Increasing the Recruitment of Neutrophils to the Site of Infection Dramatically Attenuates Borrelia burgdorferi Infectivity

Abstract

Borrelia burgdorferi infection causes an initial skin lesion called erythema migrans (EM) in human Lyme disease and in models of monkey and rabbit borreliosis. EM results from the inflammatory response triggered by spirochete replication and likely develops to contain the initial infection but allows bacterial dissemination to occur. The essential lack of neutrophil involvement in EM histopathology prompted us to examine the consequence of increasing their recruitment in the inflammatory response to the Lyme disease agent. B. burgdorferi was modified genetically to constitutively express and secrete the chemokine KC, a neutrophil chemoattractant. After inoculation into the dermis of the murine host, control spirochetes induced an infiltration of macrophages, neutrophils, and basophils within 6 h; however, the recruited neutrophils and basophils were quickly substituted by eosinophils, and the inflammatory response became macrophage dominant by 16 h. Such a response failed to contain the initial infection and allowed the spirochetes to disseminate. In contrast, B. burgdorferi with KC secretion induced an intensive neutrophil infiltration at the inoculation site, and as a result, the host’s ability to control the initial infection was greatly enhanced. Taken together, this study suggests that the failure of sufficient neutrophil recruitment and activation during the initial inflammatory response may allow B. burgdorferi to effectively colonize the mammalian host.

Dermatologic Changes Induced by RepeatedIxodes scapularisBites and Implications for Prevention of Tick-Borne Infection

“…Pathogen transmission requires tick attachment for at least 36 to 48 hours for Babesia microti or B. burgdorferi and at least 24 hours for Anaplasma phagocytophilum (Piesman and Spielman 1980, Piesman 1993, des Vignes et al 2001. Furthermore, any pathogen that might be transmitted in tickimmune hosts would likely be destroyed by neutrophils and lymphocytes at the tick-dermal interface (Xu et al 2007). Inflammatory and vascular changes in the dermis provide an explanation for the decreased incidence of tick-borne disease in tick-immune mammalian hosts.…”

Neutrophil Extracellular Traps Entrap and KillBorrelia burgdorferiSensu Stricto Spirochetes and Are Not Affected byIxodes ricinusTick Saliva

“…IrLBP (I. ricinus lipocalin binding protein) binds leukotriene B4 (LTB4) and inhibits neutrophil transendothelial migration induced by LTB4 (16). This deficit in functional neutrophils at the tick bite site appears to enhance bacterial propagation and the formation of erythema migrans (17). Ribeiro and colleagues (18) have shown that I. scapularis saliva inhibits in vitro neutrophil functions, including aggregation, and phagocytosis, as well as ROS production and granule exocytosis.…”

CD14 Signaling Reciprocally Controls Collagen Deposition and Turnover to Regulate the Development of Lyme Arthritis

“…6 This effect was reversed when Borrelia-expressed KC was neutralized by anti-KC antibodies. CD14 facilitates interactions between bacterial products and the TLR signaling machinery, which promote innate immune responses.…”

“…Neutrophils are the principal early infiltrating cell type observed in the infected joints of humans, 2 a finding mirrored in a mouse model of Lyme arthritis. [3][4][5][6] Depletion of neutrophils results in early onset of arthritis with a higher bacterial burden in murine Lyme borreliosis. 4 Conversely, B. burgdorferi genetically engineered to express KC (the murine equivalent of human CXCL8), a neutrophil-recruiting chemokine, is rapidly cleared from mouse tissues because of a faster and continuous influx of neutrophils to the site of infection.…”

“…4 Conversely, B. burgdorferi genetically engineered to express KC (the murine equivalent of human CXCL8), a neutrophil-recruiting chemokine, is rapidly cleared from mouse tissues because of a faster and continuous influx of neutrophils to the site of infection. 6 The host response to invading pathogens often is typified by a local inflammatory reaction, which generates a gradient of CXCR1/2 ligands that promotes the transendothelial migration of neutrophils into sites of infection. [7][8][9][10] Once there, neutrophils degranulate, thus releasing antimicrobial effectors, such as cathelicidin antimicrobial peptide, 11 CXC chemokines [eg, CXCL8/KC and macrophage inflammatory protein 2 (MIP-2)], 12 and extracellular matrix (ECM)-de-grading enzymes [eg, elastase and matrix metalloproteinase 9 (MMP-9)].…”