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Pathogenic Microbiology

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• Agricultural revolution of Eurasia

• Led to the formation of cities

• The domestication of animals likely resulted in transmission of infectious diseases• Cattle

• Anthrax

• Smallpox

• Swine

• Influenza

• Poultry

• Influenza

• Arboviruses

• Rodents (indirect)

• Arenaviruses

• Bubonic plague

History of Infectious Diseases


• The Plague of Athens (c. 430 B.C.)

• Thucydides described it as rapid onset, raging fever, extreme thirst, bloody tongue and throat, red skin followed by pustules and blisters

• Probably scarlet fever

• Killed about half of Athens’ population

• At the time Athens was engaged in war with Sparta• The war should have been an easy victory

for Athens

• Because of the societal impact, Athens became stagnant

• The war continued for 27 more years and Sparta won

• The Plague of Galen (c. 165 B.C.)

• Galen was a Roman physician who described the disease

• Likely the first large outbreak of smallpox

• Corresponded with arrival of the Huns from east Asia

• Invasion of the Huns resulted in westward movement of Germanic peoples and encroachment upon Rome

• Roman soldiers on the eastern front were first to be infected and upon returning to Rome brought the disease with them


• The Plague of Justinian

• By 500 A.D. the Roman Empire was seated in Constantinople (Byzantine Empire)

• Justinian I was Emperor and was battling the Goths and Vandals

• An outbreak of what resembles bubonic plague occurred that weakened the legion


History of Infectious DiseasesI Samuel: “Then said they, What shall be the trespass offering which we shall return to him? They answered, Five golden emerods, and five golden mice, according to the number of the lords of the Philistines: for one

plague was on you all, and on your lords.”Emerods = “tumors”

• Three pandemics from 540 to 1666• The Justinian Plague (540-590)

• The Black Death (1346-61)

• The Great Plague of London (1665-1666)

• Bubonic plague (Yersinia pestis)

• Rat-flea-human infection cycle

• Each started in coastal cities and moved inland

• Those who cared for the sick were at no greater risk than those who did not

• Death rates were low at the beginning, but as high as 90% toward the end• A higher incidence of pneumonic plague occurred at

the end

• Agricultural production dropped, leading to mass starvation


The Dance of Deathby Hans Holbein,

c. 1519

• Smallpox

• Likely arose in India

• Probably a zoonotic agent from cattle

• Efficient human to human transmission

• Wherever Europeans explored, they took smallpox with them

• Indigenous populations usually had high fatality rates• When Spaniards colonized Mexico the fatality rate was 100% for some

villages

• Variolation - First immunization using cowpox pustules scarified into the skin• Cross-reactive immune response

• Eradicated in the 1970s


History of Infectious DiseasesEdward Jenner (1749-1823)

performing the first vaccination against Smallpox in 1796, by

Gaston Melingue

The Cow Pock or the

Wonderful Effects of the

New Inoculation,

byJames Gillray

• Measles

• First described by Persians (c. 700 A.D.)

• Two week incubation

• Respiratory transmission

• Immunosuppressive

• Secondary bacterial infections

• 60% of deaths from pneumonia (pre-antibiotics) in small children

• In older children, death is frequently from neurological manifestations

• Measles is the next disease targeted for eradication (after smallpox and polio)


European Arrival,19th Century

EndemicMalaria


Europeancolonization

of Africa

• Colonization of the New World

• 1400s to 1600s

• Europeans migrated to the Americas

• They brought diseases that were absent in the Americas• Smallpox

• Measles

• Influenza

• Typhus

• Yellow fever (slave trade)

• Europeans had evolved with most of these diseases, thus were genetically-prepared for them

• Native American populations were not

• It is evident that most of the 58 million Native American deaths were from European diseases

• The British used smallpox as a biological weapon



Infectious diseases have shaped,and will continue to shape,

humanity

Given the opportunity, any microbe

can cause disease

•Characteristics of infectious disease• Communicable or contagious diseases are readily

transmitted person to person (e.g., influenza, measles, pertussis)

• Other diseases are not contagious (including West Nile virus, anthrax) since they are not transmitted person to person

•Infection is also a function of quantity of microbes

• The infectious dose is expressed as ID50

• The ID50 for a microbe is the number of bacteria or viruses needed to infect 50 of 100 people given the dose

• This number varies among pathogens (anthrax = 10,000)

Review of Pathogenic Microbiology

Review of Pathogenic MicrobiologySome Communicable Diseases

Disease Agent Route

Diphtheria Corynebacterium diphtheriae Respiratory

Influenza Various influenza viruses Respiratory

Bacterial Meningitis

Neisseria meningitidis, Hemophilus influnezae type B

Respiratory

Measles Rubeola virus Respiratory

Mumps Mumps virus Respiratory

Rubella Rubella virus Respiratory

Pertussis Bordetella pertussis Respiratory

Polio Polio virus Fecal/Oral

Chlamydia Chlamydia trachomatis Sexual

Gonorrhea Neisseria gonorrhoeae Sexual

HIV HIV-1, HIV-2 Sexual

Syphilis Treponema pallidum Sexual

Infectious hepatitis

Various hepatitis viruses Various


• Pathogenic - the capacity to cause disease

• Acute pathology - symptoms are apparent

• Subacute pathology - symptoms are inapparent

• Pathogenic microbe - any microbe that can cause disease

• Nearly any microbe, given the opportunity, can cause disease

• Pathogenesis - the process by which pathology occurs

• Virulence factors are responsible for pathogenesis• They are molecules encoded by genes that allow the microbe to compromise

the host

• Usually toxins for prokaryotes

• The genes in a toxin pathway are often cluster together in pathogenicity islands

• Subversion of host cellular processes

• Usually immune modulators for viruses

• The immune response often contributes to pathogenesis

• Pathogenicity

• The capacity for a microbe to cause disease

• Some microbes are primary pathogens and usually cause disease after colonization

• Others are opportunistic pathogens and cause disease only in conjunction with some other unusual event

• Immunocompromised status

• Chemotherapy

• HIV disease

• Congenital immunodeficiency

• Compromised normal flora

• Aggressive antibiotic therapy

• Clostridium difficile


• Infection - usually parasitic colonization by a microbe

• Clinical manifestations

• Subclinical (apathogenic) - none apparent

• Clinical (pathogenic) - symptoms of disease

• Course of infection

• Primary - disease caused by the initial infection

• Secondary - because of the initial infection, another microbe can establish an infection


• Distribution of the pathogen

• Most are localized to a specific tissue

• Others can be systemic

• Some localized infections can become systemic; often a poor prognostic indicator

• Microbes and their products in the blood

• Bacteremia - bacteria in blood

• Viremia - virus in the blood

• Toxemia - toxins in the blood

• Septicemia - life-threatening; bacteria replicating in the blood


• Adherence

• Mediated by glycoproteins termed adhesins

• Typically have specificity for host cell surface proteins

• Colonization

• Replication of bacteria at the site of adherence

• Secretion of factors that impair the host response, such as proteases that cleave antibodies, rendering them nonfunctional

• Expression of iron-binding molecules, termed siderophores

• Biofilms (tissues and medical devices)

• Delivery of effector molecules into host cells

• Often virulence factors that damage the host cell


•Course of Infection

• Incubation period - no symptoms

• Illness - phase of disease

•Convalescence - recovery from disease

•Some people can be carriers for some infectious agents (”Typhoid Mary”)

•Duration of Symptoms

•Acute - rapid onset, short duration

•Chronic - slow onset, long duration

• Latent - agent is never eliminated

Recrudescence is the recurrence of a latent viral infection


Koch’s Postulates of Infectious Disease Etiology

• The microbe must be present in every instance of the disease

• The microbe must be isolated and cultured from a diseased animal

• Introduction of the microbe into a susceptible animal must result in the disease

• The microbe must be reisolated from the animal

Genetic Basis of Microbial Virulence

• Genomic DNA

• Plasmid DNA

• Bacteriophage (“phage”) DNA

• Transposons

Plasmid-Encoded Virulence Factors

Organism Virulence Factor Biological Function

Enterotoxigenic E. coli

Heat-labile and -stable enterotoxins

Activation of adenylate guanylate cyclase in GI leading to diarrhea

Extraintestinal E. coli

Hemolysin Cytotoxin

Shigella sp and enteroinvasive E.

coli

Gene products involved in invasion

Induce internalization by intestinalepithelial cells

Yersinia spAdherence factors and gene products involved

in invasionAttachment, invasion

Bacillus anthracisEdema factor, lethal factor and protective

antigen

EF is an adenyl cyclase; LF is a metalloprotease that acts on cell

signalling

Staphylococcus aureus

Exfoliative toxin Causes toxic epidermal necrolysis

Clostridium tetani Tetanus neurotoxinBlocks release of inhibitory neurotransmitter, leading to

muscle spasms

Phage-Encoded Virulence Factors

Organism Virulence Factor Biologic Function

Corynebacterium diphtheriae

Diphtheria toxinInhibition of eukaryotic protein

synthesis

Streptococcus pyogenes

Erythogenic toxin Rash of scarlet fever

Clostridium botulinum

Botulism neurotoxinBlocks synaptic acetylcholine release, which leads to flaccid

paralysis

Enterohemorrhagic E. coli

Shiga-like toxinInhibition of eukaryotic protein

synthesis

Vibrio cholerae Cholera toxinStimulates adenylate cyclase in

host cells

Molecular Postulates of Infectious Disease Etiology

• The virulence factor or gene(s) must be detected in pathogenic members of a species, but not nonpathogenic members

• Introduction of the gene(s) that encodes the virulence factor into a nonpathogen must convert the microbe into a pathogenic strain

• The gene(s) must be expressed when introduced into a susceptible animal

• Antibodies or immune cells (e.g., Tc cells) must protect the animal from the disease

•Penetration of the skin

•Cuts, abrasions, or burns

•Vector (flea, mosquito)

•Penetration of the mucous membranes

•Directed uptake by cells

•Exploitation of antigen sampling by immune cells

•Dendritic cells

•Macrophages

Breaching Anatomic Barriers

Toxins• Background

• Greek toxikon

• “Bow poison” - poisons commonly applied to arrows used by Greek warriors

• Coined by Roux and Yersin

• Cell-free culture liquids of Corynebacterium diphtheriae killed animals when injected

• Many toxins are enzymes

• Synthesis and release of toxins

• Highly complex

• Usually controlled by environmental stimuli

• Toxin expression pathways are often encoded in the same regulon that allows concurrent expression of pathogenicity islands during particular stages of infection

Toxins

Host Damage•Exotoxins• Proteins secreted by various pathogenic

bacteria

• Can be local or systemic

• Fatal in small amounts• 1 gram of botulinum toxin is sufficient to kill the

Earth’s human population

• Potent antigens, but exert their effect before antibodies can be synthesized

• A-B toxins - disrupt cellular pathways to the microbe’s advantage • B subunit specifies ligand

• A subunit has enzymatic activity

• Membrane-damaging toxins - hemolysin disrupts RBC membranes

• Superantigens “trick” large numbers of helper T cells into producing inflammatory cytokines

• Type III secretion systems

• Some microbes use this system to inject enzyme toxins directly into target cells; a molecular syringe

• Endotoxins

• Endotoxins are lipopolysaccharides (LPS)

• Lipid A (toxic)

• Polysaccharide

• Normally found as outer cell membrane component of Gram- bacteria

• Bind to Toll-like receptors on phagocytic cells, which results in the release of tumor necrosis factor from the cells

• TNF causes capillary leakage and inflammation

• This can lead to hypotension and disseminated intravascular coagulation - aka, septic shock

Host Damage

Toxins

• Classification

• Chemical• Protein

• Lipid

• Lipopolysaccharide

• Cellular or tissue target of action• Enterotoxins

• Neurotoxins

• Leukotoxins

• Mechanism of action• Proteolytic toxins

• ADP-ribosylating toxins

• Adenylate cyclase toxins

• Deamidating toxins

• Classification

• Major biological effect• Small G proteins

• Heterotrimeric G proteins

• Intracellular target molecule• Enterotoxins

• Neurotoxins

• Leukotoxins

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