Role for parasite genetic diversity in differential host responses to Trypanosoma brucei infection.
The postgenomic era has revolutionized approaches to defining host-pathogen interactions and the investigation of the influence of genetic variation in either protagonist upon infection outcome. We analyzed pathology induced by infection with two genetically distinct Trypanosoma brucei strains and found that pathogenesis is partly strain specific, involving distinct host mechanisms. Infections of BALB/c mice with one strain (927) resulted in more severe anemia and greater erythropoietin production compared to infections with the second strain (247), which, contrastingly, produced greater splenomegaly and reticulocytosis. Plasma interleukin-10 (IL-10) and gamma interferon levels were significantly higher in strain 927-infected mice, whereas IL-12 was higher in strain 247-infected mice. To define mechanisms underlying these differences, expression microarray analysis of host genes in the spleen at day 10 postinfection was undertaken. Rank product analysis (RPA) showed that 40% of the significantly differentially expressed genes were specific to infection with one or the other trypanosome strain. RPA and pathway analysis identified LXR/RXR signaling, IL-10 signaling, and alternative macrophage activation as the most significantly differentially activated host processes. These data suggest that innate immune response modulation is a key determinant in trypanosome infections, the pattern of which can vary, dependent upon the trypanosome strain. This strongly suggests that a parasite genetic component is responsible for causing disease in the host. Our understanding of trypanosome infections is largely based on studies involving single parasite strains, and our results suggest that an integrated host-parasite approach is required for future studies on trypanosome pathogenesis. Furthermore, it is necessary to incorporate parasite variation into both experimental systems and models of pathogenesis.
Morrison
Liam J
LJ
Wellcome Trust Centre for Molecular Parasitology, University of Glasgow, Biomedical Research Centre, 120 University Place, Glasgow G12 8TA, United Kingdom. lm78y@udcf.gla.ac.uk
McLellan
Sarah
S
Sweeney
Lindsay
L
Chan
Chi N
CN
MacLeod
Annette
A
Tait
Andy
A
Turner
C Michael R
CM
D000740:Anemia / Q000209:etiology; D000818:Animals; D004921:Erythropoietin / Q000378:metabolism; D020869:Gene Expression Profiling; D014644:Genetic Variation; D007371:Interferon-gamma / Q000097:blood; D016753:Interleukin-10 / Q000097:blood; D018664:Interleukin-12 / Q000097:blood; D008262:Macrophage Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D045262:Reticulocytosis; D013163:Splenomegaly / Q000209:etiology; D014346:Trypanosoma brucei brucei / Q000235:genetics* / Q000276:immunology / Q000472:pathogenicity*; D014353:Trypanosomiasis, African / Q000276:immunology / Q000469:parasitology* / Q000473:pathology*
D004921:Erythropoietin; D016753:Interleukin-10; D018664:Interleukin-12; D007371:Interferon-gamma