Isogenic Serotypes ofBorrelia turicataeShow Different Localization in the Brain and Skin of Mice

Abstract

Mice with severe combined immunodeficiency (scid mice) and infected with the relapsing fever agent Borrelia turicatae develop manifestations that resemble those of disseminated Lyme disease. We have characterized two isogenic serotypes, A and B, which differ in their variable small proteins (Vsps) and disease manifestations. Serotype A but not serotype B was cultured from the brain during early infection, and serotype B caused more severe arthritis, myocarditis, and vestibular dysfunction than serotype A. Here we compared the localization and number of spirochetes and the severity of inflammation in scid mice, using immunostained and hematoxylin-and-eosin-stained coronal sections of decalcified heads. Spirochetes in the brain localized predominantly to the leptomeninges, and those in peripheral tissues localized mainly to the extracellular matrix. There were significantly more serotype A than B spirochetes in the leptomeninges and more serotype B than A spirochetes in the skin. The first tissue where spirochetes were observed outside the vasculature was the dura mater. Inflammation was more severe in the skin than in the brain. VspA, VspB, and the periplasmic flagellin protein were expressed in all tissues examined. These findings indicate that isogenic but antigenically distinct Borrelia serotypes can have marked differences in their localization in tissues.Relapsing fever is a disease of humans caused by several species of the genus Borrelia (3). During infection there may be several febrile periods and spirochetemia separated by periods of well-being. The disease is also notable for involvement of the nervous system; manifestations include encephalitis, meningitis, peripheral and cranial neuritis, myelitis, and neuropsychiatric disturbances (9). These bacteria persist in the host through antigenic variation of single surface lipoproteins of two types: variable small proteins (Vsps) of about 23 kDa, and variable large proteins (Vlps) of about 38 kDa. We found that mice with severe combined immunodeficiency (scid mice) infected with Borrelia turicatae, the agent of tick-borne relapsing fever in southwestern North America, develop manifestations that resemble those of disseminated Lyme disease (14). Two serotypes, A and B, differed in the Vsps they expressed and the disease they produced in mice. Overall, serotype B was more virulent than serotype A; it killed infant mice and caused severe arthritis, myocarditis, and vestibular dysfunction (14, 33). Serotype A, on the other hand, was more neurotropic: it infected the brain early in the infection, even though its density in the blood was 10-fold lower than that of serotype B.Serotype A is defined by the expression of VspA, and serotype B is defined by the expression of VspB. The silent and expressed genes for VspA and VspB have been cloned and characterized (13, 33). VspA and VspB are part of a larger family of proteins that includes the Vsps of Borrelia hermsii and the OspCs of the Lyme disease spirochetes B. burgdorferi, B.afzelii, and B. garinii. The sequence ...

IL-10 Prevents Apoptosis of Brain Endothelium during Bacteremia

“…Several previous studies of relapsing-remitting or persistent high-level infection in mice failed to find any evidence of cerebrovascular injury (9)(10)(11)(12)(15)(16)(17). This was the case even after 2-3 mo of persistent infection with 10 7 -10 8 bacteria per ml blood (15,17,18).…”

“…Our laboratory has been studying the neurologic complications of bacterial infection by using a neurotropic strain of the RF spirochete Borrelia turicatae (9)(10)(11)(12)(13)(14). Several previous studies of relapsing-remitting or persistent high-level infection in mice failed to find any evidence of cerebrovascular injury (9)(10)(11)(12)(15)(16)(17).…”

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

“…For this, we measured the number of spirochetes in the brain by immunohistochemistry as before. 8 Spirochetes were found within the subarachnoid space and along the leptomeninges ( Figure 6A) but not in the brain parenchyma. No spirochetes were observed free in the cerebral vasculature, as expected after effective intracardiac perfusion with buffer at necropsy.…”

“…8 Primary antibodies were rabbit anti-Vsp1 or anti-Vsp2 (1/5000). IgG of the same species (Sigma, St. Louis, MO) or nonrelevant primary antibodies matched for concentration and isotype were used as negative controls.…”

“…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.…”