Leishmania Lifecycle

Serum Lipid Profile, Apolipoprotein E Genotype and Visceral

Leishmaniasis Infection in a Northeastern Brazilian Population

Adam P. Simons1, Gloria R. Monteiro2, Nubia N. Pontes2, Taysa M. Feitosa2, Upasna Gaur3, Richard D. Pearson4, Mary E. Wilson3, Selma M. Jeronimo2

1.University of California-Davis, Sacramento, CA, 2.Federal University of Rio Grande do Norte, Natal, Brazil, 3.University of Iowa, Iowa City, IA, 4.University

of Virginia, Charlottesville, VA

Leishmania Lifecycle

Phenotypes:1. No Current Infection (N)

-Antibody Neg.2. Acute Illness (VL)3. Asymptomatic Infection (DTH+)

-Antibody +/-

?

Environmental and Host Factors Determine Response to Infection

**Wiki commons

Cholesterol Augments Leishmania Infectivity

Rodriguez, Gaur, Wilson 2006

Cohort of families in VL endemic Area in Natal, Brazil

Family Pairs Number of PairsSibling-Sibling 692

Parent-Offspring 892Grandparent-Grandchild

268

Avuncular 414Cousin 249

Serum Lipids by Phenotype

Cholesterol Level by Phenotype vs. Age

Acute VL Effects:

• ↓ TC, HDL• ↓ ApoA, ApoB, ApoC

• ↑ TG • ↑ ApoE

Barral et al (1986)Bekaert et al (1992)Nieto (1992)

InflammationDyslipidemia

Parasitic Infection (leptospirosis)

• ↓ Total Cholesterol, HDL

• ↑ TG

Bacterial infections:• ↓ Total Cholesterol,

HDL

TNFa↑ Hepatic TG

↓ Lipoprotein Lipase

Grunfeld et al 1991

IL-6↑ LDL Rec. Expression

Liberopoulous et al 2004

ApoE

Dijk et al 1999

ApoE Genotype and Leishmaniasis?

• 109 families in Natal

• Linkage Analysis– Chr 9 (VL)– Chr 15 (DTH+)– Chr 19 (DTH+)

Source: Jeronimo et al 2007

Apolipoprotein E

Jerónimo Genome-Wide Scan 2007

ApoE Genotype Founders

 Genotype

Counts  Percent

E2/E3 1 2.7

E2/E4 1 2.7

E3/E3 22 59.5

E3/E4 13 35.1

E4/E4 0 0.0

  Allele Counts  

E2 2 2.7

E3 58 78.4

E4 14 18.9

VL FAMILIES

 Genotype Counts  Percent

E2/E3 2 11.8

E2/E4 0 0.0

E3/E3 10 58.8

E3/E4 5 29.4

E4/E4 0 0.0

  Allele Counts  

E2 2 5.9

E3 27 79.4

E4 5 14.7

CONTROL FAMILIES

Selective Pressure of ApoE

Allele % Genotype %

E2 8.3 2/2 1.4

E3 77.1 2/3 11.1

E4 14.6 3/3 58.3

2/4 2.8

3/4 26.4

4/4 0

n=72 children in Ceara

Oriá et al (2005) Wiki commons

Future Directions

• Large-power study of ApoE genotype

• Lipid metabolic pathways in VL recovery– LXR, PPAR, Cholesterol Biosynthesis

pathway gene expression across disease process.

Acknowledgments

• Mary E. Wilson, University of Iowa• Richard D. Pearson, University of Virginia• Noah Craft, University of California• Edgar Carvalho, UFBA• Cristina Otonis, UFRN• Gloria Monteiro, UFRN• Upasna Gaur, University of Iowa• Selma Jerónimo, UFRN

NIH, CNPq and UC Davis for financial support