I decided to map the entire pathway(s) of Coronavirus that currently exist in literature as of 16 December 2020. This helps enumerate the mechanism of action of the varied symptoms some patients see; this helps to explains some of the more rare, adverse events that can potentially occur in patients that are infected with coronavirus. The image is over 7mb and I am trying to come up with the best way to share it with you all… hang tight!

umair-akbar-JPf6dxAa7l 1 1024x861 - Coronavirus Pathogenesis Pathway

Human coronaviruses are zoonotic (i.e., arising from other species) and cause unexpected human outbreaks of varying severity. Although they spread to many tissues, they are mainly respiratory viruses, causing severe inflammation and lung pathology (pneumonia and ARDS) that can be fatal.

These positive-sense, single-stranded RNA viruses enter epithelial cells through specific docking proteins, such as ACE2 and TMPRSS2, and replicate, in the case of SARS, in the cytoplasm. The 26 to 32 kilobase genome functions as an mRNA that is directly translated and initially encodes a polyprotein, Orf1a, that is cleaved into non-structural proteins (NSP), which interfere with host immune responses, cell cycle, replication and mRNA and protein production.

Ribosomal frameshifting enables extension of Orf1a into Orf1ab, which encodes a larger polyprotein whose extra portion encodes the viral genome replicase (nsp12; RdRp), a helicase (nsp13; HEL), and ribonucleases (nsp14; ExoN, nsp15; NeU). Several structural proteins (S, surface spike; N, nucleocapsid; M, membrane; E, envelope) and other proteins are subsequently made from sub-genomic RNAs generated during partial replication events [1].

Coronaviruses make extensive use of cellular membranes to avoid immune attack, and generate membrane-enclosed virion progeny. Viruses enter cells through endosomes after docking at the plasma membrane, but manage, with the aid of nsp6, to exit at the early endosome stage, before they encounter lysosomes. The replication proteins reside inside autophagy-derived vesicles (promoted by viral membrane proteins nsp3, nsp4 and nsp6). Virion proteins, after synthesis in the endoplasmic reticulum, are transported and assembled in endoplasmic reticulum–golgi intermediate compartments (ERGIC) [2].

Coronaviruses alter key cellular pathways to enhance their replication and virulence. nsp1 inactivates nuclear pore component Nup93, shutting down nucleocytoplasmic transport and, thus, host-cell translation, cell cycle and other essential events. nsp1 also binds to and halts 40S ribosomes, inducing mRNA degradation. N protein binds to and inhibits cyclin complexes directly. Apoptosis is a hallmark of coronavirus pathogenesis. One function of the induced apoptosis may be to liberate extra cellular metabolites for reproduction. Alternatively, apoptosis may liberate virions from host cells for propagation.

Cellular p38 MAPK, JNK, ERK and ER stress-response pathways are all activated, causing a mixture of pro- and anti-apoptotic effects, as well as inhibiting host translation. The antiviral interferon response system is heavily repressed in successful infections. The N protein binds and inhibits TRIM25, inhibiting NFkB induction of interferon production. NFkB is also inhibited by viral M protein, which inhibits IKK kinases as well as inhibiting the STING1 complex that activates IRF3 and IRF7. Viral protein 4b binds and sequesters double-stranded RNAs, preventing detection.

The nsp15 endoribonuclease is thought to prevent accumulation of dsRNA, preventing detection by sensors such as PKR. Viral nsp3 protease deubiquitinates TRAF3 and TRAF6, suppressing interferon production. STAT3 is dephosphorylated and excluded from the nucleus through an unknown viral p38-dependent mechanism [1].

Coronavirus pathogenesis often features a cytokine “storm,” inducing, among other mechanisms, inflammasomes. Protein 3a, produced with the structural proteins, binds to TRAF3 and promotes ubiquitination of NFkB and ASC, the key inflammasome nucleator. The viral E protein forms ion channels in the ERGIC compartment that make it permeable to calcium, activating inflammasomes and IL1B production and contributing to cell destruction and tissue pathogenesis [3, 4].

umair-akbar-WINWORD cUybOEPMuh 1 - Coronavirus Pathogenesis Pathway