Hypercholesterolemia and ApoE deficiency result in severe infection with Lyme disease and relapsing-fever Borrelia

Abstract

The Lyme disease (Borrelia burgdorferi) and relapsing-fever (Borrelia hispanica) agents have distinct infection courses, but both require cholesterol for growth. They acquire cholesterol from the environment and process it to form cholesterol glycolipids that are incorporated onto their membranes. To determine whether higher levels of serum cholesterol could enhance the organ burdens of B. burgdorferi and the spirochetemia of B. hispanica in laboratory mice, apolipoprotein E (apoE)-deficient and low-density lipoprotein receptor (LDLR)-deficient mice that produce large amounts of serum cholesterol were infected with both spirochetes. Both apoE- and LDLR-deficient mice infected with B. burgdorferi had an increased number of spirochetes in the joints and inflamed ankles compared with the infected wild-type (WT) mice, suggesting that mutations in cholesterol transport that result in high serum cholesterol levels can affect the pathogenicity of B. burgdorferi. In contrast, elevated serum cholesterol did not lead to an increase in the spirochetemia of B. hispanica. In the LDLR-deficient mice, the course of infection was indistinguishable from the WT mice. However, infection of apoE-deficient mice with B. hispanica resulted in a longer spirochetemia and increased mortality. Together, these results argue for the apoE deficiency, and not hypercholesterolemia, as the cause for the increased severity with B. hispanica. Serum hyperlipidemias are common human diseases that could be a risk factor for increased severity in Lyme disease.

Keywords: Borrelia; Lyme disease; cholesterol; relapsing fever; tick-borne.

Fig. 1.

The infection of apoE⁻, LDLR⁻, and WT mice with B. burgdorferi. (A) Quantitative real-time PCR analysis of spirochete burdens in joint, ear, and heart tissue. **P < 0.01; *P < 0.05 (compared with WT of the same tissue). (B) Representative photograph of a swollen ankle of apoE⁻ (right) and WT (leftL) mice. Ankles of LDLR⁻ mice were similar to those of apoE⁻ mice. Mean ± SD of ankle width of apoE⁻, LDLR⁻, and WT mice values are shown. ***P < 0.001 (n = 8). (C) Mean ± SD of total serum immunoglobulins (IgG and IgM) in apoE⁻ and WT mice. ***P < 0.001; *P < 0.05 (n = 8). (D) Mean ± SD of the OD of IgG and IgM antibodies in apoE⁻ and WT mice. **P < 0.01; *P < 0.05 (n = 8). (E) Mean ± SD of total serum Ig (IgG and IgM) in LDLR⁻ and WT mice. ***P < 0.001 (n = 8). (F) Mean ± SD of the OD of IgG and IgM antibodies in LDLR⁻ and WT mice. *P < 0.05 (n = 8).

Fig. 2.

The infection of LDLR⁻ mice with B. hispanica. (A) Mean ± SD of the spirochetemia of LDLR⁻ and WT mice (n = 8). (B) Mean ± SD of total serum Ig (IgG and IgM) of LDLR⁻ and WT mice at day 8 after infection (n = 8). (C) Mean ± SD of the OD of the IgG and IgM antibodies produced by LDLR⁻ and WT mice at day 8 after infection (n = 8).

Fig. 3.

The infection of WT mice fed the atherogenic diet with B. hispanica. (A) Mean ± SD of the spirochetemia of WT mice fed the atherogenic diet (n = 4). (B) Mean ± SD of total serum Ig (IgG and IgM). **P < 0.01 (n = 4). (C) Mean ± SD of the OD of IgG and IgM antibodies at 15 d after infection. **P < 0.01 (n = 4).

Fig. 4.

The infection of apoE⁻ mice with B. hispanica. (A) Mean ± SD of the spirochetemia in apoE⁻ and WT mice. ***P < 0.001; **P < 0.01 (n = 14). (B) Survival curve of apoE⁻ and WT mice infected with B. hispanica (n = 14). (C) Activity plot of WT mice for 9 d of infection with B. hispanica. S-MOV, slow movements; F-MOV, fast movements (n = 4). (D) Mean ± SD of total serum immunoglobulins (IgG and IgM) of apoE⁻ and WT mice at 15 d after infection. ***P < 0.001 (n = 7). (E) Activity plot of apoE⁻ mice for 9 d of infection with B. hispanica (n = 4). (F) Mean ± SD of the OD of IgG and IgM antibodies produced by apoE⁻ and WT mice at 15 d after infection. *P < 0.05 (n = 7).

Fig. 5.

(A) Mean ± SD of total serum Ig (IgG and IgM) of apoE⁻ mice at day 8 after infection. (B) Mean ± SD of the OD of the IgG and IgM antibodies produced by apoE⁻ mice at day 8 after infection (n = 4).