Infection and disease

Infection and disease

Infection: Entry of infectious organisms inside the body,
their multiplication

Disease: Cell / tissue damage, signs and symptoms

All infections may not necessarily cause disease

Microbes come in different shapes and sizes

Bacteria Protozoa

Viruses

Fungi
Parasites
Historical perspective
 Evidence from mummies

Unknown child from Naples

Egyptian pharaoh Ramses V

Source: http://plaza.ufl.edu/
Egyptian art tells us about polio

Source: The Art Archive at Art Resource, NY

Supernatural explanations for
infectious diseases

Climate, soil etc believed to make one sick

Source: Infectious Disease Epidemiology, Nelson and Williams

 Hippocrates
Dismissed supernatural
explanations

Seasonal changes in
disease patterns

Fever and swelling

immune response
Hippocrates (460-377 BC)
 Fracastoro
First to propose that
infectious diseases were
caused by invisible, minute,
self-replicating seeds

Proposed transmission by
direct contact, air and
through objects

Described several infectious

diseases
(1478-1553)
Renaissance era in medicine
(14-17 century)
 Foundations of modern medicine
Anatomy

Physiology

Circulation

Brain

Surgical instruments

hygiene
Hospitals and hygiene
 First microscope (1600s)

Focus
Sample
Lens

Leeuwenhoek
First vaccine

Edward Jenner (1749-1823)

Worlds first vaccine

against small pox

Father of immunology
Louis Pastuer (1822-1895)

Fermentation

Pasteurization

Vaccine development
Robert Koch (1843-1910)
Kochs postulates

Gold standard in
microbiology

Fathers of Microbiology
- Robert Koch
- Louis Pasteur
 Kochs postulates

First set of rules on how to link a disease to an infectious agent. Still used
Several bacterial agents were
discovered in the 1800s

Year Disease/organism
1874 Leprosy
1882 Cholera streptococcus
1884 Diptheria
1884 Typhoid
1884 Tetanus
1892 Gas gangrene
1894 Plague
Self-experimentation to prove Kochs
postulates

Inoculate organism into ones own body to prove

disease etiology / pathogenesis

Yellow fever / hookworms / Hepatitis E virus

 Reservoirs and vectors
Transmission of plague from rats to humans

Transmission of yellow fever through Aedes aegypti

First established viral disease with obligate cycle in insect

no human to human transmission

Transmission of malarial parasite (Plasmodium falciparum

through Aedes aegypti)
 Disarming the microbe

Alexander Fleming
discovered penicillin in
September 1928.

Worlds first antibiotic

Thats funny
Penicillin: Miracle cure
 Terminology
develop

Incidence Fraction of a population that

newly contracts a disease during a
specific time. (Eg. Influenza virus)

Prevalence Fraction of a population having

a specific disease at a given time. (eg. HIV)

Endemic disease Disease constantly present in a

population. (eg. Malaria)

Epidemic disease Disease acquired by many

hosts in a given area in a short
time. (Eg. Dengue epidemic in Delhi)

Pandemic disease Worldwide epidemic (eg. Influenza

pandemic).
 Major pandemics
Bubonic plague (1347-1351): ~ 200 million dead

Influenza (1918-1919): ~ 100 million dead

 Discovery of antimicrobial drugs
1928 penicillin

1928 to 1962: 15 classes of antibiotics

How does the future look?
15 classes of 3 classes of
antibiotics antibiotics

BLEAK ; increase in drug-resistance /void in drug discovery

 Normal microbiota and the host:

Locations of normal
microbiota on and in the
human body
The phrase normal microbiota refers to
the microorganisms that reside on the
surface and deep layers of skin, in the
saliva and oral mucosa, in the conjunctiva,
and in the gastrointestinal tracts of every
human being.
 Normal microbiota and the host:

Transient microbiota may be present for days, weeks, or

months

Normal microbiota permanently colonize the host

Symbiosis is the relationship between normal microbiota and

the host
 Normal microbiota: how the host
benefits ?
Through microbial antagonism, the normal bacterial flora of the body provides some
defense against disease-causing organisms
Microbial antagonism is competition between microbes.

Normal microbiota protect the host by:

comfortable positions
occupying niches that pathogens might occupy
producing bacteriocins

Probiotics are live microbes applied to or ingested into the

body, intended to exert a beneficial effect.
 Microbes
Are invisible to the naked eye

Are everywhere around us, inside us, on us, in our food, in our
homes, in the air we breathe and the water we wash in.

Are mostly useful, but some are harmful

Have been around for 3.8 bn years.

 Microbes exist in huge numbers
In one single teaspoon of garden soil, there are over 100,000
microbes.

In 1ltr of seawater, there are over 1bn microbes.

On your skin there are more microbes than there are people in the
world.

There are so many microbes, that scientists have only named <1%
of them.

Microbes outnumber all other species and make up most of the

living matter on the planet
 Reservoirs and vectors
Reservoirs
Animal, soil, water etc - source of
infection.

Vectors

Arthropods, especially fleas, ticks,

and mosquitoes

Mechanical vectors
Insects carry pathogens on feet
Biological vectors
Pathogen replicates in vector
 Microbes: Portals of entry

1) Skin:
Most microbes are not able to penetrate intact skin
Some fungi infect skin

2) Mucous membranes
Respiratory tract: eg. Influenza virus
Gastrointerstinal tract: eg. Cholera
Urogenital tract: HIV
Eye (conjunctiva): eg. adenovirus
 Microbes: Portals of entry
3) Parenteral (Blood-borne) route:
Microbe is deposited below the skin into the tissue
Eg. Blood transfusion, insect bite, tatooing (eg. HIV)

4) Vertical transmission:
Transmission from mother to child (eg. HIV)
What are bacteria ?
 Bacterial Structure

Chromosome: DNA material of the cell

Cell wall: Composed of peptidoglycan the cell wall maintains the
overall shape of a bacterial cell
Cell membrane: Lining the inside of the cell wall it provides a boundary for
the contents of the cell and a barrier to substances entering
and leaving.
Cytoplasm: Describes the inside of the cell and the contents
 Bacterial Shapes
There are 3 different shapes of bacteria

Balls or cocci
(Staphylococcus)

Rods
(Lactobacillus)
Spirals
(Campylobacter)

Bacteria with flagella are motile

 Gram stain

Diff. in
cell wall

1884: Hans Christian Gram; he developed this method to better visualize bacteria
All bacteria may be classified as Gram positive and Gram negative
 Classification of bacteria

Shape

Motility

Gram stain

Other property (eg.aerobic /ananerobic)

Mechanisms of bacterial
pathogenicity
Pathogenicity refers to the ability of an organism to cause disease
 Microbial mechanism of pathogenicity

Number of
invading
microbes

Penetration or Damage
Portals of entry evasion of to host Portal of exit
host defenses cells

Adherence

Virulence factors
Virulence factors are molecules produced by bacteria, viruses, fungi, and protozoa that
add to their effectiveness and enable them to achieve the following: colonization of a niche
in the host (this includes attachment to cells)
 (1) Adherence
Adherence (attachment) is often an essential step in bacterial
pathogenesis or infection, required for colonizing a new host
Adhesion - Process by which microorganisms attach themselves to
cells.
Requires the participation of two factors: a receptor and an
ligand
Microbial adherence to a eukaryotic cell or tissue surface involves
complementary chemical interactions between the host cell or tissue
surface and the bacterial surface.
 (1) Adherence
Adhesions/ligands bind
to receptors on host
cells
Fimbriae/ pili
Escherichia coli
Neisseria gonorrhoeae
M protein
Streptococcuspyogenes
Glycocalyx
Streptococcus mutans
 Adherence examples

M protein: Group A Streptococcus Pili /fimbriae: E.Coli / N. gonorrhoeae

 Why is adherence important ?

Ability to colonize and cause

disease

Ability to adhere
determines the host
specificity

Potential drug target

(2)Formation of bacterial biofilms

Quorum sensing: ability to sense population density and alter gene expression
 Examples of biofilms
Dental plaques
 Biofilms outside the body

Biofilm mats on stagnant water Biofilm mats on rocks Yellowstone national park
 What triggers biofilm formation ?
Bacterial attachment to surfaces

Nutritional depletion
less than required
Sub-inhibitory concentrations of antibiotics

A critical population density of bacteria

 How do biofilms help bacteria ?

Protection from immune repsonse

Protection from antibiotics

Help tide over periods of low nutrition

Microbial chatter (communication)

 Biofilms: Why do they matter ?

Key mechanism in bacterial pathogenesis

Important part of food chain

Major cause of corrosion of metal pipes

 (3) Bacterial capsule

Some bacteria have a

polysaccharide layer outside
the cellwall called capsule

Helps in attachment

Helps evade host defences

Streptococcus pneumoniae
Haemophilus influenzae
Bacillus anthracis
 How does the capsule help bacteria
evade host defences ?
Capsulated bacteria

Prevent complement binding Allows survival inside Escape TLR recognition

and phagocytosis phagocytosis
Capsule inhibits phagocytosis
Capsule allows survival inside
phagocytes

Capsule may help resist digestion by lysosomal emzymes

Capsules allow escape of TLR recognition

(TLR)

No immune response
Capsules contribute to pathogenesis

RIP Jerry
 (4) Bacterial cell wall

Outer layer

Peptidoglycan (sugars
and aminoacids)

The cell wall may carry

some surface proteins
Mycolic acid in cellwall helps resists
lysosomal digestion

Mycolic acid
in the cell wall

Mycolic acid in the cell wall resists digestion by lysosomal enzymes

Eg. Mycobacterium tuberculosis , Mycobacterium leprae

Proteins on the cell wall help evade
phagocytosis

Phagocytosis X Phagocytosis
Immune response X Immune response
X Disease Disease
 (5) Bacterial enzymes
(a) Coagulase and kinase
(b) Hyaluronidase and collagenase
(c) IgA protease
 (a) Coagulase and kinase

Inhibits phagocytosis
Immune response no access
Antibiotics not effective

Eg. Staphylococcus aureus skin infections

Strains that do not produce coagulase are not pathogenic

 (b) Hyaluronidase and collagenase
Digestion of
connective tissues
and Invasion of
tissues

Hyaluronidase: is present in Staphylococcus aureus (Skin infections)

and Streptococcus pyogenes (Sore throat)

Collagenase: is present in Clostridium perfringens (gas gangrene)

 (c) IgA protease
An enzyme that can
degrade IgA antibodies

Eg. Haemophilus influenza

causes respiratory tract
infection / meningitis

Help negotiate mucosal

defenses.
 (6) Membrane ruffling

Invasins : proteins expressed on the cell surface of various pathogens that alter actin
filaments of host cell cytoskeleton, allowing microbes to enter cells.
Infection and disease
Lecture 3
Bacterial toxins
Portals of exit
Common bacterial diseases
 (7) Bacterial toxins
Toxins - Poisonous substances produced by microorganisms
Toxigenicity - The ability to produce toxins.
Toxemia refers to the presence of toxins in the blood.
 (a) exotoxins
Mostly produced by gram positive bacteria

Soluble in body fluids

Transported throughout blood / lymph

Disease is often not due to the bacteria per se, but due to the
exotoxins

Most exotoxins are called AB toxins

- 2 components: Active and Binding
 Examples of exotoxins: Diptheria toxin

Diphtheria; nasopharyx is affected Toxin A inhibits protein synthesis

in the host cell leads to host cell
death
 Examples of exotoxins: Cholera toxin

Vibrio cholera diarrhoea

Toxin A increased cAMP

which controls the efflux of
H2O ions from cells

Increased secretion of
water and ions into the
intestine Diarrhoea
 (b) Endotoxin

Gram negative bacterial cellwall

have lipid A (lipopolysaccharide -
LPS) endotoxin

Important for pathogenesis

 How are endotoxins released ?

Complement-mediated lysis
mediated of bacteria

Phagocytic digestion of
bacterial cells

Antibiotics usage
 What does an endotoxin do ?

Secretion of
Cytokines

Inflammation Fever
ENDOTOXIN

BBB
 Endotoxin are pyrogens a substance, typically produced by a bacterium, which produces fever when
introduced or released into the blood.

Killing of bacteria by some sterilization methods may not necessarily eliminate endotoxins
Endotoxins are heat stable
 (8) Bacterial spores
Formed by some bacteria under stress / nutrient depletion

Most spore forming bacteria are Gram positive bacteria

Can become a vegetative cell (what we normally refer to as

bacteria) under favourable conditions
 Bacterial spores
Favourable condition

Unfavourable condition
https://www.youtube.com/watch?v=N
AcowliknPs
 Bacterial spores
Spores are highly resistant to heat, cold, antibiotics

Spores survive for centuries under harsh conditions

Spores are dormant no reproduction

High levels of calcium dipicolinate heat resistance /

DNA protection

High levels of sulphur

 Portals of exit
Respiratory tract
Coughing, sneezing

Gastrointestinal tract
Feces, saliva

Genitourinary tract
Urine, vaginal secretions

Blood
Biting arthropods, needles/syringes
Examples of bacterial diseases
 Tetanus
Exotoxin from Clostridium tetani

Neurotoxin causes muscle spasms

Starts with pain in the jaw inability to open jaw

Spreads to all the muscles throughout the body

10% untreated die due to the toxin

Vaccine preventable (DPT /TT)

 Tetanus

Disease causing organism symptoms Reservoir Mode of

transmission

Clostridium tetani Severe spasms, rigidity of Soil Puncture wounds

muscles, lockjaw contaminated by
bacterial spores

Source: Royal College of Surgeons of Edinburgh, Scotland

 Anthrax
Bacillus anthracis spore forming

Spores are present in soil

Common disease of grazing animals

Human infection:
Pulmonary anthrax inhalation of spores
Gastrointestinal anthrax eating of infected animal meat
Cutaneous anthrax hide porters disease (cuts in skin)
Disease is linked to exotoxin
 Anthrax

Cutaneous anthrax

Anthrax potential use in bioterrorism; Spores - inhalation

 Plague
Yersinia pestis

Major outbreak in the 14th

century 200 million deaths

Many minor outbreaks

Transmitted through infected rat

fleas (rodents are reservoirs)
Plague: the disease

Black death
 Plague: pathogenesis
Resist digestion by macrophages (Capsule)

Spread via lymphnodes /blood / shed from lungs

Human-to-human transmission cough /aerosol

Acute inflammatory response

Clogs capillaries

Reduced blood supply tissue death by necrosis

the death of most or all of the cells in an organ or tissue due to disease, injury, or
failure of the blood supply.
 Cholera
Vibrio cholera

Transmitted by contaminated food /water

Severe diarrhea (exotoxin)

Dehydration / can be fatal in young children if untreated

 Cholera

Oral /IV rehydration / antibiotics

 Typhoid fever
Salmonella typhi

Usually transmitted by contaminated food

Can affect multiple organs including brain, lungs, heart

Small proportion (<5%) asymptomatic carriers

bacteria replicates
Able to spread disease
 Typhoid Mary

Asymptomatic carrier cook; several families were infected, changed jobs.

Quarantined for 3 decades
 TB
Mycobacterium tuberculosis

Inhalation (long-term contact)

~90% - latent infection (No replication)

~10%- progression to pulmonary TB (immune system not able

to control replication)

Fever > 3 weeks, fatigue, cough, night sweat..

 TB
Extrapulmonary TB brain, bone, joint

Slow grower (~18 hours to double)

Requires special antibiotics

Requires long-term treatment

Food poisoning

Pre-formed exotoxins

Symptoms due to bacteria

take > 2 days to manifest
 Food poisoning

Vomiting, abdominal pain

Eg. Staphylococcus aureus

Eg. Salmonella species

Antibiotics may not

prevent disease
 Can normal flora cause disease ?
Yes !

Eg. E.coli (normally in the intestine) can

cause urinary tract infection