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BLAST It!

BLAST It!. Disease Diagnosis using bioinformatics. The Case Study. Whenever you see this diagram, make a diagnosis and recommend medication to your patient. You are a General Practitioner working in Melbourne, Australia. It is the first of June, the beginning of the winter season.

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BLAST It!

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  1. BLAST It! Disease Diagnosis using bioinformatics

  2. The Case Study Whenever you see this diagram, make a diagnosis and recommend medication to your patient. You are a General Practitioner working in Melbourne, Australia. It is the first of June, the beginning of the winter season. A male patient 30 years of age walks into your office…..

  3. Symptoms that began 24 hours ago During consultation, he tells you that he has just arrived home from working in China, mainly in Hong Kong. Your diagnosis (record this in your worksheet). Recommended medication. Advise to patient. Source: http://www.sla.purdue.edu/academic/fll/JapanProj/FLClipart/Medical.html

  4. After 47 Hours… The patient returns with a severe fever. You take his temperature and it is 40oC! He has a severe cough and complains of difficulty breathing. You listen to his chest and alarmingly, it sounds like there is a huge build up of fluid in the lungs. Has your diagnosis changed? Recommended medication. Advise to patient.

  5. After 48 Hours… Outside your office, he collapses and you are called to the scene. What is your recommendation for this patient? You take a blood sample and send it to pathology marked URGENT!

  6. After 60 Hours… Blood test results: • Isolation of an Influenza virus • Isolation of the bacteria Haemophilus Influenzae • What medication do you recommend? You are worried about the speed and extent of infection by the influenza virus, given your patient was young and fit. You decide to do some research into flu viruses.

  7. 3 Flu Types: What type of influenza do you think your patient is infected with? Influenza B Influenza A Spreads fast Influenza C Mild infections

  8. To identify the Flu virus… You mark a sample of the virus ‘URGENT!’ and courier it to a laboratory for Gene Sequencing. This is an accurate way to find out what type of flu virus it is. What is Gene sequencing?

  9. C G T A A T G A G T T A A A T C A T G G A What is Gene Sequencing? Gene sequencing is identifying and determining the order of the base pairs in a segment of RNA or DNA . . . T T A T G A G A A G G G A A A G A A C T T T Answer question 1 in your worksheet.

  10. Back in the sequencing laboratory… • Scientists are busy sequencing the gene that codes for the production of a particular protein found on the surface of the virus, the N protein. • This surface protein is an antigen. Influenza antigens are used to identify specific strains of this virus.

  11. Antigens identify Flu strains Influenza viruses are named according to the antigens (proteins) sticking out of their virus coat. (H) There are two types of antigen = Nand H. In different virus strains, the shapes of N and H are different. There are 9 known N and 16 known H types. (N)

  12. The role of flu virus antigens The H antigen is like a key that allows the virus to enter into cells with a matching lock. This allows the virus to replicate inside the cell. Bird Flu H allows the virus to infect bird intestinal cells. Human Flu H allows the virus to infect human lung cells. The N antigen is required to cut the virus away from the host cell so it can spread to infect more cells. The N shown above has its cutting site blocked by a drug designed stop the flu from spreading. Answer Question 2 (a)

  13. N cuts the links between the viruses and the cell surface so virus particles are free to go and infect more cells. H attaches to cell surface proteins so virus can enter cell Virus Proteins on cell surface Virus genes are released into the cell. The lung cell is ‘tricked’ into using these genes to make new virus particles. Human Lung Cell

  14. How your patient responds to antigens… The H and N antigens are like the ‘face’ of a flu virus. If the virus strain has infected you before, the virus ‘face’ is recognised and your immune system goes to war fast! The virus is killed off and sometimes you don’t even get sick. If the virus ‘face’ changes slightly (genetic drift), it can still be recognised quite quickly and your immune system will fight fast. You may be sick for a few days. If the virus ‘face’ changes radically (genetic shift), it is not recognised. it takes longer for your immune system to prepare for war. The virus takes hold and can make you very sick. Answer question 2(b) in your worksheet. Major changes to the shape of the virus ‘face’ can cause a Pandemic

  15. Pandemics Outbreak in Kansas and Africa, 1918 The Spanish Flu in 1918, killed approximately 50 million people. It was caused by the H1N1 strain of influenza A. The Asian Flu in 1957 was the H2N2 influenza A strain. Worldwide it is estimated that at least one million people died from this virus. The Hong Kong Flu in 1968 evolved into H3N2. 750,000 people died of the virus worldwide

  16. Naming the Flu • A/chicken/Korea/01(H9N2) • Influenza Avirus was isolated from achicken in Korea in 2001. • The antigen types wereH9andN2 Try some yourself: A/swine/Ehime/80(H1N1) A/Tokyo/67(H2N2) A/duck/Hainan/2004(H6N2) B/Nanchang/97 NB. Occasionally you will find more in the name. For our purposes today, ignore those letters &/or numbers Answer question 3 in your worksheet

  17. After 70 Hours…You have your Sequencing Results • Click on the ‘i’ button to view the DNA sequence for the N antigen from your patient. • Save this sequence to your desktop for later use. You can now use this sequence to find out the type of Influenza infecting your patient. • To do this launch internet explorer and type in the following URL (or click on this link): http://www.ncbi.nlm.nih.gov/

  18. Run an NCBI Search • Click on BLAST in the menu • Click on the nucleotide blast • Paste the sequence into the big text box • Ensure “others (nr etc)” is selected from the database options • Scroll down and click on the BLAST! button • When the next page appears, Click Format and Wait for your results….

  19. Your Results • Scroll down and look at the alignment for the first result. It looks like this: Compare the two Sequences: Answer questions 4 & 5 on your worksheet. • Next, Scroll back up the page until you see a list of ‘Sequences producing significant alignments:’ Click on the first one. Answer questions 6 – 9 on your worksheet.

  20. Your Results cont… • Now use the “back” arrow on the toolbar to return to the previous screen. Look down the list of matches for your gene to find other animals infected with H5N1. Answer questions 10 & 11 on your worksheet.

  21. After 80 Hours WHO Your patient lost consciousness overnight and is on life support You look up patient mortality for this virus by visiting the World Health Organisation (WHO) website (click on link button) Look at the latest report of human cases Answer question 12 in your worksheet.

  22. Could H5N1 Cause a Pandemic? The epidemic of flu caused by H5N1 began in Korea in December 2003. Since then it has spread to other Asian countries. H5N1 bird flu occasionally infects humans but at this stage humans do not pass this infection on to other humans. The spread of infection in birds means more humans will come into contact with and be infected by H5N1 bird flu. The concern? Eventually a pig will be infected with a human flu and a bird flu at the same time. They will serve as a ‘mixing pot’ for the two flu types to swap genes. The Result? A new flu subtype can emerge which easily spreads from person to person. An influenza pandemic would then occur. This process of repackaging of viral genes is called reassortment. It is illustrated in the next slides.

  23. Reassortment Influenza A infecting a human. Can spread from human to human due to H and N proteins on surface. Influenza A infecting a chicken. Can occasionally infect humans but cannot spread from human to human due to H and N proteins on surface. Pig can become infected easily with bird flu and/or human flu. Serves as a mixing pot!

  24. Virus coats break down and RNA genes move to the cell nucleus to be copied and transcribed. Repackaging of genes creates a virus that can now transfer from human to human! PANDEMIC? Viral genes are copied and prepared for packaging into new virus particles.

  25. Talking to the Parents WHO site FAQs on Avian Influenza The parents of the patient would like some information on the disease contracted by their son. How would you answer the following questions for them? Answer these questions in your worksheet. Q13. How do people contract this disease? Q14. Is it possible for this disease to spread from our son to those people he was in contact with? Q15. How did he become infected with this strain of Influenza virus? Q16. What available treatment might save his life?

  26. After 130 Hours:The Outcome You diagnosed correctly and saved your patient by prescribing the following medication: • Relenza – a drug designed by Australian scientists which stops ‘N’ from doing its job. The virus cannot spread from cell to cell. • Antibiotics – Anti-bacterial drugs first made available for use by Australian Scientists. Used to kill off the secondary bacterial infection in your patients lungs caused by Hemophilus Influenzae, the causal agent of pneumonia Answer question 17 in your worksheet.

  27. EMERGENCY MEETING Emergency influenza convention to discuss the H5N1 pending pandemic. Formulate recommendations for the Australian government and report back to the Australian Advisory Committee for Infectious Diseases.

  28. AUSTRALIAN ADVISORY COMMITTEE • Avoiding an H5N1 Influenza Pandemic • Your class consists of delegates attending a convention on influenza. Together you will: • Report on travel warnings that you believe should be issued by the Australian Government to citizens travelling to Asia. • Recommend strategies that the Government should employ to ensure H5N1 does not enter Australia. • Recommend precautions that the Government should take to ensure Australia is prepared for a H5N1 influenza outbreak • Discuss strategies that should be employed to stop H5N1 becoming the next Influenza pandemic Source for photograph: http://i.cnn.net/cnn/2003/HEALTH/03/27/illness.qa/story.hk.mystery.illness.af.jpg www.who.int/.../ 2002/illness.html

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