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.

Rhinoviruses (RVs) are responsible for the majority of upper airway infections; despite their high prevalence and the resulting economic burden, effective treatment is lacking. We report here that RV induces metabolic alterations in host cells, which offer an efficient target for antiviral intervention. We show that RV-infected cells rapidly up-regulate glucose uptake in a PI3K-dependent manner. In parallel, infected cells enhance the expression of the PI3K-regulated glucose transporter GLUT1. In-depth metabolomic analysis of RV-infected cells revealed a critical role of glucose mobilization from extracellular and intracellular pools via glycogenolysis for viral replication. Infection resulted in a highly anabolic state, including enhanced nucleotide synthesis and lipogenesis. Consistently, we observed that glucose deprivation from medium and via glycolysis inhibition by 2-deoxyglucose (2-DG) potently impairs viral replication. Metabolomic analysis showed that 2-DG specifically reverts the RV-induced anabolic reprogramming. In addition, treatment with 2-DG inhibited RV infection and inflammation in a murine model. Thus, we demonstrate that the specific metabolic fingerprint of RV infection can be used to identify new targets for therapeutic intervention.

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 and modulates cellular metabolism toward a catabolic state. Although this enzyme is known to be particularly active in regulatory T (T) cells, its impact on T helper (T)-cell differentiation is poorly understood. We investigated the impact of several AMPK activators on T-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 T-cell induction by specifically enhancing T-cell expansion. Conversely, T17 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 T 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 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/T17 axis through enhancement of fatty acid oxidation.

Background. Late antibody-mediated rejection (AMR) is a major cause of transplant failure. Potential therapeutic targets are plasma cells and natural killer (NK) cells, both expressing high levels of CD38. Methods. Here, we report the use of CD38 monoclonal antibody daratumumab (9-mo course) in a kidney allograft recipient diagnosed with smoldering myeloma and anti-HLA class II donor-specific antibody-positive chronic active AMR 13 years after transplantation. Patient monitoring included serial HLA single-antigen testing, peripheral blood immune cell phenotyping, as well as follow-up allograft and bone marrow biopsies at 3 and 9 months, including analyses of rejection-related gene expression patterns. Results. Daratumumab led to persistent CD138+ cell depletion in the bone marrow and blood and substantially decreased NK cells counts in blood and graft tissue. At the same time, donor-specific antibody in serum disappeared, and in vitro alloantibody production by CD138+ cells enriched from bone marrow aspirates was abrogated. A 3-month follow-up biopsy revealed a complete resolution of microcirculation inflammation (g+ptc: 3 to 0) and molecular AMR activity (AMR score: 0.79 to <0.2). The same biopsy showed (subclinical) tubulointerstitial inflammation, which prompted steroid treatment. Over an observation period of 12 months, graft function stabilized. Conclusions. Targeting CD38 for plasma cell and NK cell depletion may be an effective strategy to counteract AMR. Our results may encourage the design of future trials to clarify the role of this innovative treatment concept in organ transplantation.

Summary Circulating donor‐specific antibodies (DSA) do not necessarily indicate antibody‐mediated rejection (ABMR). Here, we evaluated the diagnostic value of donor‐derived cell‐free DNA (dd‐cfDNA) as an add‐on to DSA detection. The study included two independent cohorts of DSA + kidney allograft recipients, 45 subclinical cases identified by cross‐sectional antibody screening (cohort 1), and 30 recipients subjected to indication biopsies (cohort 2). About 50% of the DSA + recipients had ABMR and displayed higher dd‐cfDNA levels than DSA + ABMR − recipients (cohort 1: 1.90% [median; IQR: 0.78–3.90%] vs. 0.52% [0.35–0.72%]; P < 0.001); (cohort 2: 1.20% [0.82–2.50%] vs. 0.59% [0.28–2.05%]; P = 0.086). Receiver operating characteristic (ROC) analysis revealed an area under the curve (AUC) of 0.89 and 0.69 for dd‐cfDNA, and 0.88 and 0.77 for DSA mean fluorescence intensity (MFI), respectively. In combined models, adding dd‐cfDNA to DSA‐MFI or vice versa significantly improved the diagnostic accuracy. Limited diagnostic performance of dd‐cfDNA in cohort 2 was related to the frequent finding of other types of graft injury among ABMR − recipients, like T cell‐mediated rejection or glomerulonephritis. For dd‐cfDNA in relation to injury of any cause an AUC of 0.97 was calculated. Monitoring of dd‐cfDNA in DSA + patients may be a useful tool to detect ABMR and other types of injury.