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Immunological Aspects of

Parasitic Diseases in
Immunocompromised Individuals
Acquired immunodeficiencies
Deficiencies of the immune system often
develop because of abnormalities that are not

Two main types of pathogenic mechanisms:

Immunosuppression may occur as a biologic
complication of another disease process.
Iatrogenic immunodeficiencies may develop as
complications of therapy for other diseases.
HIV Infection
CD4 was a viral HIV Infection
destruction of CD4 Infecting CD4 T lymphocyte,
T cells in HIV macrophages, & dendritic
infected inviduals. cells

Dysfunction of the immune


Inducing opportunistic
Iatrogenic immunodeficiencies
Due to some drugs either for the treatment
of inflammatory diseases or to prevent
rejection of tissues allografts
e.g. corticosteroids, cyclosporine

The drugs cause cytotoxic both mature and

developing lymphocyte as well as tp
granulocyte and monocyte precursors.
Strongyloides stercoralis
Exposure to contaminated faeces can result
in transmission of this disease.

The worm has an autoinfective cycle that

allows infection to persist in the host
indefinitely without the need for an
external enviroment Transformation
of rhabditiform larvae into invasive
filariform larvae in the gut of human host
Increase number of larvae completing the
autoinfectious cycle large numbers of
worms can enter the systemic circulation
hyperinfection syndrome.
Concept of hyperinfection and
Hyper infection syndrome

Immunosuppression caused by:

Iatrogenic: use of systemic corticosteroids)
Intercurrent illness HTLV-1/Human T
cell Lymphotropic Virus-1, HIV infection,
organ transplantation

High risk of hyper infection syndrome in

patients with strongyloidiasis
Impact of corticosteroid to parasite
Corticosteroids (endogenous & exogenous)
increase ecdysteroid like substances (naturally
occurring non-hormonal anabolic effects) in the
body mainly in the intestinal wall.

Molting signals for eggs and rabditiform larvae

Number of filariform larvae

Immunosuppression by Corticosteroid

Corticosteroids (endogenous & exogenous)

affect the immunity by
Increasing the apoptosis of Th2 cells
Reducing the eosinophil count
Inhibiting the mast cells response
Immunosuppression by Corticosteroid
Mucosal Immunity against Strongyloides sp.

Humoral and cell mediated immunity

Rodent models: Induction of goblet cells and
intestinal mastocytosis by IL-13 secreted by Th2
cells expulsion of worm from GI tract
Human: Lack of cell activation in the mucosa
no change in jejunal morphology, different T cell
subset numbers, mast cells, eosinophils and goblet
cells, BUT a decrease of mature macrophages and
dividing enterocytes in the crypts of intestinal walls
may preserve the architecture of mucosa and
absence of immune mediated diarrhea
Th2 role in strongyloidiasis
IL-4: important regulator of IgE production & mast
cell activation
Il-5: innate immunity (induce eosinophil production,
differentiation, maturation, survival) and adaptive
immunity (IgM production by plasma cells)
B cells: important role in subsequent challenge
infections (increased parasite-spesific IgM)
Specific IgE against filariform larvae: Protective role
not clear, maybe useful for immunodiagnosis?
ADCC (IgE activation of eosinophils & IgG activation
of neutrophils) in strongyloidiasis: not effective
against larvae?
In severe strongyloidiasis:

Compared to asymtomatic or mildly

symptomatic: lower levels of IgA, IgG,
IgM specific for primary infective
filariform larvae is not effective against
autoinfective filariform larvae (have
different surface antigens)
In severe strongyloidiasis:

Eosinophils can cause destruction of

helminth larvae
filariform larvae, BUT not sufficient for
complete protection
Lower eosinophil counts in severe
strongyloidiasis: suppression of
eosinophils esp. in disseminated

Stool culture for larvae

Serology test (ELISA)

Ivermectin not registered for human use
in Indonesia
Cryptosporidium parvum

Transmission occurs by the fecal-oral spread of


Fecal contamination of drinking water sources

can serve as a vehicle for transmission of
oocysts and is a subtantial public health concern

Oocyts are ingested by the host, Life cycle includes both
then excyst to be sporozoites which asexual multiplication and
attach to epithelial cells of small sexual reproduction.
intestine. They become enveloped
by the host apical cell membrane,
resulting a parasitophorous vacuole
with membrane components from
both the host & Cryptosporidium, and
differentiate into the trophozoites
which resides intracellularly but
outside of the cytoplasm.
During maturation of trophozoite,
asexual multiplication occurs
resulting in the formation of a type 1
schizont contains 6-8 merozoites.
Rupture of the schizont results in
the release of merozoites which can
invade adjacent host epithelial cells
then develop subsequently into type 1
or type 2 schizonts.
Oocyts retain viability, and therefore
infectivity, under moist and cool conditions
for several months.

Oocyts lose infectivity when undergoing heat

treatment above 65 C pasteurization,
sterilization for food, ozone or exposure to
UV for water (chlorination is not effective).
Life cycle
Type 1 schizonts contain merozoites important in asexual
Type 2 schizonts initiate sexual reproduction
(gametogony) by differentiating into male microgamonts or
female macrogamonts.
Male microgamonts release microgametes that can fertilize
the macrogametes inside the female macrogamont. The
oocysts that are generated then sporulate.

There are two types of oocysts, thin-walled oocyts and

thick-walled oocyts.
Thin-walled oocyts excyst and reinfect the host
Thick-walled oocyts exit the intestinal tract and can
infect a new host.
Host responses
The parasite resides at the apical surface of
intestinal epithelial cells and does not invade
deeper layers of the human gasrointestinal

Moderate to severe infection with this

intraepithelial parasite is characterized by
mucosal inflammation with neutrophils and
macrophages in the lamina propria underlying
epithelial cell.
Host responses

After infection, increased epithelial Interleukin

8 (IL-8) and GRO production (potent neutrophil
chemoattractants) could attract inflammatory
cells into the mucosa.

The infection in the intestinal epithelial cells also

rapidly upregulate the production of IFN
(proinflammatory cytokine) important for
host innate and reacuired immunity to clearance
the infection but the mechanism has not defined
Host responses
In addition, increased mucosal prostaglandine
production (PGE2) following infection with
enteroinvasive bacteria can inhibit neutral NaCL
absorption and result in secretory diarrhea.

PGE2 can downregulate inflammatory cytokine

production by macrophages explaining why diarrhea
can develop during C. parvum infection in the absence
of significant mucosal inflammation.
Host responses
In mice model, Humoral immunity is not an absolute
requirement for clearing infection.

The ability to clear acute and chronic parasite in

human correlates with host CD4 T-cell levels.

CD4+ T cells play the dominant role in resistance to

C. Parvum.

In addtion to CD4+ T cells, Th1 cytokine (IFN as

innate response) play a major role to prevent
initiation as well as limit the extent of infection
Clinical symptoms
Diarrhoea is the most common symptom of C.
parvum infection, followed by abdominal pain
and vomiting.

In immunocompromised individuals, the

disease may be much more severe and
persistent, with invasion of other organ
systems including the lungs and the bile duct,
and it is life threatening.
Finding oocysts in stool specimens by
light microscopy.

PCR to detect the DNA of parasite

Highly active antiretroviral therapy (HAART)
aspartyl protease inhibitors of the human
immunodeficiency virus which directly interfere
with the life cycle of the parasite.
In AIDS patients without antiretroviral
therapy, AZT therapy should be started
In these patients, a relationship between
disease severity and CD4+ count.
Patients with AIDS may need higher doses
and long-term maintenance treatment.

In immunocompromised hosts direct alteration in

host defense mechanism rather than changes in the
microbial flora

Defects in inflammatory and immune functions

permit infections due to opportunistic pathogens

Congenital disorders
underlying acquired disease (AIDS)
Drug therapy
Malignancies or irradiation
Abnormalities in immunologic function
Individual who defects in cell-mediated immunity is at risk for
reactivation of infection

patients with HIV reactivation if CD4+ Tcell count :

- < 100 cells/L
- < 200 cells/L (+ concomitant opportunistic infection
or malignancy)

cerebral toxoplasmosis
Immunocompetent host cell-mediated
immunity :
- controls acute Toxoplasma infection
- prevents disease reactivation

Tachyzoites (blood) activates CD4+ T cells

CD154 (CD40 ligand) triggers dendritic cells
and macrophages secrete interleukin (IL)-12
activates T-cell production of IFN-
IFN- stimulates macrophages and other
nonphagocytic cells antitoxoplasmic

Tumor necrosis factor- (TNF-) important

role in controlling T. gondii by developing a
strong T-cell response against this infection

tachyzoites bradyzoites
In immunocompromised :
dormant bradyzoites into rapidly dividing
tachyzoites reactivation (cyst rupture)
life-threatening toxoplasmosis with
encephalitis, necrotic lesions in CNS
Toxoplasmosis in HIV
impaired CD4+ T cells CD154 expression
IL-12 and IFN-

Impaired cytotoxic T-lymphocyte activity

host defense

reactivation of chronic Toxoplasma

infection (CD4+ count < 100 cells/L)
The cytokines involved in
Toxoplasmic encephalitis

the number of cysts IFN-



T.gondii Mo meningeal inflammation

Mo IL-15 dan IL-12 production of IFN-

T-cell activation
Il-15 IFN-

NK cell
Mechanisms of parasite evasion

These are of several types:

- the role of the parasitophorous vacuole
- the various parasite stages
- molecular mimesis
- immunosuppression: immuno-modulation of
immune response. During the course of
Toxoplasma infection: IL-12 , IL-10
- apoptosis: the parasite induces apoptosis of
CD4+ cells in the acute phase