Transcriptome-guided metabolic network analysis reveals rearrangements of carbon flux distribution in Neisseria gonorrhoeae during neutrophil co-culture

• Published in: mSystems 2023-06, Vol.8 (4), p.e0126522
• Main Authors: Potter, Aimee D, Baiocco, Christopher M, Papin, Jason A, Criss, Alison K
• Format: Article
• Language: English
• Subjects: Annotations; Antibiotics; Antimicrobial agents; Automation; Bacteria; Bacteriology; Biomass; Carbon; Carbon sources; Cell culture; Coculture Techniques; Datasets; Drug development; Drug resistance; Environmental conditions; Genes; genome-scale metabolic network reconstruction; Genomes; Genre; Gonorrhea; Gonorrhea - genetics; Guanylate cyclase; Humans; Infections; Innate immunity; Leukocytes (neutrophilic); Leukocytes (polymorphonuclear); metabolic network analysis; Metabolic networks; Metabolic Networks and Pathways - genetics; Metabolic pathways; Metabolism; Metabolites; Neisseria gonorrhoeae; Neisseria gonorrhoeae - genetics; Neutrophils; Pathogens; Phenotypes; Research Article; Strains (organisms); Therapeutic targets; Transcriptome; Transcriptomes; transcriptomics; Virulence
• ISSN: 2379-5077; 2379-5077
• DOI: 10.1128/msystems.01265-22

The ability of bacterial pathogens to metabolically adapt to the environmental conditions of their hosts is critical to both colonization and invasive disease. Infection with (the gonococcus, Gc) is characterized by the influx of neutrophils [polymorphonuclear leukocytes (PMNs)], which fail to clear the bacteria and make antimicrobial products that can exacerbate tissue damage. The inability of the human host to clear Gc infection is particularly concerning in light of the emergence of strains that are resistant to all clinically recommended antibiotics. Bacterial metabolism represents a promising target for the development of new therapeutics against Gc. Here, we generated a curated genome-scale metabolic network reconstruction (GENRE) of Gc strain FA1090. This GENRE links genetic information to metabolic phenotypes and predicts Gc biomass synthesis and energy consumption. We validated this model with published data and in new results reported here. Contextualization of this model using the transcriptional profile of Gc exposed to PMNs revealed substantial rearrangements of Gc central metabolism and induction of Gc nutrient acquisition strategies for alternate carbon source use. These features enhanced the growth of Gc in the presence of neutrophils. From these results, we conclude that the metabolic interplay between Gc and PMNs helps define infection outcomes. The use of transcriptional profiling and metabolic modeling to reveal new mechanisms by which Gc persists in the presence of PMNs uncovers unique aspects of metabolism in this fastidious bacterium, which could be targeted to block infection and thereby reduce the burden of gonorrhea in the human population. IMPORTANCE The World Health Organization designated Gc as a high-priority pathogen for research and development of new antimicrobials. Bacterial metabolism is a promising target for new antimicrobials, as metabolic enzymes are widely conserved among bacterial strains and are critical for nutrient acquisition and survival within the human host. Here we used genome-scale metabolic modeling to characterize the core metabolic pathways of this fastidious bacterium and to uncover the pathways used by Gc during culture with primary human immune cells. These analyses revealed that Gc relies on different metabolic pathways during co-culture with human neutrophils than in rich media. Conditionally essential genes emerging from these analyses were validated experimentally. These results show that metaboli