ROS/RNS Balancing, Aerobic Fermentation Regulation and Cell Cycle Control – a Complex Early Trait (‘CoV-MAC-TED’) for Combating SARS-CoV-2-Induced Cell Reprogramming

Abstract

In a perspective entitled ‘From plant survival under severe stress to anti-viral human defense’ we raised and justified the hypothesis that transcript level profiles of justified target genes established from in vitro somatic embryogenesis (SE) induction in plants as a reference compared to virus-induced profiles can identify differential virus signatures that link to harmful reprogramming. A standard profile of selected genes named ‘ReprogVirus’ was proposed for in vitro-scanning of early virus-induced reprogramming in critical primary infected cells/tissues as target trait. For data collection, the ‘ReprogVirus platform’ was initiated. This initiative aims to identify in a common effort across scientific boundaries critical virus footprints from diverse virus origins and variants as a basis for anti-viral strategy design. This approach is open for validation and extension. In the present study, we initiated validation by experimental transcriptome data available in public domain combined with advancing plant wet lab research. We compared plant-adapted transcriptomes according to ‘RegroVirus’ complemented by alternative oxidase (AOX) genes during de novo programming under SE-inducing conditions with in vitro corona virus-induced transcriptome profiles. This approach enabled identifying a major complex trait for early de novo programming during SARS-CoV-2 infection, called ‘CoV-MAC-TED’. It consists of unbalanced ROS/RNS levels, which are connected to increased aerobic fermentation that links to alpha-tubulin-based cell restructuration and progression of cell cycle. We conclude that anti-viral/anti-SARS-CoV-2 strategies need to rigorously target ‘CoV-MAC-TED’ in primary infected nose and mouth cells through prophylactic and very early therapeutic strategies. We also discuss potential strategies in the view of the beneficial role of AOX for resilient behavior in plants. Furthermore, following the general observation that ROS/RNS equilibration/redox homeostasis is of utmost importance at the very beginning of viral infection, we highlight that ‘de-stressing’ disease and social handling should be seen as essential part of anti-viral/anti-SARS-CoV-2 strategies.

Adaptive Reprogramming During Early Seed Germination Requires Temporarily Enhanced Fermentation-A Critical Role for Alternative Oxidase Regulation That Concerns Also Microbiota Effectiveness

“…Ethanol has been shown to reduce ROS levels and led to high induction of alternative oxidase (AOX) and glutathione-S-transferase transcripts (Nguyen et al, 2017). Transcriptome analyses at 2,4-dichlorophenoxyacetic acid (2,4-D) induced reprogramming indicated that the extent of aerobic fermentation is connected to cell proliferation and is regulated by interacting levels of sucrose and AOX (Costa et al, 2021). Transient upregulation of genes related to alcoholic and lactic acid fermentation is shown to be associated with glycolysis and modified complex stress signaling patterns with enhanced superoxide dismutase (SOD) and decreased transcript levels of nitric oxide (NO) producing nitrate reductase (NR).…”

“…Considering the generality of these observations, we proposed a reference transcriptome profile to identify virus traits that link to harmful reprogramming (Arnholdt-Schmitt et al, 2021). This approach helped to identify an early trait for combating SARS-CoV-2 that covers ROS/reactive nitrogen species (RNS) balancing, aerobic fermentation regulation, and cell cycle control (Costa et al, 2021).…”

“…Integrated in silico studies on experimental data revealed that endophytes interact with AOX expression in species-, stress-, and developmental-dependent manner. Also, Costa et al (2021) highlighted the importance of microbiotaplant genotype interaction and its impact on early carrot seed germination which can be modified by SHAM.…”

“…In Figure 2, we present a simplified scheme that summarizes our conclusion based on wet-lab experiments, state-of-the-art knowledge, and our hypothetical inferences related to the dynamic metabolic interplay between sucrose, aerobic fermentation, COXmediated respiration, AOX regulation/AR, and microbiota on cell reprogram functioning. In this scheme, we separated AOX as a macromolecule (gene/protein) from its functional pathway, AR, to highlight the outstanding position of AOX as the key and only enzyme of the pathway that, if present in an organism, is recognized to provide a central metabolism-coordinating function for efficient survival (Mohanapriya et al, 2019;Arnholdt-Schmitt et al, 2021;Costa et al, 2021). We consider that under development-and/or environment-induced conditions of rapid sucrose increase, the COX pathway is stimulated via enhanced glycolysis, pyruvate production, and increased tricarboxylic acid (TCA) cycle, in a way that the respiratory chain can get overloaded by electrons followed by enhanced ROS/RNS levels and, on the other hand, restricted due to rapidly consumed oxygen and/or yet low numbers of functional mitochondria concerning the presence of oxygen during germination.…”

“…We consider that under development-and/or environment-induced conditions of rapid sucrose increase, the COX pathway is stimulated via enhanced glycolysis, pyruvate production, and increased tricarboxylic acid (TCA) cycle, in a way that the respiratory chain can get overloaded by electrons followed by enhanced ROS/RNS levels and, on the other hand, restricted due to rapidly consumed oxygen and/or yet low numbers of functional mitochondria concerning the presence of oxygen during germination. In response, aerobic alcoholic and lactic fermentation are stimulated (refer points a, b, and c; Costa et al, 2021). At the same time, AOX is activated [refer point d and in Mohanapriya et al (2019), Costa et al (2021)] mainly through AOX gene sequence-dependent pyruvate regulation and ROS/RNS.…”