Bio 151 lecture 15 continued

IMMUNITY & INFECTIOUS
DISEASES
(Continued.....)
Parungao-Balolong 2011
Saturday, March 12, 2011

CONTINUATION...
Overview: Innate and Adaptive Immune Response

Immunity to Viruses

TODAY:

Immunity to Bacteria

Immunity to Fungi

Immunity to Helminths

Emerging and re-emerging Infections

SPECIAL CASES

IMMUNITY AND
BACTERIAL INFECTIONS

PARUNGAO-BALOLONG 2011

Achieved by means of antibody : unless
the bacterium is capable of intracellular
IMMUNITY TO
growth (delayed-type hypersensitivity)
BACTERIA
ROUTES OF ENTRY: respiratory tract, the
gastrointestinal tract, and the
genitourinary tract OR inaccessible routes
opened up by breaks in mucous
membranes or skin

ROLE OF number of organisms entering
and their virulence to host defense

LOW inoculum size + LOW virulence =
localized tissue phagocytes may be
able to eliminate the bacteria with an
innate, nonspecific defense

HIGH inoculum size + HIGH virulence
= induce an adaptive, specific immune
response

Primary steps in bacterial infection: Invasion of host tissue

Attachment to host cells Toxin-induced damage to host
cells
Proliferation


RESPONSE TO EXTRACELLULAR &
INTRACELLULAR BACTERIA
Infection by extracellular bacteria
induces production of humoral
antibodies, which are ordinarily
secreted by plasma cells in
regional lymph nodes and the
submucosa of the respiratory
and gastrointestinal tracts

The humoral immune response is
the main protective response
against extracellular bacteria

The antibodies act in several
ways to protect the host from
the invading organisms, including
removal of the bacteria and
inactivation of bacterial toxins


RESPONSE TO EXTRACELLULAR &
INTRACELLULAR BACTERIA
While innate immunity is not very
effective against intracellular
bacterial pathogens, intracellular
bacteria can activate NK cells,
which, in turn, provide an early
defense against these bacteria

Intracellular bacterial infections
tend to induce a cell-mediated
immune response, specifically,
delayed- type hypersensitivity

In this response, cytokines
secreted by CD4+ T cells are
important—notably IFN-gamma,
which activates macrophages to
kill ingested pathogens more
effectively

IMMUNITY AND PROTOZOA,
PARASITIC HELMINTHS
INFECTIONS


IMMUNITY TO PROTOZOAN
DISEASES
EXAMPLE: Amoebiasis, Chagas’ disease, African sleeping sickness,
Malaria, Leishmaniasis, and Toxoplasmosis

IMMUNE RESPONSE: depend in part on the location of the parasite
within the host (NOTE: Life cycle is unique for each)

HUMORAL ANTIBODY: effective when life-cycle stages are free within
the bloodstream

CELL-MEDIATED: effective during intracellular growth

IMPORTANT: In the development of vaccines for protozoan diseases, the
branch of the immune system that is most likely to confer protection
must be carefully considered


IMMUNITY TO PROTOZOAN
DISEASES
Both humoral and cell-mediated immune responses have been
implicated in immunity to protozoan infections

In general, humoral antibody is effective against blood-borne stages of
the protozoan life-cycle, but once protozoans have infected host cells,
cell-mediated immunity is necessary

Protozoans escape the immune response through several mechanisms

EXAMPLE: Trypanosoma brucei—are covered by a glycoprotein coat
that is constantly changed by a genetic-switch mechanism (see photos
on next slide)

EXAMPLE: Plasmodium, the causative agent of malaria slough off their
glycoprotein coat after antibody has bound to it


EVASION OF IMMUNE RESPONSE:
PROTOZOA


IMMUNITY TO HELMINTHS
Helminths are more accessible to the
immune system than protozoans

Immune system is not strongly
engaged and the level of immunity
generated to helminths is often very
poor (since only FEW can have this)

EXAMPLE: Ascaris, Schistosoma,
Taenia (tapeworm), Trichinella
(roundworm)


IMMUNITY TO HELMINTHS
Helminths are large parasites that normally
do not multiply within cells

Because few of these organisms are carried
by an affected individual, immune-system
exposure to helminths is limited;
consequently, only a low level of immunity is
induced

Although helminths generally are attacked by
antibody-mediated defenses, these may be
ineffective

A cell-mediated response by CD4+ T cells
plays a critical role in the response to
Schistosoma

IMMUNITY AND FUNGAL
INFECTIONS


IMMUNITY
TO
FUNGI

Anti-fungal vaccines:
promising

A better understanding
of the role of the host/
pathogen interaction will
probably lead to further
development of these
and other potential
novel antifungal
therapies

SPECIAL CASES
1. Inﬂuenza
2. HIV/AIDS
3. Tuberculosis
4. Malaria
5. Schistosomiasis
6. Aspergillosis

INFLUENZA


WHAT DETERMINES
VIRULENCE?
Host factors: Viral factors:

Presence of target receptors on host cells Ability to bind to host cells and Ability of virus
shedding
Availability of enzymes in host cells which
are essential for viral entry and replication Restriction of cytopathogenic effects to allow
for an appropriate balance between viral
State of immunocompetence of the replication and control by the host
individual host
Escape from immunosurveillance by evolution
Specific immunity against certain viral of antigenic variation driven by selective
epitopes in the individual host and target pressure of the immune response
population
Escape from immunosurveillance by
Ability of the immune system to control the recombination with different virus strains from
viral replication effectively without causing zoonotic disease
serious collateral damage for the host by
its inflammatory response Modulation of the immune response to
attenuate effective host defense mechanisms


THE VIRUS AND ITS IMMUNOLOGICAL
DETERMINANTS

neuraminidase : enables the virus to be released from the
host cell; cleave SIALIC ACID groups from glycoproteins;
required for influenza virus replication
hemagglutinin: an antigenic glycoprotein for binding the
virus to infected cell Parungao-Balolong 2011

ANTIGENIC SHIFT VS ANTIGENIC DRIFT


INFLUENZA SUBTYPES:
CHALLENGE FOR VACCINES


HIV/AIDS


HIV/AIDS: T CELLS
CD4 cell count: This measures how
many infection-fighting cells are in a
sample of blood

way to track how well your immune
system is working

HIV treatment should increase your
CD4 (T-cell) count or at least keep it
from going down

CD4 (T-cell) cell counts above 500
cells/mm3 are said to be normal

CD4 (T-cell) count below 200 cells/mm3
means that the immune system is very
weak; it is also one of the ways to tell
that someone with HIV has AIDS

HIV/AIDS INHIBITORS: POTENTIAL DRUGS

TUBERCULOSIS


TUBERCULOSIS
Upon infection with M. tuberculosis, the most
common clinical pattern, termed pulmonary
tuberculosis, appears in about 90% of those
infected. In this pattern, CD4+ T cells are
activated within 2–6 weeks after infection,
inducing the infiltration of large numbers of
activated macrophages

RIGHT PHOTO: These cells wall off the organism
inside a granulomatous lesion called a tubercle

The massive activation of macrophages that
occurs within tubercles often results in the
concentrated release of lytic enzymes

These enzymes destroy nearby healthy cells,
resulting in circular regions of necrotic tissue,
which eventually form a lesion with a caseous TUBERCULE: consists of a few small lymphocytes
and a compact collection of activated
(cheese-like) consistency
macrophages, which sometimes differentiate into
epithelioid cells or multinucleated giant cells
As these caseous lesions heal, they become
calcified and are readily visible on x-rays, where
they are called Ghon complexes.

TUBERCULOSIS
The intracellular growth of M. tuberculosis makes it difficult for drugs to reach the bacilli
(THUS : drug therapy must be continued for at least 9 months to eradicate the bacteria)

Presently, the only vaccine for M. tuberculosis is an attenuated strain of M. bovis called
BCG (Bacillus Calmette-Guerin)

The vaccine appears to provide fairly effective protection against extrapulmonary
tuberculosis but has been inconsistent against pulmonary tuberculosis

BCG: provided protection in anywhere from 0% to 80% of vaccinated individuals; in
some cases, BCG vaccination has even increased the risk of infection

BCG vaccination, the tuberculin skin test cannot be used as an effective monitor of
exposure to M. tuberculosis because of the variable effectiveness of the BCG vaccine
and the inability to monitor for exposure with the skin test after vaccination

The alarming increase in multidrug-resistant strains has stimulated renewed efforts to
develop a more effective tuberculosis vaccine


MALARIA


IMMUNOLOGICAL
PROCESSES:
MALARIA


SPECIAL CASE: MALARIA
A number of factors may contribute to the low levels
of immune responsiveness to Plasmodium

The maturational changes from sporozoite to
merozoite to gametocyte allow the organism to keep
changing its surface molecules, resulting in continual
changes in the antigens seen by the immune system

The intracellular phases of the life cycle in liver cells
and erythrocytes also reduce the degree of immune
activation generated by the pathogen and allow the
organism to multiply while it is shielded from attack

Furthermore, the most accessible stage, the
sporozoite, circulates in the blood for only about 30
min before it infects liver hepatocytes; it is unlikely
that much immune activation can occur in such a
short period of time

And even when an antibody response does develop
to sporozoites, Plasmodium has evolved a way of
overcoming that response by sloughing off the
surface CS- antigen coat, thus rendering the
antibodies ineffective

TREATMENT?
An effective vaccine for malaria should maximize the most effective immune defense mechanisms

Unfortunately, little is known of the roles that humoral and cell-mediated responses play in the
development of protective immunity to this disease

Current approaches to design of malaria vaccines focus largely on the sporozoite stage

One experimental vaccine, for example, consists of Plasmodium sporozoites attenuated by x-
irradiation

Results are encouraging, but translating these findings into mass immunization remains
problematic

Sporozoites do not grow well in cultured cells, so an enormous insectory would be required to
breed mosquitoes in which to prepare enough irradiated sporozoites to vaccinate just one small
village.

Current vaccine strategies are aimed at producing synthetic subunit vaccines consisting of epitopes
that can be recognized by T cells and B cells

While no effective vaccine has been developed, this is an active area of investigation


REGULATION OF IMMUNE
RESPONSE TO MALARIA


SCHISTOSOMIASIS


SPECIAL CASE: SCHISTOSOMIASIS
Most of the symptoms of schistosomiasis
are initiated by the eggs

A chronic state can then develop in which
the adult worms persist and the
unexcreted eggs induce cell-mediated
delayed-type hypersensitive reactions,
resulting in large granulomas that are
gradually walled off by fibrous tissue

Although the eggs are contained by the
formation of the granuloma, often the
granuloma itself obstructs the venous
blood flow to the liver or bladder

Antigens present on the membrane of
cercariae and young schistosomules are
promising vaccine components because
these stages appear to be most
susceptible to immune attack

SPECIAL CASE: SCHISTOSOMIASIS
The humoral response to infection with S. mansoni
is characterized by high titers of antischistosome
IgE antibodies, localized increases in mast cells and
their sub-sequent degranulation, and increased
numbers of eosinophils

These manifestations suggest that cytokines
produced by a TH2-like subset are important for
the immune response: IL-4, which induces B cells
to class- switch to IgE production; IL-5, which
induces bone-marrow precursors to differentiate
into eosinophils; and IL-3, which (along with IL-4)
stimulates growth of mast cells

Degranulation of mast cells releases mediators that
increase the infiltration of such inflammatory cells
as macrophages and eosinophils

The eosinophils express Fc receptors for IgE and
IgG and bind to the antibody-coated parasite

Once bound to the parasite, an eosinophil can
participate in antibody- dependent cell-mediated
cytotoxicity (ADCC), releasing mediators from its
granules that damage the parasite

IMMUNE
CELLS AT
VARIOUS
LIFE
STAGES:
SCHISTOSOMIASIS


SCHISTOSOMIASIS: GRANULOMA


SCHISTOSOMIASIS: PATHOLOGY


EVASION: SCHISTOSOMIASIS


ASPERGILLOSIS


IMMUNE RESPONSE TO ASPERGILLOSIS
An essential aspect of the immune response to Aspergillus
is recognition and killing of conidia and activation of
appropriate host defenses to confront fungi that have
escaped killing and transitioned to the hyphal form

In highly compromised patients, early detection of IA,
institution of antifungal therapy and improvement in host
immune status are crucial determinants in the outcome of
infection

Humoral factors participate in the host response to
Aspergillus

Resting conidia, germinating conidia and hyphae are
potent activators of the complement cascade and induce
deposition of complement components upon the fungal
surface

Resting conidia activate the alternative pathway and
induce neutrophil chemotaxis

As the fungus matures into swollen
conidia and then hyphae there is
progressive dependence on the
classical pathway (Kozel et al, 1989)

Macrophages and dendritic cells
activate host defenses in response to
Aspergillus

At the surface of these cells are TLRs
that identify microbial products (Akira
et al, 2001)

Signalling pathways associated with
each TLR vary and activation of
different receptors may result in
dissimilar biological responses

Dendritic cells modulate the
antifungal host response

Aspergillus antigens induce activation
and maturation of these cells

Ingestion of Aspergillus conidia and
hyphae proceeds through distinct
phagocytic mechanisms and elicited
responses differ depending upon the
morphotype encountered.

Following exposure to Aspergillus,
dendritic cells migrate to the spleen
and draining lymph nodes and induce
local and peripheral Th cell reactivity
to the fungus

EMERGING & RE-
EMERGING INFECTIONS


EMERGING & RE-EMERGING
INFECTIONS: TIMELINE


INFECTIONS
Emerging and re-emerging pathogens include some that
are newly described and others that had been thought
to be controlled by public-health practices

Factors leading to the emergence of such pathogens
include increased travel and intense crowding of some
populations


THREAT TO BIOTERRORISM


INFECTIONS


NEXT: VACCINES...

Bio 151 lecture 15 continued

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