Major Complex Trait for Early De Novo Programming 'CoV-MAC-TED' Detected in Human Nasal Epithelial Cells Infected by Two SARS-CoV-2 Variants Is Promising to Help in Designing Therapeutic Strategies.

Birgit Arnholdt-Schmitt,José Hélio Costa,Shahid Aziz,Carlos Noceda

doi:10.3390/vaccines9121399

Birgit Arnholdt-Schmitt, José Hélio Costa + Show 2 more

Open Access

https://doi.org/10.3390/vaccines9121399

Copy DOI

Abstract

Background: Early metabolic reorganization was only recently recognized as an essentially integrated part of immunology. In this context, unbalanced ROS/RNS levels connected to increased aerobic fermentation, which is linked to alpha-tubulin-based cell restructuring and control of cell cycle progression, were identified as a major complex trait for early de novo programming (‘CoV-MAC-TED’) during SARS-CoV-2 infection. This trait was highlighted as a critical target for developing early anti-viral/anti-SARS-CoV-2 strategies. To obtain this result, analyses had been performed on transcriptome data from diverse experimental cell systems. A call was released for wide data collection of the defined set of genes for transcriptome analyses, named ‘ReprogVirus’, which should be based on strictly standardized protocols and data entry from diverse virus types and variants into the ‘ReprogVirus Platform’. This platform is currently under development. However, so far, an in vitro cell system from primary target cells for virus attacks that could ideally serve for standardizing the data collection of early SARS-CoV-2 infection responses has not been defined. Results: Here, we demonstrate transcriptome-level profiles of the most critical ‘ReprogVirus’ gene sets for identifying ‘CoV-MAC-TED’ in cultured human nasal epithelial cells infected by two SARS-CoV-2 variants differing in disease severity. Our results (a) validate ‘Cov-MAC-TED’ as a crucial trait for early SARS-CoV-2 reprogramming for the tested virus variants and (b) demonstrate its relevance in cultured human nasal epithelial cells. Conclusion: In vitro-cultured human nasal epithelial cells proved to be appropriate for standardized transcriptome data collection in the ‘ReprogVirus Platform’. Thus, this cell system is highly promising to advance integrative data analyses with the help of artificial intelligence methodologies for designing anti-SARS-CoV-2 strategies.

Highlights

Transcript profile level changes for SARS-CoV-2 infection are given in Figure 1A and demonstrate similar increases for ASMTL and ADH5 (207% and 197%) at 8 hpi and indicate unbalanced ROS/RNS at 24 hpi (94% ASMTL and 159% ADH5), which is supported by near-basal SOD1 and SOD2 transcript levels (112% and 108%) in relation to an increased transcript level of NOS2 (163%)
SARS-CoV-2 ∆382 shows at 72 hpi a slower decrease in mTOR transcript accumulation (109% vs. 86% for original virus), and this, together with the slower decrease for E2F1 transcription (72% vs. 62% for original virus), might indicate slightly delayed cell cycle progression and arrest for the mutant
The high relevance of metabolism-driven, early cell re-organization that we observed by studying CoV-MAC-TED in infected primary target cells for two respiratory viruses, SARS-CoV-2 and influenza A H3N2, stimulates re-thinking of our current understanding of the immunological system and its determinants

Summary

Introduction

It is well understood that plants and animals have similar responses and cell memory mechanisms to manage immunology [1,2]. Effective immunologic protection requires a variety of innate and adaptive cell responses and cell memory tools [1,2,3,4]. Immunologic responses are energy-consuming and require efficient metabolic reprogramming, but metabolic reorganization is not fully recognized as an integrated part of immunology [5,6,7,8]. Viruses have comparatively low Gibbs energy due to their chemical compositions [9,10]. This makes their replication highly competitive and is the basis for their ‘structural violence’

Methods

Results

Discussion

Conclusion