1. Emerging Infectious Diseases (EID). Where do they originate
Emerging Infectious Diseases (EID). Where do they originate? What do we do? Why do we care?
Most major human diseases have come from animals and our interaction with them. With increase in globalization of products (agricultural, particularly animal) and movement of individuals, the spread can be much faster and harder to contain. We care because we may not have appropriate treatments for the resulting diseases and because of their economic impact. Distribution is not related to the seriousness of the disease as some of the African diseases include hemorrhagic fevers and many of the high population areas represent flu.
Global richness map of the geographic origins of EID
events from 1940 –

2. The Realities in Global Trends
•EIDs are a significant burden on global economies &
public health.
•EID emergence thought to be driven by socio-economic
environmental & ecological factors.
The economic data are for The damage to livestock may be greater than $60 billion in the last 15 years. Call for new drugs and vaccines totals multiple billions of dollars. This excludes the monetary value of illness and death of individuals.

3. Definition of a Pandemic: Tracking Swine Flu using Google Maps
Introduce the definition of a pandemic using H1N1 Swine Flu pandemic of 2009 as an example Also, illustrates modern technology using Google maps who take data from WHO. At the time of this capture from Google Maps, 103 people had died in Mexico showing a recent update. Purple marker is confirmed or probable. Pink marker is suspect. Yellow marker is negative. Fatal cases have no dot. For most recent data go to
pandemic – occurring over wide geographical area and affecting an exceptionally high proportion of the population.

4. zoonotic diseases or zoonosis: infectious diseases that can be transmitted from other vertebrate animals to humans. May be direct or via a vector.
Seventy five percent of recent emerging diseases are transmitted between animals to humans, some using an intermediate vector. Sixty percent of all human pathogens are classified as zoonosis with bacterial, fungal, viral and parasitic representatives.

5. Zoonotic Diseases: Five Stages through which pathogens
of animals evolve to cause disease in humans.
Critical transitions:
•Stage 1 to Stage 2: from animal to human
•Stages 3 & 4: pathogen’s ability to sustain cycles of human to human transmissions
Ex. modern Ebola outbreaks are stage 3.
There is a tendency for greater transmission between animals in areas with high biodiversity. Human interactions in these areas allow for infectious agents to jump hosts. Different infectious agents behave at the levels shown in this figure.
2007 Nature 447,

6. Global Trends Results •EIDs events have risen significantly over time.
•Peak 1980s attributed to HIV.
•EIDs dominated by zoonoses (60.3%).
•71.8% of zoonoses originate in
wildlife (SARs, Ebola) and this
trend is increasing.
•54.3% caused by bacteria or
rickettsia.
•25.4% by viruses or prions.
•Drug-resistant microbes are
Increasing.
•Data reveal substantial risk
of zoonotic & vector-borne EIDs
at lower altitudes (below equator)
where reporting effort low.
2008 Nature 451,

7. List of NIAID Emerging and Re-emerging Diseases
Group I—Pathogens Newly Recognized in the Past Two Decades
Acanthamebiasis Australian bat lyssavirus Babesia, atypical Bartonella henselae Ehrlichiosis Encephalitozoon cuniculi Encephalitozoon hellem Enterocytozoon bieneusi Helicobacter pylori Hendra or equine morbilli virus Hepatitis C Hepatitis E Human herpesvirus 8 Human herpesvirus 6 Lyme borreliosis Parvovirus B19
Group II—Re-emerging Pathogens
Enterovirus 71 Clostridium difficile Mumps virus Streptococcus, Group A Staphylococcus aureus
The list does not include agents of biological warfare.
Acanthemebiasis- meningoencephilitis caused by A. castellani
Australian bat lyssavirus (ABLV) is virus similar to rabies
Babesia- protozoan parasite causing hemolytic disease
Bartonella henselae- causes cat scratch fever and endocarditis, etc.
Ehrlichiosis- tick borne bacterial infection similar to Rocky Mountain Spotted Fever
Encaphalitozoon sp. Are eukaryotic parasite species of Microsporidia, opportunistic pathogens in immunocompromised and can affect brain, respiration, cause diarrhea
H. pylori are causes of ulcers.
Hendra or equine morbilli virus- zoonotic virus causing respiratory and neurological disease and death. Severe disease in horses.
Parvovirus B19- transmitted in preschoolers by contact, causes rash, fever, severe impact on pregnant women.
Enterovirus 71- potential to cause severe neurological disease but can be asymptomatic.
Clostridium difficile- severe diarrhea, often recurrent and more antibiotic resistant.

8. Why are many EIDs linked to Viruses?
Viruses have
•High rate of mutation, contact between species, spread from
isolated populations.
•RNA viruses – unusually high rates of mutation
lack the proofreading mechanisms seen in DNA replication
•Examples of RNA virus EIDs: common cold, measles, mumps, polio
HIV or AIDs
Ebola – hemorrhagic fever
West Nile & other emerging viruses causing encephalitis
SARS – severe acute respiratory syndrome ( )
•Examples of DNA virus EIDs:
hepatitis, chicken pox, herpes infections
Ebola virus

9. Infectious Disease Cycle & Persistence
Outbreak
Spread
Resistance
Dependent on duration of infectivity in host.
•Rate of infection of new hosts.
•Rate of development of host protective immunity
•Population density, size, and structure: may eradicate
locally but persists regionally.
Persistence of transmission among humans depends upon the duration of the infectivity in its host, rate of infection of new hosts, rate of development of human immune response, and population density, etc. Critical transitions include transmission from animal to human and sustaining cycles of transmission; thus the outbreak, spread and resistance factors.

10. How does an Influenza Pandemic Occur?
Video
Backup copy of the Video

11. Schematic diagram of the influenza
viral life cycle.
Animation: Influenza Virus Replication
Entry into cell is by endocytosis and caused by attachment of viral proteins to cell surface receptor. (HA viral protein to sialic acid on surface of host cell membrane). Viral genome escapes endosome and moves into nucleus where the segmented genome can be replicated (first because viral genome is negative sense) and then transcribed to make protein products. Viral surface proteins are packed in the Golgi apparatus into vesicles that fuse with the host plasma membrane. Viral genome segments are also packaged at the plasma membrane. This provides the opportunity for mixing of viral segments when a single cell is infected with different viral genomes.
Figure 2: G Neumann et al. Nature 459, (2009)

12. Experts predict next epidemic will start in animals.
USA Today. October 22, 2008.
First known case Swine Flu (H1N1): March 28, 2009.
First known case US: April 17, 2009
April 26th: New Zealand, France, Israel, Brazil, Spain report cases.
86 deaths in Mexico attributed to swine flu.
June 11th: Pandemic declared by WHO. The first influenza pandemic in the last 40 years.
July 14th: WHO authorizes pharmacy companies to manufacture vaccines.
August 27th: US colleges see spike in number of cases.
September 4th: WHO announced 625 deaths in the last week.
October 5th: vaccine ready.
October 24: President declares a national emergency.

13. What is the greatest fear of scientists and policy makers?
Attendance exercise:
Why did the President declare a national emergency concerning swine flu?
What is the greatest fear of scientists and policy makers?
What do we need to know to Predict and Prevent? 1. interspecies transmission, 2. assortment of genome segments, and 3. human to human transmission. In addition to causing deaths, particularly among younger individuals for this epidemic, there are economic impacts and fear.

14. containing 11 viral genes.
Swine Flu or H1N1 is an influenza A virus
containing 11 viral genes.
Genome consists of
8 segments of single
stranded RNA.
Genes encoded include:
polymerase PB2
polymerase PB1& PB1-F2
polymerase PA
hemagglutinin HA
nuclear protein NP
neuraminidase NA
matrix proteins M1 & M2
nonstructural proteins NS1 & 2
Naming of Influenza A viruses is dependent upon the two surface proteins or surface antigens- HA and NA. HA is needed for entry into host cell and NA is needed for viral exit from cell. Changes to HA and NA cause the virus to have a different type, i.e. H5N1 or H2N2.
Neumann et al Nature 459,

15. Where did most recent H1N1 come from?
Original reservoir was birds
1918: human influenza A (H1N1) pandemic – transfer from chickens
1918: Cedar Rapids Swine Show influenza A transmitted to pigs from humans.
1931: documented infectious transmission
1933: used ferret model to document transmissibility for human & swine viruses.
1918-present: evolution of virus in humans.
1957: H1N1 abruptly disappeared from humans.
Illustrates mixing of segments of genomes and alterations to HA and NA antigens over ~90 years and through various hosts.
Morens et al NEJM

16. Genesis of 2009 Swine-origin H1N1 Influenza Viruses.
This representation follows the mixing of the segmented genome to provide the 2009 version of H1N1.
Neumann et al Nature 459,

17. Monitoring for Influenza viruses
MSNBC Video: H1N1 Virus
We can watch virus evolution.
This requires large-scale sequencing of viruses isolated from patients.
After this, bioinformatic analysis shows which ones are evolving most rapidly. These are, on evolutionary principles, the most likely to be problematic in the future.
video backup link

18. US Vaccine Evaluation Centers

19. Prevention and Control
Possibility #1

22. Each of the three chosen viruses is mixed individually with a non-pathogenic variant of influenza that grows well in eggs. The virulent strains do not grow well in eggs and genome shuffling is used to move the genome segments for HA and NA into the non-pathogenic virus.

26. Prevention and Control Possibility #2
Antiviral drugs interfere with viral specific proteins:
adamantanes: block ion channel formed by M proteins (M proteins used for escape from endosome).
Oseltamivir (Tamiflu) and aznamivir: neuraminidase inhibitors block release of new virus particles.
M protein with 2 adamantanes bound
Blue protein is the M protein and orange/yellow spheres are adamantanes (
A 10 pack of Tamiflu B

27. + Why? Dengue Fever on the watch list. Why? Video from ABC News
•Caused by one of 4 different, but related viruses.
•Carried by mosquito, Aedes aegypti
•4-6 days for symptoms to appear.
Often referred to as break-back fever
Mosquito borne diseases that were mostly confined to tropical regions are moving further north. Wet conditions provide environment for successful crops of mosquitos. +
Why?
video backup link

28. Antibiotic resistance: MRSA Infections
•Methicillin-resistant Staphylococcus aureus.
•Resistant to broad range of antibiotics.
•Harmless unless enters body through cut or wound.
•Deadly to those with weakened immune systems.
•Hospitals, assisted living facilities.
•Teams, locker rooms.
•2M people/year infected in hospitals. ~100,000 deaths.
Kellen Winslow played tight end for the Cleveland Browns in He was one of many athletes to be infected with MRSA as this resistant bacterium makes its way out of the hospital and into the community.
Kellen Winslow, Oct 21, 2008

29. MRSA Infections – RPI News: August 16, 2010
•Develop antimicrobial coatings for hospital surfaces
•Carbon nanotube-enzyme conjugates made with
Lysostaphin, a cell wall degrading enzyme
•Lysostaphin from non-pathogenic strains of Staph bacteria
had >99% MRSA killed within 2 hours.
Can’t kill the bugs- protect the surfaces from providing a resting site for the infectious bacteria. Obviously work on smaller surfaces best at this time.
R Pangule et al. JS Dordick
2010 ACS Nano 4,

30. Antibiotics: An Uphill Battle
April 14, 2008
•Short period of effectiveness.
•Emerging drug-resistant pathogens.
•Cost of R&D without promise of profit margin.
•Mother nature more clever than humans!
•Focus on natural products- novel compounds
Bacteria acquire resistance in short time periods of less than a year to maybe 10 years for some antibiotics. Chemists fight back by modifying the chemical structure of the antibiotic and overcome resistance. Evolution shows this as a battle between bacteria and chemists. Who do you think wins? Thus fewer new antibiotics are developed. They are expensive and have very limited time of application. It is a better business plan to develop drugs for cholesterol, high blood pressure, erectile dysfunction as these have a more lucrative future.

31. Focus on Under Developed Nations
The Need for New Ideas
Focus on Under Developed Nations
•Focus on Tuberculosis- second most lethal infectious disease
•Bill and Melinda Gates Foundation – October 21, 2008
•X PRIZE to fight tuberculosis worldwide-effective diagnosis
Gates Foundation was one of the sponsors for conference on TB diagnostics. India has been adept at developing generic drugs for AIDS and vaccines for hepatitis. Now moving toward diagnostics for disease like TB where most TB is treatable. However, TB is becoming drug resistant in certain environments. Foundation also supports new drug development and would like to see a vaccine for TB.
The X PRIZE is a competition to create point-of-care-diagnostics to help eradicate TB in developing countries. Help prevent 2 million deaths annually in 22 high-incidence developing countries.