Interferon signaling drives epithelial metabolic reprogramming to promote secondary bacterial infection.

Carreno-Florez, Grace P.; Kocak, Brian R.; Hendricks, Matthew R.; Melvin, Jeffrey A.; Mar, Katrina B.; Kosanovich, Jessica; Cumberland, Rachel L.; Delgoffe, Greg M.; Shiva, Sruti; Empey, Kerry M.; Schoggins, John W.; Bomberger, Jennifer M.

Clinical studies report that viral infections promote acute or chronic bacterial infections at multiple host sites. These viral-bacterial co-infections are widely linked to more severe clinical outcomes. In experimental models in vitro and in vivo, virus-induced interferon responses can augment host susceptibility to secondary bacterial infection. Here, we used a cell-based screen to assess 389 interferon-stimulated genes (ISGs) for their ability to induce chronic Pseudomonas aeruginosa infection. We identified and validated five ISGs that were sufficient to promote bacterial infection. Furthermore, we dissected the mechanism of action of hexokinase 2 (HK2), a gene involved in the induction of aerobic glycolysis, commonly known as the Warburg effect. We report that HK2 upregulation mediates the induction of Warburg effect and secretion of L-lactate, which enhances chronic P. aeruginosa infection. These findings elucidate how the antiviral immune response renders the host susceptible to secondary bacterial infection, revealing potential strategies for viral-bacterial co-infection treatment. Author summary: Viral infections can make the host susceptible to secondary bacterial infections. Increasing evidence indicates that viral-bacterial co-infections cause worse clinical manifestations and lead to life-threatening acute or chronic bacterial infections. The host immune response against a viral infection promotes secondary bacterial infection; however, our understanding of how the antiviral response favors a subsequent bacterial infection is limited. Here, we aimed to assess the role of a suite of genes induced by the antiviral response, known as interferon-stimulated genes (ISGs), in the enhancement of Pseudomonas aeruginosa infection, which is frequently found in viral-bacterial co-infections in the airways of immunocompromised individuals. We found that the ISG hexokinase 2 (HK2), which drives metabolic reprogramming and mediates the secretion of the metabolite lactate by the respiratory epithelium, promotes chronic P. aeruginosa infection. These findings improve our understanding of how the antiviral response changes the host mucosal environment, enabling a subsequent bacterial infection.

TYPE I interferons; BACTERIAL diseases; PSEUDOMONAS aeruginosa infections; INTERFERONS; VIRUS diseases; SYMPTOMS; METABOLIC reprogramming

PLoS Pathogens, 2023, Vol 19, Issue 11, p1

1553-7366

Academic Journal

10.1371/journal.ppat.1011719