Shigella effector IpaH9.8 binds to a splicing factor U2AF(35) to modulate host immune responses.
Shigella effectors injected into the host cell via the type III secretion system are involved in various aspects of infection. Here, we show that one of the effectors, IpaH9.8, plays a role in modulating inflammatory responses to Shigella infection. In murine lung infection model, DeltaipaH9.8 mutant caused more severe inflammatory responses with increased pro-inflammatory cytokine production levels than did wild-type Shigella, which resulted in a 30-fold decrease in bacterial colonization. Binding assays revealed that IpaH9.8 has a specific affinity to U2AF(35), a mammalian splicing factor, which interferes with U2AF(35)-dependent splicing as assayed for IgM pre-mRNA. Reducing the U2AF(35) level in HeLa cells and infecting HeLa cells with wild-type caused a decrease in the expression of the il-8, RANTES, GM-CSF, and il-1beta genes as examined by RT-PCR. The results indicate that IpaH9.8 plays a role in Shigella infection to optimize the host inflammatory responses, thus facilitating bacterial colonization within the host epithelial cells.
Okuda
Jun
J
Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8039, Japan.
Toyotome
Takahito
T
Kataoka
Naoyuki
N
Ohno
Mutsuhito
M
Abe
Hiroyuki
H
Shimura
Yoshiro
Y
Seyedarabi
Arefeh
A
Pickersgill
Richard
R
Sasakawa
Chihiro
C
D000818:Animals; D000942:Antigens, Bacterial / Q000276:immunology* / Q000378:metabolism*; D001426:Bacterial Proteins / Q000276:immunology* / Q000378:metabolism*; D004405:Dysentery, Bacillary / Q000276:immunology* / Q000378:metabolism*; D006367:HeLa Cells; D000949:Histocompatibility Antigens Class II / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007155:Immunologic Factors / Q000276:immunology / Q000378:metabolism; D008168:Lung / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009687:Nuclear Proteins / Q000276:immunology* / Q000378:metabolism*; D012326:RNA Splicing / Q000276:immunology; D012261:Ribonucleoproteins / Q000276:immunology* / Q000378:metabolism*; D000072668:Splicing Factor U2AF
D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D000949:Histocompatibility Antigens Class II; D007155:Immunologic Factors; D009687:Nuclear Proteins; D012261:Ribonucleoproteins; D000072668:Splicing Factor U2AF; C076753:U2AF1 protein, human; C063500:ipaH protein, Shigella flexneri