Functional and Genomic Architecture of Borrelia burgdorferi-Induced Cytokine Responses in Humans

Despite the importance of immune variation for the symptoms and outcome of Lyme disease, the factors influencing cytokine production during infection with the causal pathogen Borrelia burgdorferi remain poorly understood. Borrelia infection-induced monocyte- and T cell-derived cytokines were profiled in peripheral blood from two healthy human cohorts of Western Europeans from the Human Functional Genomics Project. Both non-genetic and genetic host factors were found to influence Borrelia-induced cytokine responses. Age strongly impaired IL-22 responses, and genetic studies identified several independent QTLs that impact Borrelia-induced cytokine production. Genetic, transcriptomic, and functional validation studies revealed an important role for HIF-1 alpha-mediated glycolysis in the cytokine response toBorrelia. HIF-1 alpha pathway activation and increase in glycolysis-derived lactate was confirmed in Lyme disease patients. In conclusion, functional genomics approaches reveal the architecture of cytokine production induced by Borrelia infection of human primary leukocytes and suggest a connection between cellular glucose metabolism and Borrelia-induced cytokine production.</p

B. burgdorferisensu lato-induced inhibition of antigen presentation is mediated by RIP1 signaling resulting in impaired functional T cell responses towards Candida albicans

Antigen presentation is a crucial innate immune cell function that instructs adaptive immune cells. Loss of this pathway severely impairs the development of adaptive immune responses. To investigate whether B. burgdorferi sensu lato. spirochetes modulate the induction of an effective immune response, primary human PBMCs were isolated from healthy volunteers and stimulated with B. burgdorferi s.l. Through cell entry, TNF receptor I, and RIP1 signaling cascades, B. burgdorferi s.l. strongly downregulated genes and proteins involved in antigen presentation, specifically HLA-DM, MHC class II and CD74. Antigen presentation proteins were distinctively inhibited in monocyte subsets, monocyte-derived macrophages, and dendritic cells. When compared to a range of other pathogens, B. burgdorferi s.l.-induced suppression of antigen presentation appears to be specific. Inhibition of antigen presentation interfered with T-cell recognition of B. burgdorferi s.l., and memory T-cell responses against Candidaalbicans. Re-stimulation of PBMCs with the commensal microbe C.albicans following B. burgdorferi s.l. exposure resulted in significantly reduced IFN-γ, IL-17 and IL-22 production. These findings may explain why patients with Lyme borreliosis develop delayed adaptive immune responses. Unravelling the mechanism of B. burgdorferi s.l.-induced inhibition of antigen presentation, via cell entry, TNF receptor I, and RIP1 signaling cascades, explains the difficulty to diagnose the disease based on serology and to obtain an effective vaccine against Lyme borreliosis.</p

Antigen-Independent Restriction of Pneumococcal Density by Mucosal Adjuvant Cholera Toxin Subunit B

For many bacterial respiratory infections, development of (severe) disease is preceded by asymptomatic colonization of the upper airways. For Streptococcus pneumoniae, the transition to severe lower respiratory tract infection is associated with an increase in nasopharyngeal colonization density. Insight into how the mucosal immune system restricts colonization may provide new strategies to prevent clinical symptoms. Several studies have provided indirect evidence that the mucosal adjuvant cholera toxin subunit B (CTB) may confer nonspecific protection against respiratory infections. Here, we show that CTB reduces the pneumococcal load in the nasopharynx, which required activation of the caspase-1/11 inflammasome, mucosal T cells, and macrophages. Our findings suggest that CTB-dependent activation of the local innate response synergizes with noncognate T cells to restrict bacterial load. Our study not only provides insight into the immunological components required for containment and clearance of pneumococcal carriage, but also highlights an important yet often understudied aspect of adjuvants

Identifying platelet-derived factors as amplifiers of B. burgdorferi-induced cytokine production.

Previous studies have shown that monocytes can be ‘trained’ or tolerized by certain stimuli to respond stronger or weaker to a secondary stimulation. Rewiring of glucose metabolism was found to be important in inducing this phenotype. As we previously found that Borrelia burgdorferi (B. burgdorferi), the causative agent of Lyme borreliosis (LB), alters glucose metabolism in monocytes, we hypothesized that this may also induce long-term changes in innate immune responses. We found that exposure to B. burgdorferi decreased cytokine production in response to the TLR4-ligand lipopolysaccharide (LPS). In addition, B. burgdorferi exposure decreased baseline levels of glycolysis, as assessed by lactate production. Using GWAS analysis, we identified a gene, microfibril-associated protein 3-like (MFAP3L) as a factor influencing lactate production after B. burgdorferi exposure. Validation experiments proved that MFAP3L affects lactate- and cytokine production following B. burgdorferi stimulation. This is mediated by functions of MFAP3L, which includes activating ERK2 and through activation of platelet degranulation. Moreover, we showed that platelets and platelet-derived factors play important roles in B. burgdorferi-induced cytokine production. Certain platelet-derived factors, such chemokine C-X-C motif ligand 7 (CXCL7) and (C-C motif) ligand 5 (CCL5), were elevated in the circulation of LB patients in comparison to healthy individuals