Rickettsial infection of endothelial cells induces cellular damage leading to detachment. Those infected endothelial cells circulate in the blood 85 ,86 and are likely to be the source of new foci of infection once they lodge in distal capillaries. Several mechanisms are likely to contribute to the increased vascular permeability observed in clinical cases. They include production of vasoactive prostaglandins as a consequence of increased expression of COX-2, 87 endothelial production of nitric oxide, 88 effects of inflammatory cells and their mediators, 89 and endothelial detachment and denudation of vessels.
Such damage may be caused by phospholipase activity, 79 mechanical damage to the membrane caused by exiting rickettsiae under actin propulsion, 90 or lipid peroxidation of the cell membrane. However, it should be emphasized that reliance on serological methods for diagnostic confirmation may lead to underestimation the actual case-fatality rate.
This was well illustrated in a recent report of nine fatal cases with negative serological results that were confirmed by immunohistochemical demonstration of the antigen in tissues.
Although multiple coagulation abnormalities have been described during the course of clinical and experimental rickettsiosis , 99 disseminated intravascular coagulation occurs only rarely in lethal cases and is not a common feature of rickettsiosis. The cells that are infected immediately after inoculation have not been identified.
Many of the rickettsiae that result in less severe disease also produce an eschar area of necrosis with a rich inflammatory infiltrate and local rickettsial proliferation at the bite site.
Rocky Mountain spotted fever, the most severe of the spotted fever rickettsioses, does not manifest with an eschar or local lymphadenitis. This could be due to a more rapid hematogenous dissemination. The recommended antibiotic treatment for all rickettsioses is doxycycline. Rickettsiae are resistant to many antibiotics. Rickettsial virulence. Many rickettsial genes have been predicted to participate in virulence based on bioinformatics analyzes ; 72 several toxin-antitoxin systems are examples.
A large number of intracellular bacteria use type IV secretion systems to inject proteins into the host in order to produce a favorable niche. Interestingly, genomic analysis showed that multiple genes with the potential to encode a reduced type IV secretion system are conserved in Rickettsia. The phospholipase D encoded by the gene pld , a likely mediator of phagosomal escape, is a virulence factor as suggested by the milder disease produced in guinea pigs infected with R. Previous studies using the difficult techniques of genetic manipulation of Rickettsia , including transposon-mediated mutagenesis, indicated that mutation of the open reading frames ORFs , , and of R.
Also, R. Loss of regulation due to genome decay has also been proposed as a mechanism of increased virulence; however, this argument does not explain why R.
In the absence of genetic approaches that work well and consistently for Rickettsia , other methods have been introduced to identify virulence factors. One example is the comparison of the genomes of closely related Rickettsia with different pathogenicity. The Dermacentor andersoni endosymbiont R. Those genes include DsbA a catalyzer of disulfide bond formation , RickA , Sca0, Sca1 , a gene encoding Protease II, and a gene encoding a putative phosphoethanolamine transferase that could play a role in the formation of the prominent slime layer found in the pathogenic spotted fever-group rickettsiae.
This hypothetical protein has ankyrin repeats; similar proteins in other members of this order i. In addition, the genomic study that compared the pathogenic strains R and Sheila Smith with strain Iowa also found 23 deletions within predicted ORFs of R. Also, rompB has four single nucleotide polymorphisms SNPs that may explain the defective processing of this important membrane protein in strain Iowa.
Another system to study the physiology of Rickettsia in the absence of more efficient genetic systems is the use of E. For example, to identify proteins transported out of the rickettsial cytoplasm, bioinformatic tools were used to uncover predicted secreted proteins based on the presence of N-terminal signal peptides.
The signal peptides of those proteins from R. Those proteins include sca, sca5, Pld, and proteins that are believed to be part of a type IV secretion system. Immunity and vaccines. An often overlooked but critical factor in the pathogenesis of rickettsial diseases is the transmission by arthropod vectors because their saliva is not a passive vehicle for transmission.
Proteins in the tick saliva modulate host hemostasis, innate and adative immuntiy, complement activation, angiogenesis, and extracellular matrix regulation. Evidently, all of those factors could determine the final outcome of the infection. Furthermore, tick saliva can modulate the physiology of endothelial cells, the main target cells of Rickettsia. For example, salivary gland extracts from D.
Endothelial cells are not passive actors in the anti-rickettsial immune response. Despite the fact that rickettsiae are intracellular parasites and that cellular adaptive immunity is critical during a primary infection, there is clear evidence that the humoral immune response is very important in preventing the development of disease during secondary infections or after a lethal challenge following passive serum transfer.
In fact, it was Ricketts himself who demonstrated this fact. It is an immunodominant protein and antibodies against it are protective. Inactivated vaccines for R.
Later on, inactivated vaccines were produced from Rickettsia cultivated in eggs but antigenicity was variable and protection was poor. It was an attenuated strain denominated Madrid E; however, spontaneous reversion to a virulent phenotype precluded further development and testing. Deletion of the entire gene would permit the production of a safer vaccine.
Alternatively, strains with multiple genetic differences could prove to be safe vaccines. In this regard, it is interesting to note that the strain Iowa of R.
Other recent efforts have focused on the production of a subunit vaccine. Fragments of rickettsial proteins that may trigger protective immunity were tested. They included rOmpA , and rOmpB and results were encouraging; however, these approaches are limited and biased because of their focus on proteins that elicit a strong humoral response.
A major effort for identification of immunogenic antigens is clearly needed, and the antigen discovery effort will need new tools to identify relevant conserved antigens recognized by T cells.
It will be possible to produce vaccines that cover more than one species of Rickettsia given the evidence of cross-protective immunity within the typhus or spotted fever groups or even across groups. Firstly, some rickettsioses are highly lethal not only to humans but also to companion animals i. Secondly, clinical diagnosis of rickettsioses is very difficult due to the non-specific initial clinical presentation. Thirdly, there are no commercially available diagnostic tests that can be used during the acute stage when antibiotic intervention is helpful.
The contemporary development of a vaccine has two initial essential aspects, namely identification of the relevant antigens and definition of immunological correlates of protection to guide the selection of vehicles, vectors, schedules, and adjuvants. In the case of infections caused by Rickettsia , due to the availability of excellent murine models, relevant correlates of protective immunity can be derived from the characterization of experimental infections because animals as well as humans that survive the infection become solidly immune to reinfection.
In regard to immunological correlates of protection, the magnitude of a response assessed by a single parameter e. Now we know that there is functional heterogeneity of the T cell effector responses including cytokine secretion, cytolytic activity, and development of various memory phenotypes and that there are particular subsets of T cells, which express unique combinations of effector functions, that are more protective. For infections in which cellular immunity plays a predominant role, there is evidence from experimental models that multifunctional T cells are the best correlate of protection described thus far.
More importantly, this has been demonstrated in humans as well. The technologies for understanding the integrated functioning of the immune system are now available and accessible. That is certainly the case for infections caused by Rickettsia because it is unlikely that we will be able to collect sufficient human samples from clinical cases with diverse outcomes in order to define broad signatures of protective immunity. A promising solution to this problem is to use our current understanding of well-known effective immune responses as guiding principles.
The study of the response to two of the most successful human vaccines in history, the yellow fever vaccine , and the smallpox vaccine, is likely to yield relevant paradigms that we could use as guiding posts in rickettsiology. From the perspective of antigen identification for vaccine development, until recently it was almost exclusively biased towards the humoral immune response.
This bias was partly due to the effectiveness of antibodies in protection against almost all of the currently approved vaccines for human use, the relative technical simplicity of working with serum and antibodies, and the methodical challenges of working with T-cells.
Presently, the barriers to identify potent vaccine antigens recognized by T-cells need to be addressed because most of the vaccines that remain to be produced require a strong T-cell component to afford significant protection.
In particular, there is an urgent need to develop appropriate techniques to identify antigens recognized by T-lymphocytes because antigen discovery is the most important aspect of any vaccine development project; without appropriate antigens, a vaccine is unlikely to succeed.
Several approaches to more directly identify antigens recognized by T-cells have been used; many of them rely on Reverse Vaccinology, a branch of Systems Biology that analyses entire microbial genomes to predict immunogenic proteins based on predefined rules derived from the analysis of large empirical datasets.
Moreover, at least for bacterial proteins, known protective antigens actually have less predicted epitopes than randomly selected bacterial protein sets used as a control.
Empirical methods for identification of antigens recognized by T-lymphocytes rely on T-cells from animals or individuals that are immune to the pathogen.
Those memory T-cells had been selected during the physiological immune response to persist and recognize a limited number of antigens i.
Thus, methods that use memory T-cells for antigen identification are more likely to miss potentially protective subdominant antigens. One strategy for T-cell antigen identification that is not biased towards immunodominant antigens is genomic immunization or Expression Library Immunization ELI.
The animals are then challenged with lethal doses of the microbial pathogen. The gene pools that trigger protection are subsequently deconvoluted by testing each component of the pool one at a time. Although ELI has been successfully used , it has its own problems as it relies on a DNA immunization strategy; thus, antigen expression is not guaranteed in all cases. Accordingly, it is not possible to know which pathogen genes were not screened validly; a negative response can be due to lack of an immunological response or to failed expression of the microbial gene.
As an alternative, we produced a new in vivo screening platform; the idea is to easily produce antigen presenting cells APCs expressing individual open reading frames ORFs from any sequenced Rickettsia and use them for immunization of naive mice. Immunization with pooled APCs containing 4 to 5 rickettsial ORFs is followed by challenge with live virulent pathogen and measurement of an indicator of protection such as decreased bacterial load.
Once protective pools are identified, each member of the pool is tested individually to identify ORF s responsible for a protective immune response. With this platform, one can easily test for cross-protective responses by immunizing with the ORFs of one species of Rickettsia and challenging with another.
Importantly, the proposed methodology is not biased by immunodominance because T cells from immune animals are not used to select antigens. This aspect is potentially important for vaccine development because subdominant or cryptic antigens have been shown to elicit protective immune responses in other systems.
The history of epidemic typhus. Infect Dis Clin North Am ; Azad AF. Pathogenic rickettsiae as bioterrorism agents. Clin Infect Dis ; 45 Suppl 1:S Tick-borne rickettsioses around the world: emerging diseases challenging old concepts. Clin Microbiol Rev ; The genomic and metabolic diversity of Rickettsia. Res Microbiol ; Intracellular pathogens go extreme: genome evolution in the Rickettsiales.
Trends Genet ; Reductive genome evolution from the mother of Rickettsia. PLoS Genet ; 3:e Valbuena G, Walker DH. Infection of the endothelium by members of the order Rickettsiales. Thromb Haemost ; King WW. Experimental transmission of Rocky Mountain spotted fever by means of the tick. Public Health Rep ; Ricketts HT. The transmission of Rocky Mountain spotted fever by the bite of the wood-tick Dermacentor occidentalis.
JAMA ; Gross L. How Charles Nicolle of the Pasteur Institute discovered that epidemic typhus is transmitted by lice: reminiscences from my years at the Pasteur Institute in Paris. Plotz H. Preliminary communication. On the etiology of typhus fever. En: Hahon N, ed. Selected papers on the pathogenic rickettsiae.
Boston : Harvard University Press, Wolbach SB. The etiology of Rocky Mountain spotted fever. Occurrence of the parasite in the tick. J Med Res ; A preliminary report.
The etiology and pathology of Rocky Mountain spotted fever. Third preliminary report. Philip CB. Nomenclature of the pathogenic rickettsiae. Am J Hygiene ; Ormsbee RA. Rickettsiae as organisms. Annu Rev Microbiol ; Weiss E. Growth and physiology of rickettsiae. Microbiol Mol Biol Rev ; The genome sequence of Rickettsia prowazekii and the origin of mitochondria. Nature ; Mechanisms of evolution in Rickettsia conorii and R.
Science ; Plasmids and rickettsial evolution: insight from Rickettsia felis. PLoS One ; 2:e Rickettsia phylogenomics: unwinding the intricacies of obligate intracellular life. PLoS One ; 3:e Merhej V, Raoult D. Rickettsial evolution in the light of comparative genomics. Biol Rev Camb Philos Soc ; Lateral gene transfer between obligate intracellular bacteria: evidence from the Rickettsia massiliae genome.
Genome Res ; Serologic typing of rickettsiae of the spotted fever group by microimmunofluorescence. J Immunol ; Antigenic relationships between the typhus and spotted fever groups of rickettsiae. Am J Epidemiol ; Classification of Rickettsia tsutsugamushi in a new genus, Orientia gen. Int J Syst Bacteriol ; Warmer weather linked to tick attack and emergence of severe rickettsioses.
Rocky mountain spotted fever in the United States, interpreting contemporary increases in incidence. Am J Trop Med Hyg ; Rickettsioses of Central America. Evidence of rickettsial spotted fever and ehrlichial infections in a subtropical territory of Jujuy, Argentina. Evidence of rickettsial and leptospira infections in Andean northern Peru.
Prevalence of antibodies against spotted fever group rickettsiae in a rural area of Colombia. Rocky Mountain spotted fever in Argentina. An increase in human cases of spotted fever rickettsiosis in Yucatan , Mexico , involving children.
Rickettsia felis in Ctenocephalides felis from Guatemala and Costa Rica. Vector Borne Zoonotic Dis ; Rickettsia parkeri : a newly recognized cause of spotted fever rickettsiosis in the United States. Clin Infect Dis ; Paddock CD. Rickettsia parkeri as a paradigm for multiple causes of tick-borne spotted fever in the western hemisphere.
Ann N Y Acad Sci ; Rickettsia parkeri infection after tick bite, Virginia. Emerg Infect Dis ; Rickettsia parkeri rickettsiosis and its clinical distinction from Rocky Mountain spotted fever. Rickettsia D: a newly recognized cause of eschar-associated illness in California. Rickettsia massiliae human isolation. A patient from Argentina infected with Rickettsia massiliae. Assessing the magnitude of fatal Rocky Mountain spotted fever in the United States : comparison of two national data sources.
Unrecognized spotted fever group rickettsiosis masquerading as dengue fever in Mexico. Fatal cases of Rocky Mountain spotted fever in family clusters--three states, Hidden mortality attributable to Rocky Mountain spotted fever: immunohistochemical detection of fatal, serologically unconfirmed disease.
J Infect Dis ; Risk factors associated with life-threatening rickettsial infections. Risk factors leading to fatal outcome in scrub typhus patients. Penetration of cultured mouse fibroblasts L cells by Rickettsia prowazeki.
Infect Immun ; Li H, Walker DH. Microb Pathog ; The Rickettsia conorii autotransporter protein Sca1 promotes adherence to nonphagocytic mammalian cells. Ku70, a component of DNA-dependent protein kinase, is a mammalian receptor for Rickettsia conorii. Cell ; The Sca2 autotransporter protein from Rickettsia conorii is sufficient to mediate adherence to and invasion of cultured mammalian cells.
Martinez JJ, Cossart P. Early signaling events involved in the entry of Rickettsia conorii into mammalian cells. J Cell Sci ; Rickettsial outer-membrane protein B rOmpB mediates bacterial invasion through Ku70 in an actin, c-Cbl, clathrin and caveolin 2-dependent manner. Cell Microbiol ; Effect of antibody on the rickettsia-host cell interaction. Identification and characterization of a phospholipase D-superfamily gene in rickettsiae.
Identification and molecular analysis of the gene encoding Rickettsia typhi hemolysin. Expression of the Rickettsia prowazekii pld or tlyC gene in Salmonella enterica serovar Typhimurium mediates phagosomal escape. J Bacteriol ; Functional characterization of a phospholipase A 2 homolog from Rickettsia typhi.
The phenomenon of in vitro hemolysis produced by the rickettsiae of typhus fever, with a note on the mechanism of rickettsial toxicity in mice. J Exp Med ; Rickettsial hemolysis: adsorption of rickettsiae to erythrocytes. Progress in rickettsial genome analysis from pioneering of Rickettsia prowazekii to the recent Rickettsia typhi. Winkler HH. Rickettsial permeability. J Biol Chem ; Complete genome sequence of Rickettsia typhi and comparison with sequences of other rickettsiae. Transmembrane electrical potential in Rickettsia prowazekii and its relationship to lysine transport.
In vitro studies on Rickettsia -host cell interactions: lag phase in intracellular growth cycle as a function of stage of growth of infecting Rickettsia prowazeki , with preliminary observations on inhibition of rickettsial uptake by host cell fragments. Infection cycle of Rickettsia rickettsii in chicken embryo and L cells in culture. The organism replicates in both the nucleus and cytoplasm of infected cells and exhibits early cell-to-cell spread without detectable host-cell injury.
Most users should sign in with their email address. If you originally registered with a username please use that to sign in. To purchase short term access, please sign in to your Oxford Academic account above. Don't already have an Oxford Academic account? Oxford University Press is a department of the University of Oxford. It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide. Sign In or Create an Account.
Sign In. Advanced Search. Search Menu. Article Navigation. Close mobile search navigation Article Navigation. Volume Silverman , David J. Oxford Academic. Google Scholar. Sheila B. Revision received:. Cite Cite David J. Select Format Select format. Permissions Icon Permissions. Abstract Rocky Mountain spotted fever is caused by Rickettsia rickettsii an obligate intracellular bacterial parasite. Issue Section:.
You do not currently have access to this article. Download all slides. Sign in Don't already have an Oxford Academic account?
0コメント