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 |  Subject: Ketogenic diet activates protective γδ T cell responses against influenza virus infection  Tue Nov 19, 2019 5:53 pm | |
| Putting mice on a keto dietOur immune responses to infections are influenced by several extrinsic factors, including weather, social interactions, and diet. Here, Goldberg et al. report that feeding mice a high-fat, low-carbohydrate ketogenic diet confers protection in the context of lethal influenza infection. By characterizing the immune response in the lungs, the authors identified that ketogenic diet promoted the expansion of γδ T cells in the lung. Using mice lacking γδ T cells, the authors have established the functional importance of these cells in conferring protection. Their findings suggest that γδ T cells improve barrier function in the lungs by modifying differentiation and function of the airway epithelial cells.
AbstractInfluenza A virus (IAV) infection–associated morbidity and mortality are a key global health care concern, necessitating the identification of new therapies capable of reducing the severity of IAV infections. In this study, we show that the consumption of a low-carbohydrate, high-fat ketogenic diet (KD) protects mice from lethal IAV infection and disease. KD feeding resulted in an expansion of γδ T cells in the lung that improved barrier functions, thereby enhancing antiviral resistance. Expansion of these protective γδ T cells required metabolic adaptation to a ketogenic diet because neither feeding mice a high-fat, high-carbohydrate diet nor providing chemical ketone body substrate that bypasses hepatic ketogenesis protected against infection. Therefore, KD-mediated immune-metabolic integration represents a viable avenue toward preventing or alleviating influenza disease.
INTRODUCTIONRespiratory influenza A virus (IAV) infections are a major source of human morbidity and mortality, causing more than 20,000 deaths annually in the United States and incurring an economic burden in excess of $87 billion each year (1, 2). Although an efficacious universal IAV vaccine is highly desirable and is under development (3, 4), in its absence, novel therapeutic approaches are vital for the treatment of influenza diseases. Such therapeutic strategies can entail either improvements in viral resistance or enhancement of disease tolerance that alleviates lethal consequences of the viral infections (5, 6). Disease tolerance strategies include providing energy substrates that aid in the metabolic adaptation required for host survival (7–9).
Inflammasome activation and neutrophil-mediated toxicity can promote tissue damage associated with IAV infections (10–12). In light of our recent findings that the ketone metabolite, β-hydroxybutyrate (BHB), inhibits Nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome–dependent interleukin-1β (IL-1β) secretion from neutrophils and macrophages (13, 14), we hypothesized that ketogenic diet (KD) might also reduce IAV disease severity. To probe the effects of KD-induced BHB production on IAV disease in a physiologically relevant setting, we conducted all experiments in myxovirus protein 1 (Mx1)–congenic C57BL/6 mice (hereafter referred to as Mx1 mice). Mx1 is a dynamin-like guanosine triphosphatase that is a critical interferon (IFN)–inducible gene important for the control of primary IAV infections in mice (15, 16). Most inbred mouse strains, including C57BL/6 mice, however, lack a functional copy of the Mx1 gene (17). Whereas wild-type C57BL/6 mice are extremely susceptible to IAV infection, succumbing to as few as 100 plaque-forming units (PFU) of A/PR8 IAV, Mx1 mice are highly resistant to infection with doses of more than 106 PFU (10, 18, 19). Therefore, in this study, we use Mx1 mice to probe the impact of KD on influenza infection and disease in the setting of intact innate immunity.
RESULTSAfter intranasal challenge with IAV (108 PFU), Mx1 mice that had been fed KD for 7 days before infection were protected from body weight loss and had improved survival relative to mice on a normal chow diet (Fig. 1, A and B). In addition, KD-fed mice were able to better maintain blood O2 saturation, suggesting improved gas exchange as compared with chow-fed mice (Fig. 1C). This observed protection was associated with improved antiviral resistance because viral titers were significantly lower in the lungs of KD-fed mice (Fig. 1D). To gain insight into the mechanisms underlying KD-enhanced antiviral immunity in the lungs of these mice, we performed transcriptome analysis of infected whole lung tissue samples (fig. S1 and table S1). KD did not result in enhanced IFNs or IFN-stimulated genes (ISGs). Instead, ingenuity pathway analysis (IPA) indicated enrichment in T cell activation pathways (fig. S1C). The results suggested that KD protects mice against IAV through nonconventional mechanisms with potential contribution from T cells early after IAV infection. Of the top 10 significantly regulated genes in KD-fed mice was a γδ T cell receptor (γδTCR) gene segment (Tcrg-C1), and by comparing our dataset with Immunological Genome Project γδ T cell datasets (20), we identified four additional genes in this list that are highly associated with γδ T cells (Cxcr6, Blk, Cd163l1, and Ccr4) (Fig. 1E). By flow cytometry, we observed significant increases in the frequencies and absolute numbers of γδ T cells in the lungs of KD-fed mice (Fig. 1, F to H), whereas no differences were found for other cell types tested (fig. S2A). Similar observations were also made in the bronchoalveolar lavage (BAL) (fig. S2, B to D). Intracellular cytokine staining identified these γδ T cells to be an IL-17–competent, but not IFN-γ–competent, subset (fig. S2, E and F). These IL-17–producing γδ T cells were recently shown to mediate neonatal influenza protection by inducing a type 2 innate lymphoid cell/regulatory T cell tissue repair response (21) and were essential for control of pulmonary bacterial infections (22–24). We did not detect differences in BAL IL-17 (fig. S2G), and we observed lower BAL IFN-γ levels (fig. S2H) in KD-fed mice compared with chow-fed mice on day 3 after infection. Although IPA indicated “TH2 (T helper 2) activation” as a significantly regulated pathway in our dataset (fig. S1C), our transcriptome analysis did not reveal KD-induced enhancement of type 2 immunity genes identified by Guo et al. (21) (fig. S2I).
https://immunology.sciencemag.org/content/4/41/eaav2026 |
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