Replication of Coronavirus- Easy to Understand

1. Covid-19 is caused by SARS-Co, a beta coronavirus
2. Covid-19 stands for Coronavirus Disease 2019.
3. SARS-Co(Severe Acute Respiratory Syndrome) is caused by bats and had a outbreak in 2003.In 2012 coronavirus also caused MERS-Co (Middle East Respiratory Syndrome).
4. Coronavirus has positive stranded RNA protected by lipid bilayer. The lipid bilayer is also covered with protein called spikes.
   
   
   
5. The segmented positive stranded RNA weighs about 30kb.
6. The incubation period of virus is about 2 to 14 days.
7. Covid-19 invades alveolar cells of lungs.
8. Virus binds to peptides receptor ACE-2 (Angiotensin-converting enzyme 2) present at alveolar surface using viral surface protein on RBD (Receptor Binding Domain) region of S1 (spikes).
9. S protein receptor interaction is primary determinant for coronavirus and also governs tissue tropism of virus.
   
   
   
   Note:many Alpha coronavirus utilise Aminopeptidase N (APN) as their receptor.
   
   
10. Host protein such as cathepsin and TMPRSS 2 (transmembrane protease, serine 2) cleaves S protein which leads to exposure of fusion peptide.
11. Virus can also enters the cell by endocytosis.
12. Uncoating of viron and release of genome takes place in cytoplasm.
13. The next step is translation of replicase gene from viral RNA genome.
     
14. The positive stranded RNA genome will be translated using host ribosomes which will make poly proteins, PP1a and PP1ab.
15. Most interesting part of replication of coronavirus is frameshifting during production of viral genome.
    The replicase gene contains ORF-1a(Open Reading Frame) and ORF-1b and the frameshifting is occurring between these two.
16. ORF-1a and ORF-1b together called as replicase polyproteins.
    
    

    

    
    
    
17. PP1a and PP1ab are again converted into bunch of smaller protein by proteolysis.
18. This bunch of protein will act as RNA polymerase for reading of positive RNA strand leading to replication.This will give rise to negative stranded RNA.
19. Now this single stranded negative RNA can make viral RNA genome and can also help for making sub genomic mRNA by discontinuous transcription.
20. The negative stranded RNA can we make different mRNAs that can be translated into different proteins.
    RNA dependent RNA polymerase transcribes negative stranded RNA at different sites giving rise to different mRNA strands with different lengths.
21. These are nothing but viral proteins which will be packaged again in the virus.This protein formation takes place in ribosomes present on endoplasmic reticulum.
    
    
22. Attachment of body parts of viron takes place at Golgi apparatus.
23. The progeny virus is released by the host cell using secretary vesicles by endocytosis.
    
    
    
    IMMUNE RESPONSE 1:

1. Now that is it all about the life cycle, of moving on to the chemicals released during replication and their effects.
   during replication virus also damages the alveolar cell which leads to inflammatory response by the cell.
2. Damaged alveolar cells release interferons, cytokines and intracellular components.
3. Alveolar macrophages detect the cell injury as a result of cytokine presence, which leads to alula micro first release other cytokines such as TNF alpha, interleukin 1, interleukin 6, interleukin 8 and other chemokines.
   interleukin 1, interleukin 6 and interleukin 8 are responsible for causing fever.
4. Inflammatory process in lung parenchyma also stimulates nerve endings which are responsible for initiating cough as reflex.Thus people of present dry cough in early infection.
5. TNF alpha and interleukin 1 are proinflammatory cytokines with increased vascular permeability and increase in expression of hidden molecules which enters via intercellular space and blood vessels.
6. This allows involvement of more immune cells including neutrophils and monocytes.
7. Interleukin-8 release by alveolar macrophage will recruit neutrophil another chemokines will attract monocytes.
   increase permeability leads to leakage of fluid into interstitial space causing interstitial edema and also into alveoli causing pulmonary edema.
8. As a result it will cause dyspnea and impaired oxygenation leading to hypoxemia (decrease level of oxygen in blood)
9. Increase level of neutrophils and monocytes leads to rise in WBC count in blood.
10. No doubt neutrophils are very helpful engulfing debris and bacteria but during the process it releases some toxic chemicals as their byroducts which are harmful for surrounding tissue of alveoli.
11. WBC damages Bellevue hasil mein releasing other inflammatory mediators including leukotrienes and prostaglandins. Leukotrienes causes broncoconstriction while prostaglandins causes fever.
12. Decrease oxygen level in blood stimulates chemoreceptors in the aotic arch and the brain.
13. The stimulated chemoreceptors will again stimulate cardio pulmonary centre in the brain to tell the lungs to breathe more to increase oxygen level in blood and also tell heart to come faster to deliver the oxygen to cells in the body.
    
    IMMUNE RESPONSE 2:

1. Other alveolar macrophages can also detect the virus using their special receptors called toll like receptors.
2. This macrophages can engulf virus particles by phagocytosis, process it and present it, on its the surface.
   
   Note:the studies have shown that spike protein of virus are usually presented on the surface.
   
   
3. Interleukin 6 also stimulates hepatocytes of liver for acute phase reactants including CRP, fibrinogen and hepatoxin.
   
   Note: CRP is a marker of inflammation.
   We might think accumulation of fluid, ventilation perfusion mismatch, hypoxemia  is related to heart, but it's not related to heart, it occurs due to lung injury and that's why it is called as acute respiratory disease syndrome(ARDS). Heart secrete troponin which is a marker of cardiac injury.
4. Recipe of disease may vary from mild infection to life threatening.
5. Life threading may include respiratory analogue, shock, multiorgan dysfunction like liver heart and lungs and also ctokine release syndrome.
   How will you differentiate between covid-19 and pneumonia
   
   So here are some factors which differentiate them
   Pneumonia patients have leukocytosis increased LFT, increased LDH level and increased CRP level.
   Whereas covid-19 patients suffer from lymphopenia dry cough dyspnea fever high CRP presence of troponin and interleukins.
   
   How to differentiate between covid-19 and influenza.
   
   Covid-19 and influenza similarities presentation transmission symptoms everything is same. Just the difference is influence has vaccine, covid-19 do not have vaccine. It is tough to identify and differentiate between the two.