Host transcriptome response to Borrelia burgdorferi sensu lato

Abstract

The host immune response to infection is a well-coordinated system of innate and adaptive immune cells working in concert to prevent the colonization and dissemination of a pathogen. While this typically leads to a beneficial outcome and the suppression of disease pathogenesis, the Lyme borreliosis bacterium, Borrelia burgdorferi sensu lato, can elicit an immune profile that leads to a deleterious state. As B. burgdorferi s.l. produces no known toxins, it is suggested that the immune and inflammatory response of the host are responsible for the manifestation of symptoms, including flu-like symptoms, musculoskeletal pain, and cognitive disorders. The past several years has seen a substantial increase in the use of microarray and sequencing technologies to investigate the transcriptome response induced by B. burgdorferi s.l., thus enabling researchers to identify key factors and pathways underlying the pathophysiology of Lyme borreliosis. In this review we present the major host transcriptional outcomes induced by the bacterium across several studies and discuss the overarching theme of the host inflammatory and immune response, and how it influences the pathology of Lyme borreliosis.

Keywords: Borrelia burgdorferi; Borreliosis; Host transcriptome; Lyme.

Fig. 1.

A summary of Lyme borreliosis symptoms and general timeline of the stages of the disease. A) Symptoms of Lyme borreliosis. The most common symptom is the erythema migrans (EM) rash. Arthritis is typically seen in 29 % of patients, while neurological and cardiac manifestations are less common. B) General timeline of the stages of Lyme borreliosis. The initial localized infection involves the EM rash, flu-like symptoms, and musculoskeletal pain, typically in the first month of infection. Early dissemination occurs within one to several months and can lead to heart and CNS involvement in addition to initial localized symptoms. Pathogen establishment in secondary tissue and organs during the late disseminated phase (months to years from initial infection) can lead to the addition of more severe complications including cognitive impairment and arthritis. Created with BioRender.com.

Fig. 2.

An overview of the transcriptional response of early localized infection. Infection occurs by the transmission of B. burgdorferi s.l. through the bite of a tick and is localized within the skin of the host. Following infection, several resident cells detect and initiate a transcriptional profile in response to the pathogen. Dermal fibroblasts aid in the recruitment of lymphocytes and produce matrix metalloproteinases that leads to the degradation of the extracellular matrix. Monocytes and macrophages initiate phagocytosis and play key roles in the promotion of inflammation, and activation and attraction of leukocytes. Similarly, dendritic cells aid in peripheral immune cell chemotaxis and promote their differentiation and activation. Infection may lead to an impaired migration of dendritic cells to lymph nodes. Created with BioRender.com.

Fig. 3.

An overview of the transcriptional response of early disseminated infection. The main route of dissemination for B. burgdorferi s.l. is through the circulatory system. The endothelium of blood vessels represents a barrier that must be overcome by both B. burgdorferi and immune cells – infection induces the production of several inflammatory and chemotactic cytokines and an increase in cellular adhesion molecules that promotes that binding of leukocytes. The induction of MMPs in both endothelial cells and fibroblasts can aid in the dissemination of the bacteria. Likewise, the choroid plexus epithelium, in response to B. burgdorferi, produces a similar profile conducive to the chemotaxis of peripheral immune cell and a reduction in cell-cell junction transcripts. Peripheral blood mononuclear cells produce an inflammatory response marked by Trem1 signaling, amplifying inflammation. Key mediators of the response include TNF, NF-κB, and IFN-γ, the latter which enhances the endothelial response. Created with BioRender.com.

Fig. 4.

An overview of the transcriptional response of late disseminated infection. Following hematogenous dissemination, the central nervous system and joints are common regions for B. burgdorferi s.l. to colonize. Frontal cortex tissue responds in a diverse manner representative of resident cells – highlighted by inflammatory cytokines and marked by neuronal and oligodendrocyte apoptosis. SH-SY5Y neuronal cells indicate minimal response to infection and are inclined towards a pro-survival profile. Through the activation of microglia, marked by inflammatory factors, SH-SY5Y cells shift towards cell cycle arrest and pro-apoptotic profiles. Astrocytes promote a less robust immune response compared to microglia and show a shift in transcriptional regulation. B. burgdorferi invade the synovial fluid and surrounding tissue of joints, leading to the induction of chemotactic cytokines and subsequent invasion of leukocytes – an indication of Lyme arthritis. Created with BioRender.com.