Viral replication is a process that involves an extremely high turnover of cellular molecules. Since viruses depend on the host cell to obtain the macromolecules needed for their proper replication, they have evolved numerous strategies to shape cellular metabolism and the biosynthesis machinery of the host according to their specific needs. Technologies for the rigorous analysis of metabolic alterations in cells have recently become widely available and have greatly expanded our knowledge of these crucial host–pathogen interactions. We have learned that most viruses enhance specific anabolic pathways and are highly dependent on these alterations. Since uninfected cells are far more plastic in their metabolism, targeting of the virus-induced metabolic alterations is a promising strategy for specific antiviral therapy and has gained great interest recently. In this review, we summarize the current advances in our understanding of metabolic adaptations during viral infections, with a particular focus on the utilization of this information for therapeutic application.

Significance: Rhinovirus (RV) is the causative agent of the common cold and other respiratory tract infections. Despite the vast prevalence, effective treatment or prevention strategies are lacking. Here, we analyzed metabolic alterations in infected cells and found a pronounced reprogramming of host cell metabolism toward an anabolic state, which involved enhancement of glucose uptake and glycogenolysis. We further demonstrate that these alterations can be reverted by treatment with 2-deoxyglucose, a glycolysis inhibitor, which results in a disruption of RV replication in vitro and in vivo. Thus, we show how the specific metabolic fingerprint of viral infection can be used to generate targets for antiviral therapy.

Drug-induced immunosuppression following kidney transplantation is crucial to prevent allograft rejection, but increases risk for infectious disease. Tailoring of drug dosing to prevent both rejection and infection is greatly desirable. The apathogenic and ubiquitous torque teno virus (TTV) reflects immunocompetence of the host and might be a potential candidate for immunologic monitoring. To assess TTV as an infection biomarker, virus load was prospectively quantified in peripheral blood of 169 consecutive renal allograft recipients at the Medical University Vienna. Patients with infection showed higher TTV levels compared to patients without infection (4.2 × 10⁸ copies/mL [interquartile range, IQR, 2.7 × 10⁷–1.9 × 10⁹] vs 2.9 × 10⁷ [IQR 1.0 × 10⁶–7.2 × 10⁸]; P = .006). Differences in TTV load became evident almost 3 months before infection (median 77 days, IQR 19–98). Each log level of TTV copies/mL increased the odds ratio for infection by 23% (95% confidence interval 1.04–1.45; P = .014). TTV >3.1 × 10⁹ copies/mL corresponded to 90% sensitivity to predict infections. Logistic regression demonstrated independent association between TTV levels and infection. TTV quantification predicts infection after kidney transplantation and might be a potential tool to tailor immunosuppressive drug therapy.

Hemophagocytic lymphohistiocytosis (HLH) causes multiple organ dysfunction frequently leading to intensive care unit (ICU) referral and/or death. We report on a series of critically ill adult patients treated with a non-etoposide-based regimen including interleukin 1 antagonist anakinra, intravenous immunoglobulin (IVIG), and/or corticosteroids (CS) for HLH. Eight adult (≥18 years) ICU patients having received treatment with anakinra ± IVIG ± CS for HLH between March 2014 and March 2016 at a large tertiary care university hospital (Medical University of Vienna, Vienna, Austria) were retrospectively analyzed. Eight patients (median age: 38 years; range: 20-58 years; 4 males and 4 females) received anakinra together with IVIG (n = 7) and/or high-dose CS (n = 5) for suspected reactive HLH (median H-score: 214; range: 171-288). Seven (88%) patients required vasopressors and invasive mechanical ventilation and 6 (75%) patients required renal replacement therapy (median Sequential Organ Failure Assessment [SOFA] score at HLH diagnosis: 9.5; range: 6-14). Six patients showed a significant decline in the SOFA score at 1 and 2 weeks following treatment initiation (P = .03), and the remainder 2 patients experienced early death. Five patients survived to ICU discharge, 4 of them could further be discharged from hospital (hospital survival rate: 50%). No overt treatment-related toxicity was noted. Anakinra in combination with IVIG and/or CS resulted in a hospital survival rate of 50% in 8 critically ill adult patients with HLH despite a vast degree of organ dysfunction and the need for aggressive ICU treatment. Further research on non-etoposide-based treatment strategies for HLH in critically ill adults is warranted.

T cells must tightly regulate their metabolic processes to cope with varying bioenergetic demands depending on their state of differentiation. The metabolic sensor AMPK is activated in states of low energy supply andmodulates cellular metabolism toward a catabolic state. Although this enzyme isknown tobeparticularly active in regulatory T (T _reg ) cells, its impact on T helper (T _h )‐cell differentiation is poorly understood. We investigated the impact of several AMPK activators on T _reg ‐cell differentiation and found that the direct activator AICAR (5‐aminoimidazole‐4‐carboxamide ribonucleotide), but not the indirect activators metformin and 2‐deoxyglucose, strongly enhanced Treg‐cell induction by specifically enhancing T _reg ‐cell expansion. Conversely, T _h 17 generation was impaired by the agent. Further investigation of the metabolic background of our observations revealed that AICAR enhanced both cellular mitochondrogenesis and fatty acid uptake. Consistently, increased Treg induction was entirely reversible on inhibition of fatty acid oxidation, thus confirming the dependence of AICAR's effects on metabolic pathways alterations. Translating our findings to an in vivo model, we found that the substance enhanced T _reg cell generation on IL‐2 complex–induced immune stimulation. We provide a previously unrecognized insight into the delicate interplay between immune cell function and metabolism and delineate a potential novel strategy for metabolism‐targeting immunotherapy.—Gualdoni, G. A., Mayer, K. A., Göschl, L., Boucheron, N., Ellmeier, W., Zlabinger, G. J. The AMP analog AICAR modulates the T _reg /T _h 17 axis through enhancement of fatty acid oxidation. FASEB J. 30, 3800–3809 (2016) www.fasebj.org

Deregulation of inflammasome activation was recently identified to be involved in the pathogenesis of various inflammatory diseases. Although macrolide antibiotics display well described immunomodulatory properties, presumably involved in their clinical effects, their impact on inflammasome activation has not been investigated. We compared the influence of macrolides on cytokine induction in human monocytes. The role of intracellular azithromycin-accumulation was examined by interference with Ca⁺⁺-dependent uptake. We have also analysed the signalling cascades involved in inflammasome activation and substantiated the findings in a murine sepsis model. Azithromycin, but not clarithromycin or roxithromycin, specifically inhibited IL-1α and IL-1β secretion upon LPS stimulation. Interference with Ca⁺⁺-dependent uptake abolished the cytokine-modulatory effect, suggesting a role of intracellular azithromycin accumulation in the modulatory role of this macrolide. Azithromycin’s inhibiting effects were observed upon LPS, but not upon flagellin, stimulation. Consistent with this observation, we found impaired induction of the LPS-sensing caspase-4 whereas NF-κB signalling was unaffected. Furthermore, azithromycin specifically affected IL-1β levels in a murine endotoxin sepsis model. We provide the first evidence of a differential impact of macrolides on the inflammasome/IL-1β axis, which may be of relevance in inflammasome-driven diseases such as chronic obstructive pulmonary disease or asthma.