Differential transcriptional responses to Ebola and Marburg virus infection in bat and human cells.

The unprecedented outbreak of Ebola in West Africa resulted in over 28,000 cases and 11,000 deaths, underlining the need for a better understanding of the biology of this highly pathogenic virus to develop specific counter strategies. Two filoviruses, the Ebola and Marburg viruses, result in a severe and often fatal infection in humans. However, bats are natural hosts and survive filovirus infections without obvious symptoms. The molecular basis of this striking difference in the response to filovirus infections is not well understood. We report a systematic overview of differentially expressed genes, activity motifs and pathways in human and bat cells infected with the Ebola and Marburg viruses, and we demonstrate that the replication of filoviruses is more rapid in human cells than in bat cells. We also found that the most strongly regulated genes upon filovirus infection are chemokine ligands and transcription factors. We observed a strong induction of the JAK/STAT pathway, of several genes encoding inhibitors of MAP kinases (DUSP genes) and of PPP1R15A, which is involved in ER stress-induced cell death. We used comparative transcriptomics to provide a data resource that can be used to identify cellular responses that might allow bats to survive filovirus infections.

Detecting and investigating substrate cycles in a genome-scale human metabolic network.

Substrate cycles, also known as futile cycles, are cyclic metabolic routes that dissipate energy by hydrolysing cofactors such as ATP. They were first described to occur in the muscles of bumblebees and brown adipose tissue in the 1970s. A popular example is the conversion of fructose 6-phosphate to fructose 1,6-bisphosphate and back. In the present study, we analyze a large number of substrate cycles in human metabolism that consume ATP and discuss their statistics. For this purpose, we use two recently published methods (i.e. EFMEvolver and the K-shortest EFM method) to calculate samples of 100,000 and 15,000 substrate cycles, respectively. We find an unexpectedly high number of substrate cycles in human metabolism, with up to 100 reactions per cycle, utilizing reactions from up to six different compartments. An analysis of tissue-specific models of liver and brain metabolism shows that there is selective pressure that acts against the uncontrolled dissipation of energy by avoiding the coexpression of enzymes belonging to the same substrate cycle. This selective force is particularly strong against futile cycles that have a high flux as a result of thermodynamic principles.