Transmission via airborne and surface contact. Coughing, spitting, sneezing, kissing, breathing, talking, touching, or singing are all mechanisms of spread.

Body entry through the Eye/ lacrimal duct , Naso-Oropharynx , and/or Small intestine.

  1. Viral Spike protein binding to cellular surface receptors. Heparan Sulfate, ACE-2 , Neuropilin-1/VEGF-A Receptor and possibly Integrin, and CD175.

2. Viral Fusion at the Plasma Membrane versus Endocytosis and then fusion, and/or Phagocytosis and then fusion. Endocytosis requires cellular host factors ACTR2, ACTR3, RAB7A, CCZ1B, ARPC3, ARPC4, UVRAG .

3. Membrane fusion requires Cleavage of the spike protein by furin into S1 + S2 followed by fusion protein activation via TMPSS2 (on membrane surface or endosomes) or Cathepsin L cleavage of S2 (in late endosomes + lysosomes). Other host factors for spike cleavage and membrane fusion include ATP6AP1, ATP6AP2, ATP6V0B, ATP6V0C, ATP6V0D1, TMEM199, CTSL, ATP6V1A, ATP6V1B2, ATP6V1C1, ATP6V1E1, ATP6V1G1, ATP6V1H, TOR1AIP1.

4. Endosomes recycle ACE 2 Receptors to the Plasma membrane while viral RNPs enters the cytoplasm to be Replicated into – strand RNAs or directly transcribed into Viral proteins. Transcription of Orf1a polyprotein yield NSP’s 1-11. NSP’s 3 and 4 induce the formation of Double Membrane Vesicles. Host factors for endosomal recycling include retromer (VPS26A, VPS29, VPS35, SNX27, ), commander (COMMD2, COMMD3, COMMD3-BMI1, COMMD4), P3IK (PIK3C3, WDR81, ACP5)

Justapositioning of the ER membranes in the cisterna is probably mediated by NSPs 3 and 4. Initial Fission of Fusion probably creates Double Membrane Spherules that later evolve into larger double membrane vesicles.

5a. Cellular Translation of viral proteome.

5b. Cellular transcription and replication of viral RNA via the RTC ( Replication Transcription Complex ) occurs inside Double Membrane Vesicles and + strands are exported through a NSP 3 protein based intermembrane pore. Required host factors for transcription include SLTM, and SPEN.

6. Protein synthesis (including ribosomal frameshifting) and processing at the rough endoplasmic reticulum except vsgRNA coding for some ORFs and Nucleocapsid protein may be translated elsewhere (ie. cytoplasm)

7. Viral protein processing in the ER using host factors DPM3 and ERMP1, ERGIC, Golgi apparatus requiring host factors PPID, and CHST14, and Lysosome.

8. Viral assembly and budding into the Endoplasmic Reticulum and ERGIC.

9. Virus Release or Egress via the Lysosomal Exocytosis System. Host proteins involved include FC0L1 SNARE 23, Kinesins, VAMP7, Synaptogamin iv, and the Lysosomal Calcium export channel (TRPLML1).