Lecture 1 Notes (chapter 1)

MICROBIOLOGY 20: UNIT 1

M.M.Youssef, MD, MSc
Introduction To Microbiology and Bacteria
-This unit aim to introduce Microbiology as a science and bacteria as a cell.
Note Outline for this session
-What is Microbiology?
The study of microbes, which are microscopic organisms.
-What is the importance of studying Microbiology?
-Microorganisms are part of the human environment and related to human health and
sickness.
-Microorganisms are responsible for wide range of diseases, known as infectious diseases;
also they play an important role in some malignant diseases (tumors)
-Microorganisms not always harmful, less than 1% of known microorganisms are pathogenic
(disease causing).
-In fact Microorganisms are important to the human environment.
-What are the kinds of Microorganisms?
-Algae ,Fungi , and protozoa also Helminths(worms) and Arthropods
(insects) have microscopic stages in their life cycles (Eukaryotes)
-Bacteria (prokaryotes)
-Viruses ,Viroids , and Prions ( Acellular microorganisms)
Germ Theory of Disease
Microorganisms (germs) can invade other organisms and cause disease (19th century).
It wasnt very accepted when it came to life.
The problem was how do you know something is there that you cannot see?
The key answer was the Microscope, which opened the door of the microbial world.
Anton Van Leeuwenhook invented a microscope that magnified 100-300X.
Still the question where do the microbes come from?
Spontaneous Generation Theory
Microorganisms come from nonliving material.
Do you think that life come from non-life?
What types of observation would lead to this theory?

Louis Pasteur is the one who succeeded to disapprove the spontaneous generation theory
(1860).
He used three flasks with broth;
(1) Left open to air
(2) Boiled and left open to air
(3) Boiled and left open with curved outlet to air (swan-necked flask)
(1) and (2) get turbid (3) stay clean.
So,because of Pasteurs experiments spontaneous generation theory is refused.
Kochs Postulates :
Provided method of establishing the specific infectious cause of a disease;
1-The specific causative agent must be found in EVERY case of disease.
2-The disease causing organism must be isolated in a pure culture.
3-Inoculation of a sample of the culture into a healthy susceptible animal must produce the
same disease
.
4-The disease causing organisms must be recovered from the inoculated animal.
According to these postulates he assumed that an infectious disease is caused by a single
organism (one organism-one disease concept)
Do you think it is perfect? Why?

LECTURE 2 NOTES (chapter 4)

What Is a Cell?
Cells are the fundamental units of life and carry out all the basic functions of living things.
(Cell Theory)
What do the cells need?
1-Barrier from the environment (cell membrane)
2-Genetic infomations (DNA, Nucleolus)
3-Proteins to do stuff.
Two types of cells:
PROKARYOTIC - have no membrane enclosed organelles, only one membrane surrounding
entire cell, they all are single celled organisms (bacteria)
EUKARYOTIC have membrane enclosed organelles, a nucleolus, multicellular or single celled
organisms
Prokaryotic cells (bacteria) varies in size, shape, and arrangements, but they all multiply by
Binary Fission, rather than mitosis or meiosis
Bacterial cell wall:
semi rigid cell wall lies outside cell membrane in most bacteria, and it performs two main
functions:
1-Maintain the characteristic shape of the cell.
2-prevents the cell from bursting by fluid diffusion into the cell.
-Peptidoglycan: The major component of a cell wall.
Large polymer ,covalently linked molecule, like a large, multiple layers of chain-link fence
surrounding the bacterial cell (This is a very specific bacteria thing)
It is composed of sugar and peptides.
Sugars (backbone):

N-acetylglucosamine (glu NAC)

N-acetylmuramic acid (mur NAC)

Cross-linking: Tetra peptide, (chains of four amino acids joined together),

[L-alanine, D-glutamic acid, Diamino Pimellic acid (replaced by Lysine in most gm +ve bacteria
and D-alanine]

Gram-positive bacteria have an additional molecule in the cell wall, called Teichoic acid; its a
huge polymer that sticks out of cells (extends beyond the rest of the cell wall, providing
attachment sites for bacteriophages)
N.B. Peptidolycan, forms a large supporting network around the bacterium, but doesnt hold
things in and out it is porous.
It is found in both gram-positive and gram-negative bacteria, but it is much thicker in grampositive cells.
-Outer Membrane:
It is a bilayer membrane, found primarily in gram-negative bacteria.
It forms the outermost layer of the cell wall and is attached to peptidoglycan by small
lipoproteins molecules.
Outer membrane protects the cell, exerts little control over the movement of substances in and
out the cell, it also inhibits the entrance of penicillin into gram-negative bacteria.
Lipo polysaccharide (LPS)
It is also called Endotoxin. It is important part of cell membrane and it is an integral part of the
cell wall and it is not released until the death of bacteria (cell wall lyses).
It is composed of polysaccharide (sugars that identify gm-ve cells) and lipid A (toxic part), its
release causes fever and blood vessels dilatation, which causes drop of blood pressure
(hypotenstion).
N.B. Antibiotics given late in gm-negative infection may worsen the condition and cause death.
-Periplasmic space:
Highly evident in gram-negative bacteria, it is a gap between the cell membrane and the cell
wall.
It represents a very active area of cell metabolism, as it contains peptidoglycan. Many digestive
enzymes and transport proteins,that destroy harmful substances and transport metabolites into
bacterial cytoplasm.
In gram-positive, the periplasm (not periplasmic space) is where metabolic digestion occurs and
where new cell wall peptidoglycan is attached (it is more like a part of the cell wall).
Distinguishing bacteria by cell walls
Certain properties of cell walls produce different staining reactions, which can distinguish
between gm-positive, gm-negative and acid fast bacteria.
1- Gram-positive bacteria:

Peptidoglycan layer
periplasm .
Cell membrane

Cell wall is relatively a thick layer of peptidoglycan (60-90% of cell wall), which is closely
attached to the outer surface of cell membrane (no periplasmic space)

They retain gram stains because of their thick layer walls and their structures. At time, cell
walls are weaker breakdown of peptidoglycan), which could become Gram-variable or even
Gram-negative.

2-Gram-Negative Bacteria: Cell wall is thinner but more complex than gram-positive
bacteria.
Only 10-20% of cell wall is peptidoglycan, the remainder consists of polysaccharides,
proteins and lipids.
They fail to retain Crystal Violet-iodine dye because of their thin walls and its structure
(lipoproteins and lipopolysaccharides).
3-Acid-Fast Bacteria (Mycobacteria):
-Lipids around cell protects from most stains (60% of cell wall).
-Lipid wall likely inhibits nutrients, so it grows slowly.
-They stain gram-positive.
-Large layer of lipids in the cell wall protects from acids, alkalis and detergent. But requires a
lot of nutrients.
Members of Mycobacteria family include Mycobacterium tuberculosis, Mycobacterium
leprae, and Mycobacteria avium.
Wall-deficient Organisms
Mycoplasma have no cell walls. The cell membrane contains sterols (more like Eukaryotic
cells). They dont have cell shape (pleomorphism) and are still subject to osmolarity changes.
L-Forms are wall-deficient bacteria (naturally or by chemical treatment). They can cause
chronic or recurrent infection, if they rebuild their cell walls (they dont killed by antibiotics
that affect cell wall.

Lecture 3 notes(chapter 4)
Cell Membrane (Plasma membrane, Cytoplasm membrane)
It is a living membrane that forms a barrier between the cell and its environment. Bacterial cell
membrane has a similar structure to other cell membranes ( Eukaryotic cell). It consists mainly
of phospholipid and proteins, where, phospholipids in the membrane are in fluid state and
proteins are dispersed among them. (Fluid-mosaic model).
Phospholipid membrane forms a bilayer with:
-Phosphate ends that extends toward the membrane surface. They are charged and hydrophilic
(water-loving). So, they can interact with watery environment.
-Fatty acid ends extend inward, they are non-charged and hydrophobic (water-fearing). So,
they form a barrier between the cell and its environment.
Protein molecules are interspersed among the lipid molecules.
Cell membranes are dynamic, materials move through it in a sensitive way.
What are the functions of cell membranes?
Internal Structure:
Cytoplasm:
It is a semi fluid substance inside the cell membrane. It is made up of 80% water and 20% of
dissolved stuff; it is like a suspension that contains enzymes, proteins, carbohydrates, lipids, and
inorganic ions.
Nuclear regions:
Unlike Eukaryote, there is no nuclear membrane. It contains one large circular piece of DNA
(chromosome).
There are sometimes smaller circular pieces called plasmids(plasmid is supplementary and not
critical to cell survival).
Ribosome:
Ribosome Consists of RNA and proteins.
-Can be grouped in long chains called polyribosomes.
-They are the sites of protein synthesis.
-Ribosomes are spherical in shape, they contain two subunits, large (50 S) and small (30S).
Both together are (70S), which is smaller than Eukaryotic ribosomes (80S).
N.B. Certain antibiotics, e.g. Erthromycin and Streptomycin, bind to 70S ribosomes and
disrupt bacterial protein synthesis without affecting the host cells.

Endospores:
Vegetative cellsactively metabolizing nutrients
Resting cellsNo nutrients (Resting stages)..Endospores
Endospores are very common in Bacilli and Clostridium
Bactreial endospores (single per cell),they help organism to survive, unlike fugal spores, that are
for reproduction
Endospores ,are formed within cells,they contain very little water,they are highly resistant
To heat,drying,acids,bases,radiations,and disinfectants.
They help bacteria to survive for long times in harsh conditions.
External Structures.
Flagella (movement structures in motile bacteria), Axial Filaments (in Spirochetes), Pilli
(attachment and conjugation), and Glyocalyx.
Let us move on to a Eukaryotic cell:
Plasma membrane, comparable to cell membrane
Sterols, used in plasma membrane to keep rigidity and still retain fluid mosaic model
Cell Nucleus
Surrounded by nuclear envelope
Nuclear pores let things in and out (like what)
Nucleoplasm is the inside plasma of the nucleus
Nucleoli are sites of ribosome assembly (made up of RNA and proteins)
Paired chromosomes of DNA, which are compacted together with proteins called histones.
Chromatin is the protein/DNA mix that gives the nucleus a granular appearance.
Division of eukaryotes is by Mitosis and Meiosis.
Mitochondria
Powerhouse of the cells
Many in each cell
Have Outer membrane, inner membrane and a matrix inside
These organelles make ATP (the energy source for cells)
Ribosomes
Bigger than bacterial, made up of RNA and protein (80S)
Endoplasmic Reticulum
Network of membranes
Smooth is where lipids are made
Rough has ribosomes attached for making proteins
Golgi Apparatus (named after Golgi)

A stacks of membranous sacs, gets stuff from ER and alters their chemical structures, and
packing them in secretory vesicles. It also makes the Lysosomes, which are vesicles that contain
digestive enzymes.

Lecture 4 Notes(chapter 5)
Bacterial metabolism:
Metabolism is the sum of all chemical processes carried out by living organism.
It includes anabolism and catabolism.
Anabolism is the reactions that require energy to synthesize complex molecules from simpler
ones.
Catabolism is the reactions that release energy by breaking complex molecules into simpler
ones.
All catabolic reactions involve electron transfer, which allow energy to be captured in highenergy bonds in ATP.
_Oxidation is loss of electrons.
_Reduction is gain of electrons.
How microorganisms obtain energy?
Microorganisms are classified as:
Autotrophy (self-feeding) or Hetrotrophy (other-feeding)
Nearly all microorganism infections are chemoheterotrophs.
Metabolic pathways can be catabolic (produces energy that cell can use), or anabolic (uses
energy to make structural complexes, enzymes and other functional molecules.
ATP molecules are the links that couple anabolic and catabolic pathways.
Enzymes are special category of proteins found in all living organisms.
Chemical reactions that release energy needs energy to start the reaction, which is called
Activation energy.
Enzymes lower the amount of activation energy needed to initiate the reaction, thus they make it
possible to occur at relatively low temperatures that living cells tolerate.
Enzymes also provide a surface on which reactions take place. Each enzyme has a certain area
on its surface called the Active site (binding site); it is the region at which the enzyme binds
(forms a loose association) with its substrate.
When the substrate binds to the active site of the enzyme, they form enzyme-substrate complex.
Which leads to a chemical change in substrate that results in product formation and enzyme
detachment.
Enzymes have a high degree of specificity, they catalyze only one type of reaction, and most act
on only one particular substrate.
The active site accounts for the enzyme specificity.

Enzymes are usually named by adding (suffix-ase) to the name of the substrate on which they
act.
Enzymes can be divided into endoenzymes and exoenzymes according to their site of action.
Many enzymes need to associate with non-protein substances called coenzymes or cofactors,
so they can catalyze their reactions.
A Coenzyme is a non-protein organic molecule that bounds to an enzyme. Many of them are
synthesized from vitamins, e.g. coenzyme A, NAD, and FAD.
A cofactor is usually an inorganic ion, e.g. iron, zinc, or magnesium. Cofactors often improves
the fit of an enzyme with its substrate, also they are essential for the reaction to proceed.
N.B. Carrier molecules such as coenzymes carry hydrogen atoms and electrons in many
oxidative reactions.
The cells need to inhibit (control) its enzyme activities by different methods;
A- Competitive inhibition
B- Non-Competitive inhibition
C- Feedback inhibition
Factors that affect the rate of enzyme reactions include: temperature, PH, and concentrations of
substrate, product and enzyme.
Most human enzymes and those of human- infecting microbes have an optimum temperature
near normal body temperature and an optimum PH near neutral, at which they catalyze reactions
most rapidly.

LECTURE 5 NOTES(chapter 5)
Glycolysis, Fermentation, and Aerobic respiration are the metabolic processes used by most
microorganisms to capture energy.
-Glycolysis ( Embden-Meyerhof pathway) is the metabolic pathway used by most organisms
(both aerobes and anaerobes) to breakdown glucose.
It consists of 10 steps, but the most important steps are:
1- Phosphorylation of glucose (transfer of phosphate group from ATP to glucose).
2- Breaking of glucose (six-carbon molecule) into two (three carbon molecule).
3- Transfer of two electrons to the coenzyme NAD.
4- The capture of energy in ATP.
Glycolysis (glucose oxidation or breakdown) result in a net energy capture of only two ATPs
per glucose molecule, as one glucose molecule is metabolized by glycolysis into two molecules
of pyruvic acid. Also, two molecules of reduced NAD (NADH) are also produced.
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Once the sugar has entered glycolysis , it is metabolized to pyruvic acid and then fermented or
metabolized aerobically.
-Fermentation, is a process by which pyruvic acid undergoes subsequent metabolism in
absence of oxygen.
Fermentation aim to pass the electrons from reduced NAD (NADH) off to other molecules
(NAD recycling). It doesnt result in capture of energy in ATP, but it helps energy capture
indirectly by keeping glycolysis going.
The most important and commonly occurring pathways are Homolactic acid fermentation and
Alcholic fermentation.
Other kinds of fermentations are performed by some microorganisms can be important in
diagnosis of microbial infection and identifying the causative agent.
Aerobic organisms obtain some energy from glycolysis and they use it to produce more energy
from glucose by aerobic respiration via the krebs cycle and oxidative phosphorylation .
-Krebs cycle ( tricarboxylic acid cycle or citric acid cycle)
It is a sequence of reactions in which, acetyl groups are oxidized to carbon dioxide. Hydrogen
atoms are also removed, and their electrons are transferred to coenzymes that serve as electron
carriers. (The hydrogens are eventually combined with oxygen to form water).
Certain events in the krebs cycle are of special significance:
-Oxidation of carbon. (Give carbon dioxide)
-Transfer of electrons to coenzymes.
-Substrate level energy captures.

Electron transport and oxidative phosporylation:

They can be modeled as a waterfall series. As the electrons are passed from carrier to carrier in
the chain, they decrease in energy, and some of the energy they lose is directed to make ATP
molecules (energy stores).
From the metabolism of a single glucose molecule, 10 paris of electrons are transported by NAD
and only 2 pairs by FAD.
Krebs cycle give atotal yield of 38 ATPs per glucose molecule(10 pairs of electrons from NAD
produce 30 ATPs, 2 pairs from FAD produce 4 ATPs, in addition to 2 ATPs from glycolysis and 2
GTPs from krebs cycle that transferred eventually into 2 ATPs)
Oxidative phosphorylation generates much more energy than fermentation, which produces only
2 ATPs (about 5%).
The theory of chemiosmosis explains how energy is used to synthesize ATP.

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Anaerobic respiration done in anaerobes that dont use free oxygen as their final electron
acceptor.
They only use parts of kerbs cycle and the electron transport chain; thus, they produce less ATP
molecules than aerobic organisms.
Fat metabolism . fats (lipids) are hydrolyzed into glycerol and fatty acids. The glycerol is
metabolized by glycolysis and the fatty acids are oxidized by beta-oxidation after they combine
with coenzyme A ,forming Acetyl-CoA that enters the krebs cycle.
Proteins can also be metabolized for energy. They are first hydrolyzed into amino acids that are
deaminated (amino group is removed), and then the deaminated molecules can enter glycolysis,
fermentation or the krebs cycle.
What are the uses of energy in microorganism?

Lecture 6&7 (chapter 7) Microbial genetics

Gene (a specific segment of DNA) is the basic unit of heredity; it is a linear sequence of
nucleotides that form a functional unit of chromosome.
DNA structure is a:
Double helix
Anti-parallel (5-> 3 and 3<- 5)
Strands are bound by lots of weak hydrogen bonds
A to T
G to C
DNA replication occurs by three main things happening:
Unwind the DNA (by a helicase)
Prime the strand of DNA (by a primase)
Make more of the DNA polymer (by a DNA polymerase)
DNA replication is important to make more of the genome for the daughter bacteria cells
DNA replication occurs in a semi-conservative manner in which one strand of the double helix
is new and one is old..
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Moving on to Transcription
Central Dogma:
DNA is TRANSCRIBED to RNA that is TRANSLATED to PROTEIN
Transcription will turn DNA into RNA. (in cytoplasm for bacteria, in nucleus for eukaryotes)
Notice that :
ORF = open reading frame, the information that will be translated to a protein
Promoter = the DNA that marks the area where an ORF starts
RNA: mainly single strand of nucleic acid. Same bases as DNA, except T is a U so if you see
U in a sequence it is RNA, T in the sequence and it is DNA!
RNA polymerase comes to a promoter and the big protein set will begin to unwind the DNA a
little bit. Then it starts putting RNA bases there and keeps on extending the length of RNA, in 5
to 3 direction. RNA and DNA both grow in 5 to 3 direction.
When the RNA polymerase reaches the end of the gene, the mRNA is finished and ready to do
something. The mRNA will be the RNA version of the DNA strand and complementary to it.

Notice the differences and similarity:

DNA Polymerization
RNA Polymerization
Starts at
Origin of replication
Promoter
DNA opens by
DNA Helicase
RNA polymerase
Primer protein
DNA primase
no primer required
Primer type
RNA
no primer required
Grows in
5 to 3
5 to 3
Polymerase
DNA polymerase
RNA polymerase
Stops at
When done
End of Gene
Types of RNA
RNA does things, there are 3 types
mRNA = messenger RNA
this is RNA that will be directly translated by ribosomes,it serves as a template for protein
synthesis as it consists of codons(sequence of three bases).Each codon specifies a particular a
particular amino acid or acts as a terminator codon.
rRNA = ribosomal RNA

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this is RNA that will be incorporated into the ribosome (the ribosome is special and made up of
RNA and proteins together), it is responsible for reading of mRNA and serves as a binding site
for tRNA .
tRNA = transfer RNA
this is RNA that is a bridge between RNA and proteins. Its function is to transfer amino acids
from the cytoplasm to the ribosome for placement in a protein molecule.
Remember: Proteins are made of amino acids, there are twenty in all
mRNA is translated because of a few features of it. First it has a string of bases that can be
translated to proteins. This translatable bases are actually as set of codons, or three bases of
RNA that work as a group so RNA is read three letters at a time each of these codons is a
word to the ribosome.
The mRNA ORF is started by a start codon and stopped by a stop codon. The start codon is
AUG. once the ribosome notices a start codon, it will start translating the RNA in steps of three
(one codon at a time) making each codon into a new amino acid linked to the growing protein.
Draw a tRNA showing anticodon (to bind to mRNA codon) and clover like and also charged
amino acid at top
Ribosomal Translation
Central Dogma: DNA is transcribed to RNA which is translated to proteins
Always happens in cytoplasm though ribosomes and RNA made in nucleus for eukaryotic cells.
A ribosome recognizes the beginning of the mRNA and will attach to it and look for the Start
codon.
Once there is stops and brings in a tRNA whose anti-codon matches AUG. That tRNA has a
Methionine amino acid always. Then is holds it there, looks at the next codon.
GUCAUCCUGGUCUGCA AUG GAU GAU GAU AUC GCC GCG CUC GUC GUC
M D D D I A A L V V
The next codon is for aspartic acid and so the ribosome gets a tRNA whose anti-codon matches
the GAU and then links Methionin and Aspartic acid amino acids by a peptide bond. (Same type
of bond as in peptidoglycan). The Methionine is let loose from its tRNA and the free tRNA exits
the ribosome as the ribosome moves to the next codon.
This continues to go one label the acceptor site (where a new tRNA comes in), the protein site,
where all the amino acids are linked and the exit, where the free tRNA leaves it continues until
it reaches a stop codon and then free protein is made.
Mutation:
Is a heritable change (permanent alteration) in the sequence of nucleotides in DNA.
-Genotype refers to the genetic information contained in the DNA of the organism.
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-Phenotype refers to the specific characteristics displayed by the organism (physical

expression of genotype).
-Mutations always change the genotype. Such a change may or may not be expressed
in the phenotype depending on the nature of the mutation.
Point mutation : is a single base substitution (nucleotide replacement).
This mutation changes a single codon in the mRNA, and may or may not change
the amino acid sequence in a protein.
Silent mutation is a point mutation that produces the same original amino acid (no change in
phenotype)
Frameshift mutation : is a mutation in which there is a Deletion or an insertion of one
Or more bases. Such mutations alter all the three-base sequences beyond the deletion
Or insertion and change the amino acid sequence in a protein or stop the protein synthesis when
a terminator codon is introduced.
-Spontaneous mutations occur in absence of any known mutagen due to errors in base pairing
during DNA replication, while Induced mutations produced by mutagens.
-Mutagens are chemical and physical agents that increase the mutation rate above the
spontaneous mutation rate.
What are the commonly known mutagens??

LECTURE 8&9 (Chapter 10 VIROLOGY & CANCER BIOLOGY )

Viruses are microbes that REQUIRE a host cell to replicate. By themselves they cannot
replicate.
They border on the edge of living and non-living. Without a host cell, they cannot reproduce or
do anything. With a host cell, they can make more of themselves.
Viruses are composed of several components:
1) Nucleic Acid (either DNA or RNA) which holds the genetic information for the virus
2) A capsid (protein coat) to protect the nucleic acid
3) An envelope
When a virus exits the cell, it does so by exocytosis in which the virus buds out through
the plasma membrane and thus creates a surrounding bubble of plasma membrane
4) Spikes (outer surface projections)
These are glycoproteins in the envelope that allow the virus to interact with a host cell
and begin its entry (by receptor endocytosis)
Viruses can infect animals, plants or bacteria (bacteriophage)
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Cell specificity: Just because a virus is near a cell, does not mean a virus can infect the cell. If it
does not have the right type of receptor to interact with the spike, it will not enter. If it does not
have the right cell machinery it will not infect.
Host range is the types of cells inside an organism that a virus can infect. Host range also means
what animals a virus can infect. Not all viruses can infect all animals.
Classification: The old scheme was based on the host range. All neurotropic viruses are the
same, all lung-tropic viruses are the same Tropism is where a virus can infect.
Now, classification is based on the genetic material (DNA or RNA) inside a virus.
Viruses can have either RNA or DNA (but rarely both).
It can be double stranded (ds) or single stranded (ss)
Positive Stranded vs Negative stranded
(+) RNA is like mRNA: It can be directly translated to proteins
(-) RNA is the reverse complement of mRNA: It CANNOT be directly translated into
proteins; it must be turned into a (+) RNA
Naked versus Enveloped
Naked: Just a protein coat around nucleic acid of the virus
Enveloped: a sphere of plasma membrane surrounding the protein coat that is surrounding the
nucleic acid of the virus.

RNA families of viruses :

Picorna Virus
+RNA, naked
Enteroviruses Polio virus: Caused severe paralysis due to nerve damage
(Remember FDR, the president, he was in a wheel chair)
Hepatovirus Hepatitis A: Causes liver damage. Hepatitis is a general term for
Liver damage, thus each Hepatitis virus is in a different family
Rhinovirus Causes the common cold, more than a 100 types
Toga viruses
+RNA, enveloped
Rubella Common in children, MMR has stopped commonality in USA
Flavi viruses
+RNA, enveloped
Yellow fever Causes a hemorrhagic fever, which is uncontrolled bleeding
Major problem in central America during panama canal
Hepatitis C Causes severe liver damage and influences liver cancer
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Paramxyo viruses
-RNA, enveloped
Mumps, Measles gone in US due to MMR (measles mumps rubella vaccine for young
children)
Rhabdo viruses
-RNA, enveloped, looks like a bullet
Rabies is major disease
Orthomyxo viruses
-RNA, enveloped, has multiple segments of RNA (segmented genome)
Influenza A different strains infect different animals and birds.
Influenza B mainly infects humans
Filo viruses
-RNA, enveloped, long filaments
Marburg and Ebola viruses are the only two members of this family
Highly pathogenic hemorrhagic viruses (causes a lot of bleeding)
Filo viruses can infect MANY cell types their receptor for the spikes are on many cells
throughout the body and thus cause a lot of damage.
Bunya virus
-RNA, enveloped
Hantavirus- causes hantavirus pulmonary syndrome (HPS).
Arena viruses
-RNA, enveloped
Lassa fever and hemorrhagic fevers.
Reo viruses
dsRNA, naked
Rotaviruses cause severe diarrhea in infants and young children
DNA Families of viruses:
Adeno viruses
Linear dsDNA
Causes acute (quick) respiratory and other infections.
Herpesviruses
Large, linear dsDNA characterized by Latency
Herpes Simplex 1 Mouth Sores
Herpes Simplex 2 Genital Sores
Varicella Zoster Chicken Pox (varicella)and Shingls(zoster).
Cytomegalovirus Dangerous for children at birth if mother is secreting virus from
vagina during birth (birth defects).
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Roseolla virus causes roseolla (fever and rash)in children.

Epstein-Barr virus cause of infectious mononucleosis, also linked with cancers such as
Burkitts lmphoma and Hodgkins disease.
Kaposis Sarcoma Associated Virus cause of Kaposis Sarcoma in AIDS patients and
also causes other cancers in the elderly as well
Poxviruses
Large dsDNA viruses
Cause of Smallpox
Smallpox is eradicated except for two vials in the world
Vaccine was made from vaccinia, a virus that infected cows
Vaccinia is also a pox virus
Cause of Moscullum Contagium
A relatively uncommon disease, , it presents as small raised white tissue on
gentials, especially the penis and is especially common in AIDS patients
Papova viruses
Small dsDNA
Papilloma- common infection of woman (and men) but targets the cervix and vaginal
walls and some papilloma strains are highly associated with cervical cancer. Vaccination
against these cancer-inducing strains can reduce the incidence of cervical cancer ,other
strains cause warts in humans.
Polyoma viruses cause renal disease in immunodeficient.
Vacuolatis SV40 causes cancer in monkeys, used in research.
Hepadna viruses ONLY member is Hepatitis B Virus
dsDNA enveloped
Persistant infections of the liver
Long term causes a lot of liver damage, can lead to hepatocellar carcinoma.
Parvo virus
Naked, linear ssDNA
Adeno associated virus can make adeno virus infections worse
Erythro(B19) virus Cause of fifth disease
Hepatitis D only seen in Hepatitis B infected patients, caused by the additional infection of
Hepatitis delta, a viroid (the only human one)
Hepatitis D, causes massive, rapid liver damage
IV: Viral Carcinogenesis
(Mainly from Notes)
Development of Cancer
Cancer is a disease of uncontrolled growth of our cells. Normally our cells only grow enough
for what is needed in the body. The growth of cells is controlled by two types of proteins in our
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cells (1) proto-oncogenes and (2) tumor suppressors. These proteins either allow a cell to grow
right (for the proto-oncogenes) or stop the cell from growing wrong (tumor suppressors).
Mutations that develop in one particular cell in our body could affect the function of either of
these two types of proteins and lead to uncontrolled growth of the cell. This leads to massive
growth of the cell over many years and the inability for our body to handle it. This process of
cancer development if oncogenesis or neoplastic transformation. A neoplasm is another word
for a cancer. Multiple mutations are required for cancer development.
Some retroviruses can actually start the process of oncogenesis directly. Examples of human
cancer causing retroviruses are HTLV1 and HTLV2 (Human T Cell Leukemia Virus). A cancer
causing retrovirus transduces cells and begins producing its own genetic information, BUT it
also brings in its own genes. There are two ways it can start oncogenesis (1) is by making
proteins that bind to tumor suppressors or (2) by bringing in mutant forms of proto-oncogenes,
theses mutated proteins are called oncogenes. Thus the virus is making a cell grow uncontrolled.
This allows for an indirect expansion of the virus because now there are more cells that have the
virus and thus more copies of the virus around. But, this also leads to more cells and later to
mutations in those cells that lead to full blown cancer. Viruses usually only initiate cancer,
cancer takes a long time to develop and usually becomes a major disease after many mutations.
There are other types of cancer causing viruses. Examples are te Herpesviruses such as EpsteinBarr Virus (EBV) and Kaposis Sarcoma Virus (KSHV). EBV causes Burkitts Lymphoma and
KSHV causes Kaposis Sarcoma (a cancer like disease of the skin) and other lymphomas.
Herpesviruses do not transduce the cells they infect, but rather, they
often setup a Latent infection where their genomes (DNA genomes already) persist in
the nucleus of the infected cells. When the cells are stressed, they exit the Latent form and
switch to a Lytic form that kills the cell, but produces many new virions.
Latency often enhances cells growth by virus made oncogenes, These proteins enhance cell
growth to make more of the latent virus and often will lead to cancer as well. Here we focus on
HPV-16, a very oncogenic form of papilloma virus. Recently, a vaccination against this virus has
been developed which is very efficacious against the development of HPV-16 induced cancers.
Cancer will not develop just with a viral infection, a second hit or mutation is required for full
blown cancer.
How do you stop cancer?
Even though mutations started cancer, enough mutations in a cell will eventually lead to the
cancer cells death. Thus the drugs that are given cause mutations in cells that grow very fast.
Unfortunately, this includes the cells of our hair, intestinal tract and our white blood cells. Cancer
therapy is a balance between killing our cells and killing the cancer.
V: AIDS and HIV
(Mainly from Notes)

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Human Immunodeficiency Virus is the virus that causes AIDS (acquired immuno deficiency
syndrome).
AIDS patients were first reported in 1981 as five men in Los Angeles.
In the early 1980's AIDS was a very deadly disease, which was manifested as people coming
down with VERY rare diseases.
AIDS is the state where the immune system is so weak that it cannot fight off infections (viral,
bacterial, fungal, etc) or cancer (leukemias, lymphomas, Kaposi's Sarcoma) that it normally
could fight off.
In 1986, HIV was discovered. It is a retrovirus that is able to infect immune cells.
The cellular tropism, or cellular specificity of HIV is for T cells, or CD4 Cells of the immune
system. In addition, HIV can infect all CD4 cells.
Another CD4 cell is a macrophage. Macrophages as you remember are able to phagocytoze and
degrade bacteria in their lysosomes.
HIV has three main genes, (1)gag, (2)pol, and (3)env. gag is the gene for the protein coat, pol is
the gene for the reverse transcriptase and env is the gene for the outer spike that attach to the
receptor on the cell it will infect.
In 1987, the first anti-HIV drug was released: AZT (Azidothymidine)
AZT targets the reverse transcription step of the HIV replication. There it forces the reverse
transcription to make a lot of errors and thus mutate the virus beyond its ability to function.
Over time, many of these reverse transcription inhibitors, or nucleoside inhibitors were
developed, but in time, the virus was able to mutate to avoid this drug.
The second class of anti-HIV drugs developed, in 1996, were the protease inhibitors.
These drugs target the HIV protease, which is a HIV protein that changes the proteins coat from
the initial immature form that is released from an infected cell, to a mature form. Without the
protease, the immature HIV is not able to infect as well.
These two types of drugs were in a combinatorial, or cocktail type of treatment (2 nucleoside
inhibitors, 1 protease inhibitor) to target multiple genes and stop the ability for HIV to mutate
against the drugs.
This was called HAART, Highly Active Anti-Retroviral Therapy.

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The biggest problem with this therapy is that the virus can in fact mutate over time, and this is
often due to patients unable to follow the treatment (nonadherance) or unable to pay for so many
drugs.
Thus mutant forms of HIV exist that are resistant to HAART.
A third target of anti-HIV drugs is the fusion step. When a viruss spikes attach to the receptors
of the cell that it will be infecting, HIV gets closer and allows the spikes to fuse the envelope and
the plasma membrane of the cell that it is infecting.
Fusion inhibitors have been developed which bind to the spikes right before they start fusion and
freeze the virus in place. No fusions occur and thus no infection happens.
The first fusion inhibitor was released a couple of years ago and is called Fuzeon.
The major problem is that this drug is only injectable because it is a protein and proteins are
degraded by the stomach. Thus this drug is effective but used only after HAART fails.As of yet,
there is no cure for HIV, only the ability to control the virus.

Lecture Notes 10&11: Chapter 16 (Nonspecific Host Defenses and Host Systems) some
Chapter 14 and 17

Normal flora is the set of bacteria that normally live on (skin) or in (intestines) our body.
These bacteria does not overgrow and lives a very plain existence
The body keeps these bacteria in check.
Normal flora is the set of bacteria that live on or in us
An infection begins when a microbe begins to grow in our body and it is not a normal flora.
Usually it overcomes our many natural defenses.

Infections are diseases that are not part of normal flora or are no longer controlled,
or have access to new parts of our body.

There are two types of defense systems in our body

1)Specific Respond to a particular pathogen, but even more specific than just that, they
respond to a particular antigen. (For example, we respond very specifically against influenza
that we were vaccinated against, but we don not respond to a new strain of influenza.) .
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The specific defenses induce a much stronger action against the second round of infection of the
same organism versus the first round (this is immune memory and the basis behind vaccination).
Specific Defenses involve the production of proteins called antibodies(Immunoglobulins)
Antibodies can specifically recognize a small part of an infection often as little as a few amino
acids. Often particular cells are involved in this process, lymphocytes.
Nonspecific Nonspecific defenses are against general types of infection, or all infections.
These often work before the specific defenses are activated.
Nonspecific defenses include:
Physical barriers such as the skin and mucous membrane. They are physical barriers
and also, there is much surface to secrete anti-microbial substances.
Skin is a physical barrier, but a major site of infection is when a cut or tear occurs.
Skin also has a chemical in it call defensins which can poke holes in bacteria
Skin also has Langerhans cells, which are skin macrophages

The Skin is a major physical barrier to infection, only breaks or tears in skin allow
for entry of microbes
Defensins are anti-microbial proteins released by cells.

Mucous Membranes, cover the inner linings of the insides that are exposed to the outside
environments (lungs, nose, mouth, digestive tract, vaginal lining)
Mucous membranes in the nose and respiratory systems present have hairs and mucus,
which is a mechanical barrier to entering.
Mucous membranes often have movements that move mucus around and also the hairs
move in patterns.

Mucus physically stops the movement of microbes.

Physical movements within these areas also are defenses:

Cough, Sneeze, Vomiting, Diarrhea, also do tears, saliva, and urine flow.
Severe physical movements often are to expel potential pathogens.
Chemical barriers are in body fluids such as Lysozyme in tears, saliva and mucus.
Skin sweat and sebum and gastric acidity,and transferring in blood all are anti-microbial.
CELLULAR DEFENSES
Normally blood is composed of 60% plasma (the liquid) and 40% formed elements, the cells.
Cells in the blood include erythrocytes (red blood cells), platelets (the blood clotting things)
and white blood cells (lymphocytes and the such).

Erythrocytes = Red Blood Cells

Platelets = Blood clotting agents
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White Blood Cells = Immune Cells

Cells that are in the nonspecific defenses

Granulocytes are cells that are have a lot of granules (small distinct sphere like things in
the cytoplasm) and often release what is stored in granules near an infection.
These types of cells include:
Basophils release histamine which induces inflammation of the area
Mast Cells also release histamine and are associated with allergies
Eosinophils important in worm infections and also turn off inflammation
Neutrophils first to respond to an infection (arrive at location of infection)
INTRACELLULAR KILLER
Macrophages are nongranule and are important in the uptake of bacteria (and the
subsequent degradation of the bacteria)
There are many tissue specific (fixed)types of Macrophages
Alveolar (lungs), Kupffer (liver), microglia (brain), osteoclast (bone), M (intestines),
Langerhanh (skin)

Macrophages are important in the degradation of microbes that are small and also
the activation of the immune response All of these cells arrive at a site of infection by
the process called chemotaxis. Chemotaxis is the movement of cells toward chemicals
(Chemokines),that released by phagocytes and pathogens.

Intracellular killing (phagocytosis): Include four successive steps;

1-Chemotaxis , 2-Adherence , 3-Ingestion , 4-Digestion.
(Neutrophils and Macrophages are the main phagocytic cells)

EXTRACELLULAR KILLERS
Eosinophils are key in the attack of large microbes (fungus, worms, parasites) and release toxic
enzymes such as major basic proteins(MBPs) that destoy the microbe.
Natural Killer Cells are a type of lymphocytes that also release cytotoxic proteins to attack cells
that being infected with virus or that are small lymphomas/cancers.
Chediak-Higashi syndrome is the disease where patients have no Nature Killer Cells and are
very prone to massive, virus infection.
THE LYMPHATIC SYSTEM
The Lymphatic system is parallel to the cardiovascular system.
Main Functions:
(1) Collect excess fluid from the spaces between the body cells and inside tissues
(2) Transport digested fats to the cardiovascular system
(3) Transport and keep many of the innate and adaptive systems of the immune system
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The cardiovascular system moves blood by the heart, the lymphatic system moves the lymph by
the contractions and movement of the musculoskeletal system.
Cardio vascular system has blood/blood vessels/organs
Lymphatic system has lymph/lymphatic vessesl/lymph nodes
Lymphoid Organs They are mainly filters and monitor what is passing by them
Lymph Nodes
Filter the lymph from the area around them
Located in the thoracic region (chest), the neck, armpits, groin
Lots of Immune cells are present in them
Bacteria are often brought to the lymph nodes by phagocytic cells to destroy them(innate
Immune defense) or antigen-presenting cells that presenting them to lymphocytes (adaptive
immune defense)
Types of Immune Cells
B cells and T Cells
Both begin in the bone marrow
B cells go from the bone marrow straight to the lymph nodes and spleen.
T cells are different
They go from the bone marrow to the thymus to the lymph nodes and spleen.
Thymus is an organ located directly beneath the sternum/breastbone. It is nice and healthy at
birth and grows until around puberty. Then it begins to shrink(atrophy) until it is very small and
not usable by adulthood.
Why is this important? Think of the decline of the immune system as old age comes on
Spleen
This the largest single lymphatic organs and its main purpose is to filter blood
It is very similar to a lymph node but has more access to the blood vessels
Thus it is very prone to clear out erythrocyes (red blood cells) and is very important in
monitoring the blood for signs of infections
GALT
Located inside the small intestines are Gut Associated Lymphatic Tissues
They have large area of lymphocytes (B and T Cells) and monitor the intestines
Tonsils
Located in the back of the throat, also have lots of lymphocytes.. probably monitor the throat and
surrounding organs systems
Why do lymph nodes swell?
Since there are so many immune cells present in lymph nodes, if bacteria are brought in, a major
battle begins and thus there is massive expansion in the numbers of immune cells in the lymph
nodes. This is grossly manifested as a swollen lymph node that can be detected by lightly
pressing into the area and feeling the swollen lymph nodes. Feel like lumps right under the skin.

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INFLAMMATION
It is the bodys defensive response to tissue damage from microbial infection,
mechanical(cuts),physical(burns) , chemical injuries or allergies.
When an infection begins, this general, red, warm, swollen, pain feeling that happens in the
immediate area. For example at the site of a scratch or tear in the skin. This is the bodys
defense to microbe induced tissue damage.
Classic Signs of Inflammation
(1) Calor Increase in Temperature
(2) Rubor Redness in area
(3) Tumor Swelling of the area
(4) Dolor Increased pain sensitivity
Acute Inflammation (Acute = Rapid)
Functions of Acute inflammation
(1) Kill invading Microbe
(2) Clear tissue Debris
(3) Repair injured tissue
Process of Inflammation
(1) Cuts in outer physical barrier allows a microbe to enter
(2) Leads to damaged cells
(3) Damaged cells leads to activation of basophils and mast cells (remember they are innate
granular cells)
(4) Basophils and mast cells release histamines
(5) Histamines diffuse into nearby capillaries and venules
(6) Walls of vessels dilate (Vasodilation)
(7) Vessels are thus more permeable
Vasodilation
Allows for increased blood flow into the are (skin becomes red and increased blood flow leads
to the area being warmer (more blood from the body core to the external areas of the skin makes
the area feel warmer than it is)
Allow for increased fluid flow from vessels to the area. This leads to edema or swelling of the
area. Blood also allow clotting factors and platelets to arrive at the area and thus allow for
clotting of the damaged area. Extra nutrients are brought in, waste leaves. Many macrophages
are brought in and they start destroy microbes as well as releaseing cytokines while makes
cells chemotax to the area.
Histamine Released by the basophils and mast cells
Too much histamine, triggered by pollen for example, can lead to hay fever, allergies. Pollen in
eye areas leads to red eyes and runny nose, pollen in throat can lead to throat constriction.
Anti-histamines block histamine interacting with the cellular receptor for histamine and thus
stop swelling effects, etc.
Pain sensitization
A small peptide called Bradykinin is released at the site of inflammation and this leads to
increased sensitivity to pain at the site (now a touch hurts when it normally doesnt)
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Prostoglandins are also released. These increase the ability of Bradykinin to intensify pain.
Aspirin blocks the production of prostoglandins and thus leads to a lowering of pain.
Pus
Inflammation leads to leukocytosis, which is an increase in the number of leukocytes in the
blood. Many are attracted to the site of infection by the release of chemokines (which leads ot
chemotaxis).
When phagocytes like macrophages arrive, they try to engulf all the bacteria present. Many are
engulfed, but many phagocytes die in the process.
Leads to the accumulation of
(1) Dead phagocytes
(2) Injured damaged cells
(3) Remains of ingested organims
(4) Tissue Debris
This manifests as a white or yellow fluid called pus
Pus is a sign of a bacterial infection. It is not often associated with a viral infection
Hollowed out cavity of pus is called an abscess such as boils or pimples
Pros and Cons of Inflammation
Great approach to get site clear of microbes
Too much can be harmful though
Edema of area surrounding brain or spinal cord can lead to meningitis
Around throat can lead to constriction of throat
Walling off of area can lead to scars as well as blocking antibiotics from entering the area such as
in a boil. That is why you must lance (stick a needle) into a boil, to get drugs into the area.
Once inflammation is over and decreases you must repair the area
Capillaries enter the area to provide lots of nutrients
Fibroblasts (a type of cell in tissues) replace the destroyed tissue
Granulation tissue is the reddish gray tissue around the area
Then a new epidermis forms. Scar is not as elastic, but much more durable
Chronic inflammation Long term, the microbes are never cleared
Standoff battle, neither the immune system nor the microbe wins
Years long
Try and wall of the area by the host
Example Granuloma
Microbe surrounded by epithelial cells and macrophages, which is then itself surrounded
by collagen (tough protein fibers) and lymphocytes.
This is seen in tuberculosis in lungs and also leprosy in extremeties
Over time it turn to a hard lesion (everything is dead in time, unless one side wins)

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FEVER
Local inflammation at the site of an infection produces calor because of the increase in blood
flow to the area.
Microbial infection is also characterized by a systemic (all over the body) increase in
temperature this is fever.
Body temperature was first characterized in 1868 with a foot long thermometer in the armpit for
30 minutes
Febrile illness is a feverish illness (weak, etc)
Normal body temp
Variation Allowed
Clinical Fever
Oral
Rectal
Infection Max
Mortal Max

37 degrees C
(36.1-37.5)

98.6 degrees F
(97-99.5)

>37.8
>38.4
40
43

>100.5
>101.5
104.5
109.4

The hypothalamus controls much of the physiology of the body including temperature
Fever is the resetting of the normal body temperature caused by infection, vaccinations, tissue
injury. It is Not increasing the temp, but resetting to a higher temp.
Caused by pyrogen release into the blood.
Exogenous pyrogens are from infectious agents (like a toxin from a microbe)
Endogenous pyrogens are from the body, often released by the detection of a microbe or
exogenous pyrogen. Chief amongst these is Interleukin 1 (IL1)
This protein goes to the hypothalamus and causes the neuronal secretion of prostoglandins
(sound familiar right)
Within about 20 minutes, the prostoglandins reset the normal body temperature to the new
temperature.
Also leads to an increase in involuntary muscle contraction and increased in vasoconstriction
(blood vessels shrink)
Involuntary muscle contraction increases heat production
Increased vasoconstriction insulates the body from heat loss
So our bodies now have a New Temperature
Thus anything at normal 98.6 fells cold to us! This is the chills
When there is a loss of infection , there is a decrease in prostoglandins which quickly resets the
temperature of the body so we begin to sweat and have vasodilation. This rapidly brings up
back to normal.
What is the function of Fever?
(1) Raise Body Temp Normal body temp is optimum for microbe growth, now they can not
grow right
(2) Inactivates some bacterial toxins and enzymes
(3) Increases our bodys chemical reactions and increases the immune system functions
(some of our enzymes function well at higher temps)
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(4) Forces a rest (febrile), we feel weak, we are forced to rest and get better.
Aspirin again!
Aspiring stop protoglandin production, right (look at bradykinin). And is often given to
reduce pain AND fever. Now, it is recommended to let the fever run its course, unless the fever
is very high. Why?
INTERFERONS
Mainly antiviral proteins made by the body in response to viral infection
Two types Type I and Type II
Type I alpha and beta, block virus replication (produce AVPs into nearby cells).
Type II gamma, activate macrophages, lymphocytes and NK cells.
Both Type I and II are directly antiviral
They tell cells around the infected cell to enter an Anti-viral state
First administered as a drug in 1986 against Hairy Cell Leukemia. Which is caused by HTLV.
Interferon alpha was used here. It was a treatement, NOT a cure
HCV infection is treated with Interferon alpha. Interferon alpha is not stable in the blood.
Interferon alpha causes many side effects such as fatigues nausea headaches vomit, weight loss.
COMPLEMENT
Complement system is a set of more than 20 large regulatory that plays a key role in host
defense. They are produced by liver and circulate to blood.
Functions of the complement system:
1-Inhance the process of phagocytosis (by Opsonization)
2-kill bacteria and enveloped viruses by causing lysis of their membranes (immune cytolysis)
3-Regulate the inflammation and immuneresponse.
Host-Microbe Relationships and the Disease Process
Signs are observable by someone. These include (1) Swelling, (2) Redness, (3) Rash, (4) Cough,
(5) Runny nose, (6) Puss, (7) Fever, (8) Vomit, or (9) Diarrhea Just think of anything that you
can visible see or notice.
Symptoms are what a patient feels. These include (1) pain, (2) shortness of breath, (3) nausea,
(4) sore throat, (5) headache, or (6) malaise (feeling discomfort). Just think of things that you
have to ask a patient about.
Syndrome is a combination of the S&S (Signs and Symptoms) that are unique for a specific
disease
Response is seen as a fever, malaise, swollen lymph nodes and leukocytosis. We didnt mention
leukocytosis in the class a lot, but you should be able to think of it. Leukocytosis is the state of
having a high level of WBC in the blood
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If after recovery from an infection, there is another infection of the same kind, it is called a
sequelae.

TYPES OF INFECTIONS
Acute Rapid, often severe. Examples are measles, a cold, the flu etc
Chronic Slow, often less severe at first (can turn worse as time progresses). Examples are
tuberculosis and leprosy.
Subacute Between the Acute and Chronic Gingivitis is an example
Latent Disease Quiet form of a disease. Often cycles between acute and latent disease.
Herpes Simplex (HSV) is an example. Also Chickenpox is an acute disease that then goes latent
for years and then becomes the acute disease shingles after a person gets older (and the immune
system goes down)
Local Infection Restricted to a particular area
Focal Infection One main site, but microbes or toxins are released all over the system. An
example is an abseced tooth which can lead to bacteria in the blood
IMPORTANT TERMS
Bacteremia Bacteria in the blood
Viremia Virus in the blood
Septicemia Pathogen in the blood or blood poisoning
Toxemia Released toxins in the blood
Sapremia fungal release of toxins
Why are these terms so important? Remember: When an infection occurs, it must be walled off
from the rest of the body to provide an effective response against it. Bacteremia/Viremia.. Any
of the -emias show that this defense has failed and now bacteria or other microbes are now
systemic. This is bad. Patient may go into septic shock (gram negative bacteria because of their
LPS).
Primary infection this is the first infection of a previously healthy individual
Secondary infection is another infection in the individual, possible because the patient was
weak from the first infection. Remember, the immune system often focuses on one infection at a
time and will leave the body open to attack from different types of microbes
Subclinical infection This is an infection by a particular microbe that does not show the full
spectrum of S&S of the normal infection.

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THE END

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