Impairment of dendritic cells and adaptive immunity by anthrax lethal toxin.
Anthrax poses a clear and present danger as an agent of biological terrorism. Infection with Bacillus anthracis, the causative agent of anthrax, if untreated can result in rampant bacteraemia, multisystem dysfunction and death. Anthrax lethal toxin (LT) is a critical virulence factor of B. anthracis, which occurs as a complex of protective antigen and lethal factor. Here we demonstrate that LT severely impairs the function of dendritic cells--which are pivotal to the establishment of immunity against pathogens--and host immune responses by disrupting the mitogen-activated protein (MAP) kinase intracellular signalling network. Dendritic cells exposed to LT and then stimulated with lipopolysaccharide do not upregulate co-stimulatory molecules, secrete greatly diminished amounts of proinflammatory cytokines, and do not effectively stimulate antigen-specific T cells in vivo. Furthermore, injections of LT induce a profound impairment of antigen-specific T- and B-cell immunity. These data suggest a role for LT in suppressing host immunity during B. anthracis infections, and represent an immune evasion strategy, where a microbe targets MAP kinases in dendritic cells to disarm the immune response.
Agrawal
Anshu
A
Emory Vaccine Research Center, 954 Gatewood Road, Atlanta, Georgia 30329, USA.
Lingappa
Jai
J
Leppla
Stephen H
SH
Agrawal
Sudhanshu
S
Jabbar
Abdul
A
Quinn
Conrad
C
Pulendran
Bali
B
D019264:Adoptive Transfer; D000818:Animals; D000942:Antigens, Bacterial; D017209:Apoptosis; D001408:Bacillus anthracis / Q000276:immunology / Q000472:pathogenicity*; D001427:Bacterial Toxins / Q000378:metabolism / Q000494:pharmacology*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000637:transplantation; D016207:Cytokines / Q000276:immunology; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D006801:Humans; D007109:Immunity / Q000187:drug effects* / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000276:immunology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D017737:Macrophages, Peritoneal / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010047:Ovalbumin / Q000276:immunology; D010766:Phosphorylation / Q000187:drug effects; D013154:Spleen / Q000276:immunology
D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D016207:Cytokines; C030325:anthrax toxin; D010047:Ovalbumin; D020928:Mitogen-Activated Protein Kinases