Early and early disseminated phases of Lyme disease in the rhesus monkey: a model for infection in humans

Abstract

We demonstrate that Borrelia burgdorferi infection in the rhesus monkey mimics the early and early disseminated phases of human Lyme disease. Clinical, bacteriological, immunological, and pathological signs of infection were investigated during 13 weeks after inoculation of the spirochete. Three animals were given B. burgdorferi (strain JD1) by needle inoculations, six animals were exposed to the bite of B. burgdorferi-infected Ixodes dammini ticks, and three animals were uninfected controls. B. burgdorferi could be recovered from all animals that were given the spirochete. Bacteria were detectable until week 6 postinoculation (p.i.) in blood, until week 8 p.i. in skin biopsies, and at 10 weeks p.i. in the conjunctiva of one of two animals which developed conjunctivitis. Erythema migrans (EM) appeared in one of the three animals infected by needle inoculation and in five of the six animals infected by ticks. Deep dermal perivascular lymphocytic infiltrations (characteristic of human EM) were observed in all animals showing EM clinically. Both EM and conjunctivitis were documented concomitantly with the presence of the spirochete. Lethargy, splenomegaly, and cerebrospinal fluid pleocytosis were also noted in some animals, but the direct connection of these signs with the infection was not shown. The appearance rate of immunoglobulin M and immunoglobulin G antibodies to B. burgdorfieri, as well as the antigen spectra recognized, were remarkably similar to those seen in humans. Serum antibodies from infected animals were able to kill B. burgdorfieri in vitro in the presence of rhesus complement. The rhesus monkey model appears to be useful for the investigation of the immunology and pathogenesis of Lyme disease and for the development of immunoprophylactic, diagnostic, and chemotherapeutic protocols.

Pathogenesis of Lyme neuroborreliosis: Borrelia burgdorferi lipoproteins induce both proliferation and apoptosis in rhesus monkey astrocytes

“…Five 2-4-year-old male rhesus macaques (Macaca mulatta) of Chinese origin were used. Four of the animals were needle-inoculated with low-passage B. burgdorferi, as described previously [7], and one animal was shaminoculated and served as control. Animals received spirochetes of the neurotropic (NT)-1 strain of B. burgdorferi.…”

“…Initial (localized) infection was assessed in all animals by in vitro cultivation of skin punch biopsy samples taken from the periphery of the site of inoculation. Specimens were obtained at weekly intervals for 4 weeks following inoculation and were cultured in BSK-H medium (Sigma Chemical Co., St. Louis, MO) as described previously [7]. Infection of the CNS was assessed by PCR applied to CSF.…”

“…Lyme disease is chiefly an inflammatory disease. Perivascular cellular infiltrates have been found in peripheral nerves after tick bites [2] and in the brain of Lyme disease patients [3][4][5], as well as in numerous tissues in animal models of Lyme disease [6][7][8][9]. The rhesus macaque is the only animal model that exhibits signs of Lyme disease in all of the organ systems that are affected by the disease in humans, including the peripheral nervous system (PNS) and CNS [7][8][9][10][11][12][13][14][15].…”

“…Astrocyte proliferation, with concomitant apoptotic cell death, are features commonly seen in astrogliosis [16]. Since astrocytes are located perivascularly, as they cooperate with brain endothelial cells in maintaining the blood-brain barrier [17], and spirochetes also tend to localize perivascularly in most tissues [6][7][8][9], we reasoned that B. burgdorferi could thus directly affect the astrocyte microenvironment. Moreover, activated astrocytes could modulate the immune response in the CNS by virtue of their ability to produce cytokines in response to microbial stimulants [18].…”

Mononeuropathy multiplex in rhesus monkeys with chronic lyme disease

“…Of the 3 uninfected control animals, 1 was given a sham needle inoculation, and 2 were exposed to the bites of uninfected ticks. The methods of in vitro cultivation of Bb, tick infection, and monkey inoculation are described in detail elsewhere [5].…”