Host-Parasite Interactions Patrick Duffy

Outline of class Antigenic variation –Background –Primary literature Parasite modulation of immune response –T cell epitopes and immunomodulation –Parasite modulation of DC function –Primary literature Parasite co-opting the immune response Host resistance versus host immunity

Richie & Saul 2002 Malaria life cycle

ANTIGENIC VARIATION

SULFA Antigenic variants within strains Plasmodium knowlesi Brown & Brown 1965 Nuri strain in Rhesus VARIANT SPECIFIC IMMUNITY VARIANT TRANSCENDING IMMUNITY

Brown 1973 Nuri strain in Rhesus Antibody-induced variation NO VACCINEVACCINATED (variant A + IFA) Variant-specific immunity in monkeys P. knowlesi

Parasitemia Hommel 1985 Saimiri monkeys Strain A Inoculum (Indo-1) Strain B Inoculum (UgPA) Strain-specific immunity in monkeys P. falciparum

Parasitemia Yount & Coggeshall 1949 Joilet, IL prison studies QUININE Strain A inoculum Strain B inoculum Strain-specific immunity in humans P. vivax

Variant antigens on the IE surface P. falciparum Leech/Barnwell/Howard 1984 (P. knowlesi) MC extractSL extract IP with sera:  SL  MC 200 kD-- 1.Large MW 2.Tx100 insoluble/SDS soluble 3.Surface iodinatable (I125) 4.Strain-specific IP (similar to cytoadherence) 5. Trypsin-sensitive (similar to cytoadherence) Variant surface antigen: Serum antibodies from monkeys infected with Malayan Camp (MC) or Santa Lucia (SL) parasites

Exon-1 (Extracellular domain) Acidic Terminal Segment Exon-2 (Cytoplasmic domain) Semi-conserved head structure Tandem association TM Tandem association DBL1  CIDR1  DBL2  C2 CIDR2  ATS DBL4  DBL1  CIDR1  CIDR2  ATS DBL2  DBL5  DBL3  RosettingCD36ICAM-1PECAMCSA NTS Exon-1 Exon-2 CR1 HS Blood group A Heparin CD31 IgM CSA CSA/C IgG Cell 1995 Su & Wellems Smith & Miller Baruch & Howard Many years later… PfEMP1

CD36 Binding and Non-binding PfEMP1 Groups CD36 binding Non-CD36 binding Joe Smith ~60 copies per haploid genome Majority are subtelomeric

Switching in T. brucei

PRIMARY LITERATURE Bull et al., J Infect Dis 182:252

SICK RECOVERED ISOLATE SICK RECOVERED ISOLATE AGGLUTINATION SCORE MONTH OLD CHILD 26 MONTH OLD CHILD Bull & Marsh 1999 Serum agglutination of field isolates: Evidence for variant specific immunity

FIELD ISOLATES SERUM SAMPLES Serum agglutination of field isolates: Rare Variants and Prevalent Variants Bull & Marsh 1999

IMMUNE MODULATION

HLA Class I molecules may be involved in liver stage immunity Hoffman, S. L and Doolan, D. L. ( 2000) Nature Medicine

HLA Class I antigen associated with resistance to severe malaria Hill et al., Nature, 1991

Expected at Parasite Rate of CSP variantObserved100%50%10% cp *195* cp *329*378* cp * cp *134* cp26 & cp * 6* cp27 & cp29499*53*11 cp26 & cp *8216* cp26 & cp *P<.05 Frequency of CSP variants in parasites collected from 795 Gambians with malaria. Reciprocal CTL antagonism in PBMC cultures by two naturally occurring P. falciparum CS protein variants. Gilbert et al., Science, 1998 CS protein and HLA B35: Evidence for Host-parasite Co-evolution?

Taylor et al., 2000

Urban et al. Figure 2

MF Good commentary Nature 1999

PRIMARY LITERATURE

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CO-OPTING THE IMMUNE SYSTEM

S. mansoni expresses host-like molecules on its surface Trottein, JI, 1997

Immune masking Ig and associated complexes affinity-purified from S. mansoni with protein G McManus, 2001

Adsorption of human Ig on the surface of red cells infected with P. falciparum IgG IgM Flick, 2001

Schistosomes develop poorly in RAG -/- mice McKerrow 2001

S. mansoni development in mouse liver requires CD4+ T cells McKerrow 2001

IS RESISTANCE IMMUNITY? Resistance to malaria during childhood and adolescence

Parasitemia Pregnancy malaria Severe childhood malaria Prevalence Age (years) Epidemiology and Immunity 11020

>40 Age group (years) migrants after 8 months exposure migrants after 20 months exposure Adults acquire resistance more rapidly than children Baird 1995

Age and susceptibility Weeks after treatment Age Age Age P < n = 243 Volunteers infected (%) Tanner Stage Age group (yrs)

Mean Parasitemia Age (yrs) DHEA-S level: low medium high DHEA-S levels predict resistance to malaria

Culture of Plasmodium falciparum Effect of DHEAS in vitro Serum+ DMSOSerum + DHEAS Time (hours) % Parasitemia

IS RESISTANCE IMMUNITY? Resistance to pregnancy malaria

Parity-related Susceptibility to Placental Malaria (1500 deliveries in Kisumu, Kenya) Rate (%) Mean parasite density (%IE) Primigravid Secundigravid Multigravid

Parasites infecting pregnant mothers are different than other parasites Parasite adhesion to placenta ex vivo Placental parasitesParasites from adult males Fried, Duffy 1996 Parasites of Pregnancy Malaria

BSACSACD36 Placenta Placenta Male Male Parasite source Parasites bound* Ex vivo assay: Placental parasites ( ) bind to lining of placenta *per 20 hpf Villus

Birth weight (kg) Anti-adhesion Ab Level PrimiSecundiMulti Antibodies and Pregnancy Outcomes 5/21 2/47 LBW Gravidity Antibodies against Parasites of Pregnancy Malaria

Take Home Lessons Antigenic variation– multigene families, mechanisms differ between parasites Parasites modulate the immune response Parasites co-opt the immune system Resistance to parasites may or may not be immune-mediated