Variability of a bacterial surface protein and disease expression in a possible mouse model of systemic Lyme borreliosis.

Abstract

SummaryDuring persistent infection of scid mice with Borrelia turicatae, an agent of relapsing fever and neuroborreliosis, there was variation in the surface proteins the bacteria expressed and in disease manifestations over time. Two serotypes, A and B, were isolated from the mice, doned by limiting dilution, and further characterized. The only discernible difference between the two variants was in the size of the major surface protein they expressed: serotype A had a variable major protein (Vmp) of 23,000, and serotype B had a Vmp of 20,000. When other scid mice were inoculated with clonal populations of A and B, the infections were similar with respect to onset and degree of spirochetemia, involvement of the eye and heart, and occurrence of a peripheral vestibular disorder. However, there were differences between the serotypes in other respects: (a) serotype B but not A caused reddened and significantly enlarged joints, markedly impaired performance on a walking bar, and severe arthritis by histologic examination; (b) serotype A but not B invaded the central nervous system during early infection; and (c) serotype A penetrated monolayers of human umbilical vein endothdial cells more readily than did serotype B. The combination of arthritis, myocarditis, and neurologic disease resembled human Lyme borreliosis. The findings indicate that differences in disease expression are determined by variable surface proteins of the bacterium and that scid mouse infections with R turicatae provide a model for the study of the pathogenesis of Lyme borreliosis and other persistent spirochetal diseases.

Role of Interleukin 10 during Persistent Infection with the Relapsing Fever Spirochete Borrelia turicatae

“…scored infected and uninfected control mice of both genotypes for signs of ocular, skin, joint, and vestibular disease previously found to characterize infection of SCID mice. 3 Unexpectedly, the results showed that Rag1 Ϫ/Ϫ mice despite their higher spirochetemia had significantly less clinical disease than Igh6 Ϫ/Ϫ mice ( Figure 2). Clinical disease started with purulent conjunctival discharge and ruffled fur by week 1, followed by tibiotarsal joint swelling by week 2, and signs of vestibular dysfunction by week 3, resembling the pattern seen in SCID mice.…”

“…3 IgM produced by B1b cells independently of T cells are responsible for resolution of infection with RF borrelias, 5,6 which can occur independently of complement. 20 Unlike B cells, little is known about the role of T cells in RF borreliosis.…”

“…3,7,11 Spirochetes were cultured as described. 12 Before infection, borrelia viability was assessed by microscopy and serotype identity was confirmed by Western blot with monoclonal antibodies.…”

“…2 Several organs are involved including the skin, the heart, and the brain. 3 The hallmark of RF is febrile periods concurrent with high-level spirochetemia alternating with periods of well being with low spirochetemia. RF borrelias evade the host's serotype-specific antibody response through variation of immunodominant outer membrane lipoproteins known as variable major proteins (VMPs).…”

“…In contrast, serotype 1 (Bt1, formerly known as BtA), defined by expression of Vsp1 (formerly VspA), is more neurotropic: it enters the central nervous system earlier and in higher numbers despite 10-fold lower spirochetemia than Bt2. 3,7,8 During RF, there is a significant inflammatory response to the infection characterized by production of several cytokines, including tumor necrosis factor (TNF)-␣, interleukin (IL)-6, IL-8, and IL-10. 9 The levels of cytokines further increase after treatment with antibiotics resulting in sudden fever, rigors, and persistent hypotension known as the Jarisch-Herxheimer reaction.…”