The immune response to herpes simplex virus encephalitis in mice is modulated by dietary vitamin E

Abstract

Herpes simplex virus encephalitis (HSE) is the most common fatal sporadic encephalitis in humans. HSE is primarily caused by herpes simplex virus (HSV)-1 infection of the brain. HSE results in increased levels of oxidative stress, including the production of reactive oxygen species, free radicals, and neuroinflammation. The most biologically active form of vitamin E (VE) is alpha-tocopherol (alpha-TOC). In cellular membranes, alpha-TOC prevents lipid peroxidation by scavenging free radicals and functioning as an antioxidant. Supplementation with VE has been shown to decrease immunosenescence, improve immune function, and may be neuroprotective. To determine how VE deficiency and VE supplementation would alter the pathogenesis of HSE, we placed weanling male BALB/cByJ mice on VE-deficient (VE-D), VE-adequate (VE-A), or 10x VE-supplemented diets for 4 wk, and then infected the mice intranasally with HSV-1. VE-D mice had more severe symptoms of encephalitis than VE-A mice, including weight loss, keratitis, hunched posture, and morbidity. VE-D mice had increased cytokine and chemokine expression in the brain and increased viral titers. In contrast, VE supplementation failed to decrease cytokine production and had no effect on viral titer. We demonstrated that adequate levels of VE are important in limiting HSE pathology and that 10x supplementation does not enhance protection.

FIGURE 1

α-TOC concentrations in the liver and brain of mice fed VE-D, VE-A, and VE-S diets for 4 wk. Data are the mean ± SEM, n = 4. *Different from VE-A at that time point, P < 0.05. α-TOC MW = 430.7.

FIGURE 2

Forebrain IL-6 (A), TNFα (B), IL-1β (C), and IL-10 (D) gene expression in VE-D, VE-A and VE-S mice. Data are the mean ± SEM, n = 6 or 7, and are expressed as the fold of the mean of the UNI VE-A group (d 0). *Different from VE-A at that time point, P < 0.05.

FIGURE 3

Forebrain IFNβ (A), IFNγ (B), and iNOS (C) gene expression in VE-D, VE-A and VE-S mice. Data are the mean ± SEM, n = 6 or 7, and are expressed as the fold of the mean of the UNI VE-A group (d 0). *Different from VE-A at that time point, P < 0.05.

FIGURE 4

Forebrain monocyte chemotactic protein (MPC)-1 (A), RANTES (B), macrophage inflammatory protein (MIP)-1α (C), and intercellular adhesion molecule (ICAM)-1 (D) gene expression in VE-D, VE-A and VE-S mice. Data are the mean ± SEM, n = 6 or 7, and are expressed as the fold of the mean of the UNI VE-A group (d 0). *Different from VE-A at that time point, P < 0.05.

FIGURE 5

Brain stem production of IL-1β (A), TNFα (B), and RANTES (C) in VE-D, VE-A and VE-S mice. Data are the mean ± SEM, n = 6 or 7, and are expressed as pg/brain stem. *Different from VE-A at that time point, P < 0.05.

FIGURE 6

Brain HSV titer is expressed as means ± SEM, n = 5, of PFU per hemisphere of brain in VE-D, VE-A and VE-S mice (A). HSV-1 genomic DNA and mRNA in olfactory bulb (B), brain stem (C), and forebrain (D), respectively. Data are expressed as means ± SEM, n = 6 or 7. Abbreviations: N.Det., not detected; N.D., not done. *Different from VE-A at that time point, P < 0.05.