The document discusses microbial pathogenicity and the progression of infection and disease. It provides details on: 1) The factors that influence a microbe's pathogenicity, including host factors like age and immune status, and microbial factors like virulence factors and inoculum size. 2) The steps in pathogenesis which include a microbe gaining access to the host, adhering to tissues, penetrating defenses, and damaging the host directly or through toxins. 3) The two qualities that allow microbes to cause disease - invasiveness and toxigenesis. It also discusses bacterial adherence, biofilm formation, and how pathogens prevent host defenses.

1. Man, Microbes and
Environment

2. MICROBIAL PATHOGENICITY AND DISEASES
● Pathogenicity is the ability to produce disease in a host organism.
● Microbes express their pathogenicity by means of their virulence, a
term which refers to the degree of pathogenicity of the microbe.
● Hence, the determinants of virulence of a pathogen are any of its
genetic or biochemical or structural features that enable it to
produce disease in a host.
● The relationship between a host and a pathogen is dynamic.
● The outcome of such a relationship depends on the virulence of the
pathogen and the degree of resistance and susceptibility of the host,
due to the effectiveness of the host defense mechanisms.
Two qualities of pathogenic microbes by which they cause disease to
the host:
● Invasiveness is the ability to invade tissues. It consists of
colonization, production of extracellular substances which facilitate
invasion and ability to bypass or overcome host defense
mechanisms.
● Toxigenesis is the ability to produce toxins.

3. FACTORS INFLUENCING PATHOGENICITY
Factors that Influence the degree of Pathogenicity and the Progression of
Infection and Disease are
Host factors:
● Age, sex, ethnicity, nutrition (diet), hormonal status; personal hygiene and
immune status; Underlying disease or medical condition; Antibiotic or drug
usage; Presence of foreign object (e.g., splinter, catheter, sutures, etc.);
Innate differences between hosts
Microbial factors:
Bacterial virulence factors; Inoculum size (dosage)
● Numbers of Invading Microbes: The chances of causing diseases
increase as the numbers of invading pathogens increases. This expressed
by infectious dose (ID50) and lethal dose (LD50).
● The ID50 (Infectious Dose) is the number of microbes required to produce
infection in 50% of the population. The ID50 is different for different
pathogens i.e. different ID50 for different portals of entry for the same
pathogen.
● The LD50 (Lethal Dose) amount of toxin or pathogen necessary to kill
50% of the population in a particular time frame.
External factors
● e.g., crowding; seasonal variations; hygiene, sanitation and public health;
food processing, storage and preparation; etc.

4. STEPS OF PATHOGENSIS
To cause disease a pathogen must:
● Gain access to the host.
● Adhere to host tissues.
● Penetrate or evade host defenses.
● Damage the host, either directly or
accumulation of microbial wastes.

6. BACTERIAL PATHOGENESIS
● Although the vast majority of bacteria are harmless or beneficial, quite a
few bacteria are pathogenic.
● Pathogenic bacteria are bacteria that cause bacterial infection.
● One of the bacterial diseases with highest disease burden is
tuberculosis, caused by the bacterium Mycobacterium tuberculosis,
which kills about 2 million people a year, mostly in sub-Saharan Africa.
● Pathogenic bacteria contribute to other globally important diseases,
such as
○ pneumonia, which can be caused by bacteria such as
Streptococcus and Pseudomonas, and
○ food borne illnesses, which can be caused by bacteria such as
Shigella, Campylobacter, and Salmonella.
● Pathogenic bacteria also cause infections such as tetanus, typhoid
fever, diphtheria, syphilis.

7. PROGRESSION OF INFECTION AND DISEASE
● ENTRANCE ( PORTAL OF ENTRY )
● COLONIZATION
● DAMAGES TO THE HOST CELL

8. PROGRESSION OF INFECTION AND DISEASE
1. ENTRANCE ( PORTAL OF ENTRY )
● Mucous membrane:
○ It is most common route for most pathogens. The mucous
membranes are respiratory tract, gastrointestinal tract,
urinary/genital tracts and conjunctiva.
● Skin (keratinized cutaneous membrane):
○ Some pathogens infect hair follicles, sweat glands and colonize
surface. But unless broken, skin is usually an impermeable
barrier to microbes.
● Parenteral route:
○ Penetrate skin, punctures, injections, bites, cuts, surgery and
deposit organisms directly into deeper tissues.
The microbes must enter through preferred portal of entry in order to
cause disease. But some can cause disease from many routes of entry.

9. 2. COLONIZATION
The first stage of microbial infection is colonization: the establishment of the
pathogen at the appropriate portal of entry. Pathogens usually colonize host tissues
that are in contact with the external environment. Organisms that infect these
regions have usually developed tissue adherence mechanisms and some ability to
overcome or withstand the constant pressure of the host defenses at the surface.
Bacterial Adherence to Mucosal Surfaces.
In its simplest form, bacterial adherence or attachment to a eukaryotic cell or tissue
surface requires the participation of two factors:
● a receptor and
● a ligand.
The receptors so far defined are usually specific carbohydrate or peptide residues
on the eukaryotic cell surface. The bacterial ligand, called an adhesin, is typically a
macromolecular component of the bacterial cell surface which interacts with the
host cell receptor. Adhesins and receptors usually interact in a complementary and
specific fashion with specificity comparable to enzyme-substrate relationships and
antigen-antibody reactions.
Biofilms are formed when microbes adhere to a surface which usually moist and
contains organic matter. The microbe secretes glycocalyx allowing other microbes
to adhere a large mass is formed. The biofilms are resistant to disinfectants and
antibiotics.

10. PREVENTION OF HOST DEFENSES:
1. Some pathogenic bacteria are inherently able to resist the bactericidal components
of host tissues.
○ The outer membrane of Gram-ive bacteria is a formidable permeability barrier
that is not easily penetrated by hydrophobic compounds such as bile salts
which are harmful to the bacteria.
○ Pathogenic mycobacteria have a waxy cell wall that resists attack or digestion
by most tissue bactericides.
○ And intact LPS of Gram-ive pathogens may protect the cells from complement-
mediated lysis or the action of lysozyme.
2. Enzymes (exoenzymes):- The microbes produce many enzymes to prevent host
defenses are-
○ Coagulases: clot fibrin in blood to create protective barrier against host
defenses.
○ Kinases: dissolve clots (fibrinolysis) to allow escape from isolated wounds
e.g.Streptokinase (Streptococcus pyogenes) Staphylokinase (Staphylococcus
aureus)
○ Hyaluronidase: Hydrolyzes hyaluronic acid that holds together connective
tissues and epithelium barriers allowing deeper invasion e.g. Clostridium sp.
○ Collagenase: breaks down collagen (fibrous part of connective tissue) for
invasion into muscles and organs e.g. Clostridium species
○ IgA proteases : destroy host IgA antibodies found in mucous secretions to
allow adherence and passage at mucus membranes e.g. Neisseria species that
infect CNS.

11. 3. Antigenic Variation
● There are many pathogens which alter its surface
antigens to escape attack by antibodies and immune
cells
● e.g. Neisseria gonorrhoeae has many variety of Opa
gene, which can alter one is being expressed
● e.g. influenza virus constant genetic recombination
between flu viruses always new spike proteins.

12. 3. DAMAGE TO HOST CELLS
The direct damages are:
● Tissue damage, cell components and metabolic by-products, toxins
and enzymes.
● Organ necrosis: - Sum of morphological changes indicative of cell
death and caused by the progressive degradative action of cellular
components, metabolic by-products, enzymes and/or toxins.
● Metabolic Effects: Pathogenic organisms can affect any of the body
systems with disruptions in metabolic processes.
Indirect Damage:
○ Damage to host from excessive or chronic immune response
(immunopathogenesis)

13. Production of Toxins
Toxins are poisonous substance produced by microbes tend to cause widespread
damage/disease in host may be necessary for virulence. There are two types of
toxins produced by bacteria.
Exotoxins:
● Exotoxins produced inside the bacteria and either secreted or released
following microbe lysis and toxin genes are often found on plasmids or via
lysogenic phages. The most exotoxins are enzymes and function to destroy
certain host cell parts or inhibit particular metabolic functions or damage from
toxin results in the particular signs or symptoms of a disease. The named for
the disease, type of cell attacked or organism that produces it e.g. tetanus
toxin: causes tetanus (contraction) of muscle.
Three types of exotoxins:
● A-B toxins have two parts: A is the enzyme that disrupts some cell activity and B
binds surface receptors to bring A into the host cell e.g. botulinum & tetanus toxin.
● Membrane disrupting toxins cause lysis of the host cell by disrupting the plasma
membrane e.g. leukocidins: make protein channels in phagocytic leukocytes e.g.
hemolysins: make protein channels in RBCs (hemolysis: Steptococcus pyogenes).
● Superantigens bacterial proteins that cause proliferation of T cells and release of
cytokines and excessive cytokines can cause fever, nausea, vomiting, diarrhea,
shock and death (septic shock) e.g. toxic shock syndrome (Staphylococcus) e.g.
enterotoxins: Staphylococcal food poisoning.

14. Endotoxins:
Endotoxin is part of the outer membrane portion of the cell wall of gram
negative bacteria. Lipopolysaccharide (LPS) released when dead cells
lyse in blood, causes macrophages to release high levels of cytokines
resulting in chills, fever, weakness, aches, small blood clots,tissue
necrosis, shock and death e.g. endotoxic shock: critical loss of blood
pressure due to bacterial endotoxins (LPS).
Models of action of toxins
Modeling has become a common used tool to predict modes of toxic
action in the last decade.
● The models are based in Quantitative Structure-Activity
Relationships (QSARs), which are mathematical models that relate
the biological activity of molecules to their chemical structures and
corresponding chemical and physicochemical properties. QSARs
can then predict modes of toxic action of unknown compounds by
comparing its characteristic toxicity profile and chemical structure to
reference compounds with known toxicity profiles and chemical
structures.

15. ● It has been proposed that modes of toxic action could be estimated
by developing a data set of critical body residues (CBR).
○ The CBR is the whole-body concentration of a chemical that is
associated with a given adverse biological response and it is
estimated using a partition coefficient and a bioconcentration
factor.
○ The whole-body residues are reasonable first approximations of
the amount of chemical present at the toxic action site(s).
○ Because different modes of toxic action generally appear to be
associated with different ranges of body residues, modes of toxic
action can then be separated into categories.
○ However, it is unlikely that every chemical has the same mode of
toxic action in every organism, so this variability should be
considered.
○ The effects of mixture toxicity should be considered as well,
even though mixture toxicity it's generally additive, chemicals
with more than one mode of toxic action may contribute to
toxicity.

16. MAJOR TYPES OF MODES OF TOXIC ACTION
There are two major types of modes of toxic action:
● non-specific acting toxicants and
● specific acting toxicants.
NON-SPECIFIC TOXICANTS
● Non-specific acting modes of toxic action result in narcosis;
therefore, narcosis is a mode of toxic action.
● Narcosis is defined as a generalized depression in biological activity
due to the presence of toxicant molecules in the organism.
● The target site and mechanism of toxic action through which
narcosis affects organisms are still unclear, but there are hypotheses
that support that it occurs through alterations in the cell membranes
at specific sites of the membranes, such as the lipid layers or the
proteins bound to the membranes.
● Even though continuous exposure to a narcotic toxicant can produce
death, if the exposure to the toxicant is stopped, narcosis can be
reversible.

17. SPECIFIC TOXICANTS
Toxicants that at low concentrations modify or inhibit some biological
process by binding at a specific site or molecule have a specific acting
mode of toxic action. However, at high enough concentrations, toxicants
with specific acting modes of toxic actions can produce narcosis that
may or may not be reversible. Nevertheless, the specific action of the
toxicant is always shown first because it requires lower concentrations.
There are several specific acting modes of toxic action:
● Uncouplers of oxidative phosphorylation. Involves toxicants that
uncouple the two processes that occur in oxidative phosphorylation:
electron transfer and ATP production
● Acetylcholinesterase (AChE) inhibitors. Enzyme associated with
nerve synapses that it’s designed to regulate nerve impulses by
breaking down the neurotransmitter Acetylcholine (ACh). When
toxicants bind to AChE, they inhibit the breakdown of ACh. This
results in continued nerve impulses across the synapses, which
eventually cause nerve system damage. Examples of AChE
inhibitors are organophosphates and carbamates, which are
components found in pesticides

18. ● Irritants.
These are chemicals that cause an inflammatory effect on living
tissue by chemical action at the site of contact. The resulting effect
of irritants is an increase in the volume of cells due to a change in
size (hypertrophy) or an increase in the number of cells
(hyperplasia). Examples of irritants are benzaldehyde, acrolein,
zinc sulphate and chlorine.
● Respiratory blockers.
These are toxicants that affect respiration by interfering with the
electron transport chain in the mitochondria. Examples of
respiratory blockers are rotenone and cyanide.
● Central nervous system (CNS) seizure agents.
CNS seizure agents inhibit cellular signaling by acting as receptor
antagonists. They result in the inhibition of biological responses.
Examples of CNS seizure agents are organochlorinepesticides.