Infection of Mice with Lyme Disease Spirochetes Constitutively Producing Outer Surface Proteins A and B

Abstract

Outer surface protein A (OspA) of the Lyme disease spirochete is primarily produced in the tick vector. OspA, which is a receptor for attaching spirochetes to the tick gut, is down regulated as the spirochetes leave the tick and enter the mammalian host. Although OspA is not a major antigen produced in the mammal, the protein appears to be produced under some conditions and production has been linked to more severe disease. A Lyme disease vaccine based on recombinant OspA has been approved for human use. However, the vaccine is no longer available, in part because of fears that OspA causes arthritis in people. To further understand the consequences of OspA production in the host, we created a Borrelia burgdorferi mutant that was unable to down regulate OspA. C3H/HeN mice infected with this mutant developed a specific anti-OspA immune response, and the spirochetes were unable to persist in these mice. In contrast, immunodeficient SCID mice were persistently infected with the mutant. We conclude that spirochetes producing OspA and B from the flaB promoter in immunocompetent mice stimulate an immune response that clear the bacteria without any signs of disease development in the mice.The Lyme disease spirochete Borrelia burgdorferi produces an array of outer surface lipoproteins (Osps). While some of the lipoproteins are chromosomally produced, the majority are produced on extrachromosomal plasmids. As many as 91, or 14.5%, of the genes encoded on plasmids are putative lipoproteins (7). Many plasmid-encoded lipoproteins are differentially expressed in the tick vector or the vertebrate host, indicating that they function at specific stages in the life cycle of the spirochete. The function of several lipoproteins has been studied using genetic and biochemical approaches, but there still remains much to be learned about these proteins.OspA and B are two proteins encoded by a single operon on linear plasmid 54 (lp54). These two surface proteins are produced in abundance by spirochetes grown in culture. OspA, in particular, has been the focus of study because the gene encoding OspA was among the first B. burgdorferi genes to be cloned and a recombinant OspA vaccine has been approved for use in people and animals. However, the vaccine is no longer available, in part because of fears that the protein or an immune response against the protein could induce arthritis. OspA is differentially produced during the natural transmission cycle of the spirochete. When spirochetes first enter a tick, OspA is upregulated and the protein is required for tick colonization. OspA serves as a ligand for tethering spirochetes to a receptor in the tick gut (20). When infected ticks feed again, the spirochetes multiply within the vector, downregulate the production of OspA and infect the host via the salivary glands of the tick. Nonspecific natural antibody in a host may be one signal that down regulates ospA expression (16). Mutants missing OspA and B are able to infect mice and cause disease (28).There is conflicting data about the role of ...

The Early Dissemination Defect Attributed to Disruption of Decorin-Binding Proteins Is Abolished in Chronic Murine Lyme Borreliosis

“…IgM dominates the antiborrelial immune response (50), and though it may be too large and unwieldy to penetrate collagenous tissues, it is present in blood and lymph (54). The caveat remains that evidence exists to refute the hypothesis that steric hindrance alone prevents the antibody response from targeting spirochetes embedded in collagen (55,56). As for non-antibody-mediated clearance, recent investigations into invariant natural killer T (iNKT) cells are reminders that there are alternate immune mechanisms to consider (57,58).…”

Increasing the Interaction of Borrelia burgdorferi with Decorin Significantly Reduces the 50 Percent Infectious Dose and Severely Impairs Dissemination

“…Based on these observations, DbpA appears to be ineffectively targeted by protective antibodies in mammalian tissues, in sharp contrast to other surface antigens, such as OspC and OspA/B. Constitutive expression of either OspC or OspA/B completely diminishes the ability of B. burgdorferi to cause persistent infection in immunocompetent mice (43,49). A previous study suggested that the interaction of DbpA with decorin may provide B. burgdorferi a protective strategy to evade specific humoral immunity (23).…”

“…A fresh blood meal down-regulates OspA/B and up-regulates OspC and other proteins, a process that prepares B. burgdorferi for infection of mammals (12,18,29,42). Repression of OspA/B expression during mammalian infection is critical for the maintenance of the enzootic cycle because their expression would ultimately induce strong humoral responses to effectively block acquisition by the vector (10,45,46), regardless of whether OspA/B can be effectively targeted by borreliacidal antibodies in mammalian tissues (43). B. burgdorferi abundantly expresses OspC during early infection, when the antigen is required (26,44).…”

Modification of Borrelia burgdorferi to overproduce OspA or VlsE alters its infectious behaviour

“…A fresh blood meal downregulates OspA/B and upregulates OspC and others, a process that prepares B. burgdorferi for infection of mammals (Fingerle et al, 2007;Grimm et al, 2004;Pal et al, 2004;Stewart et al, 2006). The downregulation of OspA and OspB during mammalian infection is critical for the maintenance of the enzootic cycle because their expression would ultimately induce strong humoral responses to effectively block acquisition by the vector (de Silva et al, 1997;Tsao et al, 2001Tsao et al, , 2004, regardless of whether OspA or OspB can be effectively targeted by borreliacidal antibodies in mammalian tissues (Strother et al, 2007). B. burgdorferi abundantly expresses ospC only during early infection when the antigen may be crucial (Grimm et al, 2004;Stewart et al, 2006;Tilly et al, 2006).…”