Confronting the COVID-19 Pandemic with Systems Biology Posted April 10, 2020. [Everything we "know" about SARS-CoV-2 now in question!] https://www.biorxiv.org/content/10.1101/2020.04.06.028712v1

The commonly accepted view that SARS-CoV-2 enters host cells via ACE2 expressed in the lung is unlikely because ACE2 is undetectable there.

Given the greater target space of ACE2-positive nasal, oral, and gastrointestinal tissues, a more likely scenario suggests initial infection in those tissues is followed by a secondary infection via migration through the lymphatic system and bloodstream to lung microvasculature

The elimination of macrophages and complete lack of activated cytokine signature in COVID-19 lung samples suggest that a major component of SARS-CoV-2’s virulence is its net effect of causing a functional immune deficiency syndrome.

Structural analysis of the SARS-CoV-2 proteome suggests involvement of the highly conserved nsp5 protein as part of a major mechanism that suppresses the nuclear factor transcription factor kappa B (NF-κB) pathway, eliminating the host cell’s interferon-based antiviral response.

In all independent simulations of RBD1-ACE, a significant reorientation of the RBD1 is observed, so that the loop ß5-6 slides towards the center of the α1 helix of ACE.

Persistent interactions are established involving the formation of three salt bridges, namely, Asp407-Arg53, Lys447-Glu49, Asp493-Lys94, from RBD1 and ACE, respectively

RBD2-ACE: loop ß4-5 anchors the RBD2 to the N terminal of α1 helix and the nearby region of α2 helix of ACE, mostly involving only hydrophobic contacts between Phe456 and Tyr489 of RBD2 at the N-terminal of α1.

SARS-CoV-1 binds to major vault protein (MVP major component of Vault ribonucleoprotein particles - a central component of the rapid innate immune response in cells exposed to pathogens.) and myosin 1B (MYO1b necessary for internalization of feline coronavirus) need investigation

MVP is recruited to lipid rafts including 127 other proteins (“raft-127 genes”) that mediate internalization of serveral pathogens via endocytosis is likely hijacked by SARS-CoV-2. 7 of these proteins bind to SARS-CoV-2 (4 to nsp7) in an affinity purification mass spectrometry.

With a relaxed filter 33 more raft-127 binding targets were identified including Cathepsin D (CTSD), which is substantially downregulated in cells from bronchoalveolar lavage samples taken from COVID-19 which binds to ORF8.

In bronchoalveolar lavage (BAL) samples 57 of the 127-raft genes were significantly deferentially expressed (55 downregulated and two upregulated) including a gene signature for lung cells but not for macrophage, neutrophil, lymphocytic cells nor were there inflammatory sig.

Genes that were significantly downregulated in BAL samples are typical markers for myeloid and lymphoid lineages, particularly CSFR1+ macrophages & is consistent with parenchymal cells from a distant location into the fluid phase of the lung.

3CLpro (nsp5) may have adopted by the substitution Ala46 Ser to cleaves the NF-kB essential modulator (NEMO) at the Gln231 reaction center and may be a good target for drug development to allow normal immune response.

The β3-4 loop may have enhanced pathogenicity do to mutations: Nsp1 Leu77 Arg, Thr79 Ala, Asn80 Pro and Lys84 Val which in impair host-translational activity.

The route of infection via nasal/oral that leads to strong
intestinal colonization (non-respiratory) may be why there is a lag in typical symptoms while asymptomatic shedding occurs.