title: Toll-like receptor modulation of murine cerebral malaria is dependent on the genetic background of the host.
abstract: Infection with Plasmodium berghei ANKA is a well-established model of human cerebral malaria (CM). We show herein that Toll-like receptor (TLR) signaling influences the development of lethal CM in P. berghei ANKA-infected mice. Modulation of outcome was dependent on genetic background, such that deletion of myeloid differentiation factor (MyD) 88 on the susceptible C57BL/6 background resulted in resistance to CM, whereas deletion of MyD88 on the resistant BALB/c background led to increased mortality. Our data show that MyD88 influenced the production of T helper-polarizing cytokines, including interferon (IFN)- gamma, interleukin (IL)-4, and IL-17, as well as the total number of Foxp3(+) regulatory T (T(reg)) cells in a manner dependent on host genetic background. In addition, mRNA levels of IFN- gamma, CXCL10, and CXCL9 were strongly up-regulated in the brains of susceptible wild-type but not MyD88(-/-) infected mice. These results suggest that TLR signaling and host genetic background influences the pathogenesis of CM via modulation of cytokine production and T(reg) cell numbers.
authors.affiliation: Department of Internal Medicine, Yale University, 300 Cedar Street, New Haven, CT 06520, USA.
authors.forename: Jason W
authors.initials: JW
authors.lastname: Griffith
authors.forename: Christine
authors.initials: C
authors.lastname: O'Connor
authors.forename: Ken
authors.initials: K
authors.lastname: Bernard
authors.forename: Terrence
authors.initials: T
authors.lastname: Town
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Goldstein
authors.forename: Richard
authors.initials: R
authors.lastname: Bucala
mesh_terms: D000818:Animals; D016207:Cytokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D004198:Disease Susceptibility / Q000276:immunology; D005260:Female; D007371:Interferon-gamma / Q000096:biosynthesis; D020381:Interleukin-17 / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis; D016779:Malaria, Cerebral / Q000235:genetics / Q000276:immunology* / Q000469:parasitology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D053594:Myeloid Differentiation Factor 88 / Q000276:immunology*; D010962:Plasmodium berghei / Q000276:immunology*; D051193:Toll-Like Receptors / Q000276:immunology*
chemical_list: D016207:Cytokines; D020381:Interleukin-17; D053594:Myeloid Differentiation Factor 88; D051193:Toll-Like Receptors; D015847:Interleukin-4; D007371:Interferon-gamma