YL6: 04.

23 General Principles of Microbial Pathogenesis

10/12/2019 Basic Pathologies 2
12:30-14:30 Greg Cortez, MD, DPSP
MICROBIOLOGY

TABLE OF CONTENTS • Pathogenicity: capacity of microorganism to produce or cause

disease
SUBMODULE ORIENTATION ................................................................... 1 → Disease impact
I. INFECIVITY ............................................................................................ 1 → Severity of the disease that will be caused by a single
II. DETERMINANTS OF VIRULENCE ........................................................ 1 microorganism
A. RELEASE & TRANSMISSION....................................................... 2 → Magnitude
B. CELLULAR HOST RESPONSES .................................................. 2 • Virulence: characteristic/inherent quality of microorganism to
III. MECHANISM OF MICROBIAL RESISTANCE TO HOST IMMUNITY .... 3
produce this impact or degree of disease
A. EVASION ...................................................................................... 3
B. ANTIGENIC ALTERATIONS ......................................................... 3 → ‘Very potent virulent factor’ – means there is something in
C. INFECTION OF INNATE IMMUNITY ............................................. 3 that microorganism that causes the disease
D. ANTIBIOTIC THERAPY ................................................................ 3 • Resistance: how good is the immune system in fighting these
QUICK REVIEW ........................................................................................ 3 infections
SUMMARY OF TERMS ..................................................................... 3 → The host cells’ resistance
REVIEW QUESTIONS ...................................................................... 4 ▪ Physical barriers (skin, GI, respiratory tract)
REFERENCES .......................................................................................... 5 ▪ Innate immune system
REQUIRED ....................................................................................... 5 → For example, a normal person’s resistance is different from
that of an immunocompromised person
▪ What is mild to the former, is already life-threatening to
SUBMODULE ORIENTATION the latter with a very depressed immune system
Goals
• Identify if a pathology is infectious
NEED TO KNOW
• Know the pathogenesis of an infection
• The relationship I = V / R is only true if resistance is coming
• Determine appropriate antimicrobial drugs for microbes from host cell
• Implement as strategy for infectious disease program in the • However, if we are talking about how the pathogen itself is
hospital or community resistant to host defenses, the relationship becomes:
Grading System I=VxR
Table A1. Grading system for BP2
• Pathogenicity becomes directly proportional to the virulence
Component Percentage factor and to the PATHOGEN’s resistance against host
Major exams 60 factors (innate immunity) or external factors (like
Overall lab grade (pathology exam) 20 antibiotics/antimicrobials)
Formative assessment 7
SGD/Integrative activity 5
Patient encounter 3 II. DETERMINANTS OF VIRULENCE
OSCE & Comprehensive exam 5 • Inherent microbial cell
TOTAL 100 → The mere presence of the cell itself or a structure within
the cell (organelle) can cause disease
Topics → E.g. H. pylori – characteristic organelle within this
microorganism causes ulcer formation
Table A2. Infectious diseases submodule topics • Host immune cellular reaction
Topic Percentage → Symptoms are caused by the host immune system’s reaction
Medicine 25.8 • Microbial products
Pharmacology 25.8 → The bacterial secretion or production causes the disease
Microbiology 16.1 → Not directly the cell or microbe itself but its products
Pathology 16.1 → e.g. Production of toxins mostly by bacteria
Laboratory 9.7 • Mode of transmission
Patient encounter 6.5 → Easier mode of transmission = more likely to spread the
TOTAL 100 infection from one host to another = More pathogenic
→ Major determinant of whether a microbe is capable of
NOTE ON THIS TRANS epidemics, pandemics, etc.
Doc said he removed a lot of slides in his presentation since most of
it had already been discussed in previous lectures and this current Types of Toxins
topic is only introductory. Hence, we only followed Doc’s discussion Endotoxin
and did not add additional info anymore. • Inherent components of the bacterial cell found usually in the
capsule
→ e.g. flagella, cell wall
I. INFECIVITY • Not formally a toxin
• The environment is filled with many microorganisms we are → Just the structure of the bacteria
exposed to → Rarely used term
→ In response to this, our innate immune system should • Mostly seen in Gram negative bacteria (-)
function optimally in order for us to become resistant to most
infections Exotoxin
→ But once microbes overcome these barriers, disease will • Secreted by the bacterial cell itself
take place
→ Chemicals secreted in order to produce symptoms in the
• I = V/R: patient
→ Infectivity or pathogenicity = virulence / host body resistance • Mostly seen among Gram positive bacteria (+) with a few
→ Infectivity is exceptions
▪ Directly proportional to virulence • Enzymes, neurotoxin, superantigens, signal pathway toxins
▪ Inversely proportional to the host body resistance
→ e.g. Classic toxin production such as the Botulinum and
→ Shows the relationship of the factors—not a mathematical Cholera toxin or neurotoxins in C. tetani
equation per se
→ Almost all microorganisms follow this ‘simple’ rule/principle
▪ Virus, bacteria, parasites

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 A. RELEASE & TRANSMISSION
1. Direct contact
2. Aerosolization
→ Pathogens are aerosolized in droplets and are released into
the air when an infected person coughs
→ Size of droplets formed dictate how far the pathogen in the
air can go
▪ Large droplets travel only a short distance
o Influenza virus
▪ Small droplets may travel much further
o M. tuberculosis
o Varicella-Zoster virus
3. Body fluids Figure 1. An infected ingrown nail with pus formation. The pus
→ Contact with urine, feces, blood, saliva formation may be encapsulated or not. Perforation of the capsule will
▪ EBV may be spread through kissing cause the pus to ooze out.
▪ Rabies may be spread through biting
4. Vectors
→ Animals or insects
▪ Zoonotic infections – pathogens transmitted from
animals to humans
▪ Consumption/ingestion of animal products may also
transmit pathogens
→ Examples of carriers that may cause disease
▪ Flies, mosquitoes, ticks, rats, etc.
5. STIs
→ Involves prolonged and intimate mucosal contact
→ Transfer of body fluids
▪ HIV, HSV, Candida, HPV

B. CELLULAR HOST RESPONSES

• Another determinant of virulence Figure 2. Histologic characteristics of an acute suppurative infection.
• Your body will respond accordingly depending on the kind of the Note of the presence of neutrophils.
invading bacterial pathogen

Suppurative Inflammation
 Aka purulent inflammation
• Acute in nature
→ Usually lasts at least a week, two weeks
• Usually due to pyogenic (pus-producing) bacteria or parasites
→ Viruses rarely cause pus production
• Neutrophils are the inflammatory cells that are mostly
responsible for this reaction
• Characterized by the production of pus
→ Pus is an exudate containing dead immune cells, debris from
the damage cells, and edema fluid
→ If a pus accumulates in one area, it will form a mass,
lesion, or nodule called an abscess
▪ Can be encapsulated or non-encapsulated
▪ Normally abscess formations are liquid in form
(liquefactive necrosis)
• The abscess can be big or small
→ If the abscess is big, incision and drainage procedure is
done
→ The pus collected during the procedure will be sent to the lab
for culture
▪ To identify the infecting bacteria
o Under the microscope, you will see neutrophils
▪ To determine the appropriate antibiotic that will be
given to the patient
→ Removal of abscess does not indicate elimination of bacteria
from the patient
Take note that even if you already drained the pus, it doesn’t
mean that the infecting agent is not there anymore. You just
basically popped the balloon but the one causing the abscess is
still there, thus you are just providing a temporary relief to the
patient.
(Cortez, 2019)
• The bigger the abscess, the more the patient is predisposed to
sepsis
→ Sepsis is a reaction caused by a widespread infection
→ Once the bacteria reach the bloodstream, it can go and
implant itself anywhere in the body
Figure 3. Incision and drainage procedure of a larger abscess
formation (see references for video link)
Mononuclear Reaction
• Chronic in nature
→ Usually, lasts at least a month
• Mononuclear cells and lymphocytes are the inflammatory cells
that is mostly responsible for this reaction
• Usually, it is viral in nature
→ If it is a long-standing infection, it can also be bacterial and
fungal in nature
▪ Mycobacterium tuberculosis
• Characterized by formation of granulomas, fibrosis and
scarring
• Example: Granuloma formation in the lungs due to tuberculosis
→ Tuberculosis is caused by an infection with Mycobacterium
tuberculosis (a slow growing microorganism)
→ The body will respond to a TB infection by forming a
granuloma around the pathogen
▪ Macrophages fuse together and line the periphery in
order to contain the infection of the microorganism
▪ The granuloma (fibrotic areas in the lung) causes the
symptoms of the patient (e.g. dyspnea, coughing, etc.)
▪ Air can no longer go in the area granulomatous areas in
the lung → causes difficulty breathing in patient
→ Thus, it is not the bacteria that is directly attacking the lung
tissue directly and causing the disease, but the response of
the immune system to the pathogen damages the organ.

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 Formation of caseous necrosis will not always be seen in all
cases of tuberculosis infection. However, the presence of
Langhans giant cell and granuloma are characteristic of a
tuberculosis infection.
(Cortez, 2019)
Figure 4. Caseous necrosis of the lungs due to tuberculosis. Note the
cheese- or curd-like appearance of the necrotic tissue
Microscopically, mononuclear reaction is the same as with the
suppurative reaction. The only difference is the type of
inflammatory cell that is predominant.
(Cortez, 2019)
III. MECHANISM OF MICROBIAL RESISTANCE TO HOST
IMMUNITY
A. EVASION
Infection of Less Immune Accessible Areas
• Microbes try to escape the immune response by infecting less
immune accessible areas
• Less immune accessible areas refer to the parts of the body
that are less vascular
→ When microorganisms “hide” in these areas, diseases are
considered to be in their dormant state
→ They reactivate when the host becomes
immunosuppressed/immunocompromised
• Why will microorganisms go to less immune accessible areas?
→ More blood supply (increased vascularity) in an organ
means there is more chance for immune cells to travel and
be exposed to that area
→ Similarly, less vascularity would decrease the chances of
immune cells becoming exposed to that area
→ Hence, the immune cells will not be exposed to the
microorganisms as well, allowing the latter to evade host
immune response
Intracellular Absorption
• In this process, microorganisms allow themselves to be
consumed by the body’s macrophages or monocytes
• However, instead of being dissolved within these cells, they resist
phagocytosis and infect the macrophage/monocyte as well

B. ANTIGENIC ALTERATIONS
• More common in viruses
• The immune system is very specific, especially the B cell
mediated response (antibodies)
→ Antibodies can only respond to a certain organism with a
specific antigen on its surface
→ If this antigen is altered even slightly (via DNA or protein
alterations), the antibody will not be effective for that
particular strain of microorganism anymore
 The immune system would already recognize this
antigen as coming from a new strain, eliciting a different
or even absent immune response
Figure 5. Schistosomiasis (liver fluke) granuloma in the liver. The • Example: Influenza
arrow pointing to Schistosoma mansoni egg. The immune cells are → Because there are many (and increasing) strains of
forming a granuloma around the parasite. Nice to know: parasite influenza, vaccines for flu is only good for one year
infections rarely cause suppurative formation because once they are → One vaccine cannot cover every strain of the flu
embedded into the organs they are already considered long standing.
C. INFECTION OF INNATE IMMUNITY
• Immune cells themselves are the ones being attacked by the
NEED TO KNOW: RULE OF THUMB FOR INFECTION
microorganisms
• There are some bacteria that can cause both suppurative and
• Example: HIV, intracellular microorganisms (like mycoplasma)
mononuclear inflammation
→ Bacterial infection will usually start at suppurative
inflammation
D. ANTIBIOTIC THERAPY
→ But once it becomes long standing, it will shift to • This is an external factor contributing to microbial resistance
mononuclear inflammation • Antibiotics are very common nowadays
• Viruses can rarely produce suppurative reactions—they usually → However, most antibiotics (e.g. penicillin G) are not as
cause mononuclear reactions effective as they were before
→ Viruses also have a tendency to become self-limiting → Decrease in effectiveness is due to the unregulated and
→ Rare for them to produce long-standing infections but careless use of antibiotics
there are some exceptions → Hence, microorganisms—especially bacteria—are becoming
• Parasites can rarely produce an abscess formation resistant to conventional antibiotic therapy
→ Having a parasite embedded in an organ is an indication • Microorganisms resist antibiotics through:
of a long-standing infection, thus mononuclear → Enzymatic degradation of antibacterial drugs
inflammation occurs → Alteration of bacterial proteins that are antimicrobial
→ targets
→ Changes in membrane permeability to antibiotics
Table 1. Characteristics of the two host responses  Thicker capsules protect against antibiotic absorption
Suppurative Mononuclear • The bacteria nowadays tend to evolve faster than the
Characteristics
Inflammation Reaction development of new antibiotic drugs
Timing Acute Chronic → Because of this, the World Health Organization is trying to
Monocyte/ lymphocyte promote proper antibiotic use so that resistance to antibiotics
WBC involved Neutrophil dominant
dominant will not be rampant
• Usually viral in
nature QUICK REVIEW
Pyogenic bacteria/ • May be from SUMMARY OF TERMS
Pathogen
foreign bodies bacteria / fungus / Infectivity
parasitic if long • I = V/R
standing → Infectivity is directly proportional to virulence
Characteristic
Pus leading to abscess
Formation of → Inversely proportional to host body resistance
Lesion granulomas (fibrosis) • Pathogenicity: capacity of microorganism to produce or cause
disease

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• Virulence: characteristic quality of microorganism to produce
this impact or degree of disease
• Resistance: how good the immune system is in fighting the
infection
→ Physical barriers (e.g. skin, GI, respiratory tract)
→ Innate immune system
Determinants of Virulence
• Inherent microbial cell
• Host immune cellular reaction
→ Symptoms of the patient with respect to the infection
• Microbial products
• Mode of transmission
→ Major determinant whether a microbe is capable of
epidemics, pandemics, etc.
Types of Toxins
• Endotoxin
→ Inherent components of the bacterial cell usually in the
capsule
→ Not formally a toxin
▪ Just the structure of the bacteria
→ Common in Gram negative bacteria (-)
• Exotoxin
→ Secreted by the bacterial cell
→ Common among Gram positive bacteria (+)
→ Enzymes, neurotoxin, superantigens, signal pathway toxins
Release and Transmission
• Direct contact
• Aerosolization: Size of droplets formed dictate how far the
pathogen in the air can go
→ Large droplets travel only a short distance
→ Small droplets may travel much further
• Body fluids: Contact with urine, feces, blood, saliva
• Vectors: Animals or insects
→ Zoonotic infections – pathogens transmitted from animals
to humans
→ Consumption/ingestion
• STIs: HIV, HSV, Candida, HPV
Cellular Host Response
• Suppurative Inflammation
→ Aka purulent inflammation
→ Acute in nature
→ Usually due to pyogenic (pus-producing) bacteria or parasite
→ Neutrophils are the inflammatory cells that are mostly
responsible for this reaction
→ Characterized by production of pus
▪ If a pus accumulates in one area, it will form an
abscess
→ The bigger the abscess, the more the patient is predisposed
to sepsis
• Mononuclear Reaction
→ Chronic in nature
→ Mononuclear cells and lymphocytes are the inflammatory
cells that is mostly responsible for this reaction
→ Usually, it is bacterial, viral, and fungal in nature
→ Characterized by formation of granulomas, fibrosis and
scarring
Mechanism of Microbial Resistance to Host Immunity
Evasion
• Infection of less immune accessible areas
→ Less immune accessible areas refer to the parts of the
body that are less vascular
▪ When microorganisms “hide” in these areas, diseases
are considered to be in their dormant state
▪ They reactivate when the host becomes
immunosuppressed
→ Why will microorganisms go to less immune accessible
areas?
▪ Similarly, less vascularity would decrease the
chances of immune cells becoming exposed to that
area
▪ Hence, the immune cells will not be exposed to the
microorganisms as well, allowing the latter to evade
host immune response
YL6: 04.23 Basic Pathologies 2: General Principles of Microbial Pathogenesis
• Intracellular absorption
→ In this process, microorganisms allow themselves to be
consumed by the body’s macrophages or monocytes
→ However, instead of being dissolved within these cells, they
resist phagocytosis and infect the
macrophage/monocyte as well
Antigenic Alterations
• Antibodies can only respond to a certain organism with a specific
antigen on its surface
• If this antigen is altered even slightly (via DNA or protein
alterations), the antibody will not be effective for that particular
strain of microorganism anymore
Infection of Innate Immunity
• Immune cells themselves are the ones being attacked by the
microorganisms
• Example: HIV, intracellular microorganisms (like mycoplasma)
Antibiotic Therapy
• Most antibiotics (e.g. penicillin G) are not as effective as they
were before due to the unregulated and careless use of
antibiotics
• Microorganisms resist antibiotics through:
→ Enzymatic degradation of antibacterial drugs
→ Alteration of bacterial proteins that are antimicrobial
targets
→ Changes in membrane permeability to antibiotics
REVIEW QUESTIONS
1. One of the ways microorganisms resist host immunity is via
evasion by infecting less immune accessible areas. Which of the
following is true about this mechanism?
a) Less immune accessible areas receive less blood flow so
immune cells wouldn’t be able to target the microorganisms
there
b) Microorganisms stay in these areas because they are
nutrient-rich, allowing them to survive longer
c) Microorganisms use these areas to hide and stay dormant,
waiting for the chance to attack when the host is
immunocompromised
d) All of the above
e) A and B only
f) A and C only
2. Antibiotic resistance continues to be a problem because:
a) Bacteria tend to evolve faster than the development of new
antibiotics that are effective against them
b) Antibiotics are just not as effective as they were before due
to unregulated and careless use
c) Bacteria can alter their proteins that are being targeted by
antimicrobials
d) All of the above
e) None of the above
3. Which reactions and inflammatory cells are correctly paired?
a) Suppurative inflammation: Neutrophils
b) Immune complex deposition: Plasma cells and B-
Lymphocytes
c) Mononuclear Reaction: Mononuclear cells and Lymphocytes
d) A and B only
e) A and C only
4. Which of the following are true?
a) Endotoxins are common in gram-positive bacteria
b) Gram-negative bacteria usually secrete endotoxins
c) Exotoxins are inherent components of a gram-negative
bacteria
d) Superantigen is an example of exotoxin
e) None of the above
5. All of the following statement are true except:
a) Large droplets travel only a short distance
b) Size of droplets formed dictate how far the pathogen in the
air can go
c) Small droplets may travel much further
d) Pathogens are aerosolized in droplets and are released into
the air when an infected person coughs
e) None of the above
4 of 5
6. Which is NOT a determinant of virulence?
a) Host Immune Reaction
b) Inherent microbial cell
c) Microbial products
d) Mode of Transmission
e) None of the above

7. Infectivity is directly proportional to host body resistance.

Infectivity is inversely proportional to virulence.
a) Only the first statement is true
b) Only the second statement is true
c) Both statements are true
d) Both statements are false

Answers
1F, 2D, 3E, 4D, 5E, 6E, 7D

REFERENCES
REQUIRED
(1) Cortez, G. 12 October 2019. General Principles of Microbial
Pathogenesis [Lecture slides].
(2) ASMPH 2022. 2018. General Principles of Microbial
Pathogenesis [Trans].
(3) Figure 3. Incision and drainage. Retrieved from
https://www.nejm.org/doi/full/10.1056/NEJMvcm071319
(4) Figure 4. Caseous necrosis. Retrieved from
https://greek.doctor/pathology-1/theoretical-exam-topics/6-
caseous-necrosis-and-adiponecrosis/
(5) Figure 5. Schistosomiasis. Retrieved from
https://www.frontiersin.org/articles/10.3389/fimmu.2013.00089/full

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