Borrelia and System Evasion

[LymeEnigma]

Clocking the Lyme Spirochete
Stephen E. Malawista and Anne de Boisfleury Chevance

Abstract:

In order to clear the body of infecting spirochetes, phagocytic cells must be able to get hold of them. In real-time phase-contrast videomicroscopy we were able to measure the speed of Borrelia burgdorferi (Bb), the Lyme spirochete, moving back and forth across a platelet to which it was tethered. Its mean crossing speed was 1,636 µm/min (N = 28), maximum, 2800 µm/min (N = 3). This is the fastest speed recorded for a spirochete, and upward of two orders of magnitude above the speed of a human neutrophil, the fastest cell in the body. This alacrity and its interpretation, in an organism with bidirectional motor capacity, may well contribute to difficulties in spirochete clearance by the host.

Full article: www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2237901

[LymeEnigma]

Pathogen escape from host immunity by a genome program for antigenic variation.

Alan G Barbour, Qiyuan Dai, Blanca I Restrepo, Herbert G Stoenner, Steven A Frank

Departments of Microbiology and Molecular Genetics and Medicine, University of California, Irvine, CA 92697-4028;

Abstract:

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.

lib.bioinfo.pl/pmid:17101971
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Within-host dynamics of antigenic variation.

Steven A Frank, Alan G Barbour

Department of Ecology and Evolutionary Biology, University of California, Irvine, CA 92697-2525, USA.

Abstract:

Genomes of some parasites contain dozens of alternative and highly diverged surface antigens, of which only a single one is expressed in any cell. Individual cells occasionally change expression of their surface antigen, allowing them to escape immune surveillance. These switches appear to occur in a partly random way, creating a diverse set of antigenic variants. In spite of this diversity, the parasitemia develops as a series of outbreaks, in which each outbreak is dominated by relatively few antigenic types. Host-specific immunity eventually clears the dominant antigenic types, and a new outbreak follows from antigenic types that have apparently been present all along at low frequency. This pattern of sequential dominance by different antigenic types remains unexplained. We review the five most prominent theories, which have developed mainly from studies of the protozoans Trypanosoma and Plasmodium, and the bacterial spirochete Borrelia. The most promising theories depend on some combination of mechanisms to create favored connectivity pathways through the matrix of transitions between variants. Favored pathways may arise from biased switches at the molecular level of gene expression or from biases imposed by immune selection. We illustrate the concept of connectivity pathways by reanalysis of data on transitions between variants from Borrelia hermsii.

lib.bioinfo.pl/pmid:16461018
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A genome-wide proteome array reveals a limited set of immunogens in natural infections of humans and white-footed mice with Borrelia burgdorferi.

Alan G Barbour, Algimantas Jasinskas, Matthew A Kayala, D Huw Davies, Allen C Steere, Pierre Baldi, Philip L Felgner

Pacific Southwest Center for Research on Emerging Infections, Department of Microbiology and Molecular Genetics, Department of Medicine, Department of Computer Science, and Institute of Genomics and Bioinformatics of the University of California Irvine, Irvine, CA; ImmPORT Therapeutics Inc., Irvine, CA; Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, MA.

Abstract:

Humans and other animals with Lyme borreliosis produce antibodies to a number of components of the agent Borrelia burgdorferi, but a full accounting of the immunogens during natural infections had not been achieved. Employing a protein array produced in vitro from 1292 DNA fragments representing approximately 80% of the genome, we compared the antibody reactivities of sera from patients with early or later Lyme borreliosis to those of sera from controls. Overall, approximately 15% of the open reading frames (ORF) of B. burgdorferi in the array detectably elicited an antibody response in humans with natural infections. Among the immunogens, 103 stood out by statistical criteria. The majority of these ORFs were also immunogenic with sera obtained from naturally-infected Peromyscus leucopus mice, a major reservoir. The high-ranking set included several B. burgdorferi proteins hitherto unrecognized as immunogens, as well as several proteins established as antigens. High-ranking immunogens were more likely to have these characteristics in comparison to non-reactive ORFs: (1) plasmid- rather than chromosome-encoded, (2) a predicted lipoprotein, and (3) a member of a paralogous family of proteins, notably the Bdr and Erp proteins. The newly-discovered antigens included several ORFs of the lp36 linear plasmid, such as BBK07 and BBK19, and proteins of the flagellar apparatus, such as FliL. These results indicate that the majority of deduced proteins of B. burgdorferi do not elicit antibody responses during infection and that the limited sets of immunogens are similar for two different host species.

lib.bioinfo.pl/pmid:18474646

[LymeEnigma]

Antigenic variation with a twist - the Borrelia story.

Steven J Norris

Departments of Pathology & Laboratory Medicine and Microbiology & Molecular Genetics, University of Texas Medical School at Houston, PO Box 20708, Houston, TX 77225-0708, USA.

Abstract:

A common mechanism of immune evasion in pathogenic bacteria and protozoa is antigenic variation, in which genetic or epigenetic changes result in rapid, sequential shifts in a surface-exposed antigen. In this issue of Molecular Microbiology, Dai et al. provide the most complete description to date of the vlp/vsp antigenic variation system of the relapsing fever spirochaete, Borrelia hermsii. This elaborate, plasmid-encoded system involves an expression site that can acquire either variable large protein (vlp) or variable small protein (vsp) surface lipoprotein genes from 59 different archival copies. The archival vlp and vsp genes are arranged in clusters on at least five different plasmids. Gene conversion occurs through recombination events at upstream homology sequences (UHS) found in each gene copy, and at downstream homology sequences (DHS) found periodically among the vlp/vsp archival genes. Previous studies have shown that antigenic variation in relapsing fever Borrelia not only permits the evasion of host antibody responses, but can also result in changes in neurotropism and other pathogenic properties. The vlsE antigenic variation locus of Lyme disease spirochaetes, although similar in sequence to the relapsing fever vlp genes, has evolved a completely different antigenic variation mechanism involving segmental recombination from a contiguous array of vls silent cassettes. These two systems thus appear to represent divergence from a common precursor followed by functional convergence to create two distinct antigenic variation processes.

lib.bioinfo.pl/pmid:16796669

[LymeEnigma]

Bacterial pathogenesis: A variation on variation in Lyme disease

Michael Koomey, E-mail The Corresponding Author

Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA

Available online 10 April 2004

Relapsing fever, caused by Borreliae hermsii and related species, is arguably the best understood disease involving antigenic variation. The initial infection occurs during the bite from an infected tick, or a louse during epidemics, and following this the infected animal undergoes waves of spirochetemia and accompanying fever. The relapses are associated with the clonal emergence in the bloodstream of a variant expressing a novel variable major protein [6]. After up to ten such waves of parasitemia, occurring every four to seven days, the individual or animal can succumb or recover completely.

Lyme disease is a tick-borne infection caused by the spirochete B. burgdorferi, which is related to the relapsing fever borreliae [7]. In stark contrast to relapsing fever, which has been relatively quiescent for almost 50 years, Lyme disease is currently the most common arthropodborne disease in both North America and Europe. Although rarely fatal, the manifestations of Lyme disease can be physically and emotionally debilitating [7]. Early human infection is usually characterized by a spreading skin rash (erythema migrans) and flu-like illness, which is self-limiting. In the following weeks to months, most untreated infected individuals proceed into a chronic late disease characterized by systemic involvement of the joints, brain, nerves, eyes and heart [8].

From these presentations alone, it seemed likely that antigenic variation would play a role in the immune evasiveness displayed by B. burgdorferi. Subtle differences in highly expressed surface lipoproteins were found between B. burgdorferi strains, but no compelling evidence for major antigenic changes [9] or gross genetic rearrangements [10] was initially forthcoming, despite indirect evidence suggesting that antigenic shifts can occur during mouse infection [11] and [12].

Full article: www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6VRT-4C4DHV8-CH&_user=10&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=e7764720b0acc22d11fc0bfce830f65b