RSV Induced Metabolic Perturbations Suppresses Dendritic Cell Antiviral Properties and Promotes Pulmonary Pathology

• DOI: 10.7302/23984
• Publication Date: 2024-01-01
• Authors: Mire, Mohamed
• Keywords: Innate immunity; Immunometabolism; Microbiology and Immunology; FOS: Clinical medicine; Science; Immunology; Host Pathogen Response; Respiratory syncytial Virus; Dendritic cells

The intricate interplay between immunometabolism and immune cell function is particularly evident in Dendritic Cells (DCs), which modulate immune responses to pathogens. A paramount example is how Respiratory Syncytial Virus (RSV), a prevalent lung pathogen infecting most infants by age two, influences DC metabolism to undermine antiviral immune defense responses. Our studies reveal novel insights into how RSV infection impacts DC immunogenic processes through metabolism. Initial findings identified key metabolic components, especially poly(ADP-ribose) polymerase 1 (PARP1), being significantly activated at the protein level within DCs upon RSV infection. Real-time cell metabolic analysis further revealed that glycolytic enhancement equips DCs with an improved response to RSV, implicative of a 'priming' effect integral to optimizing antiviral properties. Our studies reveal PARP1 as a critical enzyme facilitating heightened RSV induced pathology in a DC centric manner. PARP1, a responder to DNA damage, exerts effects by poly-ADP-ribosylating cellular proteins, thereby potentially modifying their functions and contributing to metabolic manipulation. Crucially, our data demonstrate that genomic ablation of PARP1 abrogates RSV induced DC metabolic alterations. Our data show enzymatic inhibition or genomic ablation of PARP1 resulted in increased Ifnb1, Il12 and Il27 in RSV-infected DC, which together promote a more appropriate antiviral environment. The protective role of PARP1 blockade was corroborated in vivo. PARP1- KO mice and those treated with PARP1 inhibitor showed resistance to RSV-induced immunopathology, including airway inflammation and mucus hypersecretion, as evidenced by periodic acid-schiff (PAS) staining lung tissue. However, delayed treatment with PARP1 inhibitor in RSV infected mice provided only partial protection, suggesting PARP1 is most important during the earlier innate immune stage of RSV infection. Our study also explores the impact of KDM5B—a histone demethylase—on DCs. Specifically, we found that a DC-specific genomic knockout of KDM5B guards against RSV-induced dampening of TolI-like receptor (TLR) responses. KDM5B is a histone demethylase whose enzymatic function depends on iron ions and alpha-ketoglutarate, a metabolite that is dependent upon a skewed cell metabolism. The altered immune phenotype in KDM5B deficient responses is characterized by increased type I interferons and associated genes such as Cxcl10, Oasl1, and Mx2. Utilizing the transcription factor prediction tool BART reveals IRF3, IRF7, STAT1 and SIRT6 as potential regulatory factors for the differentially expressed genes following TLR re-stimulation of RSV infected KDM5B-KODC. Collectively, these findings put forth compelling evidence that targeting metabolic pathways in DC might present as a viable strategy to mitigate RSV-induced immunopathology. This research brings us closer to formulating targeted interventions that could alleviate the burden of RSV by ameliorating disease severity and promoting effective immune responses. We show RSV induced PARP1 activity contributes to DC metabolic perturbation, including NAD depletion. Furthermore, RSV induced metabolic changes likely facilitate enhanced enzymatic function of epigenetic element KDM5B which has been shown to suppress type I interform production. These results emphasize the significance of metabolic processes as crucial regulators of immune responses against RSV, pinpointing metabolic enzymes and metabolism-regulated epigenetic modifiers as targets for potential therapeutic intervention. Notably, our research paves the way for future studies aimed at understanding and manipulating immunometabolism pathways to develop novel treatments for RSV and other viral infections that exploit host metabolism for immune evasion, as well as improve vaccine design.