Intracellular invasion by Orientia tsutsugamushi is mediated by integrin signaling and actin cytoskeleton rearrangements.
Orientia tsutsugamushi, the causative agent of scrub typhus, is an obligate intracellular pathogen. Previously, we reported that the 56-kDa type-specific antigen (TSA56), a major outer membrane protein of O. tsutsugamushi, binds to fibronectin and facilitates bacterial entry into the host cell, potentially via an interaction with integrins. Here, we demonstrated that O. tsutsugamushi colocalizes with integrin alpha 5 beta 1 and activates integrin signaling effectors, including focal adhesion kinase, Src kinase, and RhoA GTPase, and also recruits signaling adaptors, such as talin and paxillin, to the site of infection. Inhibition of protein tyrosine kinases or RhoA reduced intracellular invasion. We also observed substantial actin reorganization and membrane protrusions at the sites of infection of nonphagocytic host cells. Finally, we identified a region in the extracellular domain of TSA56 that binds to fibronectin. A peptide containing this region was able to significantly reduce bacterial invasion. Taken together, these results clearly indicate that O. tsutsugamushi exploits integrin-mediated signaling and the actin cytoskeleton for invasion of eukaryotic host cells.
Cho
Bon-A
BA
Department of Microbiology and Immunology, Seoul National University College of Medicine, Jongno-Gu, 28 Yongond-Dong, Jongno-Gu, Seoul 110-799, Republic of Korea.
Cho
Nam-Hyuk
NH
Seong
Seung-Yong
SY
Choi
Myung-Sik
MS
Kim
Ik-Sang
IS
D000818:Animals; D000942:Antigens, Bacterial / Q000378:metabolism; D002460:Cell Line; D003599:Cytoskeleton / Q000378:metabolism*; D004705:Endocytosis; D006801:Humans; D039081:Integrin alpha5beta1 / Q000378:metabolism*; D051379:Mice; D018613:Microscopy, Confocal; D012285:Orientia tsutsugamushi / Q000472:pathogenicity*; D051419:Paxillin / Q000378:metabolism; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D015398:Signal Transduction; D016608:Talin / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism
D000942:Antigens, Bacterial; D039081:Integrin alpha5beta1; D051419:Paxillin; D016608:Talin; D019061:src-Family Kinases; D020742:rhoA GTP-Binding Protein