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Frontiers in Cellular and Infection... 2017, the causative agent of tularemia, is a Gram-negative bacterium that infects a variety of cell types including macrophages, and propagates with great efficiency in the... (Review)
Review
, the causative agent of tularemia, is a Gram-negative bacterium that infects a variety of cell types including macrophages, and propagates with great efficiency in the cytoplasm. Iron, essential for key enzymatic and redox reactions, is among the nutrients required to support this pathogenic lifestyle and the bacterium relies on specialized mechanisms to acquire iron within the host environment. Two distinct pathways for iron acquisition are encoded by the genome- a siderophore-dependent ferric iron uptake system and a ferrous iron transport system. Genes of the Fur-regulated operon direct the production and transport of the siderophore rhizoferrin. Siderophore biosynthesis involves enzymes FslA and FslC, while export across the inner membrane is mediated by FslB. Uptake of the rhizoferrin- ferric iron complex is effected by the siderophore receptor FslE in the outer membrane in a TonB-independent process, and FslD is responsible for uptake across the inner membrane. Ferrous iron uptake relies largely on high affinity transport by FupA in the outer membrane, while the Fur-regulated FeoB protein mediates transport across the inner membrane. FslE and FupA are paralogous proteins, sharing sequence similarity and possibly sharing structural features as well. This review summarizes current knowledge of iron acquisition in this organism and the critical role of these uptake systems in bacterial pathogenicity.
Topics: Animals; Biological Transport; Disease Models, Animal; Ferric Compounds; Ferrous Compounds; Francisella tularensis; Humans; Iron; Metabolic Networks and Pathways; Virulence
PubMed: 28421167
DOI: 10.3389/fcimb.2017.00107 -
Journal of Clinical Microbiology Mar 2020The highly infectious and zoonotic pathogen is the etiologic agent of tularemia, a potentially fatal disease if untreated. Despite the high average nucleotide identity,...
The highly infectious and zoonotic pathogen is the etiologic agent of tularemia, a potentially fatal disease if untreated. Despite the high average nucleotide identity, which is >99.2% for the virulent subspecies and >98% for all four subspecies, including the opportunistic microbe subsp. , there are considerable differences in genetic organization. These chromosomal disparities contribute to the substantial differences in virulence observed between the various subspecies and subtypes. The methods currently available to genotype cannot conclusively identify the associated subpopulation without using time-consuming testing or complex scoring matrices. To address this need, we developed both single and multiplex quantitative real-time PCR (qPCR) assays that can accurately detect and identify the hypervirulent subsp. subtype A.I, the virulent subsp. subtype A.II, subsp. (also referred to as type B), and subsp. , as well as opportunistic subsp. from each other and near neighbors, such as , , and -like endosymbionts found in ticks. These fluorescence-based singleplex and non-matrix scoring multiplex qPCR assays utilize a hydrolysis probe, providing sensitive and specific subspecies and subtype identification in a rapid manner. Furthermore, sequencing of the amplified targets provides clade confirmation and informative strain-specific details. Application of these qPCR- and sequencing-based detection assays will provide an improved capability for molecular typing and clinical diagnostics, as well as facilitate the accurate identification and differentiation of subpopulations during epidemiological investigations of tularemia source outbreaks.
Topics: Francisella; Francisella tularensis; Humans; Tularemia
PubMed: 31941692
DOI: 10.1128/JCM.01495-19 -
Frontiers in Cellular and Infection... 2014Francisella tularensis is the causative agent of the acute disease tularemia. Due to its extreme infectivity and ability to cause disease upon inhalation, F. tularensis... (Comparative Study)
Comparative Study Review
Francisella tularensis is the causative agent of the acute disease tularemia. Due to its extreme infectivity and ability to cause disease upon inhalation, F. tularensis has been classified as a biothreat agent. Two subspecies of F. tularensis, tularensis and holarctica, are responsible for tularemia in humans. In comparison, the closely related species F. novicida very rarely causes human illness and cases that do occur are associated with patients who are immune compromised or have other underlying health problems. Virulence between F. tularensis and F. novicida also differs in laboratory animals. Despite this varying capacity to cause disease, the two species share ~97% nucleotide identity, with F. novicida commonly used as a laboratory surrogate for F. tularensis. As the F. novicida U112 strain is exempt from U.S. select agent regulations, research studies can be carried out in non-registered laboratories lacking specialized containment facilities required for work with virulent F. tularensis strains. This review is designed to highlight phenotypic (clinical, ecological, virulence, and pathogenic) and genomic differences between F. tularensis and F. novicida that warrant maintaining F. novicida and F. tularensis as separate species. Standardized nomenclature for F. novicida is critical for accurate interpretation of experimental results, limiting clinical confusion between F. novicida and F. tularensis and ensuring treatment efficacy studies utilize virulent F. tularensis strains.
Topics: Animals; Disease Models, Animal; Francisella tularensis; Humans; Sequence Homology, Nucleic Acid; Tularemia; Virulence
PubMed: 24660164
DOI: 10.3389/fcimb.2014.00035 -
Frontiers in Cellular and Infection... 2019Bacteria alter gene expression in response to changes in their environment through various mechanisms that include signal transduction systems. These signal transduction... (Review)
Review
Bacteria alter gene expression in response to changes in their environment through various mechanisms that include signal transduction systems. These signal transduction systems use membrane histidine kinase with sensing domains to mediate phosphotransfer to DNA-binding proteins that alter the level of gene expression. Such regulators are called two-component systems (TCSs). TCSs integrate external signals and information from stress pathways, central metabolism and other global regulators, thus playing an important role as part of the overall regulatory network. This review will focus on the knowledge of TCSs in the Gram-negative bacterium, , a biothreat agent with a wide range of potential hosts and a significant ability to cause disease. While TCSs have been well-studied in several bacterial pathogens, they have not been well-studied in non-model organisms, such as and its subspecies, whose canonical TCS content surprisingly ranges from few to none. Additionally, of those TCS genes present, many are orphan components, including KdpDE, QseC, QseB/PmrA, and an unnamed two-component system (FTN_1452/FTN_1453). We discuss recent advances in this field related to the role of TCSs in physiology and pathogenesis and compare the TCS genes present in human virulent versus. environmental species and subspecies of .
Topics: Animals; Bacterial Proteins; DNA-Binding Proteins; Francisella tularensis; Gene Expression Regulation, Bacterial; Histidine Kinase; Humans; Protein Domains; Signal Transduction; Tularemia; Virulence
PubMed: 31263682
DOI: 10.3389/fcimb.2019.00198 -
Comparative Immunology, Microbiology... Mar 2014In recent years, several emerging zoonotic vector-borne infections with potential impact on human health have been identified in Europe, including tularaemia, caused by... (Review)
Review
In recent years, several emerging zoonotic vector-borne infections with potential impact on human health have been identified in Europe, including tularaemia, caused by Francisella tularensis. This remarkable pathogen, one of the most virulent microorganisms currently known, has been detected in increasingly new settings and in a wide range of wild species, including lagomorphs, rodents, carnivores, fish and invertebrate arthropods. Also, a renewed concern has arisen with regard to F. tularensis: its potential use by bioterrorists. Based on the information published concerning the latest outbreaks, the aim of this paper is to review the main features of the agent, its biology, immunology and epidemiology. Moreover, special focus will be given to zoonotic aspects of the disease, as tularaemia outbreaks in human populations have been frequently associated with disease in animals.
Topics: Animals; Biological Warfare Agents; Bioterrorism; Disease Outbreaks; Disease Reservoirs; Europe; Francisella tularensis; Humans; Immune System; Phylogeography; Tularemia; Zoonoses
PubMed: 24480622
DOI: 10.1016/j.cimid.2014.01.002 -
Frontiers in Cellular and Infection... 2015Francisella tularensis is a highly-infectious bacterium that causes the rapid, and often lethal disease, tularemia. Many studies have been performed to identify and... (Review)
Review
Francisella tularensis is a highly-infectious bacterium that causes the rapid, and often lethal disease, tularemia. Many studies have been performed to identify and characterize the virulence factors that F. tularensis uses to infect a wide variety of hosts and host cell types, evade immune defenses, and induce severe disease and death. This review focuses on the virulence factors that are present in the F. tularensis envelope, including capsule, LPS, outer membrane, periplasm, inner membrane, secretion systems, and various molecules in each of aforementioned sub-compartments. Whereas, no single bacterial molecule or molecular complex single-handedly controls F. tularensis virulence, we review here how diverse bacterial systems work in conjunction to subvert the immune system, attach to and invade host cells, alter phagosome/lysosome maturation pathways, replicate in host cells without being detected, inhibit apoptosis, and induce host cell death for bacterial release and infection of adjacent cells. Given that the F. tularensis envelope is the outermost layer of the bacterium, we highlight herein how many of these molecules directly interact with the host to promote infection and disease. These and future envelope studies are important to advance our collective understanding of F. tularensis virulence mechanisms and offer targets for future vaccine development efforts.
Topics: Francisella tularensis; Host-Pathogen Interactions; Immune Evasion; Immunity, Innate; Virulence; Virulence Factors
PubMed: 26779445
DOI: 10.3389/fcimb.2015.00094 -
Frontiers in Cellular and Infection... 2018Tularemia is a zoonotic disease caused by the facultative intracellular bacterium . This microorganism can infect a plethora of animal species and its ecology is... (Review)
Review
Tularemia is a zoonotic disease caused by the facultative intracellular bacterium . This microorganism can infect a plethora of animal species and its ecology is particularly complex. Much research was performed to understand its biology but many questions are still open, especially concerning the life cycle of this bacterium in the environment related to physical and biological parameters. Numerous animals are major hosts of but precise reservoir species are not yet well defined. Moreover, the exact range of species susceptible to tularemia is not clear and is complicated by the differences in virulence and ecology observed among the subspecies of . Indeed, different life cycles in nature, including the animal species concerned, were previously described for subsp. and subsp. . Recently, molecular techniques showing adequate discrimination between strains were developed, leading to the possibility to investigate links between phylogenetic lineages and infection in animals. New perspectives in research are now possible thanks to the information available and the simplicity of the molecular procedures. Current studies are unfolding the evolution of and these developments will lead to the elucidation of geographical and ecological differences observed by veterinarians, microbiologists and conservation biologists. However, systematic, coordinated collection of data and extensive sampling are important to efficiently assemble the findings of future research.
Topics: Animals; Francisella tularensis; Phylogeny; Tularemia
PubMed: 30109216
DOI: 10.3389/fcimb.2018.00258 -
Microbiology and Molecular Biology... May 2020is a tier 1 select agent responsible for tularemia in humans and a wide variety of animal species. Extensive research into understanding the virulence factors of the... (Review)
Review
is a tier 1 select agent responsible for tularemia in humans and a wide variety of animal species. Extensive research into understanding the virulence factors of the bacterium has been ongoing to develop an efficacious vaccine. At least two such virulence factors are described as capsules of : the O-antigen capsule and the capsule-like complex (CLC). These two separate entities aid in avoiding host immune defenses but have not been clearly differentiated. These components are distinct and differ in composition and genetic basis. The O-antigen capsule consists of a polysaccharide nearly identical to the lipopolysaccharide (LPS) O antigen, whereas the CLC is a heterogeneous complex of glycoproteins, proteins, and possibly outer membrane vesicles and tubes (OMV/Ts). In this review, the current understanding of these two capsules is summarized, and the historical references to "capsules" of are clarified. A significant amount of research has been invested into the composition of each capsule and the genes involved in synthesis of the polysaccharide portion of each capsule. Areas of future research include further exploration into the molecular regulation and pathways responsible for expression of each capsule and further elucidating the role that each capsule plays in virulence.
Topics: Animals; Bacterial Capsules; Francisella tularensis; Humans; Polysaccharides, Bacterial; Tularemia; Virulence; Virulence Factors
PubMed: 32051235
DOI: 10.1128/MMBR.00065-19 -
Frontiers in Cellular and Infection... 2018subsp. is an intracellular bacterial pathogen and the causative agent of the life-threatening zoonotic disease tularemia. The Pathogenicity Island encodes a large... (Review)
Review
subsp. is an intracellular bacterial pathogen and the causative agent of the life-threatening zoonotic disease tularemia. The Pathogenicity Island encodes a large secretion apparatus, known as a Type VI Secretion System (T6SS), which is essential for to escape from its phagosome and multiply within host macrophages and to cause disease in animals. The T6SS, found in one-quarter of Gram-negative bacteria including many highly pathogenic ones, is a recently discovered secretion system that is not yet fully understood. Nevertheless, there have been remarkable advances in our understanding of the structure, composition, and function of T6SSs of several bacteria in the past few years. The system operates like an inside-out headless contractile phage that is anchored to the bacterial membrane via a baseplate and membrane complex. The system injects effector molecules across the inner and outer bacterial membrane and into host prokaryotic or eukaryotic targets to kill, intoxicate, or in the case of , hijack the target cell. Recent advances include an atomic model of the contractile sheath, insights into the mechanics of sheath contraction, the composition of the baseplate and membrane complex, the process of assembly of the apparatus, and identification of numerous effector molecules and activities. While T6SS appears to be an outlier among T6SSs, with limited or no sequence homology with other systems, its structure and organization are strikingly similar to other systems. Nevertheless, we have only scratched the surface in uncovering the mysteries of the T6SS, and there are numerous questions that remain to be answered.
Topics: Animals; Francisella tularensis; Genomic Islands; Humans; Macrophages; Signal Transduction; Tularemia; Type VI Secretion Systems
PubMed: 29740542
DOI: 10.3389/fcimb.2018.00121 -
Emerging Microbes & Infections 2019is a Gram-negative, intracellular bacterium causing the zoonosis tularemia. This highly infectious microorganism is considered a potential biological threat agent.... (Review)
Review
is a Gram-negative, intracellular bacterium causing the zoonosis tularemia. This highly infectious microorganism is considered a potential biological threat agent. Humans are usually infected through direct contact with the animal reservoir and tick bites. However, tularemia cases also occur after contact with a contaminated hydro-telluric environment. Water-borne tularemia outbreaks and sporadic cases have occurred worldwide in the last decades, with specific clinical and epidemiological traits. These infections represent a major public health and military challenge. Human contaminations have occurred through consumption or use of -contaminated water, and various aquatic activities such as swimming, canyoning and fishing. In addition, in Sweden and Finland, mosquitoes are primary vectors of tularemia due to infection of mosquito larvae in contaminated aquatic environments. The mechanisms of survival in water may include the formation of biofilms, interactions with free-living amoebae, and the transition to a 'viable but nonculturable' state, but the relative contribution of these possible mechanisms remains unknown. Many new aquatic species of have been characterized in recent years. likely shares with these species an ability of long-term survival in the aquatic environment, which has to be considered in terms of tularemia surveillance and control.
Topics: Animals; Culicidae; Francisella tularensis; Humans; Tularemia; Waterborne Diseases; Zoonoses
PubMed: 31287787
DOI: 10.1080/22221751.2019.1638734