Immune response to parasite infection

Sitti Wahyuni, MD. PhD Department Parasitology Medical Faculty Hasanuddin University

What are Parasites???

What makes them different from viruses and bacteria?

Parasites: diversity in size

Taenia saginata

Plasmodium falciparum

Parasites: tropical/subtropical infection

Classification of parasites
Protozoa (Unicellular) Like: Entamoeba Giardia Toxoplasma Plasmodium Metazoa (multicellular) Helminths (worms) Like: Schistosoma Strongyloides Taenia Echinococcus Aedes

Unicellular (Protozoan) parasites

Parasite Plasmodium Trypano somes Leishmania Toxoplasma Entamoeba Trichomonas Disease Malaria Sleeping sicknes Leishmaniasis Toxoplamosis Diarrhea Flour albus Predilection Liver & RBC Macrophages/ cell muscle Macrofag Macrophag & other cells Gastrointestinal Urogenitalia
Location

Intra Intra/ extra Intra Intra extra extra

Multicellular parasites
Parasite Ascaris Wuchereria/ Brugia Schistosome Loa loa Disease Ascariasis Lymphatic filariasis Schistosomiasis River blidness Predilection Gastro intestinal Lymphatic system Blood vessel Orbita & subcutaneus
Location

extra extra extra extra

A glance about immune responses

Bodys defenses against infection

Physical barrier-- prevent pathogen entering the body tissue Innate immunity-- attack an infection from its very beginning (Action of plasma protein, stimulation of macrophages, recruitment of effector cells, complement, macrophag, TLR, neutrophil, Adaptive immune response- respond to infection in a very specific fashion

Immunity against infection

Stages of infection and body defense

Action of plasma protein Recruitment of effector cells Establishment of state inflammation

CD4 TH1 CD8 T cell CD4 TH2 Plasma cells

T-cell activation

Free from infection

HOWEVER-> In parasite infection Chronicity

Plasmodium (months-years) E. coli (long live) Ascaris (1 years) Filaria (15 years) Hookworm (5 years)

If two organisms can live together for such long time, there must be co-adaptation between them

co-adaptation?
a biological process that evolved over a period of time as a consequence of natural selection characterized by functional, behavioral or structural changes that lead to a better fitness and can affect either the phenotype or the genotype (Horwitz & Wilcox 2005, West-Eberhard 2005).

Hence, Co-adaptation is a process of mutual adaptation involving two or more partners.

Human & Plasmodium

Human & Plasmodium

Outcome of the introduction of plasmodium into the human organism: (a) absent or minimal clinical manifestations, with low & long-lasting parasitemia; (b) mild or moderate clinical manifestations, with variable parasitemia, which can be cleared by the immune system after several months; (c) severe or complicated malaria, frequently with high parasitemias, which can lead to death. Outcomes depend on: the degree of adaptability Central in the determination of the levels of adaptation is the immune system.

 The deficient immune system: unable to control the growth of the parasite Over-active If the immune system: due to the tremendous amount of antigenic material released in the circulation during schizogony: several pathological manifestations involving the endothelial lining of the vessels, particularly of the central nervous system, kidneys, and lungs, can cause the death of infected people. Well balanced, a state of equilibrium with the parasite will be reached, with minimal aggressions to the involved parts, and so it can be maintained for a long while.

Host strategies

Inefficient

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Epidemiology finding
98 - 99% of the 350 - 500 million cases of malaria that occur yearly (WHO 2005a) present a mild or moderate clinical course Chronic feature represents a high degree of adaptability between host and parasite. Generally asymptomatic or present very mild clinical manifestations, and usually have low parasitemias, Asymptomatic infections have been described in areas of high endemicity & in lower transmission (Andrade et al. 1995, Alves et al. 2002, In both epidemiological contexts, asymptomatic infections exceedingly outnumber the symptomatic cases.

Conclusion
the state of equilibrium (adaptation) is the rule in human host-plasmodium relationships, and that clinical manifestations of malaria can be considered as a stage before equilibrium was reached or was lost

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Human & Mosquitoes

Human & Mosquitoes

Humans are living in close association with mosquitoes probably since their emergence. This association involves exchange of material between them: the mosquitoes suck human blood, and humans receive mosquito's saliva. In individual terms, the tiny amount represented by the salivary material of one mosquito may be considered inexpressive. In some areas of Sub-Saharan Africa during the course of a single night, several hundred mosquitoes of the Anopheles gambiae complex are collected in a room, 15% of which are infectious, and people may receive over 1000 infected bites per year (Greenwood & Mutabingwa 2002) = total 19,800 - 99,000 anopheline bites/ year.

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Mosquito salivary products

Capable to affect blood clotting, platelet aggregation, vascular contraction, host immunity, inflammation, and angiogenesis Possess several antihemostatic components to facilitate acquisition of blood A set of ~70 proteins and peptides possibly secreted in saliva The introduction a variety of antigenic components will induce a complex array of responses of the immune system.

Immune response & local reaction

dermal macrophages & dendritic cells will capture the antigen activate T lymphocytes, both locally or, mainly, in the draining lymph nodes to where antigen loaded dendritic cells migrate. B lymphocytes are also activated by cross-signaling with T lymphocytes and antibodies of different specificities are produced, particularly IgE and IgG Local immune response is amplified by the attraction of inflammatory cells due to the chemotactic effect of some components of mosquito saliva An important manifestation: degranulation of dermal mast cells & release of histamine and leukotriene C4

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immunomodulatory effects
mosquito saliva components capable able to depress host immune response Can also exacerbate (in very rare cases) - severe lymphoproliferative syndrome and oncogenesis can occur in association with the inhibition of T and B lymphocytes and of the inflammatory response - Severe hypersensitivity to mosquito bites is characterized by intense local skin reactions & systemic symptoms such as high fever, lymphadenopathy, and hepatosplenomegaly.

adaptive meaning of host immune response to mosquito bites?

The continuous contact with salivary antigenic components-- development of immunoregulatory mechanisms -balanced immune response. Consequence: decrease of the skin hypersensitivity reactions to mosquito saliva.

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Human & helminth

In human body, helminths live in lymphatics, bloodstream, or gastrointestinal tract-- safely

Helminth infection:

Commonly asymptomatic Do not simply ward off immune attack Most hosts are able to tolerate the presence of parasites for considerable time without ill effects.

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Immune response in helminth infections

Typically, the response involves: production of the cytokines interleukin-4 (IL-4), IL-5, and IL-13 production of immunoglobulin E (IgE) and the expansion and mobilization of specific effector cells, such as mast cells, eosinophils, and basophils. This responses is known as the T-helper 2 (Th2) immune response

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Allergies are increasing in the West and Urban centres of developing countries
(between 1985 and 2000 nr of people with allergy doubled) ? Environmental changes: Exposure to allergens Physical exercise Diet Pollution Microbial exposure/infections

Allergy is marked by Th2 immune responses

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In developing countries

Th2 is high but no allergy

Studies of two school in Makassar with different socio economic

30 25 20 15 10 5 0

% SPT Positivity HDM

Wahyuni, 2005

Poor

Rich

Rich school showed a higher prevalences of allergic disorders (socioeconomic status, nutrition and infections are very different)

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Inverse association of helminth infections and allergic parameters

Schistosome infections: negatively associated with atopy to house dust mite negatively associated with severity of asthma (Araujo 2000, van den Biggelaar 2000, Medeiros 2003)

Intestinal helminth infections: -negatively associated with atopy to house dust mite (Hagel 1993, Lynch 1993, Nyan 2001, Cooper 2003) -negatively associated with wheeze (Scrivener 2001)

Antigen specific T cell responses are down modulated during chronic infection some spill over suppression

IL-10, TGF Antigen specific T cell responses Chronic infection Spill over suppression

Worm burden or Time after infection

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The effect of immunohyporesponsiveness

Regulate the host immune response to create niches that optimize successful feeding and reproduction. they influence and direct immune responses away from the modes most damaging to them Pathology is more closely associated with heightened immunological reactivity

High expression of suppressory molecules in Helminth Infected Subjects

10.0

CTLA-4
P=0.005

30

IL-10
P<0.0001

7.5

r mRNA

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5.0
10

2.5

0.0

infected

uninfected

infected

uninfected

Foxp3 Natural Treg Schoolchildren in Ghana infected orAPC uninfected with helminths: Tr1 mRNA expression in whole blood CTLA-4

IL-10
TGF-

IL-10

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Pro-inflammatory

Anti-inflammatory

Treg

Th1

Th2

autoimmunity

allergy

APC

IL-12

APC

IL-10

Helminths are associated with a lower prevalence of allergies Helminths carry molecules that can drive regulatory Immune responses

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What happens when the helminth burden is reduced?

Treatment: Praziquantel and Mebendazol every three months Examined for skin test reactivity every six months
Prevalence of Ascaris & Trichiuris Prevalence (%)
100 80 60 40 20 0 0 6 12 18 24 30 25%

Cumulative positive SPT reactions to House Dust Mite

50%

Time (months)

12

18

24

30

Time (months) treatment

Treated group Placebo
Van den Biggelaar et al J Infect Dis 2004

placebo

Another fact about helminth

Colitis (Myeloperoxidase activity) in Mice reduced by inoculate T.spiralis. (Khan et.al. 2002)

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Trails to treat IBD with Trichuris suis

Joel Weinstock Whipworm (Trichuris app)

Patients recieved 2500 mature eggs every two weeks during 12 weeks

Double-blind placebo-controlled cross-over trail with T. suis in 54 ulcerative colitis patients

Clinical Colitis Activity Index improved significantly by week 6 after initiation of T.suis treatment Significant differences in response rate to treatment with T. suis or placebo
(Response rate = a decrease of 4 points in disease activity index)

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Schistosoma mansoni carries signature molecules capable of inducing Treg- build in antigen specificity
IL-10 inducing component
Lyso-PS
O O O O OH P OO NH2 COOH

TLR-2

Naive T cell

O-glycan N-glycan Glycosaminoglycans GPI-anchor Ser/Thr Glycolipids Ser Asn

Treg

IL-10 Van der Kleij et al 2002

SAD STORIES

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non infected (7)

Infected (7)

WBC Stimulated BCG before 30 day 90 day

BCG vaccination Ferreira et al, J.Infect.Dis. 2002

Placebo

PBMC albendazole

Elias et al, Clin.Exp.Immunol. 2001.

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Sad stories
Author
Elias D (2001)

Vaccine
BCG

Parasite
Int. helminth Int. helminth O. volvulus filariasis & schistosoma S. mansoni W.bancrofti O. volvulus

Indicator
T-cell proliferative & IFN-g to PPD IFN-g & IL-10 to BCG T-cell proliferative, IFN-g & IL-5 to tuberculin IFN-g to PPD 10-14m after BCG vaccination IFN-g & IL-4 to TT IFN-g & IL-10 to TT after 6m vaccination

Ferreire AP (2002) BCG Cooper PJ(1997) Tuberculin Malholtra I (1999) BCG Sabin EA TT Nookala S (2004) TT Cooper PJ (1998) TT Cooper PJ (2001) live oral cholera

The proliferative, cytokine, & abs response to TT after 6m vaccination A.lumbricoides cytokine responses to cholera toxin B subunit (CT-B) post vaccination

What should be done?????

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Rich sources of modulatory molecules can be studied to identify novel therapies

helminth

PRRs cell surface molecules signaling molecules

+/_
Treg Th1 Th2

MAP kinases/ NF-B nucleus cytokines

Pro-inflammation

Anti-inflammation

Fig. 1 Binding of microbial compounds to pattern recognition receptors (PRR) on cells of the innate immune system, for example macrophages or dendritic cells, resultsProper in signaling events that ultimately development of the lead to induction or up- or down-regulation of PRRs and other cell surface receptors, and production of inflammatory immune system cytokines. This will affect the adaptive immune system by influencing the balance between Th1, Th2 and regulatory T cells.

INNATE

ADAPTIVE

Internet information on parasitic infections: (life cycle, clinical features, distribution etc.) www.dpd.cdc.gov/DPDx/

More information about the lecture: wahyunim@indosat.net.id

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