Myeloid Differentiation Antigen 88 Deficiency Impairs Pathogen Clearance but Does Not Alter Inflammation inBorrelia burgdorferi-Infected Mice

Abstract

The spirochete Borrelia burgdorferi causes acute inflammation in mice that resolves with the development of pathogen-specific adaptive immunity. B. burgdorferi lipoproteins activate innate immune cells via Toll-like receptor 2 (TLR2), but TLR2-deficient mice are not resistant to B. burgdorferi-induced disease, suggesting the involvement of other TLRs or non-TLR mechanisms in the induction of acute inflammation. For this study, we used mice that were deficient in the intracellular adapter molecule myeloid differentiation antigen 88 (MyD88), which is required for all TLR-induced inflammatory responses, to determine whether the interruption of this pathway would alter B. burgdorferi-induced disease. Infected MyD88 ؊/؊ mice developed carditis and arthritis, similar to the disease in wild-type (WT) mice analyzed at its peak (days 14 and 28) and during regression (day 45). MyD88 ؊/؊ macrophages produced tumor necrosis factor alpha only when spirochetes were opsonized, suggesting a role for B. burgdorferi-specific antibody in disease expression. MyD88 ؊/؊ mice produced stronger pathogen-specific Th2-dependent immunoglobulin G1 (IgG1) responses than did WT mice, and their IgM titers remained significantly elevated through 90 days of infection. Despite specific antibodies, the pathogen burden was 250-fold higher in MyD88 ؊/؊ mice than in WT mice 45 days after infection; by 90 days of infection, the pathogen burden had diminished substantially in MyD88 ؊/؊ mice, but it was still elevated compared to that in WT mice. The elevated pathogen burden may be explained in part by the finding that MyD88 ؊/؊ peritoneal macrophages could ingest spirochetes but degraded them more slowly than WT macrophages. Our results show that MyD88-dependent signaling pathways are not required for B. burgdorferi-induced inflammation but are necessary for the efficient control of the pathogen burden by phagocytes.Infection of humans with the Lyme disease spirochete, Borrelia burgdorferi, results in a characteristic pattern of skin lesions, arthritis, carditis, and neurologic abnormalities that can resolve over time despite the incomplete eradication of the pathogen (12). In the murine model of Lyme borreliosis, spirochetes inoculated into the skin disseminate within days to infect all organ systems, but disease is primarily manifested in the joints and heart (8). The severity of inflammation peaks at these sites about 2 to 4 weeks after infection and then regresses in the presence of B. burgdorferi-specific adaptive immune responses. For this animal model, disease is believed to reflect the innate immune response to spirochetes because histopathology reveals mainly neutrophils and macrophages within inflamed joints and hearts, respectively, and arises in the absence of adaptive immunity (11,26,33,35). B. burgdorferi infections of severe combined immunodeficiency (SCID) and rag-deficient mice, which lack both T and B cells (11,26,33,35

Toll-like Receptors, Notch Ligands, and Cytokines Drive the Chronicity of Lung Inflammation

“…Interestingly, the lack of IL-12 production via limited TLR activation during the inflammatory/immune response appears to lead to Th2 responses, suggesting that this type of response is a default pathway that occurs in the absence of IL-12. Investigations have demonstrated that MyD88 knockout mice were not able to generate a Th1 response when challenged with an infectious agent (57)(58)(59)(63)(64)(65)(66). Also, MyD88-mediated cytokines appear to provide a suppressive signal for a Th2-type response.…”

IL-10 Deficiency Promotes Increased Borrelia burgdorferi Clearance Predominantly through Enhanced Innate Immune Responses

“…The lipoproteins expressed by B. burgdorferi are known to vary widely under the different environmental conditions they encounter during their natural infection cycle between arthropod and vertebrate hosts (15)(16)(17), but all of these proteins are predicted to possess similar triacyl modifications on their N-terminal cysteine residues (18). Studies from a number of laboratories have shown that these triacylated lipoproteins directly activate different host immune cells by signaling through TLR2 (19 -23) and the common intracellular adaptor molecule MyD88 (24,25). These interactions are further enhanced by the binding of lipoproteins to CD14 (26,27), which can increase the sensitivity of TLR2-lipoprotein interactions at physiological levels and augment TLR2-mediated activation (28).…”

Biology of Infection with Borrelia burgdorferi

“…Mice deficient in TLR2 have increased spirochete loads and ankle swelling. However, mice lacking MyD88, an adapter required for signaling through TLR2 and several other pattern receptors, have even higher spirochete loads, suggesting multiple pathways respond to B. burgdorferi antigens [79][80][81][82]. Most likely, the phenotypes of these mutations result from poor recognition of B. burgdorferi components by phagocytic and antigen-presenting cells.…”