Suchman Virology 2005

What is New in Virology?: 

What is New in Virology? Erica Suchman, Ph.D. Colorado State University Department of Microbiology, Immunology and Pathology Chairperson Technology Enhanced Education Committee American Society for Microbiology (NOTE: Materials in RED added after session with updates from ASM 2005)

What’s new in virology?: 

What’s new in virology? Re-emerging viral diseases Emerging Viral Diseases TSEs Fact or Fiction? RNAi to fight arboviral diseases (and HIV? Nature May 2005) What should micro students know? Virology in the MicrobeLibrary

Re-emerging viruses: 

Re-emerging viruses Dengue, DHF, DSS Yellow Fever West Nile Encephalitis Decreases in mosquito control programs increased mosquito ranges Infected mosquitoes moving to new areas

Aedes aegypti mosquito distribution: 

Aedes aegypti mosquito distribution CDC

Dengue Occurrence : 

Dengue Occurrence CDC

Historical background, WNV encephalitis: 

Historical background, WNV encephalitis discovered in 1937 woman with a fever in the West Nile District of Uganda. Thousands of infections recognized: Africa, but most have been characterized by headache, fever and rash only. 1st in N. America, New York City in 1999, with encephalitis reported in humans and horses Primary vector: Culex pipiens

Slide8: 

CDC

WNV in humans:Most People asymptomatic~20% West Nile Fever, fever headache, trunk rash (very much like the flu)<1% West Nile Encephalitis, can have permanent neurological dysfunction: 

WNV in humans: Most People asymptomatic ~20% West Nile Fever, fever headache, trunk rash (very much like the flu) <1% West Nile Encephalitis, can have permanent neurological dysfunction

WNV spreads from NYC focus, 1999 (the politics of virology): 

WNV spreads from NYC focus, 1999 (the politics of virology) States try to calm the public. Announce that WNV is “just another virus we will have to deal with” Hoped it would not survive winter. No such luck! Some said that WNV would not be found in their states because they have excellent mosquito control programs. No such luck! Arbovirology in the U.S.A. has been under funded for two decades. The same situation exists in Europe CDC begins to fund upgrades of state and local arbovirus programs

Who else at risk?: 

Who else at risk? 20,506 diagnosed equid infections in 44 states (2003) Dead squirrels, wolves, dogs, mountain goats, sheep, llamas, many raptors (hawks, eagles, other predators/scavengers) Hit the raptors in Colorado very hard, over 100 birds taken to CSU raptor center summer 2002!

1999: 

1999 APHIS

2000: 

2000 APHIS

2001: 

2001 APHIS

2002: 

2002 APHIS

2003: 

2003

Human cases/deaths caused by WNV, 1999-2003: 

Human cases/deaths caused by WNV, 1999-2003

Additions about West Nile from 2005 ASM general meeting: 

Additions about West Nile from 2005 ASM general meeting A talk by Dr. Petersen from the CDC Fort Collins. He indicated that although we are seeing a great reduction in cases in a state after a initial large numbers of infection, he does not believe that is going to be the norm or a trend, in essence he believes it is a coincidence. He believes the number of cases is associated with an increased temperature in the region at the time of the outbreaks. His theory, which only time can test, is that if a region with the virus has an unusually hot summer they will see an increase in cases. However, during the Presidents Forum, Dr Gubler from UHawaii (formerly at CDC FC), indicated that he did not believe that increase in temperature plays a role in increased arboviral diseases (although he was not specifically talking about WNV), so you decide!!!

Emerging Viral Diseases: 

Emerging Viral Diseases ~ every 18 months a new viral disease discovered Are we just better at recognizing new viruses? Are we creating new ecological niches for viral evolution? Increased human population Deforestation Behavioral changes Changing travel patterns High densities of animals and humans together Examples: SARs, Nipah, Hanta, Ebola, Marburg, Avian Influenza, MDR HIV

Avian Influenza: 

Avian Influenza Virus has 8 segments of negative sense RNA 15 subtypes based on HA & NA envelope protein combinations Capable of antigenic drift & shift: reduced herd immunity RNA replication polymerases notoriously sloppy: high mutation rates (drift) minor epidemics Segment re-assortment: cells infected with multiple serotypes (shift) pandemics Animals (pigs and birds) often site of re-assortments: pigs best; can be infected with avian, pig & human viruses.

Avian influenza movement to humans: 

Avian influenza movement to humans Nichol, Arikawa, & Kawaoka. PNAS Vol 97, 23:12411-12412 (2000)

More Avian Influenza: 

More Avian Influenza HA requires cleavage: less pathogenic strains only cleaved by trypsin in lungs & gut, more virulent strains can be cleaved by proteases ubiquitous in avian tissues, replicate everywhere! H5 & H7 most likely to be highly pathogenic Certain combinations of H/N more likely to be transmitted from birds to humans H5N1, H7N1(much less severe) Infections all of avian origin 1957, 1968, 2004; re-assortment in pigs 1918, 1997 (2005? just found in pigs in Asia). (Note: see next slide for additions) Hard to control, feral birds move Current outbreak H5N1: very little human to human transmission has been documented to date Theoretical risk of major pandemic if this changes

Avian Influenza: Added after meeting: 

Avian Influenza: Added after meeting I would like to correct an error I had on the previous slide at the meeting: I indicated that H5N1 was the virus responsible for all the past epidemics, I miss-read the article, it was NOT, it was different in different outbreaks. You will notice if you look at influenza literature that they are often vague about the exact virus responsible in outbreaks. Talk at ASM 2005 by Dr. Taubenberger Armed forces Institute of Pathology (Influenza 1918). He suggested that the 1918 virus did NOT re-assort in pigs as is the common theory, it was not clear to me where he thinks it originated. However, he also discussed why we will probably never know the real cause of this epidemic’s virulence, there are very few samples from before 1918 to compare the virus with, so it is hard to know what the virus looked like BEFORE the pandemic began, so we will probably never really know!

Other emerging viruses: 

Other emerging viruses Ebola recently (May 2005) linked to consumption of bush meat particularly gorillas, chimps, & antelopes (duikers) Reservoir still unknown, humans, gorillas, chimps all dead end hosts Nipah 1998-1999 300 humans 35% mortality: fruit bats to pigs to humans SARs 2003 coronavirus faulty plumbing and civet cats bought live at Asian markets

The TSE story: 

The TSE story TSE: Transmissible Spongiform Encephalopathies Examples: Mad Cow Disease (1990’s) CJD disease (humans) Kuru (humans) Scrapie (sheep, goats) (known for 250 years) Chronic Wasting Disease (Deer and Elk known since 1960s)

Kuru the first TSE: 

Kuru the first TSE Carlton Gajdusek in the 1950s went to study the Fore tribe of Papua New Guinea (1976 Nobel prize award) Fore tribe was cannibalistic: was a sign of respect to eat ones dead relatives Many years later developed Kuru (laughing death) Lack of coordination Slurred speech Coma Death within 6-12 months of first symptoms Much more common in woman then men Thought to be a genetic disease Gajdusek took brain material from Fore that died of Kuru injected into the brains of monkeys, who developed Kuru like symptoms, showed that this was an infectious disease. Called these slow virus diseases due to long incubation period. Convinced the Fore to give up cannibalism, Kuru now extinct

How do TSEs cause disease?: 

How do TSEs cause disease? Stanley Prusiner develops Prion theory (1997 Nobel Prize Award) Infectious prions (PrPsc) are thought to be rouge prion proteins that cause normal prion proteins (PrPc) in the brain to become misshapen. Everyone thought it was a virus, but no nucleic acid could be found (RNA might play a role in protein folding though!!) When this happens the proteins clump together large accumulations of clumps kill the brain cells.

S. Prusiner with normal and abnormally shaped prion proteins: 

S. Prusiner with normal and abnormally shaped prion proteins

Prion Proteins: 

Prion Proteins

Effects of TSEs on the brain: 

Effects of TSEs on the brain

TSEs today: 

TSEs today Early 1990s a cluster of 20 year olds in England develop CJD, which is normally only seen in people over 65 years of age. Concurrently England has been struggling with a baffling new disease in cattle called Mad Cow Disease. (MCD) It is shown that MCD is in fact a TSE Speculation begins that CJD is contracted from eating cows with Mad Cow Disease.

Evidence?: 

Evidence? Large Cats in zoos in UK also developed TSE after eating cows that died of MCD. Domestic cats, Ferrets in UK developed TSE. In a test tube PrPsc can precipitate normal prion proteins. Transgenic mice PrPc knockout mice injected with PrPsc no disease. Transgenic mice over expressing PrPc no disease, over expressing PrPsc disease. Disease prions but not normal ones are resistant to cleavage by proteases that would normally digest proteins Radioactively labeled disease prions have been shown to cross the intestines and the blood brain barrier

How did this happen?: 

How did this happen? Current theory: sheep that died of scrapie were rendered and made into cow protein chow 1980’s Regulations on how dead animals used for feed were rendered were relaxed allowing for less stringent treatment Cows developed mad cow after eating sheep Humans developed new variant CJD after eating hamburger that contained brain or spinal cord material Currently 110 known cases world wide (all M/M at codon 129: genetics play a role) The practice of feeding dead ruminants to ruminants has now been banned in US and UK

Problems in US: 

Problems in US Chronic Wasting in Deer and Elk, Front range CO is main area; spreading rapidly No documented cases of humans getting nvCJD from CWD Yet!! This year first case of MCD in a US cow, that came from Canada Even though the cow could not walk, was made into hamburger, mixed with 19 other cows and ended up in 10,000 pounds of beef that was distributed BEFORE test results came back positive. Feed ban initiated in 1997 not well enforced US does not have as stringent testing as most of Europe and Japan (we do random testing)

Questions that remain: 

Questions that remain Can humans get nvCJD from eating animals with scrapie or CWD? Can we get it from eating tissues other than brain and spinal cord? Where did prion diseases come from? How are they transmitted naturally? What accounts for prion strains? What is the role of RNA in prion folding?

RNAi: 

RNAi Antiviral mechanism important in plants and invertebrates (vertebrates use interferons instead) Being manipulated to turn off viral expression in mosquitoes, possible transgenics that can not transmit RNA viruses. Nature 435:7040 May 2005 RNAi is being explored as a treatment for HIV. Activated by double stranded RNA, part of RNA virus life cycle

Slide38: 

dsRNA: Viral replicative intermediate RNAi in mosquitoes Alexander W. E. Franz, AIDL Adapted from Tijsterman & Plasterk, Cell 117, 1(2004)

What Every Student in a General Microbiology Class Should Know About Virology: 

What Every Student in a General Microbiology Class Should Know About Virology ASM Curriculum Guidelines developed at UEC 1994 and 1997 :Nothing; not considered a required course, just an elective My thoughts: Virus and prion structure and biology, Life cycle and basic replication strategies, Host defense mechanisms against viruses, Prevention, treatment, and diagnosis of viral diseases, Major viral diseases

MicrobeLibrary and Virology: 

MicrobeLibrary and Virology Visual resources: pictures of viruses and disease, animations of viral processes (NEED MORE IF YOU HAVE THEM PLEASE SUBMIT!!) Curriculum resources (must have subscription) (NEED MORE IF YOU HAVE THEM PLEASE SUBMIT!!)

Things I have used in my teaching from MicrobeLibrary: 

Things I have used in my teaching from MicrobeLibrary Pictures and animations from ML Powerpoint animations of viral life cycles Group exams examining replication and treatment of viruses with different types of genomes Viral bioinformatics activity: given sequencing gel of virus, do blast search to determine identity (virology class)

And now for a movie!: 

And now for a movie!

Authors of pictures used: 

Authors of pictures used Joan Barenfanger: Cytomegalo virus CDC: Ebola, Dengue Maps, Charts APHIS: West Nile Maps Maria Lucia Racz: Herpes infected cells Margaret Johnson: Shingles Edward Wagner virology movie Barry Beaty Dengue

References: 

Viral Ecology ed Christon Hurst 2000 Promed at: majordomo@promedmail.org To subscribe to the promed-digest, type: subscribe promed-digest Emerging viral diseases PNAS 97:12411-12412, 2000 Emerging viral infections Curr Opin Infect Dis 14:467-480, 2001 The Public Health Threat of Emerging Viral Disease Jour. Of Nutrition 127:951-957, 1997 References