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Inflammatory Signatures of Pathogenic and Non-Pathogenic Leptospira Infection in Susceptible C3H-HeJ Mice.

ABSTRACT: The exact global impact of leptospirosis is unknown due to inadequate surveillance systems in place in most low-income countries. In this study, we analyzed the differences in mouse inflammatory signatures involved in pathogenic versus non-pathogenic Leptospira recognition at 24h and 72h post infection. Injection of C3H-HeJ mice with non-pathogenic L. biflexa increased circulation of a few chemokines (5/21, 24%) without secretion of cytokines in blood that resulted in engagement of resident macrophages, dendritic cells, neutrophils and NK cells without engagement of T cells. In contrast, pathogenic L. interrogans induced circulation of a much higher panel of chemokines (18/21, 86%) and pro- and anti-inflammatory cytokines (11/19, 58%) in blood with a resulting signaling cascade leading to engagement of macrophages, dendritic cells, monocytes, NK cells and T cells without engagement of neutrophils. Although neutrophils do not appear to be engaged, a considerable number of chemokines that recruit other granulocytes such as eosinophils and basophils were also increased at 72h post infection with L. interrogans. Overall, the data suggest that prevention of dissemination of L. biflexa is associated with an early engagement of the innate immune response characterized by upregulation of a few chemokines that results in an efficacious phagocytic response without an overwhelming increase of pro-inflammatory cytokines. However, when macrophages fail to clear a pathogenic serovar such as L. interrogans, the adaptive response (T cells) is engaged to help out, but the resulting chemo-cytokine storm mediates a robust but non-resolving inflammatory response to pathogenic Leptospira that results in dissemination, kidney colonization, pathology and disease.

SUBMITTER: Shetty A

PROVIDER: S-EPMC8264587 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Lyme disease is caused by Borrelia burgdorferi, and the pathogenesis of the disease is complex with both bacterial and host factors contributing to inflammatory responses. Lyme disease affects different organs including joints and results in arthritis. Immune responses stimulated by B. burgdorferi through toll-like receptors cause infiltration of leukocytes, which produce inflammatory cytokines and facilitate spirochete clearance. However, arthritic manifestations and chronic fatigue syndrome-like symptoms persist long after completion of antibiotic treatment regimens in a significant number of patients. To counter the effects of inflammation, treatment by non-steroidal anti-inflammatory drugs, hydroxychloroquine, or synovectomy to eradicate inflammatory arthritis in the involved joint could be employed; however, they often have long-term consequences. Acupuncture has been used for a long time in Asian medicine to diminish pain during various ailments, but the effects and its mechanism are just beginning to be explored. Control of inflammation by neuronal stimulation has been exploited as a systemic therapeutic intervention to arrest inflammatory processes. Our objective was to determine whether activation of the sciatic-vagal network by electroacupuncture on ST36 acupoint, which is used to control systemic inflammation in experimental models of infectious disorders such as endotoxemia, can also alleviate Lyme arthritis symptoms in mice. This aim was further strengthened by the reports that sciatic-vagal neuronal network stimulation can lead to dopamine production in the adrenal medulla and moderate the production of inflammatory factors. We first assessed whether electroacupuncture affects spirochete colonization to attenuate Lyme arthritis. Interestingly, bioluminescent B. burgdorferi burden detected by live imaging and qPCR were similar in electroacupuncture- and mock-treated mice, while electroacupuncture induced a lasting anti-inflammatory effect on mice. Despite the discontinuation of treatment at 2 weeks, the simultaneous decrease in neutrophils in the joints and inflammatory cytokine levels throughout the body at 4 weeks suggests a systemic and persistent effect of electroacupuncture that attenuates Lyme arthritis. Our results suggest that electroacupuncture-mediated anti-inflammatory responses could offer promising healthcare benefits in patients suffering from long-term Lyme disease manifestations.

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Inflammatory Signatures of Pathogenic and Non-Pathogenic Leptospira Infection in Susceptible C3H-HeJ Mice.

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