Introductory Comments

Definition of Disease

Types (Infectious and non-infectious)

Link to Society?

Disease and Society Linked

Self-preservation and cohesion
Universal sensitivity to certain diseases

Common enemy

Outcomes
Advances/progress

Other Effects of Disease on Society

Behavior (e.g.HIV)
Policies
Outcomes of Wars
Religion (e.g. Christianity and Smallpox)
Economic Effects

Bottom Line: Diseases have shaped the World

History of Medicine
Focus: Western Medicine (800-50 BC)
Fifth Century B.C. Greece
Three Types of Healers

1)Physician-Seers
Combined Magic and Drug Treatments
2)Wound Healers
Battlefield Trauma
3)Medical Dietetics
Athletic Trainers

Father of Western Medicine: Hippocrates

Hippocratic Medicine-400B.C.
How does the environment affect health and disease?
The importance of balance: Body humors
Blood
Phlegm
Imbalance
Disease
Yellow bile
Black bile

Treating Imbalances

Conservative approach
Diet
Rest
Exercise
Limited drug use

Herophilus (330-260 BC)

Erasistratus (330-255 BC)
Greek empire spreads (Alexander the Great)
from Northern India to France to Iraq
Inhabitants (Hellenistic-Greekish)
Inferior?!!!
Point: Unwilling subjects for human dissection

Results:
Circulatory and Nervous Systems, Eye, Female
Reproductive Organs, and Physiology

Roman Medicine 250 BC to 200 AD

Galen (129 to 216 AD)

Background (Galen)
Extraordinarily wealthy
Medical Education (Hippocratic view)
longest known (age 16-28 yrs.)
Cultured
Experience
Man of influence
Travel

Galen

Contributions
Animal experiments and dissections
Patient involvement in healing (bedside manner)
Surgery skill

Early Christianity(300AD)
New Trends (Fall of Roman Empire-Middle Ages)
Healing by church and not by physicians
Downside
Healing by...
Prayer, Confessions
Laying on of Hands,
Exorcism, Miracles
Upside
Hostels

Middle Ages (1200s)

Continued emphasis: Four body humors

Formal medical training and degrees
1st pandemic in Europe: 1348
Outcomes (Sanitation):
Burial regulations
Quarantines
Water control
Cleansing & burning of contaminants

1600s (Scientific Revolution)

Descartes
Mechanical Theory

Harvey
Discovers mechanism of blood circulation

Significance
Descartes and Harveys Mechanical views contradict
humoral theory of Hippocrates and Galen

1700s
Medical Police
Enforce health regulations from the
cradle to the grave.
Why? Health facilitates dominance
e.g. Smallpox and Variolation

Early 1800s (France)

Population growth and urbanization
French emphasize (3)
1)Hospitals (Paris medical school)
lots of patients
2) Hourly observations recorded
Diagnosis and prognosis
3) Pathological anatomy
Postmortem examinations

Limitations: Causes of disease?

1830s and beyond

German Medicine
Medical research emphasized
Reductionist View (Schwann, Virchow etc.)
Body functions governed by laws of physics and
chemistry
Diagnostic Tools
X-rays, Laryngoscope
Weakness
Treatment approaches lacking
Visualize vocal cords

Mid and late 1800s

Germ Theory of Disease

Miasma-Poisonous air particles cause

disease OR
Contagion-living parasites cause disease

Which is correct?
Louis Pasteur and Robert Koch-Germ Theory
Importance:
Living creatures cause infectious disease

1900s
Microbiology
Infectious agents

Bacteriology-Bacteria cause certain

diseases
Virology-Viruses cause certain
diseases
Protection from infectious agents
Immunology-guards with great memory

History of Chinese Medicine

1000

B.C.

Premedical Health Care

Well-being of living & non-living ancestors
Cause and Cure:
communication with dead
Optimistic View

Premedical Health Part II

Next Premedical Emphasis

Disease cause: Demons

Cures: Release demons (spells & acupuncture)

Pessimistic view

Traditional Chinese Medicine

100 B.C.-Present day

De-emphasis on metaphysical health care

Human organism composed of functional units
Unit function: store, process and transport chi
Disease cause: units inability to manipulate chi

Diagnosis
Complexion
Pulse
Odors

Origin of Disease?

Two schools of thought:

1) Localistic-Ontological (localized)
Disease results from
A: Presence of hostile entity
B: Body invaded by environmental factor
(e.g. worms, wind, cold etc.)
C: Wars between functional units
Pessimistic

Origins continued...
2) Holistic view
Systemic correspondence
Definition? (a connection to everything philosophy)
Origin of disease?(loss of NORMAL harmony/balance)
Optimistic

Treatments
Holistic approach
Massage
Diet
Acupuncture
Moxa cauterization
Sexual activity

Late 1700s, 1800s, and 1900s

Fragmentation of traditional Chinese medicine1700s and 1800s

Western approaches embraced (e.g. surgery) during
1800s and 1900s
Following cultural revolution (1966-1976)...
Western and Traditional Chinese Medicine coexist

Western Vs. Traditional Chinese Medicine

The West
Four humors
Localized medicine
Invasive procedures
(e.g., surgery)

The East
Chi
Holistic & localized
Non-invasive

History of Disease

Introduction
Staying sicknesses
Wandering sicknesses
Universal tale of woe
White people bring death
e.g. Those affected: American
Indians, Hawaiians

Causes of death: Older patterns

Old patterns:
Isolation of people
competition for limited resources (hunter-gatherer)
Result:
Death from lack of resources
Modern disease incidence low
Cancer, Coronary disease, TB, Smallpox

Why did people begin to die more

from infectious diseases?
Change in patterns
Neolithic or New Stone Age (10,000 years ago)
Migration
Domestication of animals
Appearance and numbers of urban communities
Result:
Death from infectious disease, cancer, and
coronary disease increases

How do wandering diseases become staying diseases?

The domestication of diseases and the evolution of
coexistence

What are the requirements for coexistence?

Unavoidable interaction between disease and humans leading to
death of weak members of human population & elimination of most virulent microbes

History of Infectious Disease:

The European Middle Ages and Beyond

Expansion of Populations in Europe

How possible (3)?
1) farming
2) trade networks (Europe-Middle East)
3) new and larger urban centers
So much dung and filth of the garbage and entrails as well as of beasts
killed, as of other corruption, be cast and put in ditches, rivers, and
other waters, and also in many other places, within, about, and nigh
unto cities, boroughs, and towns of the realm, and the suburbs of them,
that the air is greatly corrupt and infect, and many maladies and other
intolerable diseases do daily happen. (Robertson, 1986)

Case in point maladies and intolerable

diseases 1346 and 1350

Black death pandemics

Origin: Europe from China

How? Trade routes connected by Mediterranean

Outcome: 1st wave killed 30% of Europes people
Future waves killed fewer numbers

Close of 1400s

Wandering diseases become chronic

staying diseases in Europe
TB, Gonorrhea, Measles, Mumps, Influenza,
Chicken pox, Smallpox, Scarlet fever etc..

Quick, efficient killers become slow,

inefficient killers

European Migration to Africa, Caribbean,

Americas, Australia, and Hawaii

To Africa...
African diseases: White mans grave.
Yellow fever, Dengue fever, Malaria, parasitic
worms
Europe's donation to Africa: Syphilis, TB,
Smallpox, Influenza

European Migration

To the Caribbean...
Three problems:
Isolated for centuries from others
No domesticated animals
Lack of genetic diversity

Case Study:
Loss of indigenous population

Hispaniola
1492 Columbus arrives
population of 8 million
exposed to European staying
diseases (TB, Influenza* carried by pigs,
pox viruses etc..)
Result:
people all sick at once
lack of workers to obtain nutrition
people extinguished within 50 years

The Caribbean continued

Similar fates on other islands...
Europeans create slaves out of weakened
people
Europeans turn to Africa for slaves
Enslaved Africans arrive carrying different
staying diseases
At present: Descendants of African slaves
dominate the populations of the Caribbean

The Americas: The 1500s

Europeans arrive creating a similar result: coastal

areas hit hardest (e.g. Mexico)-Christianity spreads
95% of Mexicos population eliminated within 75
years
Others:
Peru: 93% loss
Nicaragua: 92% loss
California: 98% loss
Florida: 95%
New England: Extinction of Patuxet tribe--smallpox

The Pacific: Australia to Hawaii

1500s, 1600s, and 1700s
Similar outcomes:

The last region invaded by European explorers

Long voyages screened out smallpox and influenza
TB and venereal diseases were the major offenders
Result:
Australia: 95% of Aboriginal populations die
within 60 years
Hawaii: 95% die within 100 years
Cause: never exposed and limited gene pool among
island peoples

To Consider...
Invasion of Virgin-soil conditions lead to holocausts in the past
Q: Are migration-caused health disasters now over because
virgin land is essentially non-existent?
A: NO
Mutations create new bugs (e.g. HIV and AIDS)
Ease and frequency of travel (i.e., bugs hitch a ride)

1700s and 1800s

U.S. and Europe

Intense Urbanization:
Meat Industry
Lack of city plumbing
Laissez-faire
Outcome:

Cholera

Sanitation programs (plumbing and sewers)

Looking to the Future

What are we to do?

(quiz 2 material starts)

Anticipate and prevent (How?)

Focus and sequence of the course:

Infectious agents (e.g. HIV)
Immune system (Defense)
Outbreaks of the past (epidemics e.g. smallpox)

Transmission of Diseases (3)

1)Contact transmission:
A) Direct:body contact between individuals
Horizontal (touching)
Vertical (Mom to fetus)
B) Indirect:nonliving object (fomite) to individual
Fomite examples: coins, rusty nails etc.
C) Droplets (travel less than 3ft. in air)
sneezing, speaking, coughing aerosols (TB) etc.

Transmission of Diseases
2)Vehicle transmission
A)Waterborne

Usually water contaminated

with sewage e.g. Cholera
B)Airborne
Infectious agents that travel
greater than 3ft. In the air e.g. TB
C)Foodborne
Improper cooking & toxins

Transmission of diseases
3)Vector transmission-transmission by insects
A)Mechanical vectors
Infectious agent on insect
B)Biological vectors
Infectious agent inside insect

Reservoir Host Effect on

Disease Transmission
Reservoir Hosts (Reservoirs)
An Infected organism that serves as a
breeding and potential source of
transmitting infectious disease
e.g. Rodents, Humans, Insects etc.

Types of Microbes

Viruses*
Bacteria*
Algae
Protozoa*
Fungi
Helminths*

*Microbes/Infectious

agents highlighted in this course

47

Introduction to the infectious

agents

Viruses
Infectious particles
Carry 1 nucleic acid type:(RNA or DNA)
Acellular
Obligate intracellular parasites

Virus components
1) Nucleic acid core (DNA or RNA)
ds or ss
linear, circular, segmented
2) Protein coat (capsid)-protective cover
Shapes (3)
Icosahedral
Helical
Complex

Virus components continued...

3) Envelope
What?
Lipid layer stolen from host during exit
Where obtained?
Usually from host plasma membrane
Why?
Hiding or masking feature

Q: How do viruses replicate?

A: Obligate intracellular parasites
1)Attach to surface of cell
2)Enter
*3)Use and Abuse-virus babies
made at cells expense
*4)Many virus babies leave cell to
infect other cells
*Steps

which can cause damage

Persistent infections
What?
Infection lasting from weeks, years, or
throughout entire life (Hitchhikers)
Which viruses?
DNA and retroviruses (RNA)not ordinary RNA
viruses
Result?
A) Chronic infections (blisters and warts)
B) Cancer (15%)

How do viruses cause cancer?

Two strategies:
1. Integration causes damage to host DNA
2. Integrated viral DNA contains oncogenes
Result:
Biological clock of cell is disrupted: cell
becomes immortal or cancerous

Treatment of viruses

Goal of chemotherapy (e.g. antibiotics)

Smart bomb targets unique to infectious
agent
Why are viruses a problem?
target sites lacking
Virus becomes a part of the host
Significance?
available drugs are toxic (e.g. AZT)
(Film on Ebola)

Immune defense strategy for viruses

(quiz 3 material starts)

Background (2 points)
1) Immune system needs to recognize the invader
2) Problem with recognizing viruses?
Viruses hide inside cells

Immune defense against viruses

continued
Q:How can immune system distinguish healthy
cells from problematic cells?
A:The MHC class I proteins and cytotoxic Tlymphocytes (CTL)
Evidence of problem (peptide fragment)
brought to surface

CTL
58

The Human species and new (Emerging)

Viruses: We are the problem
Destruction of Environmental Niches
(e.g.Rain Forest)
Why a problem?
Humans stumble across new
reservoirs carrying new viruses
Drug resistance (e.g. AZT)

Introduction to Infectious
Agents: Bacteria

Unicellular approach to life

Shapes (4)
Spherical (Coccus)
Rod
Spiral
Pleomorphic

Introduction to Infectious
Agents: Bacteria

Arrangements of bacteria
Strept-chains (e.g. Streptococci)

Staphylo-grape-like clusters (e.g. Staphylococci)

Virulence Factors:
Weapons of destruction
Types of Virulence Factors
Pili (Adherence)
Flagella (Movement)
Toxins (Survival)
Capsules (Escape from I.S.)
Enzymes (Movement in host)
e.g. Spreading factor

63

Introduction to Infectious
Agents: Bacteria
Antibiotic targets
Cell wall
Protein synthesis (ribosomes)
Bacteria can overcome antibiotics
How?
Extremely short generation time

Significance:
Resistance to antibiotics can emerge

Concepts of bacteriology:
Sharing antibiotic resistance
1 Chromosome

Plasmid

Plasmids
Carry genetic information for resistance
Pili
Transfer genetic information for
resistance

Conjugation

The Human species and new (Emerging)

Bacterial diseases: We are the problem
Antibiotic resistance
Hospitals (nosocomial infections)
Irresponsible physicians and patients
Destruction of Environmental niches

Leads to atypical encounters and disease

e.g. Deer, Ticks, and Lyme disease

Antibiotic Resistance
Introduction
Alexander Fleming & the late 1920s.
Mold contamination of bacteria
Zone of inhibitiona weapon?

This weapon triggers a health-care revolution

Introduction
These weapons became known as antibiotics

A compound produced by a microbe that kills

or inhibits the growth of another microbe.
Selman Waksman (Discoverer of Tetracycline)

Events in the Age of Antibiotics

**
& the rise of superbugs

WHO: One of the 3 greatest threats to human health

*Causes?
**The Future
Modified from Davies, J. et al. 2010. Microbiol. Mol. Biol. Rev. 74(3):417-433

Causes of antibiotic
resistance

Human activities
several millions of metric tons of antibiotics
released since the 1940s.

The biology of bacteria

Human Activities

7 billion humans need food

Growth promotion/Prophylactic use in
livestock
(70% of all antibiotics are consumed by farm animals)

Promotes growth, limits disease

Human Activities continued

7 billion humans are treated

Prophylactic & therapeutic overuse and misuse in humans

Complacency, arrogance, misdiagnosis

Example:

Surgeon General, Jesse Leonard Steinfeld

It is time to close the book on the problem of infectious diseases
1969

Human Activities continued

Bacteria have evolved quickly and dramatically to adapt
to this change in their environment. How?

The Biology of Bacteria

Bacteria reproduce quickly (minutes!)
Bacteria pick up genes for resistance from other bacteria

Summary of Factors

Human activities
several millions of metric tons of antibiotics
released since the 1940s.

The biology of bacteria

Future: Is it possible to reverse

resistance?

Antibiotics target important functions, such as cell wall

synthesis and gene expression. Therefore

Resistance to antibiotics usually leads to a decrease in

biological fitness (Resistant bacteria grow more slowly
than non-resistant bacteria).

Conclusion
Susceptible bacteria should outcompete resistant
bacteria provided we limit our use of antibiotics on this
planet.

Defense from Infectious

Disease: The Immune System

Innate barriers (4 types)

1) Anatomic barriers
Skin
Normal flora
Mucus and cilia

Innate forms of defense continued

(quiz 4 material starts)

2) Physiologic barriers
pH
Temperature
Complement
3) Cells (phagocytes)
Neutrophils, Eosinophils, and Macrophages

4) Inflammation

Adaptive immunity

( B-cells and T-cells)

B-lymphocytes (B-cells)
How do B-cells protect us? (Antibodies)
What do antibodies protect us from?
Bacteria, Extracellular Virus

Adaptive immunity II
T-lymphocytes (T-cells)
Thelper cells
Cytotoxic T-cells or CTL
How protect body?
Coordination (Th) or lysis (CTL)

Background on Smallpox
Killed 300 million people during 1900s
Currently eradicated
How?

Properties of Virus

Complex Capsid
DNA

Properties of Smallpox disease

Entry-mouth and nose
Incubation period (7-14 days)
mucous membranes-lymph nodesblood-internal organs-blood
Disease phase (14 days on)
High fever (106 degrees F)
Pain and vomiting
Spread to skin with pustule formation

Infectious periods
Incubation phase-coughing and nasal
secretions
Disease phase-skin lesions

Virus infectious for months without host

Exploitation of survival traits

General Amherst, American Indians,
and early biological warfare

History of Smallpox
10,000 B.C.
Earliest physical evidence-1157B.C.
Egyptian mummies with pustules
Earliest written records-1346 B.C.

Recently there have been persons suffering from epidemic

sores which attack the head, face and trunk. In a short time,
those sores spread all over the body. They have the
appearance of hard boils containing white matter. While some
of the pustules are drying up, a fresh crop appears. If not
treated early, the patients usually die. Those who recover are
disfigured by purplish scars which do not fade until after a year.

Cortez and Mexico-1500s

Battles with Montezuma and Aztecs
Cortez troops reduced by 30%
Aztecs fail to pursue and complete
victory
Why?
Smallpox carried by a slave

Outcomes
Spanish Conquistadors sparedimmunity (i.e., more of a staying sickness for the Europeans)
Aztecs killed
Interpretation
Spanish God more powerful than Aztec
Gods

Result?
Embraced Christianity and Spanish culture

Desperate measures
Variolation
dried scabs inhaled
scabs inserted into wounds

Jenner, Milkmaids, Cowpox

and Smallpoxa better way
Observation
Milkmaids get cowpox do not get
smallpox (protected)
Vaccines
1. Inject cowpox pustules
2. Inject smallpox
3. Protected

Resistance to Jenner
Medical and Religious leaders

Royal Society of Medicine-England

The Church

Support
Political leaders

Thomas Jefferson
Napoleon
American Indian Chiefs

World Eradication Plan

WHO-1953 global proposalRaise herd immunity
1970-Twenty African countries smallpox
1971-Brazil free of smallpox
1972-Indonesia
1975-Asia
1976-Ethiopia
1977-Somalia
1980-The World

Why Successful?
No animal reservoirs
No insect vectors
Infection restricted to humans
Infection is rarely subclinical (cant hide)
DNA virus (Virus is antigenically stable)
Bottom Line:

Eliminate homes--eliminate infectious agent

Are we done thinking about smallpox?

Day 28military soldier

Still
contagious

Film on bioterrorism

Yellow Fever
quiz 5 material starts

Horror of 1800s in America

Endemic to West Africa
Brought by African Slaves

Caribbean slaves devalued

African slave value increased

History of Yellow Fever: The

Americas

Earliest written record in1648

(Yucatan and Havana)

Fever
Remission
Fever (Death within 8 days)
Jaundice, Abnormal Clotting, Black
Vomit

Yellow Fever in the New World

1793 (Philadelphia is the capital)

Fleets from Santo Domingo and West Indies

Sickly refugees discharged from boats
Heavy rains during summer months
People evacuate city
By September, government
shuts down

Properties of Disease

Stage 1-High fever (105 degrees F)

Severe joint pain and vomiting
3 days

Stage 2-Remission
Loss of fever and headaches etc.
last less than a few hours

Stage 3-High fever

Organ involvement & hemorrhaging
Jaundice and death within 8 days

Yellow Fever, The Louisiana Purchase,

and Napoleon-Early 1800s
Napoleon (1801)
Plans for American Empire
Controlled parts of
Caribbean

Central America
Mexico
New Orleans
North American Midwest to Canada
Haiti

Napoleon continued...
Rebellion by African labor force in Santo
Domingo, a sugar islandcash crop
Napoleon sends Leclerc and troops
Result?
Leclerc and 27,000 troops die
Black troops suffer few casualties
Reason?
Yellow Fever

Outcomes
Because of Yellow Fever...
1. Hopes to control The sugar islands
were squashed
2. Napoleon sells Louisiana territory,
originally intended to provide grain for
workers in sugar islands.
3. U.S. is a modern Super Power

Throughout 1800s
Populations reduced by 50%
Mississippi
Memphis-1878/1879 epidemic
New Orleans
Properties in common?
Near water
Southern/warm

Common stories
Carts with 8 to 9 corpses in rough boxes are
ordinary sights. I saw a nurse stop one day
and ask for a certain mans residence....The
Negro driver just pointed over his shoulder
with his whip at the heap of coffins behind
him and answered, Ive got him here in this
coffin
The Daily Appeal, August 13, 1878

Memphis-1878
How is this disease transmitted?
person-to-person
X
food
X
drinking water
X
Unlike smallpox and others
Typical quarantines not working
Clues
Water association and warm climate

Memphis epidemic-1878/1879
Other casualties ?

111 physicians (microbe hunters) in Memphis

72 from other states
60% died

Second group of Microbe

hunters-1900
Jesse Lazear*1
James Carroll*
Aristides Agramonte*
Walter Reed
*Risked their lives by self-experimentation
1Died during self-experimentation trials

Discoveries using human

volunteers from Havana
Cause
Infectious agent passes through filters
Transmission
Mosquito-to-person
Not: person-to-person
Infectious stage
1st fever stage
Mosquito takes blood meal

Properties of Yellow Fever Virus

Spherical structure with envelope
RNA virus

Vaccine
Max Theiler
Attenuated yellow fever virus
Nobel prize 1951

Controlled but not eliminatedWhy?

1. Two varieties: urban and jungle yellow fever
Urban controlled by eliminating urban mosquito
2. Other mosquito vectors cause jungle YF
3. Monkeys are reservoirs for jungle YF

Influenza

111

Influenza Virus
The epidemic of 1918
Nothing else--no infection, no war, no
famine--has ever killed so many in as
short a period.
Alfred W. Crosby writes in Americas Forgotten Pandemic: The
Influenza Epidemic of 1918

Epidemic of 1918
(Spanish Influenza)
The numbers...
80% of U.S. war casualties died from
influenza
200K die from England and Wales
230K die from Germany
200K die from France

Epidemic of 1918
450K from Russia
500K die from Italy
257K from Japan
Bottom Line:
One of the worst plagues of all time

Properties of Influenza Virus

(To Influence)
Orthomyxovirus
Spherical shape
Helical capsid
7-8 segments of RNA
Envelope w/spike proteins
Neuraminadase (NA or N)
Hemagglutinin (HA or H)

115

Properties of virus

Three types of human influenza virus: A, B, and C

Influenza A
Responsible for epidemics
Infects humans, pigs, horses, seals, birds
Reservoir-aquatic birds (e.g. Ducks)
Different strains can coexist in certain hosts

Bird (Avian) virus grows poorly in humans

Human virus grows poorly in birds
Both grow well in pigs*

NA and HA proteins
Spike proteins
Function:
HA-allows virus to bind to host cells
NA-allows virus to exit host cells
Types in nature:
HA-16 types
NA-9 types

HA and NA proteins and

nomenclature
Naming of strains
H1N2 or H3N4

How does influenza change? (2)

1. Antigenic shift
the result of genetic reassortment that
changes spike proteins completely
e.g., (H3N2) to (H2N2)-leads to pandemics
2. Antigenic drift
the result of mutations that lead to subtle
protein changes e.g. (H3N2) and (H3N2) are
not completely identicalvaccine protection
is incomplete

Mechanism for antigenic drift

RNA viruses
1. Error-prone polymerases
Mistakes (mutations)-affect spike proteins
2. Lack of proof-reading
Mutations not corrected
Bottom line:
Changes to spike proteins are subtle and lead
to IS escape

Mechanism for antigenic shift

Genetic reassortment in pigs
e.g., Pig infected with Avian influenza and human
influenza
H2-rest Avian
Human

H3N2
Avian
Asia:
Humans, pigs and poultry

H2N2
Human

Impact of antigenic shift

Quiz 6 material starts

Last several pandemics

1890
1900
1918-(Spanish Flu)--virulent
1933-H1N1
1957-H2N2 (Asian flu) replaces H1N1 via shift
1968-H3N2 (Hong Kong flu) replaces H2N2 via shift
1977-Reappearance of H1N1
Strains can come back and cause Pandemics after periods
of hibernationWhat are the requirements?

Reappearance of H1N1
Requirements/explanations?
1. Memory/herd immunity must fade
2. Virus must persist in nature (2)
A. H1N1 still maintained in aquatic birds
unleashed
B. Escape of laboratory source of H1N1

Continuing problem
Despite vaccine...
Antigenic shift
Antigenic drift (vaccine protection incomplete)
Plethora of reservoirs (*Aquatic birds)

(no one immune, even those vaccinatedcould lead to a pandemic)

Properties of disease
Virus replicates in ciliated cells of
respiratory tract-nasal passages,
trachea, bronchi
Cells destroyed & loss of cilia defense
Death from...

Bacterial superinfection leading to pneumonia

The impact of influenza on cilia

Factors contributing to flu

resistance
Mucus and cilia action of host
Lung macrophages
Suboptimal in aged, premature, pregnant,
and immunocompromised, or the smoker

Vaccines
Current strains grown, inactivated &
injected each fall into at-risk groups
Challenges?
Antigenic drift of the above-illness possible
Antigenic shift--illness and pandemic

Final thoughts
Continuing problem (antigenic drift and shift)
1918 revisited?
Possible

Older strains maintained in aquatic birds or

Reacquainted via genetic reassortments (antigenic shifts)

Current situation

Pandemic proportions
3.1 million deaths annually
13,000 new infections/day
Over 42 million infected

The Epidemic of the 1900s

131

History of HIV and AIDS

HIV-Human immunodeficiency virus
AIDS-Acquired immunodeficiency syndrome

132

History of HIV and AIDS

June 5, 1981 (CA)

5 homosexuals
Opportunistic disease
By 1983, increase in opportunistic diseases
Conclusions
Sexually transmitted
Transmitted agent suppresses IS
Gay disease?
133

134

History continued...

Search for infectious agent...

Applied epidemiology (Whos at risk?)
Gay disease?
Hemophiliacs
Discovered by French group

135

HIV
Structure
Enveloped virus with spike proteins

RNA nucleic acid core

Preformed enzymes:
RT, Protease, Integrase
(Targets of AIDS Drugs)

136

Strains of HIV

HIV-1
Evolved from SIV in Chimps

HIV-2 (Western Africa)

Evolved from SIV in Sooty Mangabeys

137

How could HIV-1 have crossed

species?
1. Hunter theory (Most widely accepted)
SIV transferred to humans as a result of hunting,
killing and eating chimps or from chimp blood getting
into wounds of hunters

138

How could HIV-1 have crossed

species?
2. Oral Polio Vaccine (OPV) theory
Edward Hooper theory explained in The River

HIV transferred iatrogenicaly (i.e., via medical

procedures)
A million people in Africa in the 1950s exposed to
OPV grown in kidney cells from chimps infected with
SIV
Studies of remaining OPVs used in Africa were
examined for HIV and SIV in 2000samples were
free of these viruses.
139

How could HIV-1 have crossed

species?
3. The Contaminated Needle Theory
The repetitive use of contaminated,
disposable needles in the 1950s by
poor locales to save money provided
SIV the opportunity to cross.

140

How could HIV-1 have crossed

species?
4. The colonialism theory Heart of Darkness
theory by Jim Moore

Late 19th and early 20th century, much of Africa under colonial
control
Colonial rule was harshlabor camps with poor sanitation; food
was scarce and physical demands were extremeindividuals
were fed cheap food, including chimps infected with SIV.

141

When?
1959 plasma sample has tested positive
for HIV
Projection studies suggest HIV was
around in 1930 with a 15 year margin of
error. (Argues against OPV theory)

142

How emerge so quickly since

1930s?
Travel
Blood Industrydonors paidselected
for desperate people
Drug Useavailability of heroin after
Vietnam war1970s
Promiscuous sex

143

Does HIV cause AIDS?

Peter Duesberg says no
Kochs postulates
Correlation 100%
Grow infectious agent in pure form
Inject into host and observe disease
Reisolate and repeat

144

Transmission
Anal sex
Giver infects receiver (the receiver gets it)
(Source: HIV in semen)

Receiver infects giver (the giver gets it)

(Source: HIV in blood gets inside givers penis through sores or
cuts)

145

Transmission
Vaginal sex
Male infects female

Source: HIV in semen

Female infects male
Source: HIV in vaginal secretions

146

Transmission
Oral sex (lower risk)
Mouth to penis (the performer gets
infected)
Mouth to vulva (the performer gets it)not
likely

Penis to mouth (the recipient gets it)

Anus to mouth (1 published case)
147

Transmission and Drug Use

Drug use accounts for 36% of all AIDS
cases in the U.S.
1. IV Drugs- contaminated needles
2. Noninjection drugs
e.g., crack cocaine smokers 3X more likely to be
infected than non-smokerswhy? Trading sex for
drugs/money

148

Mother-to-Child
Studies with infected mothers
26% studies transmitted HIV to unborn child
39% of HIV-Positive women in Nairobi, Africa
have HIV in breast milk

149

HIV and Wisconsin

Total:

2011
150 as of June on the rise
(outpacing 201036% from Milwaukee)

Gender: 83% men

17% women
Age stats: 24% were 15-24
FilmAnd the Band Played on
150

Disease progression

--Quiz 7 material begins

1. Primary exposure (M-tropic)

If Virus can adsorb & penetrate human cell,
2. Virus replicates (Acute symptoms)
3. Immune response
4. Latency in infected cells (several years)
5. Periodic replication with mutations
6. Th cell HIV (T-tropic virus)
7. Thelper cells killed <200 Th cells/ul
blood-AIDS
151

Hope?
Resistant individuals?!!!!!!
Genetic basis for resistance
1. HIV needs CCR5 to infect cells
2. 10-14% Caucasians make only 50%
of normal levels-Resist
3. Some Caucasians (i.e., 1%) do not
make any CCR5-Complete resistance

152

Therapy?
Transplants involving stem cells that are
homozygous for the delta 32 mutation.
Gene therapy

153

Does the prevalence of the CCR5 defect

provide evidence that AIDS is an
ancient disease?

Certain populations encountered HIV or HIVlike infectious agent during ancient times
Survival required genetic resistance
(i.e., CCR5 defect)
As it turns out, the Black Death epidemic in
Europe during the 1300s was responsible for
shaping the prevalence of the CCR5 defect

AIDS may not be ancient, but affected

populations prior to the 1980s (Serum
samples from 50s)
154

The Black Death

(Bubonic and Pneumonic plague)

History
Two great pandemics of
bubonic/pneumonic plague
550 A.D. (100million deaths over 60 years)
Middle ages (30% of Europe dies)

Requirements: rat/flea population

explosion

1346
Weather favors rodent population
explosion in Mongolia
Disease travels from Asia to Europe via
trade routes
How?
Fleas carried in furs
30% of Europes population lost

Outbreaks in U.S.
1st case in U.S. in 1900
Los Angeles in the early 1920s-Last
case of urban plague
Scattered cases in rural areas: Western
Nevada, Northern New Mexico,
Northern Arizona, Southern Colorado

Properties of bacterium
Yersinia spp.
Rod-shaped bacteria
Three species cause human disease
Focus: Yersinia pestis

Transmission: 3 cycles
1st or natural cycle (Sylvatic plague)
Bacteria found in wild rodent reservoirs
Bacteria spreads from rodent-to-rodent
via flea bites

Transmission cycles
2nd cycle (Urban or Domestic plague)
Bacteria spread to urban rodents
Death usually results
Fleas seek new hosts

Transmission cycles
Third cycle (Human plague)
Infected flea from sylvatic or urban cycle
bites human

Disease: Sequence of events

Bacteria injected into blood via flea bite

Blood to lymph nodes (groin area)
Replicate in macrophages
Inflammatory response & swollen groin lymph nodes (Bubo)Bubonic plague-1 wk after bite (Fever, chills, and pain)

Disease: Sequence of events

Bacteria leak out of lymph nodes to
blood-septicemic plague
Emboli form-bacteria block blood
vessels (purple/black lesions of skin
and lung
Lesions erode into air sacs-Pneumonic
plague-infectious via aerosol-death
within 2 or 3 days

Mortality statistics
Bubonic or Septicemic plague
(50-75% mortality untreated)
Pneumonic plague
(100% mortality untreated)

Virulence factors
Enzymes that resist complement
Capsules
Iron storage molecules
Clot digestion enzymes (e.g. spreading)

Prevention and control

Vaccine (heat killed and living)
Short-term protection
Improved living conditions
e.g. contact between humans and
rodents reduced
Antibiotics: Streptomycin, Tetracycline, etc.

Tuberculosis:
Properties of bacterium

--Quiz 8 material begins

Mycobacterium spp.
Rod-shaped bacteria
Many species cause human disease
(Leprosy and TB)
Focus: Mycobacterium tuberculosis

167

History of Tuberculosis
668 B.C.-1st Written proof
1600s (Europe problem)
Consumption
Kings evil

168

History of Tuberculosis

Potts disease
1800s
Epidemic proportions in U.S. & Europe
1% of cities populations die/year
Associated with creative genius
It was the fashion to suffer from the lungs;
everybody was consumptive, poets especially; it was
good form to spit blood after each emotion that was
at all sensational, and to die before reaching the age
of thirty
Alexander Dumas
169

Cause in the 1800s?

Vampires (3)
Life gradually drained from body
Supernatural appetite of sick
Families of vampires
Recourse?

Exhume dead and look for blood in heart

170

Moments of clarity: Robert Koch

Late 1800s
Identify and isolate infectious agent
Diagnostic stain for infectious agent
Discovered tuberculin

171

Screening techniques
Tuberculin skin test (Tine test)
Stain for sputum
X-rays for chest nodules

172

What happened to TB positive

people?
Sanatoria (late 1800s)
Rest
Diet
Fresh air
This quarantine reduced numbers of
new cases

173

W.W.II

Magic bullets of chemotherapy

Isoniazid
Rifampin
Ethambutol
Pyrazinamide

174

Mid 1980s-present

MDR-TB (resistance to Isoniazid and Rifampin)

Origin?
(Complacency, arrogance, and AIDS)

Recourse?
(2 or more antibiotics for 12/24 months)

Latest threat: XDR-TB & TDR-TB

175

Disease progression
Step 1: Primary exposure
Exposure via aerosol
Fine and dry quickly
Alveoli of lungs
Enter macrophages
The usual scenario: Macrophages
unable to kill bacterium
(Skin-/X-ray-)
2/3 week duration
176

(Macrophages become infected)

Untreated after 2/3 weeks

Disease progression: Two possibilities

Latent/Dormant (1)
Who:
What:
Result:
Clinical:

Healthy Immune system

(Macrophages and T-cells respond)
Infection walled-off (tubercle)
Skin+/x-ray+/- (non-infectious)

Concern:
Life-long hitchhiker
Immunosuppression can lead to PT (Reactivationbacteria start to replicate)
Two sources of toxicity:
Replicating bacteria kill infected cells (lysosomal enzymes released)
Responding macrophages release toxic products
Tubercles can become calcified
Clinical: Sputum+ (Infectious), X-ray+ , Skin+
177

178

Untreated
Disease progression: Two possibilities
Miliary/Disseminated TB (2)
Who: Immunocompromised (e.g. AIDS)
What: Infected macrophage not
contained
Result: Small tubercles throughout body
Clinical: Skin-/X-ray+ (non-infectious by aerosol)
Significance: Reservoirs
Outcome: Death
179

180

Vaccine
Calmette-Guerin (BCG vaccine)
M. bovis mutant injected
50% effective

181

Tests
Tuberculin sensitivity skin tests (TSTs)
e.g., Mantoux, PPD, etc.
QuantiFERON-TB Gold Test
Results within 24 hours
Is not subject to reader bias
Is not affected by vaccination

182

Final notes
TB from cows to humans (M. bovis)
No longer a problem
Pasteurization
TB and poverty
DOT (Directly observed treatment)

183

Cholera:
Properties of bacterium

--Quiz 9 material begins

Vibrio cholerae
Curved or comma shape
Colonizes SI
Cholera (rice water stool) 20L/day

184

History of Cholera
1500s 1st documented epidemics
(India)
1817-1823 1st pandemic

India to China, Japan, Africa, Europe, Americas

Spread? Increased travel & urbanization

1850s Sewers in U.S.
Cholera no longer a problem
185

Transmission & Epidemiology

Fecal-oral spread (flies and/or foul fingers)
Disease of poor (Sanitation & Crowding)

Far East affected--Why?

Monsoon rains (fecal matter in drinking water)
Civil strife

186

Diagnosis

Identify bacteria in stool (10million/ml)

187

Pathogenesis (Bold=Virulence factors)

Portal of entry (mouth)
Large numbers needed to cause
disease in healthy host
Flagellum allows for speedy trip
through stomach
Attach to SI mucosa via pili and
adhesins

188

Pathogenesis continued
Mucosa and natural defense?
Rapid cell turnover
Bacteriums answer? Mucinase

189

Where does watery stool come

from?
After attaching...
Toxin (CT) injected inside SI mucosal cell
(affects G proteins)

Leads to excessive cAMP production by cell

Ions pumped across membrane & out of cell
H2O from underlying tissues and blood
follows
Result?--one of the most rapidly fatal
diseases known
bicarbonate (HCO3-)from blood lost (blood
becomes acidic)

190

Pathogenesis...

Why does the bacterium do this?

cAMP provides source of carbon

191

Treatment

IV or oral rehydration therapy (ORT) for

self-limiting bacterium

192

Prevention and control

Safe water supply
Oral vaccine

193

Shigella
Background
S. dysenteriae
Rod-shaped bacteria
Causes dysentery (bloody diarrhea)
Central & South America
20,000 cases/yr in US
Associated with poverty and crowding
Other dysentery-causing microbes?
E.coli, Amoeba

Shigella
Transmission (fecal-oral)
Water contaminated with feces
Flies contaminating food
Fomites with fecal matter
Personal hygiene is an important factor

Shigella
Pathogenesis
1. Attach to large intestine epithelial M cells
(adhesins*)
2. Induce their own phagocytosis
3. Invade adjacent cells by using host
cytoskeleton for movement
4. Macrophages and neutrophils prevent
further invasion

Pathogenesis

Neutrophil
Note:
Bacteria attaching to M cells
Bacteria phagocytosed
Bacteria using the cytoskeleton
Role of macs and neutrophils

Shigella
Pathogenesis
Cellular death?
Bacterial growth inside cells leads to cell death
Result? Lysosomal enzymes released, killing
neighboring cells & blood vessels--blood
Shiga Toxin
Function/role unclear
May be produced to get bacteria out of human
host

Shigella
Treatment & prevention
ORT
Self-limiting in healthy adults
No antibiotics needed, but do reduce severity and duration
Avoid contaminated water
Avoid foods washed with contaminated water

Shigella
Vaccine
Most effective attempts have involved invasive strains

Problem? These vaccines cause symptoms in patients

Cholera vs. Shigella

Transmission
Link to poverty
Endemic sites
Colonizes
Invasive
Diarrhea
Treatment
Toxin

Cholera

Shigella

Fecal-oral
Yes
India, Asia, Africa
SI
NO
Rice-water
ORT or IV fluids
CT

Fecal-oral
Yes
Central & S. America
LI
Yes
Dysentery (bloody)
Antibiotics and ORT or IV
ST

Plasmodium falciparum & malaria

Quiz 10 material begins

History
Hippocrates in Egypt-400 B.C.
Fall of Roman and Greek Empires
Civil War (25% of admissions)
WWII epidemic in pacific
Head for the hills and bad air
202

Plasmodium falciparum & malaria

History continued...
1955-WHO & worldwide eradication
102 countries
1976-eradication program collapses
DDT-resistant mosquitoes
Chloroquine-resistant microbe
Political unrest
Farming practice changes 203

Plasmodium falciparum & malaria

Current situation...
1.5-2.7 million deaths each year

(1 mill are

children)

300 million people in Africa and India infected

Economic losses in Africa-$1billion/year
40% of worlds population exposed
Bottom Line: One of the worlds greatest
health probs
204

P. falciparum
Type of protozoan
Unicellular microbe

Plasmodium falciparum & malaria

Life Cycle
Why examine?
Origin of disease
Why so difficult to eliminate

206

Plasmodium falciparum & malaria

Asexual reproduction
*Liver cells invaded

Merozoites

All but P. falciparum

Merozoites

Rhoptries

*RBC

Male & Femal

Gametocytes

Sporozoites

Human Stage Definitive Host

Bite
Mosquito Stage Intermediate Host

Bite
Sporozoites reach
salivary glands

Zygote

*source of disease

Male & Female

Gametocytes
Mate

Ingested
Infected RBC
Burst in gut
207

Invasion by Rhoptry action

208

Plasmodium falciparum & malaria

Disease

Chills and fever

RBC Lysed & release hemozoin
Macrophages release TNF
Fever & chills
Anemia & Jaundice
lysed RBC (anemia)
hemoglobin degraded=bilirubin
liver damage

209

Immune Evasion
Maturational changes
Anatomical seclusion
e.g. invades sporozoites <60minutes
Circumsporozoite Ag sloughing
RBC lack MHC class I molecules

210

Immunity to malaria

Inheritable anemias
e.g. Sickle-cell anemia
Hemoglobin forms Spears
Sickle
Punctures merozoites
BLine: In Africa, the lesser of two evils
211

Control?

Vector population (Draining standing water)

Reservoir
New host availability (Deet, minimize exposed skin, Mosquito
NETS)

Vaccines
Mosquito approach
Gamma rays mutate parasite inside
Infect human volunteers
Memory
212

213

Facts
-In humans, vertical transmission to
infants is rare
-Mosquitoes remain infectious for life (2-3
weeks) and bite repeatedly

214

Helminths

Two phyla
Platyhelminthes
Cestodes
Trematodes
Nematodes
e.g. Ascaris
215

Ascaris
A. lumbricoides
Three rounded lips
18 inches in length (powerful)3-6mm
wide
Originally a parasite of pigs
(domestication)
Targets SI
25% of the world infected

Each lip is lined

with minute teeth
216

Ascaris

Juveniles
penetrate intestinal wall
and enter hepatic portal system

Life Cycle

Heart

Eggs hatch in SI
Eggs ingested on raw fruit
or vegetable

Bronchiole tubes
Trachea to Esophagus

*Gagging &
Swallow

Eggs in soil

*SI
maturation &
*Disease/Death mating 217

200K/day
Dioecious life cycle

Penetrate
Alveoli*

Diagnosis & Treatment

1. Ascaris pneumonitis: examination of sputum for Ascaris larvae.
2. Intestinal ascariasis: feces are examined for the ascaris eggs.
Direct fecal film: it is simple and effective. The eggs are readily
found using this method due to significant female oviposition
(Over 200,000 eggs per day). Most widely used.
Recovery of adult worms: adults or juveniles found in feces,
vomit, tissues etc.
Mebendazole: Prevents worms from absorbing glucose.

218

Ascaris
Disease and/or death
Intestinal obstruction
Pulmonary damage
Choking
Important note:
Erratic migratory behavior due to crowding and/or
limited number of males
219

Worms from young child

220

Ascaris

Transmission
Eggs infectious after 10 years in soil
Eggs resist concentrated HCl
Children
Garden foods
Cockroaches
Night soil used as fertilizer
Night soil is produced as a result of a waste management system in areas without
community infrastructure such as a sewage treatment facility, or individual septic
disposal. In this system of waste management, the human feces are collected in
solid form (Honey pots).

221

Epidemiology
Worldwide distributionWhy?
1. Simple life cycle.
2. Prodigious egg production (240,000 eggs/day).
3. These eggs are highly resistant and remain viable for
years.
4. Social customs and living habits.
5. Mechanism for disposing feces.

222

Ascaris
Final notes...
-Unbalanced graduate student
-S.Carolina in 1969 (15%) infected
-German currency and nightsoil
-Feed off of semi-digested contents of gut
and/or bite intestinal membrane, feeding off
of blood and tissues
-85% of infections are asymptomatic
10,000deaths/yearThats one effective
parasite
223

Platyhelminthes: Trematodes
(Flukes)
Trematodes
Schistosoma
Blood fluke (certain stages in blood)

224

Platyhelminthes: Trematodes
(Flukes)
Schistosomiasis
Africa, S.America, Carribean
Disease of poor
2nd most devastating disease
200million new infections annually
1 million deaths each year

225

Platyhelminthes: Trematodes
(Flukes)
*source of disease
*Eggs w/spines
Copulate for life

Feces
or Urine

Miracidium stage
in water

Schistosomules
migrate to bvessels (bladder, LI, or SI)Human host
& mature
Invertebrate host and/or water stage

Penetrate human host

Swim & Infect

Intermediate Host

Cercariae
(swimming)

Sporocyst
Dioecious life cycle in snail
Human=definitive host

226

227

Contaminated water
228

229

Platyhelminthes: Trematodes
(Flukes)
Damage
Spiny eggs lodge in intestines or bladder

T-cells & MO form granuloma

Toxic mediators released by MACS

230

Platyhelminthes: Trematodes
(Flukes)
Worm persists--How?
Motile
Masking in host proteins
Worms do not make more worms
25 pairs in human body

231

232

233

Platyhelminthes: Cestodes
(Tape worms)
Taenia
Taenia saginata (beef worm)

234

Platyhelminthes: Cestodes
(Tape worms)
I. General information
Worldwide distribution
Undercooked beef, Travel to developing countries, Poor
hygiene, Exposure to livestock

25 year life span

Over 60 feet in length

235

Platyhelminthes: Cestodes
(Tape worms)
II. Structure
Scolex (head w/suckers)
Germinal center (neck)
Proglattids (hermaphroditic w/eggs)

236

237

Platyhelminthes: Cestodes
(Tape worms)
III. Life cycle

eggs & proglottids in feces

adults

Release from shell in SI

Ingestion of cysticerci
in porterhouse

Human
Cow/Grass

Encyst
Larvae to muscle

Eggs
& proglottids
on grass

Cows
238

Platyhelminthes: Cestodes
(Tape worms)
Disease
Intestinal obstruction

239