The multidrug resistance gene mdr1a influences resistance to ectromelia virus infection by mechanisms other than conventional immunity.
P-glycoprotein (P-gp), an ATP-dependent membrane pump encoded by mdr, plays, in addition to its ability to efflux toxins, a role in the resistance to pathogens. We employed mdr1a gene knock out (mdr1a-/-) mice and ectromelia virus (EV) to elucidate the role of P-gp in resistance to EV. Mdr1a-/- mice are more susceptible to EV infection than wild type (wt) mice, showing increased mortality and morbidity. Unexpectedly, virus titres in liver, and in vitro in macrophages and splenocytes were significantly lower in the more susceptible mdr1a-/- mice than wt littermates. Analysis of immunological mechanisms known to influence resistance to EV infection, such as NK and cytotoxic T cell responses, EV specific antibody and cytokine levels did not reveal significant differences between the two strains of mice. Only dendritic cells from mdr1a-/- mice showed impaired migration to the draining lymph nodes compared to wt mice. Our data show that P-gp plays an important role in EV infection by as yet undefined mechanisms.
Division of Immunology and Genetics, John Curtin School of Medical Research, Australian National University, Canberra, ACT 2601.
Dongmei
D
Xu
Matthias
M
Regner
Danny
D
Smith
Janet
J
Ruby
Ricky
R
Johnstone
Arno
A
Müllbacher
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000502:physiology*; D000818:Animals; D003602:Cytotoxicity, Immunologic; D004198:Disease Susceptibility; D004481:Ectromelia virus / Q000302:isolation & purification / Q000502:physiology; D004482:Ectromelia, Infectious; D007109:Immunity; D008198:Lymph Nodes / Q000166:cytology; D051379:Mice; D018345:Mice, Knockout; D009026:Mortality; D013154:Spleen / Q000166:cytology; D014779:Virus Replication
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1