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Antigenic variation in Lyme disease borreliae by promiscuous recombination of VMP-like sequence cassettes.
We have identified and characterized an elaborate genetic system in the Lyme disease spirochete Borrelia burgdorferi that promotes extensive antigenic variation of a surface-exposed lipoprotein, VlsE. A 28 kb linear plasmid of B. burgdorferi B31 (lp28-1) was found to contain a vmp-like sequence (vls) locus that closely resembles the variable major protein (vmp) system for antigenic variation of relapsing fever organisms. Portions of several of the 15 nonexpressed (silent) vls cassette sequences located upstream of vlsE recombined into the central vlsE cassette region during infection of C3H/HeN mice, resulting in antigenic variation of the expressed lipoprotein. This combinatorial variation could potentially produce millions of antigenic variants in the mammalian host.
Endogenous opioid withdrawal in the Jarisch-Herxheimer reaction.
Meptazinol, a partial opioid agonist, diminishes the Jarisch-Herxheimer reaction in relapsing fever whereas naloxone, a pure opioid antagonist, is virtually inert. Because endogenous opioid activity is probably increased in the acute phase, the efficacy of meptazinol is unlikely to be due to agonist activity. However, it is possible that in such a severe reaction there may be an exhaustion of endogenous opioids, giving rise to a naturally occurring quasi-morphine-withdrawal syndrome which responds to meptazinol.
Susceptibility of the black-legged tick, Ixodes scapularis, to the Lyme disease spirochete, Borrelia burgdorferi.
Experiments to determine whether Ixodes scapularis can be infected with the Lyme disease agent, Borrelia burgdorferi, demonstrated that infection and transstadial transmission occurs in up to 73% of larval ticks that had fed on spirochetemic rabbits. In a limited number of nymphal ticks examined, the spirochetes were found only in the midgut. Feeding nymphal I. scapularis on a normal rabbit resulted in blood infection characterized by two distinct periods of spirochetemia, suggesting the occurrence of a relapse phenomenon similar to that in tick-borne relapsing fevers. This was also indicated by the percentage of infected ticks recovered daily during the experiment. Accordingly, ticks fed during low spirochetemias or negative blood phase, showed low infection rates or were not infected whereas those fed during peak spirochetemias had high infection rates. Of 11 adult I. scapularis examined to date, 6 were infected but the spirochetes were restricted to the midgut. These preliminary findings establish the susceptibility of I. scapularis to B. burgdorferi and the potential role of this tick as an efficient vector of the Lyme disease spirochete.
Epidemics and public health in early colonial Somaliland.
The early colonial period in the Somaliland Protectorate was marked by the intrusion of new 'colonial' epidemics and diseases, such as smallpox, cholera, influenza, venereal diseases, tuberculosis, relapsing fever and the decline of the population. The aetiology of the diseases was social. They were introduced into the country through the movement of imperial armies and displaced people, the improvement in transportation and the integration of the country into the British Empire. The protectorate administration attempted to control the epidemics. However, since the medical staff and medical facilities were thin on the ground, the effect of the medical campaigns were limited. Not all the medical campaigns were a 'mirage', however. Medical campaigns played an important role in the control of venereal diseases, particularly syphilis. Overall, the incidence of epidemics declined from 1937 onwards. The cause was again social and had very little to do with medical campaigns. The ending of the campaigns of conquest, the massive movement of armies and people and the development of relative stability in the country played a key and decisive role in the decline in the incidence of diseases. The aetiology of colonial epidemics and their decline had both socio-political origins and explanations. The article deals with that neglected aspect of the history of Somaliland.
Spirochetal infection of the nervous system.
Neurologic infection is a characteristic feature of spirochetes. The neurologic manifestations of spirochetal infection are a source of continuing public concern: Lyme neuroborreliosis in endemic areas, neurosyphilis in HIV infected patients, and neuroborreliosis during outbreaks of relapsing fever. These are reviewed in this article. The techniques for diagnosis and recommendations in the management of these infections are also discussed.
Antigenic variation of Borrelia turicatae Vsp surface lipoproteins occurs in vitro and generates novel serotypes.
As a means of avoiding the host immune response, the tick-borne relapsing fever spirochete Borrelia turicatae undergoes antigenic variation in its abundant surface lipoproteins. In this study, B. turicatae strain Oz1, serotype B, was subcultured in vitro and cloned by limited dilutions after 50 passages. Four different serotypes (serotypes A, B, E, and F) differing by their expressed Vsp lipoproteins were isolated. Using pulsed-field gel electrophoresis, we showed that the variability in surface-exposed proteins is correlated with rearrangement between different linear plasmids, defining serotype-specific plasmid profiles. Moreover, we determined the nucleotide sequence of genes encoding the VspE and VspF lipoproteins, corresponding to the two novel serotypes E and F, respectively. Our results showed that antigenic variation in B. turicatae occurs spontaneously in vitro, in the absence of immune selection.
Glycoprotein patterns in Borrelia spp.
The presence of glycoproteins in several Borrelia species was investigated by the digoxigenin labelling technique. The outer surface proteins A and B of seven isolates of the Lyme disease spirochete B. burgdorferi showed to be major glycosylated proteins. Few minor polypeptides with variable molecular masses were also present, at variance, in B. burgdorferi strains. Minor glycosylated proteins with varying molecular masses have been detected in the relapsing fever borreliae B. hermsii, B. turicatae and B. parkeri. B. turicatae showed also a major glycosylated protein with a molecular mass of approximately 40 kDa. Animal pathogenic borreliae B. anserina and B. coriaceae presented only minor glycosylated proteins with variable molecular masses.
ResT, a telomere resolvase encoded by the Lyme disease spirochete.
The genus Borrelia includes the causative agents of Lyme disease and relapsing fever. An unusual feature of these bacteria is a segmented genome consisting mostly of a number of linear DNA molecules with covalently closed hairpin ends or telomeres. In this study we show that the BBB03 locus encodes the B. burgdorferi telomere resolvase, ResT. The purified protein catalyzes telomere resolution in vitro through a unique reaction: breakage of two phosphodiester bonds in a single DNA duplex (one on each strand) and joining of each end with the opposite DNA strand to form covalently closed hairpin telomeres. Telomere resolution by ResT occurs through a two-step transesterification reaction involving the formation of a covalent protein-DNA intermediate at a position three nucleotides from the axis of symmetry in each strand of the substrate.
Borrelia pathogenesis research in the post-genomic and post-vaccine era.
In the two years after publication of the genome sequence of Borrelia burgdorferi and reports on human field trials of a vaccine against Lyme borreliosis, there has been further progress in understanding of host-parasite interactions during Lyme borreliosis and relapsing fever. Some mechanisms that Borrelia spirochetes use to avoid elimination and to persist in the host are novel. In addition, the recent discovery of antigenic variation in the Lyme disease agent B. burgdorferi adds to the complexity of the possible virulence properties of this human pathogen.
Drug-induced lupus as a cause of relapsing inflammatory disease after renal transplantation.
We discuss the case of an 18-year-old-boy presenting with relapsing fever, arthralgia, myalgia and renal failure, 7 yr after renal transplantation. A thorough diagnostic work-up for infectious and inflammatory diseases revealed a mastoiditis and atypical mycobacteria, but symptoms persisted after treatment. Persistent antinuclear antibodies in combination with cardiolipin and myeloperoxidase antibodies, despite negative dsDNA antibodies, suggested a drug induced lupus-like syndrome. Six months after withdrawal of dihydralazine, all symptoms had disappeared. Drug-induced lupus should be considered as an important differential diagnosis in transplanted patients with recurrent inflammatory disease in conjunction with lupus-like symptoms and negative dsDNA antibodies. It may prevent a potentially hazardous reduction of immunosuppression in persistent inflammation.
Transposition of structural genes to an expression sequence on a linear plasmid causes antigenic variation in the bacterium Borrelia hermsii.
In Borrelia hermsii, a spirochaete that causes relapsing fever, the switch between expression of two frequent variable major protein (VMP) types (7 and 21) is associated with a DNA rearrangement. Both cell types 7 and 21 contain untranscribed 7 and 21 VMP genes on linear plasmids. The serotype 7 cells contain an additional copy of the 7 VMP gene fused to an expression sequence on another linear plasmid. Switching to the 21 serotype involves removal of the transcribed 7 VMP gene and fusion of a copy of the 21 VMP gene to this same expression sequence. Thus recombination between linear plasmids can activate different VMP genes.
Sequence-specific recognition but position-dependent cleavage of two distinct telomeres by the Borrelia burgdorferi telomere resolvase, ResT.
An unusual feature of bacteria in the genus Borrelia (causative agents of Lyme disease and relapsing fever) is a segmented genome consisting of multiple linear DNA molecules with covalently closed hairpin ends, known as telomeres. The hairpin telomeres are generated by a DNA breakage and reunion process (telomere resolution) promoted by ResT, an enzyme using an active site related to that of tyrosine recombinases and type IB topoisomerases. In this study, we define the minimal sequence requirements for a functional telomere and identify specific basepairs that appear to be important for telomere resolution. In addition, we show that the two naturally occurring and distinct telomere spacings found in B. burgdorferi can both be efficiently processed by ResT. This flexibility for substrate utilization by ResT supports the argument for a single telomere resolvase in Borrelia. Furthermore, although telomere recognition requires sequence specificity in part of the substrate, DNA cleavage is instead position dependent and occurs at a fixed distance from the axis of symmetry and the conserved sequence of box 3 in the different replicated telomere substrates. This positional dependence for DNA cleavage has not been observed previously for a tyrosine recombinase.
Case report. Successful therapy of disseminated histoplasmosis in AIDS with liposomal amphotericin B.
A 36-year-old HIV-infected male patient presented with relapsing fever episodes to 39 degrees C, night sweats and weight loss. Computerized tomography of the abdomen showed enlarged multiple lymph nodes. After surgical resection of multiple lymph nodes, disseminated infection with Histoplasma capsulatum was diagnosed. Amphotericin B desoxycholate was initiated for 24 days. Fourteen days after therapy was discontinued, the patient suffered similar symptoms again. Subsequent treatment with liposomal amphotericin B led to rapid improvement within 3 days. Upon discharge, maintenance therapy with 600-mg itraconazole capsules was initiated and decreased to 400-mg 14-days later. Itraconazole therapy was continued until the patient died more than 2 years later because of complications of the underlying disease. At autopsy there were no signs of histoplasmosis.
Pathogen escape from host immunity by a genome program for antigenic variation.
The vector-borne bacterium Borrelia hermsii, a relapsing fever agent, switches gene expression of a surface protein between different antigenic variants, thereby causing sequential waves of immune escape within hosts and increasing the likelihood of transmission. Analogous programmed systems of antigenic variation occur in African trypanosomes and Plasmodium falciparum. In these examples, switch rates to individual variants differ over a wide range. We studied how B. hermsii determines switch rates in two experimental infections: one where variants were identified by specific antisera and one based on identification by DNA sequence. Unexpressed loci of variant antigens copy into a single expression site at rates determined by extragenic features of silent loci rather than similarity between coding sequences of variants at silent sites and the single expression site. Two elements, in particular, determine switch rates. One set of elements overlaps the 5' ends of the expressed gene and the silent loci; greater sequence identity between elements was associated with a higher switch rate. The second set of elements flanks the expression site on the 3' side and occurs at variable distances downstream from silent loci; the nearer an element to a silent locus, the greater the switch rate of that locus into the expression site. In combination, these two features of the genome provide a simple mechanism to modulate switch rate whereby silent loci form a hierarchy of switch rates into the expression site. Although the switching hierarchy causes changes in individual cells that are stochastic, ordering of variants within hosts is semipredictable.
Antigen polymorphism in Borrelia hermsii, a clonal pathogenic bacterium.
The relapsing fever spirochete, Borrelia hermsii, escapes immune selection by alternating expression of surface lipoprotein alleles. The switch results from a duplicative transposition of one of several surface lipoprotein-encoding nucleotide sequences into the singular expression site. These nucleotide sequences constitute a large gene family whose diversity originated, in some cases, before the major divergences of Borrelia species. We have examined the B. hermsii vsp subfamily of alleles, which are carried on linear plasmids within each cell and maintained in several diverse copies as an antigenic archive. Each encodes a distinct serotype-specific protein. We sequenced more than 90% of the alleles within a single strain-B. hermsii strain HS1. A preponderance of allelic mosaicism suggests that intragenic recombination, coupled with selection imposed by host immune response, has driven diversification of the archived ensemble of vsp alleles. The recombinational diversification of vsp alleles generates change in the associated serotypes of the magnitude (30-40% amino acid differentiation) necessary for overcoming cross-reactivity of neutralizing antibodies. We conclude that evolution of vsp has occurred by punctuated occurrence of allelic differentiation, rather than by gradual selection of incremental point mutations that do not meet the threshold for antigenic diversity.
Juxtaposition of expressed variable antigen genes with a conserved telomere in the bacterium Borrelia hermsii.
Borrelia hermsii, an agent of relapsing fever, survives in mammals through antigenic variation. Change in serotype-specific variable outer membrane proteins (Vmps) occurs when a Vmp gene at an expression site is replaced with a previously silent gene for another Vmp. Silent and active genes are on separate linear plasmids. The upstream site for a nonreciprocal recombination between two linear plasmids is near the 5' ends of the expressed and silent genes. In the present study we sought the downstream recombination sites in two serotypes, 7 and 21. Restriction fragments containing plasmid telomeres were identified by susceptibility to digestion with BAL-31 and rapid reannealment following denaturation. Whereas both silent genes and a minority population of both expression-linked genes were several kilobases from the telomeres, the predominant population of both expressed genes had 3' ends near plasmid telomeres. Sequence analysis of the predominant expression plasmids revealed that the telomeric sequences were the same in serotypes 7 and 21. Identical sequence was also downstream of silent Vmp genes. Switching of Vmp genes appears to occur by recombination that involves both upstream and downstream sites. The expression plasmid's telomere is preserved in the recombination event.
Low-fat angiomyolipoma of the liver studied with contrast-enhanced ultrasound and multidetector computed tomography.
We report the case of a 30-year-old woman with persistent pain at the right hypochondrium, relapsing fever, and normal serum tests. Ultrasound showed a hyperechoic inhomogeneous mass; following sulfur hexafluoride injection, uniform enhancement at 14-16 s and rapid wash-out at 26 s was found. Multidetector computed tomography showed an inhomogeneously hypodense mass, with no detectable negative density values, characterized by inhomogeneous enhancement at the arterial phase and wash-out at the portal phase. Histopathology demonstrated a hepithelioid angiomyolipoma with a poor fatty component. This diagnosis should always be considered in the presence of a very rapid wash-out after intravenous contrast injection. However, a hepatocellular carcinoma cannot be excluded and the final diagnosis of low-fat angiomyolipoma must be pathologically proved based on immunohistochemistry.