1/11/2024

Lecture-1

Introduction
to
microbial pathogenesis
Md. Fakruddin, PhD (Fddn)
Assistant Professor
Department of Biochemistry & Microbiology
School of Health & Life Sciences
North South University, Dhaka, Bangladesh
Office- SAC824
Tel: +8801304206807
Email: md.fakruddin@northsouth.edu

Bacterial Pathogenesis MIC412

Microbial Pathogenesis

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Why Pathogenesis need to be studied?

1. It helps them to find answers to important

questions related to disease processes:
a) What is the cause/causes of the disease, and why
the disease is developing
b) What are the mechanisms responsible for
disease onset, progression, and recovery
c) What are the mechanisms responsible for
development of symptoms and signs of disease

2. If doctors are able to understand the causes

and mechanisms of the disease, then they are able
to find the way how to influence them rationally

Microbiology in our daily life

Some of the bacteria that grew when an 8-

yearold boy who had been playing outside
pressed his hand onto a large Petri dish.

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Contamination, infection and disease-

Contamination-microorganisms are
present.

Infection- multiplication of any parasitic

organism within or upon the host’s body-does
not necessarily result in disease

Disease- disturbance in the state of

health wherein the body cannot carry out all
its normal functions

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Pathogens, pathogenicity and virulence

Pathogenicity is the capacity to produce disease.

Pathogenicity depends on the ability of an organism to invade
and avoid the hosts defense mechanisms, and to multiply.

Virulence-refers to the intensity of the disease produced by

pathogens and it varies among different microbial species.

The virulence of a pathogen can be decreased by

attenuation, the weakening of the disease producing ability of
the pathogen. Attenuation can be achieved by repeated sub-
culturing on laboratory media or by transposal of virulence
(e.g,. Passage of rabies virus through a rabbit until it was no
longer virulent in humans).

Microbial Mechanisms of Pathogenicity:

How Microorganisms Cause Disease

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Stages in the course of an infectious disease

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Microbes and Disease:

Establishing a Connection
Koch’s Postulate

The Germ Theory of Infectious Disease

The first sightings of microbes through the microscopes

invented by Antonie van Leeuwenhoek (1632-1723)
occurred in the 1600s, but it took 2 centuries for the
connection between microbes and disease to be made.

Louis Pasteur (1822-1895), Friedrich Gustav Jacob

Henle (1809-1885), and other early advocates of what
has been called the germ theory of infectious disease
realized that the connection between a microbe and a
particular set of symptoms needed to be placed on a
sound scientific basis.

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Koch's Postulates
A German microbiologist, Robert Koch (1843-1910), proposed a set of
"rules" for establishing a connection between a microbe and a disease;
these four criteria for establishing cause and effect came to be known
as Koch's postulates (Table 1.1).

1. Koch's first postulate states that the microbe must be associated

with the lesions of the disease. That is, the microbe should be
present in all cases where symptoms of disease are evident and
must be found in diseased tissue but not in healthy tissue.
2. The second postulate directs that the microbe must be isolated
from the lesions of the disease and grown as a pure culture.
3. The third postulate states that a pure culture of the isolated
microbe should reproduce the symptoms of the disease if it is
inoculated into a susceptible host, either humans or experimental
animals.
4. The fourth postulate states that the microbe must be reisolated in
pure culture from the experimentally infected host that was used to
satisfy the third postulate.

Limitations of The Koch's Postulates

1. First, they assume that the disease symptoms are
dependent entirely on the bacterium, yet host
susceptibility due to genetic and other factors, such as
age and the proficiency of the immune system, varies in
human and animal populations and is now known to
play a major role in virulence. Some individuals can be
colonized with a potentially disease-causing bacterium
yet not develop symptoms of the disease, whereas others
are severely affected. Not all individuals respond equally
to an infectious microbe, so the disease may not take the
same course in all people. In addition, prior infection with
one microbe may influence the response of the host to
subsequent infection with another microbe.

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Limitations of The Koch's Postulates

2. Second, Koch's postulates assume that a pathogenic

bacterium can be readily isolated and cultured.
Unfortunately, not all bacteria can be cultured (or at
least we have not yet determined how to culture them)
under standard laboratory conditions. They may change
their properties upon being cultured so that they lose
some of the traits that allow them to cause disease.

Limitations of The Koch's Postulates

3. Third, Koch's postulates assume that all members of a

bacterial species are equally virulent and that a single
species causes each disease. This is clearly not the case
for all bacterial pathogens. There can be dramatic and
distinct differences in disease-causing abilities, even
between closely related bacterial strains.

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Limitations of The Koch's Postulates

4. Finally, Koch's postulates require reinoculation into a

susceptible host to reproduce the disease symptoms. For
human disease, this requires either brave volunteers in
highly structured studies or, more likely, a good animal
model. However, an animal model may not be available,
and indeed, for many diseases non-human animals are
only approximate model systems. This leads to the
question of just how closely an animal model should
mimic the disease in humans for it to serve as an
acceptable model. To illustrate why these issues might
make it difficult to satisfy Koch's postulates, it helps to
consider some examples of attempts to prove that a
particular bacterium causes a particular disease.

Modern Alternatives to Koch's Postulates

Thomas River - Postulates On Viral Diseases

• He believes that blindly following K’s P’s had became a

hindrance.

• River argued that K’s P’s not to be fulfilled in viral disease.

• Most viral infections become asymptomatic
• Viruses can’t be cultured on lifeless medium.

Postulates On Viral Diseases

a) A specific virus must be found associated with a disease with a
degree of regularity.

b) The virus must be shown to occur in the sick individual not as

an incidental or accidental finding but as the cause of the disease
under investigation.

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Modern Alternatives to Koch's Postulates

Alfred Evans - Elements of Immunological Proof of Causation

a) Antibody to the agent is regularly absent prior to the

disease and exposure to the agent.
b) Antibody to the agent regularly appears during illness and
includes both immunoglobulin G and M classes.
c) The presence of antibody to the agent predicts immunity to
the clinical disease associated with primary infection by the
agent.
d) The absence of antibody to the agent predicts susceptibility
to both infection and the disease produced by the agent.
e) Antibody to no other agent should be similarly associated
with the disease unless it is a cofactor in its production.

Evans, A. (2012). Causation and Disease: A Chronological Journey. New York

and London: Springer Science & Business Media.Ravindran, B. (2016). New
pathogen discovery. Current Science, 110(4), 549-551

Modern Alternatives to Koch's Postulates

Stanley Falkow - Molecular Koch’s Postulates

• Falkow believes that pathogenicity is caused by

genes carried in pathogenicity island.

• Explained some asymptomatic status?

• Causality based on molecular evidences.

Falkow, S. (2004). Molecular Koch’s postulates applied to bacterial

pathogenicity — a personal recollection 15 years later. Nature Microbiology, 2,
67-72

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Modern Alternatives to Koch's Postulates

Stanley Falkow - Molecular Koch’s Postulates
a) The phenotype or property under investigation should be
associated with pathogenic members of a genus or pathogenic
strains of a species.
b) Specific inactivation of the gene(s) associated with the suspected
virulence trait should lead to a measurable loss in pathogenicity
or virulence, or the gene(s) associated with the supposed
virulence trait should be isolated by molecular methods. Specific
inactivation or deletion of the gene(s) should lead to loss of
function in the clone.
c) Reversion or allelic replacement of the mutated gene should lead
to restoration of pathogenicity, or the replacement of the modified
gene(s) for its allelic counterpart in the strain of origin should
lead to loss of function and loss of pathogenicity or virulence.
Restoration of pathogenicity should accompany the
reintroduction of the wild-type gene(s).
Falkow, S. (2004). Molecular Koch’s postulates applied to bacterial pathogenicity
— a personal recollection 15 years later. Nature Microbiology, 2, 67-72

Modern Alternatives to Satisfy Koch's Postulates

Alternative Methods Used to Satisfy Koch's Postulates

1. PCR can be used to detect and identify the microbe in
diseased tissue.
2. Immunohistochemistry can be used to detect and
identify the microbe in diseased tissue.
3. Antibiotic therapy can be used to eliminate the
microbe and thereby cure the disease.
4. Vaccination can be used to prevent infection by the
microbe and thereby prevent disease.
5. Hygiene, disinfection, and health practices can be used
to prevent exposure to the microbe and thereby
prevent disease.

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Koch's Postulates
Proposed Fifth Postulate

5. Elimination of the disease-causing microbe from the

infected host or prevention of exposure of the host to
the microbe should eliminate or prevent disease.

Koch's Postulates
The Need for the Fifth Postulate

Technically, scientists working on Chlamydophila pneumoniae have

satisfied all four of Koch's postulates, if one accepts the rabbit model
as a good model for human disease. Nonetheless, there are still
skeptics, as there should be, given some of the problems described
above.
Similarly, even the use of a human volunteer to show that ingesting
Helicobacter pylori could cause a mild inflammation of the stomach
lining did not convince people skeptical of the H. pylori-ulcer
connection. What finally made true believers out of most scientists
and physicians was the development of an antibiotic therapy that
eliminated the bacteria and at the same time cured the disease.

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Modern Alternatives to Satisfy Koch's Postulates

Fredricks and Relman - Koch’s Postulates for 21st

Century

• Fredricks and Relman believe that:

• advancement in nucleic acid-based microbial detection
method
• uncultivable microorganisms made traditional K’s P’s
obsolete.
• Aim to provide a paradigm shift from clinical-based evidence
to sequence-based evidence to prove causality.
• Causality by culture-independent molecular method.

Fredrick, D. N., & Relman, D. A. (1996, Jan). Sequence-based identification of

microbial pathogens: a reconsideration of Koch’s postulates. Clinical
Microbiology Reviews, 9(1), 18-33

Modern Alternatives to Satisfy Koch's Postulates

Fredricks and Relman - Koch’s Postulates for 21st Century
a) A nucleic acid sequence belonging to a putative pathogen should
be present in most cases of an infectious disease. Microbial
nucleic acids should be found preferentially in those organs or
gross anatomic sites known to be diseased (i.e., with anatomic,
histologic, chemical, or clinical evidence of pathology)and not in
those organs that lack pathology.
b) Fewer, or no, copy numbers of pathogen-associated nucleic acid
sequences should occur in hosts or tissues without disease.
c) With resolution of disease (for example, with clinically effective
treatment), the copy number of pathogen-associated nucleic acid
sequences should decrease or become undetectable.With clinical
relapse, the opposite should occur.
d) When sequence detection predates disease, or sequence copy
number correlates with severity of disease or pathology, the
sequence-disease association is more likely to be a causal
relationship.
Fredrick, D. N., & Relman, D. A. (1996, Jan). Sequence-based identification of microbial pathogens: a
reconsideration of Koch’s postulates. Clinical Microbiology Reviews, 9(1), 18-33

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Modern Alternatives to Satisfy Koch's Postulates

Fredricks and Relman - Koch’s Postulates for 21st
Century
e) The nature of the microorganism inferred from the available
sequence should be consistent with the known biological
characteristics of that group of organisms. When phenotypes(e.g.,
pathology, microbial morphology, and clinical features)are predicted
by sequence-based phylogenetic relationships, the meaningfulness
of the sequence is enhanced.

f) Tissue-sequence correlates should be sought at the cellular level:

efforts should be made to demonstrate specific in situ hybridization
of microbial sequence to areas of tissue pathology and to visible
microorganisms or to areas where microorganisms are presumed to
be located.

g) These sequence-based forms of evidence for microbial causation

should be reproducible.
Fredrick, D. N., & Relman, D. A. (1996, Jan). Sequence-based identification of microbial pathogens: a reconsideration
of Koch’s postulates. Clinical Microbiology Reviews, 9(1), 18-33

Summary (Koch’s Postulates’ Limitations)

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Summary (Revised K’s P’s)

End Word

• “The power of Koch’s postulates comes not from their

rigid application, but from the spirit of scientific rigour
that they foster.” - Fredericks and Relman

• There is no fault in K’s P’s or any of its revised version,

they only serve as a guideline to help us assign
causality.

• Know K’s P’s and their revised form, but don’t rely on
them.

Evans, A. (2012). Causation and Disease: A Chronological Journey. New York and
London: Springer Science & Business Media.Ravindran, B. (2016). New pathogen
discovery. Current Science, 110(4), 549-551

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Any questions?

Lecture-2

Introduction to microbial
pathogenesis

Md. Fakruddin, PhD (Fddn)

Assistant Professor
Department of Biochemistry & Microbiology
School of Health & Life Sciences
North South University, Dhaka, Bangladesh
Office- SAC824
Tel: +8801304206807
Email: md.fakruddin@northsouth.edu

Bacterial Pathogenesis MIC412

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MICROORGANISM AND HOST

➢ Saprophytism – Living on dead or decaying organic matter.
➢ Parasitism – Living on or within another living organism - there are
different types of host-parasite relationships.
➢ Commensalism – parasite lives on/in the host without causing
any disease.
➢ Symbioism – mutally beneficial relationship
➢ Opportunistic pathogen – The organism is generally harmless,
but can cause disease when it gains access to other sites or tissues.
➢ Obligate pathogen – parasite always causes disease .
➢ Infectivity – It is the capacity of the organism to penetrate the tissues
of host, to survive the host defenses, and to multiply and disseminate
in host.
➢ Pathogenicity – It is the capacity of the microbial species to produce
disease.

SOURCES OF INFECTION
Sources of infection are animal and inanimate in nature.
Animal sources
➢ Normal flora
➢ Animals in incubation period of disease
➢ Animals with overt disease.
➢ Convalescent carrier animals – In these animals shedding of the
pathogen occurs for varying periods after clinical recovery. The
period may vary from weeks to months.
➢ Contact carrier or subclinical infections – They acquire pathogenic
organisms from other animals suffering with infectious disease
without contracting the disease themselves. Such animals are called as
contact or subclinical carriers. The carrier state may be temporary for
a few days or lasting for months.
Inanimate sources (fomites)
Contaminated utensils, feed and water troughs, vehicles, etc.

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TRANSMISSION
Disease can be transmitted by direct or indirect contact.
Direct contact
➢contact with discharges or aerosols from the animal.
➢Coitus.
➢Vertical transmission from mother to offspring.
Indirect contact
➢Organisms excreted by the infected animal are carried in/on
various vehicles like feed, water, litter, clothing, footwear, farm
house products and by-products, equipments, personnel, logistics,
air or dust. Such contaminated objects are called as fomites.
➢Contaminated instruments may also spread the infection.

Routes of Entry

➢ Inhalation
➢ Ingestion
➢ Inoculation through the skin or mucous membrane
➢ Coitus or artificial insemination.
➢ Transplacental / in ovo
➢ Hospital acquired infections - nosocomial infections.
➢ Physician induced infections - iatrogenic infections.

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Opportunistic infections
• compromised people/animal
– normal flora
• Skin
– Staphylococcus aureus
– S. epidermidis
– Propionibacterium acnes
• Intestine
– Bacteroides
* high numbers
– Enterobacteriaceae
* low number
– environment
– Dermatophytes
– nosocomial

Mechanisms of Bacterial Pathogenesis

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PATHOGENICITY
PATHOGENICITY: The ability to cause disease

• virulence factors
• number of initial organisms
• immune status

The "objective" of bacteria is to multiply rather than to cause

disease; it is in the best interest of the bacteria not to damage
or kill the host.
A disease ensues when the balance between bacterial
pathogenicity and host resistance is upset.

Pathogenic bacteria can be grouped into three categories on the

basis of their invasive properties for eukaryotic cells:
➢ Extracellular
➢ Obligate Intracellular
➢ Facultative Intracellular .

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VIRULENCE

VIRULENCE: is the measure of the pathogenicity of an organism to

cause disease; usually used to describe the difference in disease
causingcapabilitybetweentwodifferent strains of the samespecies.

Virulence can be expressed as LD50 (lethal dose for 50% of the

inoculated hosts) or ID50 (infectious dose for 50% of the inoculated
hosts).

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Virulence Factors
VIRULENCE FACTORS: The factors produced by a microorganism and induce
pathology in a host are called virulence factors. These factors help pathogen to
(1) invade the host,
(2) cause disease, and
(3) evade host defenses.
Virulence factors are classified into two categories –
1. Virulence factors that promote bacterial colonization of the host:
➢ Adherence Factors
➢ Invasion and/or Spreading Factors
➢ Compete for iron and other nutrients;
➢ Evasion of host immune responses
2. Virulence factors that damage the host.
➢ Exotoxins
➢ Endotoxins

PATHOGENIC ATTRIBUTES
OR
VIRULENCE FACTORS
OF BACTERIA

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Genetic Basis for Virulence

Virulence factors in bacteria may be encoded on chromosomal DNA, bacteriophage DNA,

plasmids, or transposons. For example, the heat-labile enterotoxin (LTI) of E coli is plasmid
encoded, the heat-labile toxin (LTII) is encoded on the chromosome, and diphtheria toxin of C.
diphtheriae is coded by phage. Virulence factors are acquired by bacteria by vertical or
horizontal gene transfer

Bacterial Virulence Factors that

Promote Colonization in the Host

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Factors for contact with host cells

1. Bacterial motility - e.g., non-motile mutants of Vibrio

cholerae are less virulent than the motile wild types.
2. Bacterial enzymes - e.g., Streptococcus pyogenes
produces streptokinase that facilitate spread of the
bacterium by liquefying the fibrin clot

Factors for adherence with host cells - adhesins

Adhesins are proteins found on the cell wall of various bacteria that bind
to specific receptor molecules on the surface of host cells and enable the
bacterium to adhere intimately to that cell in order to colonize and resist
physical removal, e.g. common fimbriae, capsule, biofilm, liptotechoic
acid, Fibronectin binding protein (FBP), etc.

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Adherence factors - Pili (fimbriae)

Adherence factors - capsules (biofilms)

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Adherence factors – FBP

(eg. S. pyogenes)

F-protein
lipoteichoic acid

fibronectin

Spreading Factors
"Spreading Factors" are a family of bacterial enzymes that affect the physical
properties of tissue matrices and intercellular spaces, thereby promoting the
spread of the pathogen.
➢ Hyaluronidase - depolymerize hyaluronic acid, the interstitial cement
substance of connective’ tissue; produced by streptococci, staphylococci, and
clostridia.
➢ Collagenase - breaks down collagen; produced by Clostridium
histolyticum
and Clostridium perfringens.
➢ Neuraminidase - degrades neuraminic acid (also called sialic acid) present
on epithelial cells of the mucosa; produced by Vibrio cholerae, Shigella
dysenteriae, P.multocida, and M.haemolytica
➢ Streptokinase and Staphylokinase - convert inactive plasminogen to
plasmin which digests fibrin.
➢ Edema Factor of B.anthracis - adenylate cyclase activity promote
bacterial invasion.

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Invasins
➢ Some bacteria have mechanisms by virtue of which they initiate
phagocytosis in non-phagocytic cells for invasion by:
▪ binding to some receptor on cell, eg. Yersinia pestis
▪ injecting invasins, such as Type III secretion system in
bacterial cytoplasm, eg. Salmonella
In either case changes in host cell cytoskeleton cause the bacteria to
be ingested

➢ Some pathogens can utilize actin fibres intracellularly to move

through host cells (transcytosis), eg. Listeria monocytogenes

➢ Invasins may also mediate uptake of bacteria into professional

phagocytic cells in a way that bypass normal phagosome
formation

The Type III Secretion system in Bacteria

The bacteria having the type III secretion system on contact with cells, delivers
proteins into the cells which cause polymerization and depolymerization of
actin filaments resulting in cytoskeletal rearrangement. Thus the invasins is
able to trick the non-phagocytic cell into behaving like a phagocyte and engulf
the bacterium into phagosome like vacuole. The bacteria then cause the
vacuole membrane to rupture and escape into the cytoplasm

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Transcytosis

The Ability to Compete for Nutrients and Iron

Bacteria compete for nutrients by synthesizing specific transport systems or

cell wall components capable of binding limiting substrates and transporting
them into the cell.

➢ Siderophores--low MW compounds that chelate iron with very high

affinity, eg. E.coli
➢ Direct bindingof host transferrin, lactoferrin, ferritin, or hemebybacterial
surface receptors, eg. Yersinia species
➢ Exotoxinsthat lyse host cells (can beusedto obtainother nutrients as
well), eg. haemolysins

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Bacterial Virulence Factors that helps in

Evasion of Immune Response

Evasion of Innate Immune Responses

➢ Invade or remain confined in regions inaccessible to phagocytes. e.g. the
lumen of glands and the skin are not patrolled by phagocytes.
➢ Avoid provoking an inflammatory response.
➢ Hide the antigenic surface of the bacterial cell. eg, S.aureus produces
coagulase which clot fibrin on the bacterial surface
➢ Inhibit chemotaxis of phagocytes, e.g. Streptococcal streptolysin, fractions of
Mycobacterium tuberculosis and Clostridium ø toxin suppresses neutrophil
chemotaxis
➢ Inhibit ingestion by phagocytes, e.g. capsule inhibit recognition
and
engulfment by phagocytes
➢ Resistance to complement mediated lysis (serum resistance), e.g. capsule,
LPS, S-layers, etc.

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Capsules Blocking the Attachment of Bacteria to Phagocytes

Resistance to opsonization/phagocytosis

ii. LPSOpolysaccharide
iii. S-layer
iv. Extracellular products:enzymes that inactivate C5a chemoattractant
(S. pyogenes), toxins that kill phagocytes(leukotoxins) (Mannheimia
haemolytica),inhibit migration, or reduce oxidative burst.

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Strategies for surviving phagocytosis:

I. Escape from phagosomebefore fusion with lysosome (example: Listeria

monocytogenes, mediated by listeriolysin)
II. Prevent phagosome-lysosome fusion – eg, Salmonella, Mycobacterium ,
Legionella and Chlamydia
III. Express factors that allow survival in phagolysosome

Evasion of Adaptive Immune Defenses

➢Antigen masking - Some bacteria are able to coat themselves with host
proteins such as fibrin, fibronectin, lactoferrin, or transferrin and in this way
avoid antibodies.
➢Antigenic switching or phase variation - one way certain bacteria can
evade antibodies is by changing the adhesive tips of their pili or vary other
surface proteins so that antibodies already madewill no longer "fit."
➢ Staphylococcus aureus produces protein A while Streptococcus pyogenes
produces protein G. which non-specifically binds IgG with very high affinity
➢ Immunoglobulin proteases - Bacteria such as Haemophilus influenzae ,
Streptococcus pneumoniae , Helicobacter pylori , Shigella flexneri , Neisseria
meningitidis , Neisseria gonorrhoeae and Enteropathogenic E. coli produce
enzymes that degrade the antibodies found in body secretion (IgA).

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Staphylococcus aureus Resisting

Opsonization via Protein A

The Fc portion of the antibody IgG, the portion that would normally binds to Fc receptors on
phagocytes, instead binds to protein A on Staphylococcus aureus. In this way the bacterium
becomes coated with a protective coat of antibodies that do not allow for opsonization.

Bacterial Virulence Factors

that damage the Host

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Virulence factors that damage the host include:

➢ The cell wall components that bind to host cells causing them to
synthesize and secrete pro-inflammatory cytokines and
chemokines.
➢ Toxins.
➢ Induce autoimmune responses.

Bacterial Cell Wall Components that Promote Synthesis and

Secretion of Inflammatory Cytokines and Chemokines.

➢LPS of Gram-negative bacteria, and teichoic acids and glycopeptides of

Gram-positive bacteria induces cytokine production and secretion
➢These cytokines, such as TNF-alpha, IL-1, interleukin-6 IL-6, IL-8, and
platelet-activating factor (PAF) promote inflammation and lead to activation
of the complement pathways and the coagulationpathway.
➢At moderate levels, inflammation, products of the complement pathways, and
products of the coagulation pathway are essential for body defense.
However, these when excessive produced in excessive amounts cause
exaggerated inflammatory response whichleads to MOSF.
➢ In some bacteria, lipoproteins in the outer membrane may also play a role
in leading to excessive cytokine production.

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Harmful Effects of Glycopeptides and Teichoic

Acid Released During Gram-Positive Infections

Virulence Factors that Induce

Autoimmune/Hypersensitivity Responses

➢ Producing cross-reacting antibodies or auto reactive cytotoxic T-

lymphocytes made in response to bacterial antigens that accidentally
cross-react with epitopes on host cells destroying the host cells to which
they have bound and/or activate the classical complement pathway that
stimulates the inflammatory response resulting in more tissue damage, e.g.
rheumatic fever triggered by some strains of Streptococcus pyogenes
➢ Stimulating the production of immune complexes that activate the
complement pathway resulting in inflammatory response, which destroys
tissues, e.g. acute glomerulonephritis following infection by Streptococcus
pyogenes.

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Microbial Virulence Factors in Pathogenicity

Any questions? আপনি মারা গেলেি

নিভালে !!!

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Lecture-3

Host-Microbe Interaction

Md. Fakruddin, PhD (Fddn)

Assistant Professor
Department of Biochemistry & Microbiology
School of Health & Life Sciences
North South University, Dhaka, Bangladesh
Office- SAC824
Tel: +8801304206807
Email: md.fakruddin@northsouth.edu

Bacterial Pathogenesis MIC412

Today’ Outline

1) Overview of host-microbe interactions.

2) Association of microbial metabolites in human health and

disease

3) Overview of cellular and Molecular mechanisms

4) Treatments and therapeutics targeting microbial interactions.

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Host-Microbe Interaction: A complex interplay

➢ The success or failure of a pathogen is entirely dependent
on its ability to survive, reproduce, and spread to a new host
or environment.

➢ Host fitness, meanwhile, is determined by the ability of the

host to survive and reproduce; the host must therefore
effectively curtail diseases that impair either of these abilities

➢ Host‐microbiome interactions are governed by the complex

interplay between host genotype, microbial genotype/
community composition, and the environment.

➢ Host-pathogen interactions provide information that can help

scientists and researchers understand disease
pathogenesis, the biology of one or many pathogens, as well
as the biology of the host.

Host-Microbe Interaction:
A complex interplay

Ref: Host Pathogen Interaction:

Microbial Metabolism, Pathogenicity
and Antiinfectives. Ed. Gottfried
Unden, Eckhard Thines, Anja
Schuffler (vol 6)

The complex interactions between host, microbiota, and environment. Both the host and the microbiota have a
range of characteristics unique to an individual. The health status of the host–microbiota superorganism can be
altered by a number of external environmental factors, perhaps most significantly by diet. Host factors and the
composition of the microbiota determine an individual’s response to stressors. These may or may not alter the
homeostasis of the superorganism. A number of microbial therapeutics are currently under investigation to
restore health, including bacteriotherapy, altered diet, and fecal transplantation. Probiotics and prebiotics are
also candidate interventions, but efficacy for microbiota modulation is still unclear due to lack of mechanisms of
action and inconsistency between studies.

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THE IMPACT OF HOST-PATHOGEN INTERACTIONS ON MICROBIAL EVOLUTION

➢ Inside the host, a successful pathogen will pilfer resources to survive,

replicate, and eventually escape; concomitantly, the host will attempt to
recognize and subsequently rid the body of the intruder. Coevolution
between host and pathogen naturally occurs as a result of these
. interactions.

➢ Within the last century, these natural host defenses, which take much
longer to evolve than their microbial counterparts, have been
supplemented by man-made developments, such as antibiotics and
modern medical interventions, which place added pressures on microbes
to adapt.

➢ Host innate and adaptive immune responses and modern medical

interventions are all selective pressures that contribute to pathogen
evolution within the human host.

➢ Microbial competition, against either other pathogens or commensal

bacteria, also shapes pathogen genomes.

What’s for Dinner Inside the Host?

➢ Depending on where in the host an invading bacterium
takes up residence, the food sources available within that
niche will determine whether that microbe can successfully
establish itself.

➢ Some pathogens, such as invasive streptococci, Salmonella

enterica, and Brucella abortus, can feed their “sweet tooth”
during infection by acquiring specific carbohydrates,
whereas the “low-carb” pathogen Mycobacterium
tuberculosis prefers to fuel itself with energy-rich fatty acids
during a chronic infection.

➢ In the case of the human body, a wide range of tissue types

and physiological environments exist where pathogens elicit
disease, each one being unique in terms of carbon source
content and availability.

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Energy-yielding metabolism for select pathogenic bacteria

Ion And Nutrient Acquisition By Bacterial Pathogens

➢ The human body is a rich reservoir of fundamental nutrients
for bacteria that can exploit it, and nutrient acquisition is an
essential aspect of host–pathogen interactions.

➢ transition metals such as iron, zinc and manganese are

essential for survival and proliferation of all living organisms.

➢ Therefore, all organisms possess biochemical systems to

sense and regulate metal levels, and mammals have evolved
strategies to sequester free metal ions to limit toxicity and
also to restrict availability of these metal ions to invading
microorganisms.

➢ This concept of growth restriction by limiting access to

essential metals is called nutritional immunity.

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Iron Acquisition By Bacterial Pathogens

➢ Iron (Fe) is the most abundant transition metal in the human body, but
free iron is almost undetectable. Bacteria need concentrations on the
order of 10−6 M iron to survive and proliferate, whereas circulation of free
iron in human blood is approximately 10−18M. Iron is a cofactor for many
enzymes involved in fundamental cellular processes, including DNA
replication, transcription, metabolism, and energy generation through
respiration.

➢ In vertebrates, most iron is stored intracellularly in complex with heme.

➢ The host mechanisms of iron sequestration efficiently limit the availability

of iron, but bacterial pathogens possess their own weapons to counteract
host innate defenses and to acquire Fe2+ that will be used as a nutrient
source.

➢ Bacterial mechanisms for iron acquisition can be divided into three major
categories: siderophores, heme acquisition systems, and free Fe 2+
transporters.

Iron Acquisition By Bacterial Pathogens

Nutritional Immunity and Microbial Iron Piracy. Illustration highlighting major

components of bacterial iron acquisition, including surface receptors as well as
secreted siderophores and hemophores. Host nutritional immunity proteins are
denoted in bold.

Trends in Genetics, 2015, 31(11): 627-636.

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Iron Acquisition By Bacterial Pathogens

Ways by which bacteria

acquire iron. Transferrin
receptor, lactoferrin
receptor, hemophore (Hp),
hemophore receptor, and
hemopexin. Siderophores
remove iron from
lactoferrin, ferritin and
transferrin, and also from
the environment.

Front. Immunol. 11:1221. doi: 10.3389/fimmu.2020.01221

Metabolic Interaction between host and microbes

Front. Endocrinol. 8:267.

Signals affecting host–microbiota interplay and its regulation of metabolism. Gut microbiota
composition is affected by endogenous and exogenous factors such as lifestyle interventions.
Changes in the microbiota affect its interplay with several organs and can regulate
pathophysiological conditions. This can be mediated by altered bile acids, short chain fatty
acids (SCFAs), branched-chain amino acids (BCAAs), endotoxin, trimethylamine N-oxide
(TMAO), inflammation, gut hormones and neurotransmitters, and potentially other factors.

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Metabolic Interaction between host and microbes

Front. Endocrinol. 8:267.

doi: 10.3389/fendo.2017.00267

Metabolic Interaction between host and microbes

EBioMedicine 44 (2019) 747–754

The impact of gut microbiome-derived metabolites in disease. Arrows represent a

beneficial (green) or detrimental (red) role for selected gut microbiome-associated
metabolites in different diseases. 4EPS: 4-ethylphenylsulfate. BA: Bile acid. DAT:
desaminotyrosine. GABA: gamma-aminobutyric acid. IBD: inflammatory bowel
disease. ImP: Imidazole propionate. IS: Indoxyl sulfate. LCFA: Long-chain fatty acids.
TMAO: Trimethylamine-N-oxide. SCFA: short-chain fatty acids.

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Metabolic Host Responses to Infections Front. Cell. Infect. Microbiol. 3:24.

doi: 10.3389/ fcimb.2013.00024

Summary overview showing the major metabolic pathways and reactions of a metabolically active mammalian
host cell (blue spheres and boxes) and the regulatory network with the major regulators (green box) that control
host cell metabolism. Blue arrows indicate exchange of metabolites and intermediates of the different metabolic
functional units. Green arrows indicate control of these functional units by specific regulators. The pink sphere
indicates an (intracellular) bacterial pathogen with surface components (red triangles), T3SS or T4SS effector
proteins and other secreted virulence factors (red bars and circles) that might interact with metabolic targets of the
host cell. The red dashed arrows indicate already confirmed or probable interactions.

Gut microbiota modulation

The understanding of metabolic capabilities of gut microbial inhabitants in all areas of
the human body may be the passport to understanding health- and disease-linked
mechanisms.

Gut microbiota modulation. Beneficial effect on the intestinal environment through

microbial composition modification, by using probiotic, prebiotic, and postbiotic
administration and fecal microbiota transplantation (FMT). All these approaches can be
optimized by patient-tailored treatments for the better management of the individual’s
physiology and pathology.
Int. J. Mol. Sci. 2020, 21, 3688

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Host-Microbe Interactions: Impact on Pathogenesis and Human Disease

doi:10.1128/CMR.00013-11

Schematic showing the interdependent relationships required for development of human disease. Infection is
influenced by microbe–microbe interactions, microbe–host interactions, antimicrobial host defenses, and
environmental factors. Significant changes in any of these factors can lead to the development of or
predisposition to infection. For example, microbes lacking virulence factors may become apathogenic.
Similarly, host immunodeficiencies will encourage infectious processes. It is now becoming increasingly
appreciated that inter-microbial interactions and environmental cues also determine infection outcomes such
that specific microbial populations under certain conditions may enhance or predict disease progression.

What is Microbiome?

“Ecological community of commensal, symbiotic

And pathogenic microorganisms within a body
Space or other environment” McCray
Lederberg &
2001

• Conceptual origin of commensal organisms is old (1875)

– Pierre van Beneden: “Animal Parasites and Messmates”
– 264 examples for human host

• Human Microbial cells outnumber host cells 10x

– Approximately 1011 organisms

• 1-3% total body mass

• Generally non-pathogenic
• Symbiotic with host

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Where Microbiome located in Human

Body?

-Skin and mucous

membranes
-External ear canal
-Upper respiratory tract
-Gastrointestinal tract
-Outer opening of urethra
-External genitalia
-Vagina
-External eye (lids,
conjunctiva)

Microbiome as “Human Organ”

• Healthy adult harbors ~100 trillion bacteria in gut

Alone

• This is 10X the number of human cells we

Possess

• Humans possess 23,000 genes; Microbiome

contributes ~3,300,000 genes

• Communal gut microbial genome (microbiome)

is ~150 times larger than human genome

• Found even in sterile zones (e.g. lungs & womb)

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We are more Bacteria than Human

Factors affecting Human Microbiome

Crexci & Bawden, 2015

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Microbiome Dysbiosis
Dysbiosis: Microbial imbalance or
maladaptation on or inside the body
(impaired microbiota)

Factors Promoting Microbiome Dysbiosis

Microbiome Dysbiosis in Human Disease

➢ Obesity
➢ Diabetes Dysbiosis of
➢ Metabolic syndrome gut microbiome
➢ Renal insufficiency
➢ Heart failure
➢ IBD (Inflammatory bowel disease)
➢ IBS (Irritable bowel syndrome)
➢ Rheumatoid arthritis
➢ Arteriosclerosis
➢ Allergy
➢ Premature birth ➢ Autistic spectrum
➢ Multiple sclerosis
➢ Colon cancer ➢ Demetia
➢ Liver cancer ➢ Parkinson’s disease
➢ Liver cirrhosis ➢ Alzheimer’s disease

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Prevention and Therapeutics of Microbiome Dysbiosis

Berg et al.,
2020

Prevention and Therapeutics of Microbiome Dysbiosis

Fecal Microbiota Transplantation (FMT)

Tahan et al., 2019

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Any questions?

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