Immunity To Parasite & Fungiimunity

Immunity to Parasite & Fungi
S.Wahyuni, MD, PhD

Department of Parasitology,
Medical Faculty, Hasanuddin University
5/13/2014
S. Wahyuni/lecture/Immunology
The specificity of
innate immunity & adaptive immunity
5/13/2014
The role of
innate immunity in
stimulating
adaptive immune
responses
The capture
and display of
microbial antigens
The effector functions of

CD4+ & CD8+ T cells (CMI)
The effector functions of antibodies (HMI)
Fungi
Fungi are the causal agents of a variety of serious
diseases : aspergilloses, candidoses,
coccidioidomycosis, cryptococcosis, histoplasmosis, a
variety of mycetomas, and paracoccidioidomycosis.
Opportunistic in immuno-deficiencies person:
Aspergillus, Candida, Cryptoccocus,[Histoplasma,and
Pneumocystis.
Can attack eyes, nails, hair, and especially skin, the socalled dermatophytic fungi and keratinophilic fungi and
cause a variety of conditions, of which ringworms such
as athletes foot are common.
Allergen in some people
5/13/2014
Fungal antigen recognition

PRR
Location
Recognition Molecules
Role in
Fungal
Responses
TLR
1/2
Surface
Surface
Endosomal
Surface/cytoplasmic
5
6/2
7
8
9
10
Surface
Surface
Endosomal
Endosomal
Endosomal
Surface?
5/13/2014
Lipoproteins; triacylated lipopeptides;

zymosan?
Peptidoglycan; lipoproteins; glycolipids;
lipoaribomannan; zymosan
dsRNA; poly (I:C)
Lipopolysacharide; lipid A; fungal Omannan
Flagellin
Diacylated lipopeptides; zymosan?
ssRNA; imidazoquinolines
ssRNA; imidazoquinolines
Unmethylated CpG DNA, fungal DNA?
Unknown
Possibly
Yes
Possibly
Yes
No
Possibly
No
No
Yes?
No
8
Fungal antigen recognition

PRR
Location
Lectins
C-typea
Surface/extracellular
Cytoplasm/nucleus;
Galectins
extracellular
Siglecs Surface
Body fluids
Pentraxinsb
LBP
Extracellular
Node like receptor (NLR)
NOD1/2 Cytoplasmic
NALP1 Cytoplasmic
NALP3 Cytoplasmic
RLH
RIG-I
Cytoplasmic
MDA-5 Cytoplasmic
5/13/2014
Recognition Molecules
Role in
Fungal
Responses
Variable; fungal -glucans and mannan

-Galactosides (variety of complex Nglycans)
Variable; sialic acids
Variable; bind and activate the
complement system
Lipopolysacharide
Yes
Muramyl dipeptide
Variable
Variable
Possibly
Probably
Probably
5-triphosphate ssRNA
ssRNA
Yes
No
Probably
Possibly
No
No
9
Poly (I:C), polyriboinosinic:polyribocytidylic acid;

LBP, lipopolysacharide binding protein;
NOD1/2, nucleotide-binding oligomerization domain containing 1 or
2;
NALP1/3, NACHT, LRR, and pyrin domain containing protein 1 or 3;
RLH, retinoic acidinducible gene Ilike helicases; RIG-I, retinoic
acidinducible gene I;
MDA-5, melanoma differentiation-associated gene 5.
aDectin-1/2, MR, DC-SIGN.
bPTX3 (Pentraxin 3),
CRP (C-reactive protein), SAP (serum amyloid protein),
MBL (mannose binding lectin), C1q and C3 (complement
components
5/13/2014
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Innate Immunity to Fungi

The principal mediators of innate immunity against
fungi are neutrophils and macrophages.
Patients with neutropenia are extremely susceptible to
opportunistic fungal infections.
Neutrophils presumably liberate fungicidal substances,
such as reactive oxygen intermediates and lysosomal
enzymes, and phagocytose fungi for intracellular
killing.
Virulent strains of Cryptococcus neoformans inhibit the
production of cytokines such as TNF and IL-12 by
macrophages and stimulate production of IL-10, thus
inhibiting macrophage activation.
5/13/2014
11
Neutrophils
One of phagocytes, that function is to identify,
ingest, and destroy microbes.
Called polymorphonuclear leukocytes
Most abundant population of circulating white
blood cells and mediate the earliest phases of
inflammatory responses.
5/13/2014
12
Circulate as spherical cells about 12 to 15 m in diameter

with numerous membranous projections.
The nucleus of a neutrophil is segmented into three to five
connected lobules, hence the term polymorphonuclear
leukocytes.
Cytoplasm contains granules of 2 types.
The majority, called specific granules, are filled with enzymes
such as lysozyme, collagenase, and elastase. These granules do
not stain strongly with either basic or acidic dyes (hematoxylin
and eosin, respectively), which distinguishes neutrophil granules
from those of basophils and eosinophils, respectively.
The remainder is called azurophilic granules, are lysosomes
containing enzymes and other microbicidal substances.
5/13/2014
13
produced in the bone marrow and arise from a common

lineage with mononuclear phagocytes.
Production is stimulated by granulocyte colony-stimulating
factor.
An adult human produces more than 1 1011 neutrophils
per day, each of which circulates in the blood for only about
6 hours.
Neutrophils may migrate to sites of infection within a few
hours after the entry of microbes.
If a circulating neutrophil is not recruited into a site of
inflammation within this period, it undergoes programmed
cell death and is usually phagocytosed by resident
macrophages in the liver or spleen.
5/13/2014
14
A cooperative effort of Innate & adaptive immunity, Romani L, Nature 2004

5/13/2014
15
Adaptive immunity against fungal

infections.
Cell-mediated immunity is the major mechanism
Histoplasma capsulatum, a facultative
intracellular parasite that lives in macrophages, is
eliminated by the same cellular mechanisms that
are effective against intracellular bacteria.
CD4+ and CD8+ T cells cooperate to eliminate the
yeast forms of Cryptococcus neoformans, which
tend to colonize the lungs and brain in
immunodeficient hosts.
5/13/2014
16
Cell-mediated immunity againts

fungal infection
5/13/2014
17
Cooperation of CD4+ and CD8+ T cells in defense

against intracellular microbes
3/11/2009
S. Wahyuni/lecture/immunology
18
Candida infections often start at mucosal

surfaces, and cell-mediated immunity is believed
to prevent spread of the fungi into tissues.
In all these situations, TH1 responses are
protective and TH2 responses are detrimental to
the host.
Granulomatous inflammation is an important
cause of host tissue injury in some intracellular
fungal infections, such as histoplasmosis.
5/13/2014
19
Role of T cells and cytokines in

determining outcome of infections
3/11/2009
S. Wahyuni/lecture/immunology
20
Granulomatous due to chronic infection
5/13/2014
21
Defect of host defences that predispose fungal

infection
Shoham, Brithis Jurnal of Immunology 2005

5/13/2014
22
Parasite characteristic
diversity in size
Taeni
a
sagin
ata
Asymptomatic
Plasm
odium
falcipa
rum
Multiple host
host
parasite
host
host
5/13/2014
23
Parasite characteristic
There are two classification: monocellular
multicellular parasite
Most parasites go through complex life cycles
Most parasitic infections are chronic because of
weak innate immunity and the ability of parasites
to evade or resist elimination by adaptive
immune responses.
Many antiparasite are not effective at killing the
organisms.
Vaccine are not available for most of cases
5/13/2014
24
Protozoa
Classified as unicellular eukaryotes
Live intra & extra cellular
Classification:
Flagellates (e.g. Giardia lamblia)
Amoeboids (e.g. Entamoeba
histolytica)
Sporozoans (e.g. Plasmodium
knowlesi)
Apicomplexa
Myxozoa
Microsporidia
Ciliates (e.g. Balantidium coli)

5/13/2014
25
Innate immunity to protozoa

Phagocytosis, but many of these parasites are
resistant to phagocytic killing and may even
replicate within macrophages.
5/13/2014
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Adaptive Immune Responses protozoa

Intracellular
parasite
Cell mediated
immunity
5/13/2014
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Th1 & Th2 balance for protozoa infection
5/13/2014
28
Helminth
Multi cellular organsm (metazoa)
Live extra cellular
Classification
Nematoda
Intestinal
Non intestinal
Trematode
Hermaphrodith
Bisexual
Cestoda
5/13/2014
29
Innate immunity to helminth

Phagocytosis and secrete microbicidal substances
But helminth are too large to be phagocytosed.
Have thick teguments that make them resistant
to the cytocidal mechanisms of neutrophils and
macrophages.
May also activate the alternative pathway of
complement, but parasites recovered from
infected hosts appear to have developed
resistance to complement-mediated lysis
5/13/2014
30
Adaptive Immune Responses helminth

by the activation of TH2 cells production of
IgE antibodies and activation of eosinophils.
IgE antibodies bind to the surface of the
helminth
eosinophils then attach through Fc receptors,
and the eosinophils are activated to secrete
granule enzymes that destroy the parasites
5/13/2014
31
Typically, the response involves:

production of the cytokines
IL-4), IL-5, and IL-13
production of IgE and the
expansion and mobilization
of some cells, such as mast
cells, eosinophils, and
basophils.
Known as the T-helper 2 (Th2)
immune response
08/23/2008
S. Wahyuni, Parasitology Dept, Medical Faculty, Unhas
32
Effector Mechanisms against Tissue-Dwelling Parasites

and Escape Mechanisms Developed by the Parasite
Early phase: activated macrophages induce nitric oxide production which

is toxic for the fluke. This mechanism needs to be confirmed and may be
upregulated by Th1-type cytokines and downregulated by IL-10 produced
by T regulatory cells.
Chronic phase of infection:
Antibody-dependent cellular cytotoxicity (ADCC): allows the release
of toxic mediators such as major basic protein, eosinophil cationic
protein, and reactive nitrogen intermediates. This mechanism is
upregulated by Th2-type cytokines. T regulatory cells (Treg cells)
produce IL-10 TGF which inhibit the production and function of Th1
cytokines. They downregulate any excessive Th2 response in the
immunopathogenesis of fasciolosis.
Alternative activated macrophage (AAM ) produces molecules that
are toxic to the fluke and participates in fibrosis and tissue repair.
08/23/2008
33
08/23/2008
34
Escape Mechanisms Developed by the Parasite

Tissue-Dwelling Parasites
Production of superoxide dismutase and
Glutathione S-transferase which neutralize
superoxide radicals
Cleavage of IgE and IgG involved in the ADCC
Production of blocking antibodies IgM and
IgG2 which could inhibit eosinophil adhesion
to flukes.
08/23/2008
35
08/23/2008
36
Immune response against gastrointestinal nematodes

Against larva: ADCC and type 1 hypersensitivity are involved
to block their migration in gut mucosa and to eliminate the
parasite
Against adult in the lumen of gut:
Intestinal anaphylaxis responsible for muscle contractility,
mucus secretion, and so forth, leads to the expulsion of
the parasite
IgA neutralizes the metabolic enzymes and interferes with
the worms ability to feed.
08/23/2008
37
08/23/2008
38
Immune Responses to
Disease-Causing Parasites
Parasite
Protozoa
Principal mechanisms of
protective immunity
Diseases
Plasmodium Malaria
Antibodies and CD8 CTLs
Leishmania
CD4 TH1 cells activate macrophages to

kill phagocytosed parasites
Leishmaniasis
(mucocutaneous,
disseminated)
Trypanosoma African
trypanosomiasis
Entamoeba Amebiasis
histolytica
Antibodies
Antibodies, phagocytosis
Metazoa
Schistosoma Schistosomiasis
Filaria
5/13/2014
Filariasis
ADCC mediated by eosinophils,

macrophages
Role of antibodies?
39
Immune Evasion by Parasites

Mechanism of
Immune evasion
Antigenic variation
Examples
Trypanosomes, Plasmodium
Acquired resistance to Schistosomes

complement, CTLs
Inhibition of host
immune responses
Filaria (secondary to lymphatic

obstruction), trypanosomes
Antigen shedding
Entamoeba
5/13/2014
40
Materials
Basic Immunology; function & disorders of the
immuno system by Abbas (2007)
Celliular & molecular immunology by Abbas
(2007)
Immune system by Pieter Parham (2006)
Contact: wahyunim@indosat.net.id
5/13/2014
41

Immunity To Parasite & Fungiimunity

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Immunity to Parasite & Fungi

S.Wahyuni, MD, PhD

The effector functions of

The effector functions of antibodies (HMI)

Fungal antigen recognition

Lipoproteins; triacylated lipopeptides;

Fungal antigen recognition

Variable; fungal -glucans and mannan

Poly (I:C), polyriboinosinic:polyribocytidylic acid;

Innate Immunity to Fungi

Circulate as spherical cells about 12 to 15 m in diameter

produced in the bone marrow and arise from a common

A cooperative effort of Innate & adaptive immunity, Romani L, Nature 2004

Adaptive immunity against fungal

Cell-mediated immunity againts

Cooperation of CD4+ and CD8+ T cells in defense

Candida infections often start at mucosal

Role of T cells and cytokines in

Granulomatous due to chronic infection

Defect of host defences that predispose fungal

Shoham, Brithis Jurnal of Immunology 2005

Ciliates (e.g. Balantidium coli)

Innate immunity to protozoa

Adaptive Immune Responses protozoa

Th1 & Th2 balance for protozoa infection

Innate immunity to helminth

Adaptive Immune Responses helminth

Typically, the response involves:

S. Wahyuni, Parasitology Dept, Medical Faculty, Unhas

Effector Mechanisms against Tissue-Dwelling Parasites

Early phase: activated macrophages induce nitric oxide production which

S. Wahyuni, Parasitology Dept, Medical Faculty, Unhas

S. Wahyuni, Parasitology Dept, Medical Faculty, Unhas

Escape Mechanisms Developed by the Parasite

S. Wahyuni, Parasitology Dept, Medical Faculty, Unhas

S. Wahyuni, Parasitology Dept, Medical Faculty, Unhas

Immune response against gastrointestinal nematodes

S. Wahyuni, Parasitology Dept, Medical Faculty, Unhas

S. Wahyuni, Parasitology Dept, Medical Faculty, Unhas

Antibodies and CD8 CTLs

CD4 TH1 cells activate macrophages to

ADCC mediated by eosinophils,

Immune Evasion by Parasites

Acquired resistance to Schistosomes

Filaria (secondary to lymphatic

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