Suppression of Acute Ixodes scapularis-Induced Borrelia burgdorferi Infection using Tumor Necrosis Factor-α, Interleukin-2, and Interferon-γ

Abstract

Down-regulation of mammalian cytokine production has been demonstrated during tick feeding. To examine the hypothesis that reconstitution of cytokines during tick feeding could facilitate immune containment of Borrelia burgdorferi, the following experiments were done. C3H/HeJ mice were given cytokines for 10 days after Ixodes scapularis attachment. At day 21, ear biopsies were analyzed for B. burgdorferi. Polymerase chain reaction analysis indicated a protection rate of 95% in mice receiving tumor necrosis factor (TNF)-alpha. Mice that received interleukin (IL)-2 or interferon (IFN)-gamma had infection rates of 30%-45% compared with 83% for untreated controls. No correlation was noted between neutralizing antibody, reactivity by Western blot, and subsequent protection. Culture of B. burgdorferi in cytokine-conditioned media indicated that TNF-alpha, IFN-gamma, and IL-2 were not cytotoxic for B. burgdorferi. These data suggest that cytokine-induced protection from B. burgdorferi infection was immune-mediated and that cellular immunity may be associated with protection from I. scapularis-induced infection.

Pattern of Proinflammatory Cytokine Induction in RAW264.7 Mouse Macrophages Is Identical for Virulent and AttenuatedBorrelia burgdorferi

“…Levels of IFN-␥, IL-4, and IL12p70 produced by B. burgdorferi-stimulated whole blood and PBMCs, or in EM blister fluids, differ between patients with localized or disseminated B. burgdorferi infection (4,(15)(16)(17). Similar observations connecting the nature of the cytokine response with disease outcome have been made using murine models of Lyme borreliosis (18,19). Together, these studies indicate that a strong proinflammatory response early in infection mediates host protection.…”

Tick Saliva Inhibits Dendritic Cell Migration, Maturation, and Function while Promoting Development of Th2 Responses

“…Additionally, it has been reported that polarization of the immune response toward the Th2 subset creates favorable conditions for the tick-transmitted spirochete Borrelia burgdorferi (33). Conversely, inoculation of TNF-␣, IFN-␥, and IL-2 mixture during tick feeding has been shown to suppress B. burgdorferi transmission by I. scapularis (34).…”

Characterization of a Novel Salivary Immunosuppressive Protein from Ixodes ricinus Ticks

“…It is now well established that the modulation of host immunity by tick saliva is of major importance both in the successful accomplishment of the blood meal and in the transmission of tick-borne pathogens such as Borrelia burgdorferi, the causal agent of Lyme disease (16). Although extensive information is available on the effects of tick feeding on host immune defenses, little is known about the nature of the immunomodulatory molecules expressed by tick salivary glands.…”

“…Moreover, Th1 cytokines are down-regulated during the initial spirochete transmission period in mice infested with Ixodes scapularis-infected ticks (23). IFN-␥, TNF-␣, and IL-2 given at the time of tick feeding suppress spirochete transmission by I. scapularis (16). In addition, it has been shown recently that this Th2 type immune response makes possible the transmission of the human granulocytic ehrlichiosis agent (24).…”