Discovery of pharmaceutically-targetable pathways and prediction of survivorship for pneumonia and sepsis patients from the view point of ensemble gene noise

Tristan de Jong; Victor Guryev; Yury M. Moshkin

From this intersection we inferred 13 pathways most of which have been previously implicated in sepsis ( Table 1 ). To that, 5 pathways (protein complexes) showed significant association of ensemble gene noise with H1N1 infection phase and CAP disease state and for which ensemble gene noise also increased significantly in sepsis patients ( Figure 2A) . Potentially, these . CC-BY-NC 4.0 International license author/funder. It is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the . https://doi.org/10.1101/2020.04.10.035717 doi: bioRxiv preprint pathways could be targeted for adjuvant treatment of sepsis. Especially, we consider mitochondrial respiratory chain complex I (Complex I) ( Figure 2D ) and peroxisome promising for pharmaceutical targeting. Increased ensemble gene noise for the Complex I would imply either altered stoichiometry, or increased gene expression noise for genes encoding subunits of the Complex I or both. As a result, this might lead to improper assembly of the Complex I and affecting its function. The impaired Complex I function can be bypassed by an alternative redox mediator, such as methylene blue [32, 33] . To that, methylene blue is a selective inhibitor of the nitric oxide-cyclic guanosine monophosphate (NO-cGMP) pathway [35] and increased NO levels is a hallmark of sepsis [42] . Some clinical studies have already indicated a beneficial role of methylene blue in the treatment of sepsis [34, 35] . Similar to mitochondrial respiration, peroxisomes also play an important role in the pathology of sepsis as the dysfunction of peroxisomes results in oxidative stress [43] . Again, an increased ensemble gene noise for peroxisome pathway indicates a potential mechanism for such dysfunction in H1N1, CAP and sepsis patients. Potentially peroxisome biogenesis could be restored by 4-phenylbutyrate and