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

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 Formation of caseous necrosis will not always be seen in all III. MECHANISM OF MICROBIAL RESISTANCE TO HOST
cases of tuberculosis infection. However, the presence of IMMUNITY
Langhans giant cell and granuloma are characteristic of a A. EVASION
tuberculosis infection. Infection of Less Immune Accessible Areas
(Cortez, 2019) • 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
Figure 4. Caseous necrosis of the lungs due to tuberculosis. Note the → Hence, the immune cells will not be exposed to the
cheese- or curd-like appearance of the necrotic tissue microorganisms as well, allowing the latter to evade host
immune response
Microscopically, mononuclear reaction is the same as with the
suppurative reaction. The only difference is the type of Intracellular Absorption
inflammatory cell that is predominant. • In this process, microorganisms allow themselves to be
(Cortez, 2019) 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 • Intracellular absorption
this impact or degree of disease → In this process, microorganisms allow themselves to be
• Resistance: how good the immune system is in fighting the consumed by the body’s macrophages or monocytes
infection → However, instead of being dissolved within these cells, they
→ Physical barriers (e.g. skin, GI, respiratory tract) resist phagocytosis and infect the
→ Innate immune system macrophage/monocyte as well

Determinants of Virulence Antigenic Alterations

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

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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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