{"doi":"10.1159/000540093","title":"Immunometabolites Direct the Pathogenesis of Bacterial Infection","abstract":"Exciting new technical and conceptual advances have helped define the molecular events underlying the pathogenesis of bacterial infection. Foremost among these advances is recognition of metabolic signaling as the basis for the complex interactions that occur between host and pathogen. Not only is the host innate immune response mediated by the release of pro- and anti-inflammatory immunometabolites, but bacteria also actively modulate their own metabolic activity, first to initiate infection and then to adapt to the local microenvironment to cause persistent infection. There is a complex host-pathogen metabolic interaction that is dictated by the specific properties of the infecting organism as well as the specific properties of the host tissue; replete in fatty acids and lipids such as in the skin, or dicarboxylates or carbohydrates as in the infected airway, that serve as preferred substrates for specific pathogens and direct their gene expression. There is a growing list of metabolites that individually have major immunological consequences and promote gene expression in pathogens [1]. The field of “immunometabolism” in the context of bacterial infection has grown far beyond the early descriptions of LPS-activating succinate, HIF-1α, and IL-1β production by macrophages [2]. Importantly, the contribution of both host and bacterial metabolites is increasingly recognized in shaping the local microenvironment and creating a milieu that directs the immune response.The initial host response to the recognition of bacterial pathogens is release of potent cytokines, a response that varies in different tissues and in response to specific pathogens. Both immune and stromal cells display an array of pattern recognition receptors, directly linked to central signaling cascades that transduce the recognition of bacterial components into both pro- and anti-inflammatory signaling. A highly orchestrated metabolic response accompanies recognition of bacterial components. The complexity of these host signaling cascades activated by LPS as a model is reviewed in detail by Kumar and Stewart [3]. Numerous metabolic pathways are activated to generate ATP to fuel the initial immune response and to support expression of cytokines during infection. The initial activation and release of host immunometabolites typically result in inflammation such as the release of proinflammatory metabolites and oxidants. The importance of succinate release in stimulating glycolysis in many different cell types is well appreciated [4]. However, as this response is damaging to both the host and pathogen, it must be regulated. There is an increasing literature detailing how this inflammatory response is regulated by metabolites. Posttranslational modification of host proteins, often by dicarboxylates such as itaconate and fumarate, modulates immune responses [1].The importance of itaconate, a C5 dicarboxylate, is increasingly emphasized for its central role in the host response to diverse bacterial stimuli. The specific roles of itaconate as well as many other metabolites in shaping immune responses are reviewed by Hooftman [5]. While initially described as a component of the macrophage response to LPS, the accumulation of itaconate in the setting of infection by a number of pathogens has been detailed [6, 7]. Of note, this metabolite produced by host myeloid cells has a major effect on bacteria, driving their adaptation to the host. For some pathogens, such as Pseudomonas aeruginosa, itaconate serves as a carbon source. Both Staphylococcus aureus, a major Gram-positive pathogen, as well as P. aeruginosa, alter their metabolic activity in response to host-generated itaconate to generate extracellular polysaccharides that form biofilm and promote infections recalcitrant to phagocytic clearance [7, 8].Exactly how immune cells respond to the accumulation of these itaconate and other metabolites is tremendously complex and highly relevant in shaping tolerance to infection ","journal":"Journal of Innate Immunity","year":2024,"id":480577,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9416,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":246808,"name":"Alice Prince","orcid":"0000-0002-7399-9295","position":0,"is_corresponding":true}],"reference_count":12,"raw_metadata":null,"created_at":"2026-07-19T02:07:02.142014Z","pmid":"38952110","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}