bioRxiv Science⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/2024.02.28.582462

Recalibration of macrophage lipid metabolism underlies intracellular bacterial neuroinvasion

wu, h.
View original source ↗Export metadata ↓

Abstract

Acute infection of the central nervous system is one of the most lethal diseases, yet the mechanisms by which intracellular bacteria infiltrate the brain remain poorly understood. Phagocytic cells are typically regarded as the primary site of conflict in the battle against intracellular bacteria; however, little is known about how the intracellular bacteria exploit infected phagocytes to gain access to the brain. In this study, we show that a novel CD36+ Fabp4+ Pparg+ macrophage subpopulation (CD36+macrophage) participates in penetration of the brain by intracellular bacteria without disruption of the blood-brain barrier. Biomechanical analysis reveals that the abundance of protrusions and adhesion molecules on CD36+ macrophages confers significant resistance to the mechanical stress of blood flow, thereby providing increased opportunities for these macrophages to adhere to the vascular endothelial surface. Metabolomics analysis identifies that macrophage lipid metabolism is dysregulated during bacterial neuroinvasion, and that {beta}-hydroxybutyrate promotes the formation and survival of CD36+ macrophages. Importantly, ketogenesis exacerbates symptoms during bacterial neuroinvasion, which could be halted by supplementing with physiological levels of glucose. Collectively, our findings elucidate a pathway by which intracellular bacteria hijack macrophages to invade the brain, suggesting that glycolipid metabolic homeostasis may play a role in the prevention or resolution of bacterial neuroinvasion. Highlights1. Intracellular bacteria hijack CD36+ M{varphi} for brain invasion without disrupting the BBB 2. CD36+ M{varphi} has enhanced adhesion to BMECs and increased resistance to shear flow 3. Ketogenesis promotes bacterial neuroinvasion that can be halted by glucose treatment 4. Accumulation of peripheral BHB and CD36+ M{varphi} fuels bacterial neuroinvasion in humans O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/582462v4_ufig1.gif" ALT="Figure 1"> View larger version (55K): org.highwire.dtl.DTLVardef@19fe27org.highwire.dtl.DTLVardef@7cf218org.highwire.dtl.DTLVardef@fa0d16org.highwire.dtl.DTLVardef@71366b_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical AbstractC_FLOATNO C_FIG

Source connections

Explore related subjects

microbiologyPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

wu, h.. 2024-02-28. Recalibration of macrophage lipid metabolism underlies intracellular bacterial neuroinvasion. https://doi.org/10.1101/2024.02.28.582462

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

A population-scale landscape of the subgingival microbiome reveals divergent routes to periodontal dysbiosis

Periodontitis is an archetypical mucosal inflammatory disease in which microbiome dysbiosis at the tooth-epithelial interface interacts with host genetic and behavioral risk factors to drive immune-mediated tissue destruction. Although subgingival microbiome compositional shifts are thought to parallel disease severity, microbiome variation at the population-level and its relationship to periodontal clinical phenotypes and disease-modifying factors remain poorly defined. Here, we use unsupervised manifold learning to map the compositional landscape of the subgingival microbiome in 1,355 adults spanning periodontal health to severe periodontitis. We identified eight latent microbiome states organized along a branching continuum from eubiosis to dysbiosis. An intermediate microbial configuration marked ecological destabilization and bifurcation into two distinct periodontitis-associated dysbiotic trajectories, distinguished by links to gingival inflammation and smoking. Although the microbiome trajectories broadly tracked periodontal destruction, a minority of individuals showed discordant microbiome-clinical phenotypes, with some individuals with periodontitis retaining otherwise eubiotic microbiomes enriched for low-abundance pathobionts, while some cases of health or mild disease had highly dysbiotic communities, suggesting distinct host susceptibility. Together, these findings define a population-scale ecological landscape of the subgingival microbiome, reveal divergent trajectories to periodontal dysbiosis, and highlight heterogeneity in the relationship between microbial community structure and clinical disease expression.

microbiology↗
bioRxiv2026

The iron-binding siderophore enterobactin is required for the response of multi-drug resistant Klebsiella pneumoniae to zinc limitation

To persist during infection Klebsiella pneumoniae must overcome nutrient iron and zinc limitation imposed by the host immune system through a process called nutritional immunity. Secreted small molecule siderophores are a major virulence determinant of Klebsiella pneumoniae pathogenesis and are presumed to overcome nutritional immunity by binding iron for bacterial acquisition. In this work, we set out to identify how a multi-drug resistant K. pneumoniae grows in zinc limited environments. Using unbiased transcriptomics, proteomics, and an arrayed transposon screen, we identified that synthesis and uptake of the siderophore enterobactin is required to allow for growth in low zinc conditions. Iron-specific chelators did not replicate this phenotype and addition of supplemental iron through heme in growth media could not complement severe growth defects of enterobactin mutant K. pneumoniae experiencing zinc limitation. Finally, zinc starvation induced enterobactin production independent of the canonical zinc uptake regulator (Zur) transcription factor suggesting an unidentified regulatory mechanism by which Gram-negative pathogens may respond to zinc stress. Together, these studies expand the role of enterobactin beyond iron regulation and highlight a previously unreported link between iron and zinc homeostasis in Klebsiella pneumoniae.

microbiology↗
bioRxiv2026

A microbiota-derived protease links phage susceptibility to host epithelial responses

Bacteriophages are major ecological drivers of gut microbial ecology, yet whether bacterial mechanisms that determine phage susceptibility have consequences for the mammalian host remains poorly understood. Here, we identify dipeptidyl peptidase 11 (Dpp11a), the predominant active serine protease of the prevalent gut commensal Phocaeicola vulgatus, as an unexpected bacterial defence factor. Dpp11a protects against environmental proteases and confers resistance to bacteriophage infection. Metatranscriptomic analyses further reveal increased expression of both dpp11a and P. vulgatus-associated phage transcripts in ulcerative colitis stool samples, indicating that both components of this interaction are transcriptionally active in disease-associated human microbiomes. Using the microfluidic gut-on-a-chip co-culture model HuMiX, we show that the absence of Dpp11 is accompanied by altered epithelial tight-junction remodelling during phage-bacterial infection. Together, our findings reveal that the consequences of bacterial phage defence can extend beyond phage-bacterium interactions to the mammalian epithelium.

microbiology↗