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ALCANTARA S.

Chapter 2: Host-Parasite Interaction


ALCANTARA S.Y

Outline of Topics - These microorganism are eliminated either


 Origin of Microbial Flora by (1) host inherent immune defenses or by
 Composition of Microbial flora at different body (2) competition with the resident flora
sites
 Pathogenesis of Infectious disease Some pathogenic organisms may establish themselves
 Host Defense Against infectious disease in a host.
 Microbial Factors
 Host Resistance Factors  Carrier - these hosts, called carriers, are
 Microbes Mechanism capable of transmitting the infection. The
 Route of Transmission condition of these hosts is called the carrier
state.
 Carrier State may be:
ROLE OF THE USUAL MICROBIAL
 Acute (short-lived or transient)
FLORA - An example is the Neisseria
meningitidis, may be found in the
I. ORIGIN OF THE MICROBIAL FLORA nasopharynx of asymptomatic
individuals during an outbreak of
SYMBIOSIS meningitis. After a few days or weeks
 Association of two organisms living together at most, these individuals may no
 Biological relationship between two or more longer harbor the organism.
organisms  Chronic (lasting for months, years, or
 Three different types of Symbiotic Relationship: permanently)
1. Mutualism - both (host and organism) - An example of a chronic carrier
benefit from one another state is found in post–Salmonella
 E.g. Sea anemone and clownfish, typhi infection. This organism
sea anemone attracts other fish, the may establish itself in the bile duct
clown fish gets protection and be excreted in the stool over
 Lactobacilli in the urogenital tract years.
of women offer a mutual
association The most transient of carrier states is the inoculation of
2. Commensalism - the organism benefits but a person’s hands or fingers
there is no beneficial or harmful effect to the with an organism (e.g., with Staphylococcus aureus that
host has colonized the person’s anterior nares) that is carried
 E.g. Proteus mirabilis is a only until the hands are washed.
commensal species in the
gastrointestinal tract of humans.
3. Parasitism - one species (microbe) benefits
at the expense of the other (host).
 E.g. The parasite Entamoeba
FACTORS THAT DETERMINE THE
histolytica is a pathogenic
COMPOSITION OF THE USUAL MICROBIAL
intestinal ameba that derives
FLORA
nutrients from the host at the
expense of the host, causing
Organisms that are present at a particular body site is
intestinal ulcers and amebic
influenced by:
dysentery

CHARACTERISTICS OF MICROBIAL FLORA  Nutritional factors


 Indigenous flora (normal or usual flora)  Such as the amount and types of nutrients
- Microorganisms that are commonly found on available at site
or in body sites of healthy persons  Environmental factors
 Resident microbial flora - Microorganisms  More organisms inhabit moist areas than
that colonize an area for months or years dry areas
 Transient flora - Microorganisms that are  The composition of the microbial flora is
present at a site temporarily represent also affected by pH.
- Transient flora comes to “visit” but does not  Most bacteria or microorganisms lives in
usually live or stay. at a neutral pH of 7.0 - 7.5
 An example is the female genital tract
flora it depends on the pH of that
ALCANTARA S.Y

environment (In woman of childbearing Propionibacterium spp. they reside in hair


age has pH of 4.0 to 5.0 and most bacteria follicles and colonize the sebaceous glands
do not survive at these extreme pH ranges)  Microorganisms such as P. acnes colonize the
 Another example is fecal flora found in deep sebaceous glands. Superficial antisepsis of
breast fed infants (Human milk has high the skin does not eliminate this organism, which
lactose conc. and maintains pH of 5.0 to may be found as a contaminant in culture
5.5, an environment supportive of specimens obtained by invasive procedures
Bifidobacterium spp. (e.g., blood, cerebrospinal fluid), as a result of
 Infants fed with Cow's milk do not have contamination of the needle.
high colonization by Bifidobacterium spp.
but have instead colon flora.
 Antibacterial substances
 It depends on the ability of the organisms
to resist the antibacterial effects of
substances such as bile, lysozyme, or fatty
acids.
 If ever that the microorganism were able
to resist the substances, it means that it
can live or survive to that particular site.
 Example is the Propionibacterium spp.
they can colonize the ducts of the hair
follicles because the bacteria are able to 2. Usual Flora of the Mouth
breakdown the skin lipids to fatty acids.  Contains large numbers of bacteria, with
BUT Propionibacterium acnes cannot be Streptococcus being the predominant genus.
removed by washing or scrubbing  Many organisms bind to the buccal mucosa and
tooth surfaces.
II. COMPOSITION OF THE MICROBIAL FLORA AT  Bacterial plaques that develop on teeth may
DIFFERENT BODY SITES contain 1011 streptococci per gram.
 Plaque also results in a low oxidation-reduction
1. Usual Flora of the Skin potential at the tooth surface; this supports the
 Normal skin has numerous mechanisms to growth of strict anaerobes, particularly in crevices
prevent infection and protect underlying tissue and in the areas between the teeth.
from invasion by potential pathogen
 These mechanisms are:
1. Mechanical separation of
microorganisms from the tissues
2. Presence of fatty acids that inhibit many
microorganisms
3. Excretion of lysozyme by sweat glands
4. Desquamation of epithelium

 Most of the microorganisms are found on the


most superficial layers of cells and the upper parts
of hair follicles
 90% of the bacteria present on the skin can be
reduced by scrubbing and washing
 The composition of the flora on the skin depends
on the activity of the sebaceous or sweat glands. 3. Usual Flora of the Respiratory Tract
 Organisms concentrate the most areas that are  The respiratory tract, commonly divided into
moist, such as armpit, groin, and perineum. upper and lower tracts
 The apocrine sweat glands in these areas secrete  It is responsible for the exchange of oxygen and
substances metabolized by the skin bacteria, carbon dioxide as well as for the delivery of air
releasing odorous amines from the outside of the body to the pulmonary
 Aerobic diphtheroids are usually found in moist tissues responsible for that exchange.
areas such as the axillae and between the toes.
A. Upper Respiratory Tract
 The most common bacteria that are seen in the
skin are the Staphylococcus epidermidis and  Composed of the mouth, nasopharynx,
oropharynx and larynx.
ALCANTARA S.Y

 The mouth nasopharynx and oropharynx are  The trachea, bronchi, and lungs are protected by
colonized predominantly with viridans the action of ciliary epithelial cells and by the
streptococci, such as Streptococcus mitis, movement of mucus.
Streptococcus mutans, Streptococcus milleri,  The tissues of these structures are normally
and Streptococcus sanguis; Moraxella sterile as a result of this protective action.
catarrhalis; Neisseria spp.; and diphtheroids.
 Obligate anaerobes reside in the gingival 4. Usual Flora of the Gastrointestinal Tract
crevices where the anaerobic environment  The gastrointestinal tract comprises the
supports these organisms. esophagus, stomach,small intestine, and colon.
 Opportunistic pathogens such as S. aureus,  The gastrointestinal tract is equipped with
found in approximately 30% of healthy numerous defenses and effective
individuals, colonize the anterior nares antimicrobial factors.
 Haemophilus influenzae, Streptococcus  Microorganisms usually do not multiply in the
pneumoniae, and N. meningitidis, all esophagus and stomach but are present in
potential pathogens, are also found in the ingested food and as transient flora.
nasopharynx of healthy individuals.  Most microorganisms are susceptible to the acid
 Individuals who are hospitalized for several pH of the stomach and are destroyed, with the
days may become colonized in the upper exception of spore-forming bacterial species in
respiratory tract by gram-negative their spore phase, the cysts of parasites, and
bacteria, particularly members of the Helicobacter pylori.
Enterobacteriaceae.
 The oropharynx contains a mixture of
streptococci. Many species of the viridans
group can be isolated, including S.mitis, S.
mutans, S. milleri, S. sanguis, and
Streptococcus salivarius.

5. Usual FLora of the Genitourinary Tract


 The kidneys, bladder, and fallopian tubes are
normally free of microorganisms.
 The urethra is colonized in its outermost segment
by organisms found on the skin.
 The composition of the vaginal flora is consistent
with hormonal changes and age.
 Lactobacilli metabolize glycogen in vaginal
epithelial cells to maintain a low pH, creating an
environment that is inhibitory to many organisms.
However, the low pH encourages colonization of
the vagina with lactobacilli, anaerobic gram-
negative bacilli, and gram positive cocci.

III. ROLE OF THE MICROBIAL FLORA IN THE


PATHOGENESIS OF INFECTIOUS DISEASE

 Some organisms that make up the usual microbial


flora are actually parasites that live off the host’s
nutrients
 They provide some benefit to the host, creating a
symbiotic relationship with the host.
 Opportunist - certain member of usual flora that
B. Lower Respiratory Tract causes disease when their habitat is damaged,
 Composed of the trachea, bronchi, and disturbed, or changed or when the host’s immune
pulmonary parenchyma. system is weakened or compromised.
 The host’s immune response may be reduced or
altered because of suppression by
ALCANTARA S.Y

immunosuppressive drugs, chemotherapy, or


radiation
 Members of the usual microbial flora also may PATHOGENESIS OF
initiate an infection or make an infection more INFECTION
serious in patients with chronic illnesses,
including diabetes or severe hepatic disease such I. MICROBIAL FACTORS CONTRIBUTING TO
as cirrhosis. PATHOGENESIS AND VIRULENCE
IV. ROLE OF THE MICROBIAL FLORA IN THE PATHOGENICITY
HOST DEFENSE AGAINST INFECTIOUS  It is the ability of a microbe to produce disease in
DISEASE a susceptible individual.
 An organism may be described as a frank
 The microbial flora provides beneficial effects or true pathogen or as an opportunistic pathogen.
 The development of immunologic competence
depends on this flora. 1. True Pathogens - Oganisms recognized
 Animals born and raised in a germ-free to cause disease in healthy
environment have a poorly functioning immune immunocompetent individuals. (E.g.
system. Yersinia pestis and Bacillus anthracis)
 How a sterile environment might affect a 2. Opportunistic pathogen - Can cause
newborn: disease when they are not in their normal
1. Antibody production would not be habitat.
stimulated
2. the mononuclear phagocyte system E.g. Haemophilus influenzae colonizes the
would remain undeveloped upper respiratory tract of healthy individuals
3. Serum immunoglobulin G (IgG) and without causing disease, but given the
other antibodies effective against opportunity, it may rapidly produce a life-
microorganisms would be suppressed threatening infection.
(which would make the individual Staphylococcus epidermidis under usual
susceptible to pathogenic species.) conditions do not cause disease but can
4. Without activation by microorganisms induce an infectious process in patients with
and the supporting action of antigen prosthetic devices.
resenting ells and cytokines, cell-
mediated immunity would not develop  Iatrogenic infection - an infection that occurs as
normally. the result of medical treatment or procedures.
 The microbial flora produces conditions at the For example, many patients who have
microenvironmental level that block colonization indwelling urinary catheters develop a
by extraneous pathogens. urinary tract infection. Patients who are given
immunosuppressive drugs because they have
received a transplant are more susceptible to
infection.

Any result from a physician-ordered drug


therapy can cause an iatrogenic infection.

VIRULENCE
 Relative ability of a microorganism to cause
disease or the degree of pathogenicity.
 It is usually measured by the numbers of
microorganisms necessary to cause infection in
the host.
 Organisms that can establish infection with a
relatively low infective dose are considered
more virulent than organisms that require
high numbers for infection.

 Eg. Shigella spp. cause disease with a relatively


low infective dose (100 organisms), Shigella is
considered to be a highly virulent organism.
ALCANTARA S.Y

MICROBIAL VIRULENCE FACTORS Examples of encapsulated cells are sthe strains of:
 Infectious organisms have a wide variety of  Streptococcus pneumoniae
mechanisms or virulence factors that allow them  Haemophilus influenzae
to persist in a host and cause disease.
 Virulence Factors - allow the pathogen to They are highly invasive infection and are known
evade or overcome host defenses and cause to be more virulent than non encapsulated strains
disease.
 Encompass functions such as: Protein A
1. Inhibiting phagocytosis  Another bacterial structure that protects
2. Facilitating adhesion to host cells organisms from phagocytosis.
or tissues  Found in the cell wall of Staphylococcus
3. Enhancing intracellular survival aureus; It helps organisms avoid
after phagocytosis phagocytosis by interfering with the
4. Damaging tissue through the binding of the host's antibodies to the
production of toxins and surface of the organism.
extracellular enzymes  Prevent Opsonization and Phagocytosis
 Many virulence factors are well defined,  Antibodies bind to antigens via their Fab
such as the diphtheria and cholera toxins, orantigen-binding portion.
the capsule of Streptococcus pneumoniae,  Protein A binds to the Fc portion of
and the fimbriae of Neisseria immunoglobulin G (IgG) (at the opposite
gonorrhoeae. end of the Fab), preventing opsonization
 Certain microorganisms produce and phagocytosis by turning the antibody
extracellular factors that appear to aid in around on the surface.
infection, but the exact role of these
factors is unknown. Some organisms evade phagocytic cell killing by
releasing potent materials in tissues that kill
I. Ability to Resist Phagocytosis phagocytes.
 Phagocytosis - Engulfment and digestion of
bacteria and other foreign particles by a cell; kills Hemolysin
extracellular microorganisms.  It lyses the red blood cells (RBCs)
 Phagocytic cells examples are:  Enduce toxic effects on the whte blood cells
a. Macrophages (WBCs) and macrophages
b. Polymorphonuclear cells (PMS)  E.xample of bacteria that produces hemolysin
is the Streptococci
 Phagocytic cells defends the host from microbial
infection. So the lack if phagocytic cells leaves Leukocidin
the host susceptible to overwhelming infection.  It cause lysosomal discharge into cell
 The most common mechanism for evading cytoplasm
phagocytosis that is used by many different  Digestive enzyme that is so lethal ti white
microorganisms is that of having a blood cells (WBCs)
polysaccharide capsule on the surface.  It contribute to the invasiveness of the
 Microorganisms possessing a capsule are organism
highly virulent; Until removal of the capsule at  Example of bacteria that release leukocidins
which point virulence becomes extremely low. is the Pathogenic staphylococci.
 Pantone-Valentine (Staphylococci
leukocidin) - It is lethal to leukocytes and
contributes to the invasiveness of the
Capsule organism.
 Usually found in the surface  Other organisms inhibit chemotaxis, and the
 Composed of polysaccharides but can also be host is less able to direct
made of proteins or combination of protein and polymorphonuclear neutrophils (PMNs) and
carbohydrate. macrophages into the site of infection.
 It inhibits phagocytosis by masking the cell
surface structures that are recognized by II. Surface Structures that Promote Adhesion
receptors on the phagocytic cell and in the  Most infectious agents must attach to host cells
same manner that it inhibits activation of before infection occurs
complement by masking its binding site
ALCANTARA S.Y

 The bacterium, virus, or fungus requires  Example are H. influenzae, N.


adherence to the host cell before infection and gonorrhoeae, and N. meningitidis
disease can progress
 Adhesins - the cell surface structures that Shifting Key cell Surface Ags
mediate attachment (E.g. Frimbriae or pili)  The host produces antibodies against the
 Frimbriae - is the main adhesins in the “old” antigens, which are no longer
bacteria and it enable bacteria to adhere to host effective because the organism now has
cell surfaces, offering resistance by attachment “new” antigens that do not bind to
to target cells, increasing colonizing ability. antibodies made against the old antigens.
 Polysaccharide - another main adhesins in
bacteria  Example is pathogens like influenza virus,
 Once bacteria is attached, phagocytosis is less Borrelia spp.
likely to occur.
 Example, strains of Escherichia coli iit uses Bacterial species, Chlamydia, Myobacterium,
their frimbriae to adhere to cells of the small Brucella, and Listeria these are easily engulfed by
intestine, where they secrete a toxin that causes phagocytes and able to survive and multiply
disease symptoms. intracellularly.
 Similarly to gonococci that uses frimbriae to
infect epithelial cells of genitourinary tract. Invasion
 There are antibodies in the frimbriae of N.  Pathogens ability to penetrate and grow in
gonorrhoeae which are protective by tissues
preventing the organism from attaching to the  With some organisms, the invasion is
epithelial. localized and involves deep tissues.
 Sometimes it can affect few layers of cell,
III. Ability to Survive Intracellularly & Proliferate some involves deep tissues.

Some pathogens are able to survive within the  E.g. gonococcus organism - invasive and
phagocytic cell after they have been engulfed. These may infect fallopian tubes
organisms have developed methods to prevent being
killed intracellularly. Some organisms prevent fusion of
phagosomes and lysosomes, others have a resistance to Dissemination
the effects of the lysosomal contents, and still others  Ability of an organism to spread to distant
escape from the phagosome into the cytoplasm. sites (organs or tissues)

 To establish itself and cause disease, a  E.g. Salmonella spp.


pathogen must be able to replicate after  E.g. Corynebacterium diphtheriae, it do
attachment to host cells. no spread beyond their initial site of
 Numerous host factors work to prevent infection, yet the disease they produce is
proliferation. serious and often fatal.
 The host produce secretory antibody,  Clostriudium perfringens - an example of
lactoferrin, and lysozyme to protect against highly invasive organism that may not
infection disseminate.
 To be successful in establishing infection,
 infectious agents must be able to avoid or IV. Ability to Produce Extracellular Toxins &
overcome these local factors Enzymes

For example, For example, lactoferrin competes with Disease from infection is noticeable only if tissue
bacteria for free iron; meningococci can use lactoferrin damage occurs. This damage may be from toxins, either
as a source of iron. They are not inhibited by the exotoxins or endotoxins, or from inflammatory
presence of lactoferrin and are able to use it for growth. substances that cause host-driven, immunologically
The nonpathogenic Neisseria spp. are usually unable to mediated damage.
use the iron in lactoferrin and are inhibited by its
presence. The ability of organisms to produce exotoxins and
extracellular enzymes is another major factor that
Immunoglobulin A (IgA) protease contributes to the virulence and invasiveness of
 Degrades the igA found in mucosal organisms.
surfaces.
 Toxins - are poisonous substances produced
ALCANTARA S.Y

by organisms that interact with host cells, C. ANTIMICROBIAL SUBSTANCES


disrupting normal metabolism and causing harm. D. INDIGENOUS MICROBIAL FLORA
 Exotoxin E. PHAGOCYTOSIS
○ Produced by both gram-negative and gram- F. INFLAMMATION
positive bacteria. G. IMMUNE RESPONSES
○ Secreted by the organism into the extracellular
environment, or they are released on lysis of A. PHYSICAL BARRIERS
the organism.
○ Can mediate direct spread of the  Healthy skin is an effective barrier against
microorganisms through the matrix of infection.
connective tissues and can cause cell and  The stratified and cornified epithelium
tissue damage. presents a mechanical barrier to penetration by
most microorganisms.
- They are ble to do this by producing  Which is why organism causing disease cannot
proteases and hyaluronidases that liquefy the easily penetrate an unbroken/healthy skin.
hyaluronic acid of the connective tissue  Only a few microorganisms are capable of
matrix, helping to spread bacteria in tissues, penetrating normal, healthy skin; these include
promoting the dissemination of infection. Leptospira spp., Francisella tularensis,
 Endotoxin Treponema spp., and some fungi.
○ A constituent, the lipopolysaccharide (LPS), of
the outer cell membrane of gram-negative
bacteria exclusively
○ Do not have enzyme activity
○ Secreted in only very small amounts
○ Do not have specificity in their activity on host
cells
○ Not very potent, and are not destroyed by
heating

Read book for more detailed explanation for Exotoxin


& Endotoxin (pp. 33-24)
B. CLEANSING MECHANISM
II. HOST RESISTANCE FACTORS
 Skin desquamation (pamamalat) is one of the
A. PHYSICAL BARRIERS most important or effective cleansing
B. CLEANSING MECHANISM mechanisms.
ALCANTARA S.Y

 Through desquamation or sloughing of the  The vagina contains a large population of


epithelium many of the microorganisms organisms as part of the indigenous flora.
colonizing the skin are disposed  The acidity of the vagina, resulting from
 Just like how the keratinized squamous the breakdown of glycogen by the resident
epithelium or outer layer of skin is being shed flora, tends to inhibit transient organisms from
continuously. colonizing.
 Other cleansing mechanism are the cleansing
action of the fluids of the eye and the C. ANTIMICROBIAL SUBSTANCES
respiratory, digestive, urinary, and genital
tracts.  Lysozyme A substamce that plays a major
role in resitance to infection
Eye  a low-molecular-weight (approximately
 It is continually exposed to 20,000 D) enzyme that hydrolyzes the
microorganisms, which means this organ peptidoglycan layer of bacterial cell
has some highly developed antimicrobial walls
mechanism.  Lysozyme is found in serum, tissue
 Tears bathe the cornea and sclera. Tears fluids, tears, breast milk, saliva, and
not only lubricate sweat.
 the eye but also wash foreign matter and
infectious agents  Antibodies (IgA)
 away from the surface.  Serve as opsonins, enhancing
 Tears contain IgA and lysozyme phagocytosis, or they may fix
complement and neutralize the
Respiratory tract infecting organism.
 Continuously exposed to microorganisms  Found in mucous secretions of the
and is protected by nasal hairs, ciliary respiratory, genital, and digestive
epithelium, and mucous membranes. tracts.
 A continuous flow of mucus emanates
from the membranes lining the  B-lysins is a low molecular weight cationic
nasopharynx, which traps particles and protein present in serum
microbes and sweeps them to the
oropharynx, where they are either  These proteins are lethal against gram-
expectorated or swallowed. positive bacteria and are released from
 The trachea is lined with ciliary platelets during coagulation.
epithelium. These cells have hairlike  The site of action is the cytoplasmic
extensions (cilia) that sweep particles and membrane.
organisms upward toward the oropharynx.
This material is expectorated or A combination of antibody, complement, lysozyme, and
swallowed. B-lysin is significantly more effective in killing bacteria
than each alone or than any combination in which one
Gastrointestinal tract or more are missing.
 Bacteria are swallowed into the
gastrointestinal tract either as part of the  Interferon - inhibits the proliferation of
mouth flora and upper respiratory tract or viruses
in liquids and food  A group of cellular proteins induced in
 Most bacteria are easily destroyed by the eukaryotic cells in response to virus
low pH found in the stomach. infection or other inducers.
 The gastrointestinal tract is protected by  One type of interferon, interferon-
mucous secretions and peristalsis that gamma, plays an especially important
prevent the organisms from attaching to role in the immune response. It inhibits
the intestinal epithelium. cell proliferation and tumor growth and
 Secretory antibody and phagocytic cells enhances phagocytosis by
lining the mucosa defend the macrophages, the activity of natural
gastrointestinal tract against infection. killer cells, and the generation of
cytotoxic T cells.
Genitourinary tract
 Cleansed by voiding urine. D. INDIGENOUS MICROBIAL FLORA
ALCANTARA S.Y

 Nonpathogenic microorganisms compete 1. Chemotaxis - Migration of the phagocyte to


with pathogens for nutrients and space. This the area of infection
competition lessens the chance that the  The PMNs circulate through the body,
pathogen will colonize the host followed by movement into the tissues by an
 Bacteriocins - produced by some of the action called diapedesis, which is movement
normal flora species of the PMNs/neutrophils between the
 Substances that inhibit the growth of endothelial cells of the blood vessels into the
closely related bacteria. tissues
 These proteins are produced by a  The body is under constant surveillance by
variety of gram-positive and gram- these and other phagocytic cells. When an
negative bacteria infection occurs, massive numbers of PMNs
 It can give the secreting bacterium an accumulate at the site.
advantage because they can eliminate  Chemotactic agents - It is a certain
other bacteria that would compete for components of complement, a number of
nutrients and space bacterial products, products from damaged
tissue cells, and products from responding
E. PHAGOCYTOSIS immune cells. = To know the location and
 An essential component in the resistance of bind to bind in bacteria
the host to infectious agents. 
 It is the primary mechanism in the host
defense against extracellular bacteria and
numerous viruses and fungi.
 E.g. The PMNs and macrophages (monocytes
in the peripheral blood) are the body’s first
line of defense
 Lysosomes - Membrane bound vesicles that
contain the enzymes and other substances
necessary for the killing and digestion of
engulfed particles.
 They show up as azurophilic granules
on a Wright’s stain.
 PMN - has receptors on the cell membrane
for some complement components that
stimulate cell motion, the metabolic burst,
and secretion of the lysosome contents into a
phagosome.
 An end-stage cell and has a circulating
half-life of 2 to 7 hours. It may migrate
to the tissues, where its half-life is less
than 1 week.
 Macrophages - originates in the bone
marrow where it circulates as monocytes for
1-2 days and then migrate through the blood
vessel walls into the tissues and reside in
specific tissues as part of mononuclear
phagocyte system
 widely distributed in the body and play
a central role in specific immunity and
nonspecific phagocytosis

Four activities must occur for phagocytosis to take


place and be effective in host defense:

Prior to chemotaxis we have Initiation Stage, whereas


it increases the surface receptors that allows for
adherence

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