Cross-species association of genotype and transcriptome response as driver of susceptibility and virulence

EMANUEL HEITLINGER (HUB) in partnership with Gaétan Burgio (ANU)

 

Crosses of inbred mouse strains have been used to map susceptibility to murine malaria infection to genetic loci, to identify orthologous human genes, and to inform potential intervention strategies against human infections. Murine susceptibility to Plasmodium infections can be categorized in three major outcomes: lethal cerebral malaria, death from anaemia or recovery from infection. The first outcome is limited to P. berghei infection, the latter to certain mouse strains in infections also with P. chabaudi. The collaborative cross (CC) provides mouse strains with well-characterized recombinant genotypes [1]. Those can be utilized for genetic mapping of infection outcome (Quantitative Trait Locus (QTL) mapping) or gene expression (eQTL mapping). This project additionally associates host genetics with parasite gene expression (cross-species-eQTL mapping).

 

The Burgio lab has developed a range of assays to assess phenotypes of host response to infection (e.g. [2]). It also performed a dual gene expression analysis on both host and parasites on two CC founders’ strains: CAST/Ei and C57BL/6. More host and parasite genes are up-regulated in resistant C57BL/6 mice relative to susceptible CAST/Ei. The Heitlinger lab has developed analyses to correlate parasite and host transcriptomes and performed extensive comparisons of orthologous genes across Apicomplexa species (3).

We hypothesize that gene expression networks in mice and Plasmodium are tightly interconnected and infection outcome to be associated with both genotypes and expression. We further hypothesise that parasite gene expression can be linked to host genetic loci. The PhD student will test the evolutionary conservation of such co-regulation pathways between different Plasmodium species infecting mice (P. berghei and P. chabaudi) directly and further test how far those patterns extend to human infections (with P. falciparum and P. vivax).

Infection experiments with P. berghei and P. chabaudi will be carried out in mice from the CC and phenotypes will be characterized. For both susceptible and resistant mice leukocytes and parasitized red blood cells will be sorted and transcriptomes of both will be sequenced. Gene species will be tested for correlated or anti-correlated expression patterns across species [4] and associated with host genotypes. Genomic loci and expression patterns will be assessed for congruence with orthologous genes and pathways in human infections using data available from the Mockenhaupt group on P. falciparum and P. vivax infected humans. This will analyze mechanisms of trans-species interplay using parasite and mouse mutants (see above for complementary project D2).

 

Interlinkages: Simon Foote (ANU)

 

References:

(1) Churchill, G.A. et al. (2004) Nat. Genet. 36: 1133–1137

(2) Lelliott, P.M.  et al. (2014) Malaria J. 13: 100

(3) Heitlinger, E. et al. (2014) BMC Genom. 15: 696

(4) Reid, A.J. and Berriman, M. (2012) Nucl. Acids Res. 41: 1508-1518