes nonresponsive to immune stimulation. However, these cell types are considered resistant to killing by LT. Here we show that LT kills primary human DCs in vitro, and murine DCs in vitro and in vivo. Kinetics of LT-mediated killing of murine DCs, as well as cell death pathways induced, were dependent upon genetic background: LT triggered rapid necrosis in BALB/c-derived DCs, and slow apoptosis in C57BL/6-derived DCs. This is consistent with rapid and slow killing of LT-injected BALB/c and C57BL/6 mice, respectively. We present evidence that anthrax LT impairs adaptive immunity by specifically targeting DCs. This may represent an immune-evasion strategy of the bacterium, and contribute to anthrax disease progression. We also established that genetic background determines whether apoptosis or necrosis is induced by LT. Finally, killing of C57BL/6-derived DCs by LT mirrors that of human DCs, suggesting that C57BL/6 DCs represent a better model system for human anthrax than the prototypical BALB/c macrophages.
Synopsis
Dendritic cells (DCs) are specialized white blood cells that identify and present antigens to immune cells, T cells, in order to mount an immune response targeted against specific pathogens. DCs are critical to a host's defense against infection. Previous work has shown that the anthrax bacterium disables many immune cells, including DCs, through the action of a released toxin, lethal toxin. Here the authors show that lethal toxin efficiently kills both human and murine DCs. The means by which DCs were killed by the anthrax toxin were notably distinct and dependent on their genetic background. Human DCs, as well as those derived from the murine strain C57BL/6, died over the course of 72 h via activation of apoptosis, or programmed cell death. DCs from BALB/c mice, however, died rapidly of a necrotic cell death following toxin exposure. As human and C57BL/6 DCs share an identical response to anthrax toxin, C57BL/6 mice appear to provide an excellent model for human anthrax. The study's findings suggest that specific targeting of DCs by the anthrax toxin impairs the immune response of the infected host, and the authors believe that this strategy promotes spread of the bacterium and disease progression.
doi:10.1371/journal.ppat.0010019
PMCID: PMC1266308  PMID: 16254597
7.  Serology and anthrax in humans, livestock and Etosha National Park wildlife. 
Epidemiology and Infection  1992;108(2):299-313.
Results are presented from a number of epidemiological studies using enzyme immunoassays (EIA) based on the purified anthrax toxin antigens, protective antigen, lethal factor and oedema factor. Studies on sera from a group of 62 human anthrax patients in Turkey and from cattle in Britain following two unrelated outbreaks of anthrax show that EIA using protective antigen can be a useful diagnostic aid and will detect subclinical infections in appropriate circumstances. A serological survey on wildlife in the Etosha National Park, Namibia, where anthrax is endemic, showed that naturally acquired anthrax-specific antibodies are rare in herbivores but common in carnivores; in carnivores, titres appear to reflect the prevalence of anthrax in their ranges. Problems, as yet unresolved, were encountered in studies on sera from pigs following an outbreak of anthrax on a farm in Wales. Clinical details, including treatment, of the human and one of the bovine outbreaks are summarized and discussed in relation to the serological findings.
PMCID: PMC2271992  PMID: 1582472
8.  Detection, Isolation and Confirmation of Crimean-Congo Hemorrhagic Fever Virus in Human, Ticks and Animals in Ahmadabad, India, 2010–2011 
Background
In January 2011, human cases with hemorrhagic manifestations in the hospital staff were reported from a tertiary care hospital in Ahmadabad, India. This paper reports a detailed epidemiological investigation of nosocomial outbreak from the affected area of Ahmadabad, Gujarat, India.
Principal Findings
Samples from 3 suspected cases, 83 contacts, Hyalomma ticks and livestock were screened for Crimean-Congo hemorrhagic fever (CCHF) virus by qRT-PCR of which samples of two medical professionals (case C and E) and the husband of the index case (case D) were positive for CCHFV. The sensitivity and specificity of indigenous developed IgM ELISA to screen CCHFV specific antibodies in human serum was 75.0% and 97.5% respectively as compared to commercial kit. About 17.0% domestic animals from Kolat, Ahmadabad were positive for IgG antibodies while only two cattle and a goat showed positivity by qRT-PCR. Surprisingly, 43.0% domestic animals (Buffalo, cattle, sheep and goat) showed IgG antibodies in the adjoining village Jivanpara but only one of the buffalo was positive for CCHFV. The Hyalomma anatolicum anatolicum ticks were positive in PCR and virus isolation. CCHFV was isolated from the blood sample of case C, E in Vero E-6 cells and Swiss albino mice. In partial nucleocapsid gene phylogeny from CCHFV positive human samples of the years 2010 and 2011, livestock and ticks showed this virus was similar to Tajikistan (strain TAJ/H08966), which belongs in the Asian/middle east genetic lineage IV.
Conclusions
The likely source of CCHFV was identified as virus infected Hyalomma ticks and livestock at the rural village residence of the primary case (case A). In addition, retrospective sample analysis revealed the existence of CCHFV in Gujarat and Rajasthan states before this outbreak. An indigenous developed IgM ELISA kit will be of great use for screening this virus in India.
Author Summary
A nosocomial outbreak of CCHFV occurred in January 2011, in a tertiary care hospital in Ahmadabad, Gujarat State in western India. Out of a total five cases reported, contact transmission occurred to three treating medical professionals, all of whom succumbed to the disease. The only survivor was the husband of the index case. These results highlight the importance of considering CCHFV as a potential aetiology for Hemorrhagic fever (HF) cases in India. This also underlines the need for strict barrier nursing and patient isolation while managing these patients. During the investigation presence of CCHFV RNA in Hyalomma anatolicum ticks and livestock were detected in the village from where the primary case (case A) was reported. Further retrospective investigation confirmed two CCHF human cases in Rajkot village 20 kilometres to the west of Ahmadabad in 2010, and CCHFV presence in the livestock 200 kilometres to the north in the neighbouring State Rajasthan. This report shows the presence of CCHFV in human, ticks and animals in Gujarat, India. The fact of concern is the spread of this disease from one state to another due to trading of livestock.
doi:10.1371/journal.pntd.0001653
PMCID: PMC3352827  PMID: 22616022
9.  Anthrax Lethal Factor as an Immune Target in Humans and Transgenic Mice and the Impact of HLA Polymorphism on CD4+ T Cell Immunity 
PLoS Pathogens  2014;10(5):e1004085.
Bacillus anthracis produces a binary toxin composed of protective antigen (PA) and one of two subunits, lethal factor (LF) or edema factor (EF). Most studies have concentrated on induction of toxin-specific antibodies as the correlate of protective immunity, in contrast to which understanding of cellular immunity to these toxins and its impact on infection is limited. We characterized CD4+ T cell immunity to LF in a panel of humanized HLA-DR and DQ transgenic mice and in naturally exposed patients. As the variation in antigen presentation governed by HLA polymorphism has a major impact on protective immunity to specific epitopes, we examined relative binding affinities of LF peptides to purified HLA class II molecules, identifying those regions likely to be of broad applicability to human immune studies through their ability to bind multiple alleles. Transgenics differing only in their expression of human HLA class II alleles showed a marked hierarchy of immunity to LF. Immunogenicity in HLA transgenics was primarily restricted to epitopes from domains II and IV of LF and promiscuous, dominant epitopes, common to all HLA types, were identified in domain II. The relevance of this model was further demonstrated by the fact that a number of the immunodominant epitopes identified in mice were recognized by T cells from humans previously infected with cutaneous anthrax and from vaccinated individuals. The ability of the identified epitopes to confer protective immunity was demonstrated by lethal anthrax challenge of HLA transgenic mice immunized with a peptide subunit vaccine comprising the immunodominant epitopes that we identified.
Author Summary
Anthrax is of concern with respect to human exposure in endemic regions, concerns about bioterrorism and the considerable global burden of livestock infections. The immunology of this disease remains poorly understood. Vaccination has been based on B. anthracis filtrates or attenuated spore-based vaccines, with more recent trials of next-generation recombinant vaccines. Approaches generally require extensive vaccination regimens and there have been concerns about immunogenicity and adverse reactions. An ongoing need remains for rationally designed, effective and safe anthrax vaccines. The importance of T cell stimulating vaccines is inceasingly recognized. An essential step is an understanding of immunodominant epitopes and their relevance across the diverse HLA immune response genes of human populations. We characterized CD4 T cell immunity to anthrax Lethal Factor (LF), using HLA transgenic mice, as well as testing candidate peptide epitopes for binding to a wide range of HLA alleles. We identified anthrax epitopes, noteworthy in that they elicit exceptionally strong immunity with promiscuous binding across multiple HLA alleles and isotypes. T cell responses in humans exposed to LF through either natural anthrax infection or vaccination were also examined. Epitopes identified as candidates were used to protect HLA transgenic mice from anthrax challenge.
doi:10.1371/journal.ppat.1004085
PMCID: PMC4006929  PMID: 24788397
10.  Recent outbreak of cutaneous anthrax in Bangladesh: clinico-demographic profile and treatment outcome of cases attended at Rajshahi Medical College Hospital 
BMC Research Notes  2012;5:464.
Background
Human cutaneous anthrax results from skin exposure to B. anthracis, primarily due to occupational exposure. Bangladesh has experienced a number of outbreaks of cutaneous anthrax in recent years. The last episode occurred from April to August, 2011 and created mass havoc due to its dreadful clinical outcome and socio-cultural consequences. We report here the clinico-demographic profile and treatment outcome of 15 cutaneous anthrax cases attended at the Dermatology Outpatient Department of Rajshahi Medical College Hospital, Bangladesh between April and August, 2011 with an aim to create awareness for early case detection and management.
Findings
Anthrax was suspected primarily based on cutaneous manifestations of typical non-tender ulcer with black eschar, with or without oedema, and a history of butchering, or dressing/washing of cattle/goat or their meat. Diagnosis was established by demonstration of large gram-positive rods, typically resembling B. anthracis under light microscope where possible and also by ascertaining therapeutic success. The mean age of cases was 21.4 years (ranging from 3 to 46 years), 7 (46.7%) being males and 8 (53.3%) females. The majority of cases were from lower middle socioeconomic status. Types of exposures included butchering (20%), contact with raw meat (46.7%), and live animals (33.3%). Malignant pustule was present in upper extremity, both extremities, face, and trunk at frequencies of 11 (73.3%), 2 (13.3%), 1 (6.7%) and 1 (6.7%) respectively. Eight (53.3%) patients presented with fever, 7 (46.7%) had localized oedema and 5 (33.3%) had regional lymphadenopathy. Anthrax was confirmed in 13 (86.7%) cases by demonstration of gram-positive rods. All cases were cured with 2 months oral ciprofloxacin combined with flucoxacillin for 2 weeks.
Conclusions
We present the findings from this series of cases to reinforce the criteria for clinical diagnosis and to urge prompt therapeutic measures to treat cutaneous anthrax successfully to eliminate the unnecessary panic of anthrax.
doi:10.1186/1756-0500-5-464
PMCID: PMC3493280  PMID: 22929128
Cutaneous anthrax; Clinico-demographic profile; Therapeutic response; Bangladesh
11.  Distribution and Molecular Evolution of Bacillus anthracis Genotypes in Namibia 
The recent development of genetic markers for Bacillus anthracis has made it possible to monitor the spread and distribution of this pathogen during and between anthrax outbreaks. In Namibia, anthrax outbreaks occur annually in the Etosha National Park (ENP) and on private game and livestock farms. We genotyped 384 B. anthracis isolates collected between 1983–2010 to identify the possible epidemiological correlations of anthrax outbreaks within and outside the ENP and to analyze genetic relationships between isolates from domestic and wild animals. The isolates came from 20 animal species and from the environment and were genotyped using a 31-marker multi-locus-VNTR-analysis (MLVA) and, in part, by twelve single nucleotide polymorphism (SNP) markers and four single nucleotide repeat (SNR) markers. A total of 37 genotypes (GT) were identified by MLVA, belonging to four SNP-groups. All GTs belonged to the A-branch in the cluster- and SNP-analyses. Thirteen GTs were found only outside the ENP, 18 only within the ENP and 6 both inside and outside. Genetic distances between isolates increased with increasing time between isolations. However, genetic distance between isolates at the beginning and end of the study period was relatively small, indicating that while the majority of GTs were only found sporadically, three genetically close GTs, accounting for more than four fifths of all the ENP isolates, appeared dominant throughout the study period. Genetic distances among isolates were significantly greater for isolates from different host species, but this effect was small, suggesting that while species-specific ecological factors may affect exposure processes, transmission cycles in different host species are still highly interrelated. The MLVA data were further used to establish a model of the probable evolution of GTs within the endemic region of the ENP. SNR-analysis was helpful in correlating an isolate with its source but did not elucidate epidemiological relationships.
Author Summary
Anthrax, the disease caused by Bacillus anthracis, is a neglected zoonotic diseases in the context of its impact on poor rural and periurban communities in Africa and other less developed areas of the world. Several regions of Namibia, the Etosha National Park in particular, are well known as being endemic areas for anthrax and, together, provide a good model for the investigation of the genetic diversity of B. anthracis circulating in livestock, wildlife and humans, and surrounding environments. The application of modern molecular strain typing techniques to the analysis of genotypic diversity, as it relates to the spatial and temporal distribution of B. anthracis strains in Namibia, is described in this paper. In particular, we demonstrate how it is possible to distinguish outbreaks of the disease caused by different strains from those caused by the spread of a single strain, to trace an outbreak strain back to its possible origin, and to track the routes of transmission of an outbreak strain within and between animal populations. The data described are relevant to all those concerned with monitoring, surveillance and prevention of the spread of anthrax in endemic areas.
doi:10.1371/journal.pntd.0001534
PMCID: PMC3295808  PMID: 22413024
12.  Human Neutrophils Kill Bacillus anthracis 
PLoS Pathogens  2005;1(3):e23.
Bacillus anthracis spores cause natural infections and are used as biological weapons. Inhalation infection with B. anthracis, the etiological agent of anthrax, is almost always lethal, yet cutaneous infections usually remain localized and resolve spontaneously. Neutrophils are typically recruited to cutaneous but seldom to other forms of anthrax infections, raising the possibility that neutrophils kill B. anthracis. In this study we infected human neutrophils with either spores or vegetative bacteria of a wild-type strain, or strains, expressing only one of the two major virulence factors. The human neutrophils engulfed B. anthracis spores, which germinated intracellularly and were then efficiently killed. Interestingly, neutrophil killing was independent of reactive oxygen species production. We fractionated a human neutrophil granule extract by high-performance liquid chromatography and identified α-defensins as the component responsible for B. anthracis killing. These data suggest that the timely recruitment of neutrophils can control cutaneous infections and possibly other forms of B. anthracis infections, and that α-defensins play an important role in the potent anti-B. anthracis activity of neutrophils.
Synopsis
Bacillus anthracis is the bacterium that causes anthrax, a disease that can occur through natural infections and also through intentional release. B. anthracis makes spores, which are in a dormant state, similar to seeds of a plant, and are extremely resistant to the environment. B. anthracis spores can infect through the skin or the lung. Lung infections disseminate through the body and are lethal. In contrast, skin infections often remain localized, and patients survive even without treatment. It is not well understood why these bacteria cause a localized infection through the skin and a lethal disease through the lung.
Little is known about how B. anthracis is controlled. Neutrophils are the first white blood cells recruited to a site of infection and are specialized in killing microbes. Previous studies show that neutrophils are abundant in the skin form, but not in the lung form of anthrax. The researchers report that human neutrophils can take up B. anthracis spores. Once inside, the spores germinate to form vegetative bacteria. The vegetative bacteria are extremely susceptible to neutrophil-killing mechanisms. The B. anthracis virulence factors (molecules that make bacteria cause diseases) manipulate other human cells but do not deter neutrophils. B. anthracis is indeed exquisitely sensitive to the neutrophil protein α-defensin. These data support a new model where B. anthracis skin, but not lung, infections are controlled by the antimicrobial activity of neutrophils.
doi:10.1371/journal.ppat.0010023
PMCID: PMC1283252  PMID: 16292357
13.  Anthrax: an update 
Anthrax is a zoonotic disease caused by Bacillus anthracis. It is potentially fatal and highly contagious disease. Herbivores are the natural host. Human acquire the disease incidentally by contact with infected animal or animal products. In the 18th century an epidemic destroyed approximately half of the sheep in Europe. In 1900 human inhalational anthrax occured sporadically in the United States. In 1979 an outbreak of human anthrax occured in Sverdlovsk of Soviet Union. Anthrax continued to represent a world wide presence. The incidence of the disease has decreased in developed countries as a result of vaccination and improved industrial hygiene. Human anthrax clinically presents in three forms, i.e. cutaneous, gastrointestinal and inhalational. About 95% of human anthrax is cutaneous and 5% is inhalational. Gastrointestinal anthrax is very rare (less than 1%). Inhalational form is used as a biological warefare agent. Penicillin, ciprofloxacin (and other quinolones), doxicyclin, ampicillin, imipenem, clindamycin, clarithromycin, vancomycin, chloramphenicol, rifampicin are effective antimicrobials. Antimicrobial therapy for 60 days is recommended. Human anthrax vaccine is available. Administration of anti-protective antigen (PA) antibody in combination with ciprofloxacin produced 90%-100% survival. The combination of CPG-adjuvanted anthrax vaccine adsorbed (AVA) plus dalbavancin significantly improved survival.
doi:10.1016/S2221-1691(11)60109-3
PMCID: PMC3614207  PMID: 23569822
Anthrax; Bacillus anthracis; Zoonotic disease; Contagious disease; Cutaneous anthrax; Inhalational anthrax; Gastrointestinal anthrax; Human anthrax
14.  Evidence of Local Persistence of Human Anthrax in the Country of Georgia Associated with Environmental and Anthropogenic Factors 
Background
Anthrax is a soil-borne disease caused by the bacterium Bacillus anthracis and is considered a neglected zoonosis. In the country of Georgia, recent reports have indicated an increase in the incidence of human anthrax. Identifying sub-national areas of increased risk may help direct appropriate public health control measures. The purpose of this study was to evaluate the spatial distribution of human anthrax and identify environmental/anthropogenic factors associated with persistent clusters.
Methods/Findings
A database of human cutaneous anthrax in Georgia during the period 2000–2009 was constructed using a geographic information system (GIS) with case data recorded to the community location. The spatial scan statistic was used to identify persistence of human cutaneous anthrax. Risk factors related to clusters of persistence were modeled using a multivariate logistic regression. Areas of persistence were identified in the southeastern part of the country. Results indicated that the persistence of human cutaneous anthrax showed a strong positive association with soil pH and urban areas.
Conclusions/Significance
Anthrax represents a persistent threat to public and veterinary health in Georgia. The findings here showed that the local level heterogeneity in the persistence of human cutaneous anthrax necessitates directed interventions to mitigate the disease. High risk areas identified in this study can be targeted for public health control measures such as farmer education and livestock vaccination campaigns.
Author Summary
Anthrax is a zoonotic bacterial disease that occurs nearly worldwide. Despite a large number of countries reporting endemic anthrax, persistence of the disease appears to be associated with specific ecological factors related to soil composition and climatic conditions. Human cases are most often associated with handling infected livestock or contaminated meat and most cases are in cutaneous form (skin infections). Following the collapse of the Soviet Union, the country of Georgia has undergone major restructuring in land management and livestock handling and anthrax remains a serious public health risk. Few studies have evaluated the local spatial patterns of human anthrax. Here we identify areas on the landscape where human cutaneous anthrax persisted over the last decade. Persistence was found to be associated with both anthropogenic and environmental factors including soil pH and livestock density. These findings aid in the establishment of spatial baseline estimates of the disease and allow public health officials to adopt targeted anthrax control strategies, such as livestock vaccination campaigns and farmer education.
doi:10.1371/journal.pntd.0002388
PMCID: PMC3764226  PMID: 24040426
15.  The Potential Contributions of Lethal and Edema Toxins to the Pathogenesis of Anthrax Associated Shock  
Toxins  2011;3(9):1185-1202.
Outbreaks of Bacillus anthracis in the US and Europe over the past 10 years have emphasized the health threat this lethal bacteria poses even for developed parts of the world. In contrast to cutaneous anthrax, inhalational disease in the US during the 2001 outbreaks and the newly identified injectional drug use form of disease in the UK and Germany have been associated with relatively high mortality rates. One notable aspect of these cases has been the difficulty in supporting patients once shock has developed. Anthrax bacilli produce several different components which likely contribute to this shock. Growing evidence indicates that both major anthrax toxins may produce substantial cardiovascular dysfunction. Lethal toxin (LT) can alter peripheral vascular function; it also has direct myocardial depressant effects. Edema toxin (ET) may have even more pronounced peripheral vascular effects than LT, including the ability to interfere with the actions of conventional vasopressors. Additionally, ET also appears capable of interfering with renal sodium and water retention. Importantly, the two toxins exert their actions via quite different mechanisms and therefore have the potential to worsen shock and outcome in an additive fashion. Finally, both toxins have the ability to inhibit host defense and microbial clearance, possibly contributing to the very high bacterial loads noted in patients dying with anthrax. This last point is clinically relevant since emerging data has begun to implicate other bacterial components such as anthrax cell wall in the shock and organ injury observed with infection. Taken together, accumulating evidence regarding the potential contribution of LT and ET to anthrax-associated shock supports efforts to develop adjunctive therapies that target both toxins in patients with progressive shock.
doi:10.3390/toxins3091185
PMCID: PMC3202877  PMID: 22069762
anthrax; lethal toxin; edema toxin; shock; myocardial function
16.  Rapid generation of an anthrax immunotherapeutic from goats using a novel non-toxic muramyl dipeptide adjuvant 
Background
There is a clear need for vaccines and therapeutics for potential biological weapons of mass destruction and emerging diseases. Anthrax, caused by the bacterium Bacillus anthracis, has been used as both a biological warfare agent and bioterrorist weapon previously. Although antibiotic therapy is effective in the early stages of anthrax infection, it does not have any effect once exposed individuals become symptomatic due to B. anthracis exotoxin accumulation. The bipartite exotoxins are the major contributing factors to the morbidity and mortality observed in acute anthrax infections.
Methods
Using recombinant B. anthracis protective antigen (PA83), covalently coupled to a novel non-toxic muramyl dipeptide (NT-MDP) derivative we hyper-immunized goats three times over the course of 14 weeks. Goats were plasmapheresed and the IgG fraction (not affinity purified) and F(ab')2 derivatives were characterized in vitro and in vivo for protection against lethal toxin mediated intoxication.
Results
Anti-PA83 IgG conferred 100% protection at 7.5 μg in a cell toxin neutralization assay. Mice exposed to 5 LD50 of Bacillus anthracis Ames spores by intranares inoculation demonstrated 60% survival 14 d post-infection when administered a single bolus dose (32 mg/kg body weight) of anti-PA83 IgG at 24 h post spore challenge. Anti-PA83 F(ab')2 fragments retained similar neutralization and protection levels both in vitro and in vivo.
Conclusion
The protection afforded by these GMP-grade caprine immunotherapeutics post-exposure in the pilot murine model suggests they could be used effectively to treat post-exposure, symptomatic human anthrax patients following a bioterrorism event. These results also indicate that recombinant PA83 coupled to NT-MDP is a potent inducer of neutralizing antibodies and suggest it would be a promising vaccine candidate for anthrax. The ease of production, ease of covalent attachment, and immunostimulatory activity of the NT-MDP indicate it would be a superior adjuvant to alum or other traditional adjuvants in vaccine formulations.
doi:10.1186/1476-8518-5-11
PMCID: PMC2104530  PMID: 17953756
17.  Evidence for a Lectin Specific for Sulfated Glycans in the Salivary Gland of the Malaria Vector, Anopheles gambiae 
PLoS ONE  2014;9(9):e107295.
Salivary gland homogenate (SGH) from the female mosquitoes Anopheles gambiae, An. stephensi, An. freeborni, An. dirus and An. albimanus were found to exhibit hemagglutinating (lectin) activity. Lectin activity was not found for male An. gambiae, or female Ae aegypti, Culex quinquefasciatus, Phlebotomus duboscqi, and Lutzomyia longipalpis. With respect to species-specificity, An. gambiae SGH agglutinates red blood cells (RBC) from humans, horse, sheep, goat, pig, and cow; it is less active for rats RBC, and not detectable for guinea-pigs or chicken RBC. Notably, lectin activity was inhibited by low concentrations of dextran sulfate 50–500 K, fucoidan, heparin, laminin, heparin sulfate proteoglycan, sialyl-containing glycans (e.g. 3′-sialyl Lewis X, and 6′-sialyl lactose), and gangliosides (e.g. GM3, GD1, GD1b, GTB1, GM1, GQ1B), but not by simple sugars. These results imply that molecule(s) in the salivary gland target sulfated glycans. SGH from An. gambiae was also found to promote agglutination of HL-60 cells which are rich in sialyl Lewis X, a glycan that decorates PSGL-1, the neutrophils receptor that interacts with endothelial cell P-selectin. Accordingly, SGH interferes with HL-60 cells adhesion to immobilized P-selectin. Because An. gambiae SGH expresses galectins, one member of this family (herein named Agalectin) was expressed in E. coli. Recombinant Agalectin behaves as a non-covalent homodimer. It does not display lectin activity, and does not interact with 500 candidates tested in a Glycan microarray. Gel-filtration chromatography of the SGH of An. gambiae identified a fraction with hemagglutinating activity, which was analyzed by 1D PAGE followed by in-gel tryptic digestion, and nano-LC MS/MS. This approach identified several genes which emerge as candidates for a lectin targeting sulfated glycans, the first with this selectivity to be reported in the SGH of a blood-sucking arthropod. The role of salivary molecules (sialogenins) with lectin activity is discussed in the context of inflammation, and parasite-vector-host interactions.
doi:10.1371/journal.pone.0107295
PMCID: PMC4160252  PMID: 25207644
18.  Contribution of Anopheles funestus, An. gambiae and An. nili (Diptera: Culicidae) to the perennial malaria transmission in the southern and western forest areas of Côte d’Ivoire 
The involvement of members of the Anopheles gambiae complex Giles and An. funestus Giles and An. nili Theobald groups in the transmission of Plasmodium falciparum was recently investigated in the villages of Gbatta and Kpéhiri, which lie, respectively, in forest areas in the west and south of Côte d’Ivoire.
Adult female mosquitoes were collected, using human landing catches, inside and outside dwellings. After identification and dissection, the heads and thoraces of all the anopheline mosquitoes were tested, in an ELISA, for circumsporozoite protein (CSP). All the female anopheline mosquitoes collected and identified to species using PCR were found to be An. gambiae s.s., An. nili s.s. or An. funestus s.s., with An. gambiae s.s. and An. funestus s.s. predominant in Gbatta but An. nili s.s. the most common species in Kpéhiri. In Gbatta, 3.1% of the female An. gambiae collected, 5.0% of the female An. funestus and 1.8% of the female An. nili were found CSP-positive. The corresponding values in Kpéhiri were even higher, at 5.9%, 6.2% and 2.4%, respectively. The estimated entomological inoculation rates (EIR) were very high: 302 infected bites (139 from An. gambiae, 146 from An. funestus and 17 from An. nili)/person-year in Gbatta and 484 infected bites (204 from An. gambiae, 70 from An. funestus and 210 from An. nili)/person-year in Kpéhiri.
In Gbatta, An. gambiae s.s. was responsible for most of the rainy-season transmission while An. funestus became the main malaria vector in the dry seasons. In Kpéhiri, however, An. nili appeared to be the main vector throughout the year, with An. gambiae of secondary importance and An. funestus only becoming a significant vector during the rainy season. Although, in both study sites, intense transmission was therefore occurring and the same three species of anopheline mosquito were present, the relative importance of each mosquito species in the epidemiology of the human malaria at each site differed markedly.
doi:10.1179/136485910X12851868780388
PMCID: PMC4089788  PMID: 21294945
19.  Detection of Mycobacterium ulcerans in the Environment Predicts Prevalence of Buruli Ulcer in Benin 
Background
Mycobacterium ulcerans is the causative agent of Buruli ulcer (BU). In West Africa there is an association between BU and residence in low-lying rural villages where aquatic sources are plentiful. Infection occurs through unknown environmental exposure; human-to-human infection is rare. Molecular evidence for M. ulcerans in environmental samples is well documented, but the association of M. ulcerans in the environment with Buruli ulcer has not been studied in West Africa in an area with accurate case data.
Methodology/Principal Finding
Environmental samples were collected from twenty-five villages in three communes of Benin. Sites sampled included 12 BU endemic villages within the Ouheme and Couffo River drainages and 13 villages near the Mono River and along the coast or ridge where BU has never been identified. Triplicate water filtrand samples from major water sources and samples from three dominant aquatic plant species were collected. Detection of M. ulcerans was based on quantitative polymerase chain reaction. Results show a significant association between M. ulcerans in environmental samples and Buruli ulcer cases in a village (p = 0.0001). A “dose response” was observed in that increasing numbers of M. ulceran- positive environmental samples were associated with increasing prevalence of BU cases (R2 = 0.586).
Conclusions/Significance
This study provides the first spatial data on the overlap of M. ulcerans in the environment and BU cases in Benin where case data are based on active surveillance. The study also provides the first evidence on M. ulcerans in well-defined non-endemic sites. Most environmental pathogens are more broadly distributed in the environment than in human populations. The congruence of M. ulcerans in the environment and human infection raises the possibility that humans play a role in the ecology of M. ulcerans. Methods developed could be useful for identifying new areas where humans may be at high risk for BU.
Author Summary
Buruli ulcer, a severe, cutaneous disease in West and Central Africa is caused by Mycobacterium ulcerans. Person-to-person spread of M. ulcerans is rare. There is a strong epidemiological association with residence near slow moving water, but lack of accurate case data in Africa has greatly complicated transmission studies of M. ulcerans from the environment to humans. We have combined molecular tools for identification of M. ulcerans in the environment with accurate Buruli ulcer case data based on a long standing active surveillance program to map the association between Buruli ulcer and M. ulcerans in the environment in Benin. We found a positive association between M. ulcerans in the environment and Buruli ulcer cases and show that as the numbers of M. ulcerans positive samples/village increase so does the prevalence of Buruli ulcer. Many environmental pathogens are widespread in the environment in the absence of human disease. The failure to obtain definitive proof for M. ulcerans in environmental samples where Buruli ulcer is absent raises the intriguing possibility that humans play a role in the distribution of M. ulcerans. Sampling methods we have developed could be especially useful for identifying new areas where people may be at risk for Buruli ulcer.
doi:10.1371/journal.pntd.0001506
PMCID: PMC3269429  PMID: 22303498
20.  Cytological and Transcript Analyses Reveal Fat and Lazy Persister-Like Bacilli in Tuberculous Sputum 
PLoS Medicine  2008;5(4):e75.
Background
Tuberculous sputum provides a sample of bacilli that must be eliminated by chemotherapy and that may go on to transmit infection. A preliminary observation that Mycobacterium tuberculosis cells contain triacylglycerol lipid bodies in sputum, but not when growing in vitro, led us to investigate the extent of this phenomenon and its physiological basis.
Methods and Findings
Microscopy-positive sputum samples from the UK and The Gambia were investigated for their content of lipid body–positive mycobacteria by combined Nile red and auramine staining. All samples contained a lipid body–positive population varying from 3% to 86% of the acid-fast bacilli present. The recent finding that triacylglycerol synthase is expressed by mycobacteria when they enter in vitro nonreplicating persistence led us to investigate whether this state was also associated with lipid body formation. We found that, when placed in laboratory conditions inducing nonreplicating persistence, two M. tuberculosis strains had lipid body levels comparable to those found in sputum. We investigated these physiological findings further by comparing the M. tuberculosis transcriptome of growing and nonreplicating persistence cultures with that obtained directly from sputum samples. Although sputum has traditionally been thought to contain actively growing tubercle bacilli, our transcript analyses refute the hypothesis that these cells predominate. Rather, they reinforce the results of the lipid body analyses by revealing transcriptional signatures that can be clearly attributed to slowly replicating or nonreplicating mycobacteria. Finally, the lipid body count was highly correlated (R2 = 0.64, p < 0.03) with time to positivity in diagnostic liquid cultures, thereby establishing a direct link between this cytological feature and the size of a potential nonreplicating population.
Conclusion
As nonreplicating tubercle bacilli are tolerant to the cidal action of antibiotics and resistant to multiple stresses, identification of this persister-like population of tubercle bacilli in sputum presents exciting and tractable new opportunities to investigate both responses to chemotherapy and the transmission of tuberculosis.
Studying sputum from humans with pulmonary tuberculosis, Michael Barer and colleagues detect mycobacteria containing lipid bodies. Analyses linking this cytological feature to a slow-growing phenotype sheds light on persistence.
Editors' Summary
Background.
Every year, nearly nine million people develop tuberculosis—a contagious infection usually of the lungs—and about two million people die from the disease. Tuberculosis is caused by Mycobacterium tuberculosis, bacteria that are spread in airborne droplets when people with the disease cough or sneeze. The symptoms of tuberculosis include a persistent cough, weight loss, and night sweats. Diagnostic tests include chest X-rays, the tuberculin skin test, and sputum analysis. For the last of these tests, a sample of sputum (mucus and other matter brought up from the lungs by coughing) is collected and then taken to a laboratory where bacteriologists look for M. tuberculosis using special stains—tuberculosis-positive sputum contains “acid-fast bacilli”—and also try to grow bacteria from the sample. Tuberculosis can be cured by taking several powerful antibiotics for several months. It is very important that this treatment is completed to ensure that all the M. tuberculosis bacteria in the body are killed and to prevent the emergence of drug-resistant bacteria.
Why Was This Study Done?
Strenuous efforts are being made to reduce the global burden of tuberculosis but with limited success so far for many reasons. One barrier to success is the efficiency with which M. tuberculosis spreads from one person to another. Very little is known about this part of the bacteria's life cycle. If scientists could understand more about the transmission of M. tuberculosis between people, they might identify new therapeutic and preventative targets. In the study, therefore, the researchers examine the acid-fast bacilli in tuberculosis-positive sputum samples to get a snapshot of M. tuberculosis at the point of its transmission to a new person and ask how the characteristics of these bacilli compare with those of M. tuberculosis growing in the laboratory.
What Did the Researchers Do and Find?
The researchers collected sputum samples from patients with tuberculosis in the UK and The Gambia before they received any treatment, and looked for the presence of acid-fast bacilli containing “lipid bodies.” These small structures contain a fat called triacylglycerol. M. tuberculosis accumulates triacylglycerol when it is exposed to several stresses present during infection (for example, reduced oxygen or hypoxia) and the researchers suggest that the presence of this fat may help the bacteria survive during transmission and establish a new infection. They found that all the samples contained some lipid body–positive acid-fast bacilli. Next, the researchers showed that M. tuberculosis grown in the laboratory under hypoxic conditions, which induce the bacteria to enter an antibiotic-tolerant condition called a “nonreplicating persistent” (NRP) state, also accumulated lipid bodies. This result suggests that the lipid body–positive acid-fast bacilli in sputum might be in an NRP state. To test this idea, the researchers compared the pattern of mRNAs (the templates from which proteins are produced; the pattern of mRNAs is called the transcriptome and gives an idea of which proteins a cell is making under given conditions) made by growing cultures of M. tuberculosis, by M. tuberculosis maintained in the NRP state, and by the acid-fast bacilli in several sputum samples. The transcriptome of the sputum sample revealed production of many proteins made in the NRP state. Finally, the researchers showed that the time needed to grow M. tuberculosis from sputum samples increased as the proportion of lipid body–positive acid-fast bacilli in the sputum increased, just as one would suspect if the presence of lipid bodies signifies nongrowing cells.
What Do These Findings Mean?
It has been generally assumed that the acid-fast bacilli in sputum collected from patients with tuberculosis are rapidly replicating M. tuberculosis released from infected areas of the lungs. By identifying a population of bacteria that contain lipid bodies and that are in an NRP-like state in all the samples of sputum examined from two geographical sites, this study strongly challenges this assumption. The characteristics of this population of bacteria, the researchers suggest, might help them survive the adverse conditions that M. tuberculosis encounters during transmission between people and might partly explain why complete clearance of M. tuberculosis requires extended treatment with antibiotics. To establish the clinical significance of these findings, future studies will need to examine whether antibiotic treatment affects the frequency of lipid body–positive M. tuberculosis bacteria in patients' sputum and whether there is any relationship between this measurement and infectiousness, or clinical response to treatment.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050075.
The MedlinePlus encyclopedia contains pages on tuberculosis and on sputum culture (in English and Spanish)
The US National Institute of Allergy and Infectious Diseases provides information on all aspects of tuberculosis
The US Centers for Disease Control and Prevention Division of Tuberculosis Elimination provides several fact sheets and other information resources about tuberculosis
The World Health Organization provides information on efforts to reduce the global burden of tuberculosis
doi:10.1371/journal.pmed.0050075
PMCID: PMC2276522  PMID: 18384229
21.  High mosquito burden and malaria transmission in a district of the city of Douala, Cameroon 
BMC Infectious Diseases  2012;12:275.
Background
Rapid demographic growth in Douala city, Cameroon, has resulted in profound ecological and environmental changes. Although demographic changes can affect anopheline mosquito breeding sites, there is a lack of understanding about the epidemiological impact that such changes might have on vector ecology and malaria transmission.
Methods
A 12-month entomological study was conducted in a highly populated district of Douala called Ndogpassi. Adult mosquitoes were collected using two methods: 1) human landing catches (HLC); and 2) Centers for Disease Control and Prevention (CDC) light traps; these methods were used twice monthly from January to December 2011. Mosquito genus and species were identified with morphological and molecular diagnostic tools. The sampling efficiency of the CDC light trap and HLC were compared. Anopheles gambiae infection with Plasmodium falciparum was detected using ELISA. Susceptibility to DDT, permethrin, and deltamethrin insecticides were also determined.
Results
A total of 6923 mosquitoes were collected by HLC (5198) and CDC light traps (1725). There was no equivalence in the sampling efficiency between light traps and human landing catches (P > 0.01). With 51% of the total, Culex was the most common, followed by Anopheles (26.14%), Mansonia (22.7%) and Aedes (0.1%). An. gambiae ss (M form) comprised ~98% of the total anophelines collected. An. gambiae had a biting rate of 0.25 to 49.25 bites per human per night, and was the only species found to be infected with P. falciparum. A P. falciparum infection rate of 0.5% was calculated (based on enzyme-linked immunosorbent assays using the circumsporozoite surface protein). The entomological inoculation rate was estimated at 31 infective bites per annum. Insecticide susceptibility tests on An. gambiae females revealed a mortality rate of 33%, 76% and 98% for DDT, permethrin and deltamethrin, respectively. The West African kdr allele (L1014F) was detected in 38 of the 61 An. gambiae analyzed (62.3%).
Conclusions
The present study revealed seasonal malaria transmission in Douala. High levels of An. gambiae were detected along with a high prevalence of insecticide resistance in this vector population. These findings highlight the need to promote use of insecticide-impregnated bed nets in Douala.
doi:10.1186/1471-2334-12-275
PMCID: PMC3532071  PMID: 23106909
Malaria; Transmission; Anopheles gambiae; Resistance; Douala; Cameroon
22.  Efficacy of a Vaccine Based on Protective Antigen and Killed Spores against Experimental Inhalational Anthrax▿ ‡  
Infection and Immunity  2008;77(3):1197-1207.
Protective antigen (PA)-based anthrax vaccines acting on toxins are less effective than live attenuated vaccines, suggesting that additional antigens may contribute to protective immunity. Several reports indicate that capsule or spore-associated antigens may enhance the protection afforded by PA. Addition of formaldehyde-inactivated spores (FIS) to PA (PA-FIS) elicits total protection against cutaneous anthrax. Nevertheless, vaccines that are effective against cutaneous anthrax may not be so against inhalational anthrax. The aim of this work was to optimize immunization with PA-FIS and to assess vaccine efficacy against inhalational anthrax. We assessed the immune response to recombinant anthrax PA from Bacillus anthracis (rPA)-FIS administered by various immunization protocols and the protection provided to mice and guinea pigs infected through the respiratory route with spores of a virulent strain of B. anthracis. Combined subcutaneous plus intranasal immunization of mice yielded a mucosal immunoglobulin G response to rPA that was more than 20 times higher than that in lung mucosal secretions after subcutaneous vaccination. The titers of toxin-neutralizing antibody and antispore antibody were also significantly higher: nine and eight times higher, respectively. The optimized immunization elicited total protection of mice intranasally infected with the virulent B. anthracis strain 17JB. Guinea pigs were fully protected, both against an intranasal challenge with 100 50% lethal doses (LD50) and against an aerosol with 75 LD50 of spores of the highly virulent strain 9602. Conversely, immunization with PA alone did not elicit protection. These results demonstrate that the association of PA and spores is very much more effective than PA alone against experimental inhalational anthrax.
doi:10.1128/IAI.01217-08
PMCID: PMC2643630  PMID: 19114543
23.  The dissemination of anthrax from imported wool: Kidderminster 1900–14 
Background: A century ago anthrax was a continuing health risk in the town of Kidderminster. The distribution of cases in people and in animals provides an indication of the routes by which spores were disseminated. The response to these cases provides an insight into attitudes to an occupational and environmental risk at the time and can be compared with responses in more recent times.
Aims: To assess the distribution of anthrax cases associated with the use of contaminated wool and to review the response to them.
Methods: The area studied was Kidderminster, Worcestershire, England, from 1900 to 1914. Data sources were national records of the Factory Inspectorate and local records from the infirmary, Medical Officer of Health and inquest reports, and county agricultural records, supplemented by contemporary and later review articles. Case reports and summary data were analysed, and discussions and actions taken to improve precautions reviewed.
Results: There were 36 cases of anthrax, with five deaths, one of which was the sole case of the internal form of the disease. Cases of cutaneous anthrax were most frequently found in those handling raw wool, but they also occurred in workers at later stages of the spinning process and in people with little or no recorded exposure to contaminated wool. Limited precautionary measures were in place at the start of the study period. Some improvements were made, especially in the treatment of infections, but wool with a high risk of anthrax contamination continued to be used and cases continued to arise. Major changes were made to the disposal of waste and to agricultural practice in contaminated areas to curtail outbreaks in farm animals.
Conclusions: The introduction of anthrax as a contaminant of imported wool led not only to cases in the highly exposed groups of workers but also to cases in other members of the population and in farm animals. The measures taken during the study period reduced fatalities from cutaneous anthrax but did not eliminate the disease. Public concern about the cases was muted.
doi:10.1136/oem.2002.001131
PMCID: PMC1740714  PMID: 14739375
24.  Change in composition of the Anopheles gambiae complex and its possible implications for the transmission of malaria and lymphatic filariasis in north-eastern Tanzania 
Malaria Journal  2012;11:188.
Background
A dramatic decline in the incidence of malaria due to Plasmodium falciparum infection in coastal East Africa has recently been reported to be paralleled (or even preceded) by an equally dramatic decline in malaria vector density, despite absence of organized vector control. As part of investigations into possible causes for the change in vector population density, the present study analysed the Anopheles gambiae s.l. sibling species composition in north-eastern Tanzania.
Methods
The study was in two parts. The first compared current species complex composition in freshly caught An. gambiae s.l. complex from three villages to the composition reported from previous studies carried out 2–4 decades ago in the same villages. The second took advantage of a sample of archived dried An. gambiae s.l. complex specimens collected regularly from a fourth study village since 2005. Both fresh and archived dried specimens were identified to sibling species of the An. gambiae s.l. complex by PCR. The same specimens were moreover examined for Plasmodium falciparum and Wuchereria bancrofti infection by PCR.
Results
As in earlier studies, An. gambiae s.s., Anopheles merus and Anopheles arabiensis were identified as sibling species found in the area. However, both study parts indicated a marked change in sibling species composition over time. From being by far the most abundant in the past An. gambiae s.s. was now the most rare, whereas An. arabiensis had changed from being the most rare to the most common. P. falciparum infection was rarely detected in the examined specimens (and only in An. arabiensis) whereas W. bancrofti infection was prevalent and detected in all three sibling species.
Conclusion
The study indicates that a major shift in An. gambiae s.l. sibling species composition has taken place in the study area in recent years. Combined with the earlier reported decline in overall malaria vector density, the study suggests that this decline has been most marked for An. gambiae s.s., and least for An. arabiensis, leading to current predominance of the latter. Due to differences in biology and vectorial capacity of the An. gambiae s.l. complex the change in sibling species composition will have important implications for the epidemiology and control of malaria and lymphatic filariasis in the study area.
doi:10.1186/1475-2875-11-188
PMCID: PMC3469399  PMID: 22681999
Anopheles gambiae s.s.; An. arabiensis; Longitudinal survey; Malaria; Lymphatic filariasis; Tanzania
25.  Efficacy and Safety of AVP-21D9, an Anthrax Monoclonal Antibody, in Animal Models and Humans 
Anthrax is an acute infectious disease caused by the spore-forming bacterium Bacillus anthracis. Timely administration of antibiotics approved for the treatment of anthrax disease may prevent associated morbidity and mortality. However, any delay in initiating antimicrobial therapy may result in increased mortality, as inhalational anthrax progresses rapidly to the toxemic phase of disease. An anthrax antitoxin, AVP-21D9, also known as Thravixa (fully human anthrax monoclonal antibody), is being developed as a therapeutic agent against anthrax toxemia. The efficacy of AVP-21D9 in B. anthracis-infected New Zealand White rabbits and in cynomolgus macaques was evaluated, and its safety and pharmacokinetics were assessed in healthy human volunteers. The estimated mean elimination half-life values of AVP-21D9 in surviving anthrax-challenged rabbits and nonhuman primates (NHPs) ranged from approximately 2 to 4 days and 6 to 11 days, respectively. In healthy humans, the mean elimination half-life was in the range of 20 to 27 days. Dose proportionality was observed for the maximum serum concentration (Cmax) of AVP-21D9 and the area under the concentration-time curve (AUC). In therapeutic efficacy animal models, treatment with AVP-21D9 resulted in survival of up to 92% of the rabbits and up to 67% of the macaques. Single infusions of AVP-21D9 were well tolerated in healthy adult volunteers across all doses evaluated, and no serious adverse events were reported. (This study has been registered at ClinicalTrials.gov under registration no. NCT01202695.)
doi:10.1128/AAC.02295-13
PMCID: PMC4068543  PMID: 24733473

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