Targeting Rickettsia
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《新英格兰医药杂志》
Bacteria of the genus rickettsia cause life-threatening rickettsioses such as Rocky Mountain spotted fever, typhus fever, Mediterranean spotted fever, and murine typhus. The clinical manifestations of these types of rickettsioses (for example, hypovolemia and edema of the skin, lungs, and brain) result from increased vascular permeability; the key event causing the microvascular leakage is widespread endothelial infection. The rickettsiae enter cells by binding to the membrane, inducing phagocytosis, and escaping from the phagosome into the cytosol. Martinez et al. recently identified a critical component of the first step: the protein on the host cell to which the rickettsia binds.1
Using a cell-based model of infection by Rickettsia conorii, which causes Mediterranean spotted fever, Martinez et al.1 showed that the most abundant surface protein of the rickettsiae, OmpB, engages Ku70, a protein that spans the membrane of the host cell (Figure 1). The authors found that Ku70 migrates to the host-cell membrane in response to the presence of rickettsia and elucidated downstream events that may be critical to the bacterium's ability to trigger endocytosis. The binding of Ku70 and OmpB results in the rapid recruitment of an enzyme called ubiquitin ligase to the binding site, where it adds a ubiquitin moiety to Ku70. The ablation of ubiquitin ligase in cells blocked entry by R. conorii. Thus, experimental approaches to therapy for rickettsiosis could focus on Ku70 or its ubiquitination. The finding that cells lacking Ku70 are not completely impervious to infection by R. conorii, however, implies that there are one or more alternative receptors for rickettsial attachment proteins, and there may also be one or more additional attachment proteins.1
Figure 1. A Coup against Rickettsia — Discovery of Events Critical to the Entry of R. conorii into Host Cells.
The findings of Martinez et al.1 suggest that binding of the bacterium to the host-cell surface elicits recruitment of the proteins Ku70 and a ubiquitin ligase to the site of binding. Ubiquitin ligase then catalyzes ubiquitination of Ku70 — and the ubiquitinated Ku70 is thought to set off signaling cascades that result in the rearrangement of cellular actin into ruffles that engulf the bacterium and thus bring about its endocytosis.
A previous study by the same group identified elements of the signal-transduction pathway that presumably leads from ubiquitinated Ku70 to the cytoskeletal rearrangements involved in the phagocytosis of the rickettsia.2 New treatments for rickettsiosis could target these elements, the escape of the bacteria from phagosomes (mediated by the rickettsial proteins phospholipase D and tlyC), or the cell-to-cell spread of rickettsiae through the propulsion of actin in the host cell.3,4
Why would one need more than a tetracycline or, in special circumstances, chloramphenicol to treat a rickettsiosis? More than half a century after the establishment of lifesaving antimicrobial treatment of Rocky Mountain spotted fever, patients are still dying because they are initially misdiagnosed and because a change of treatment from the ineffective beta-lactamases, aminoglycosides, and macrolides to the drug of choice, doxycycline, occurs too late in the course of illness. Patients with Rocky Mountain spotted fever who are treated with doxycycline only after the sixth day of illness are at the greatest risk for dying. Some physicians are surprised when such a patient dies, but there is no other therapy of documented value to enhance the patient's chances for survival.
Moreover, rickettsia species that are resistant to tetracyclines and chloramphenicol have been obtained in the laboratory and would be easy to develop by genetic manipulation. A terrorist could obtain a rickettsia from nature, propagate it by using readily available materials and limited skills, and maintain it in a form with stable infectivity. If R. rickettsii or R. prowazekii were made resistant to antirickettsial drugs, a very low dose inhaled as an aerosol would have a case fatality rate of 25 percent, similar to that of pathogens classified as category A by the National Institute of Allergy and Infectious Diseases.
New treatment tools could range from antibodies to OmpB, which have been demonstrated to be effective in laboratory animals,5 to inhibiting the functions of the host-cell proteins that are necessary for rickettsiae to survive (although this strategy could be tricky if it proved deleterious to the patient). Although inhibiting protein synthesis by R. rickettsii and inhibiting rickettsial growth benefit the patient, such brutal foes as the bacteria that cause Rocky Mountain spotted fever and typhus warrant a quiver of many therapeutic arrows.
No potential conflict of interest relevant to this article was reported.
Source Information
From the Center for Biodefense and Emerging Infectious Diseases, University of Texas Medical Branch, Galveston.
References
Martinez JJ, Seveau S, Veiga E, Matsuyama S, Cossart P. Ku70, a component of DNA-dependent protein kinase, is a mammalian receptor for Rickettsia conorii. Cell 2005;123:1013-1023.
Martinez JJ, Cossart P. Early signaling events involved in the entry of Rickettsia conorii into mammalian cells. J Cell Sci 2004;117:5097-5106.
Whitworth T, Popov VL, Yu XJ, Walker DH, Bouyer DH. Expression of the Rickettsia prowazekii pld or tlyC gene in Salmonella enterica serovar Typhimurium mediates phagosomal escape. Infect Immun 2005;73:6668-6673.
Gouin E, Egile C, Dehoux P, et al. The RickA protein of Rickettsia conorii activates the Arp2/3 complex. Nature 2004;427:457-461.
Feng H-M, Whitworth T, Olano JP, Popov VL, Walker DH. Fc-dependent polyclonal antibodies and antibodies to outer membrane proteins A and B, but not to lipopolysaccharide, protect SCID mice against fatal Rickettsia conorii infection. Infect Immun 2004;72:2222-2228.(David H. Walker, M.D.)
Using a cell-based model of infection by Rickettsia conorii, which causes Mediterranean spotted fever, Martinez et al.1 showed that the most abundant surface protein of the rickettsiae, OmpB, engages Ku70, a protein that spans the membrane of the host cell (Figure 1). The authors found that Ku70 migrates to the host-cell membrane in response to the presence of rickettsia and elucidated downstream events that may be critical to the bacterium's ability to trigger endocytosis. The binding of Ku70 and OmpB results in the rapid recruitment of an enzyme called ubiquitin ligase to the binding site, where it adds a ubiquitin moiety to Ku70. The ablation of ubiquitin ligase in cells blocked entry by R. conorii. Thus, experimental approaches to therapy for rickettsiosis could focus on Ku70 or its ubiquitination. The finding that cells lacking Ku70 are not completely impervious to infection by R. conorii, however, implies that there are one or more alternative receptors for rickettsial attachment proteins, and there may also be one or more additional attachment proteins.1
Figure 1. A Coup against Rickettsia — Discovery of Events Critical to the Entry of R. conorii into Host Cells.
The findings of Martinez et al.1 suggest that binding of the bacterium to the host-cell surface elicits recruitment of the proteins Ku70 and a ubiquitin ligase to the site of binding. Ubiquitin ligase then catalyzes ubiquitination of Ku70 — and the ubiquitinated Ku70 is thought to set off signaling cascades that result in the rearrangement of cellular actin into ruffles that engulf the bacterium and thus bring about its endocytosis.
A previous study by the same group identified elements of the signal-transduction pathway that presumably leads from ubiquitinated Ku70 to the cytoskeletal rearrangements involved in the phagocytosis of the rickettsia.2 New treatments for rickettsiosis could target these elements, the escape of the bacteria from phagosomes (mediated by the rickettsial proteins phospholipase D and tlyC), or the cell-to-cell spread of rickettsiae through the propulsion of actin in the host cell.3,4
Why would one need more than a tetracycline or, in special circumstances, chloramphenicol to treat a rickettsiosis? More than half a century after the establishment of lifesaving antimicrobial treatment of Rocky Mountain spotted fever, patients are still dying because they are initially misdiagnosed and because a change of treatment from the ineffective beta-lactamases, aminoglycosides, and macrolides to the drug of choice, doxycycline, occurs too late in the course of illness. Patients with Rocky Mountain spotted fever who are treated with doxycycline only after the sixth day of illness are at the greatest risk for dying. Some physicians are surprised when such a patient dies, but there is no other therapy of documented value to enhance the patient's chances for survival.
Moreover, rickettsia species that are resistant to tetracyclines and chloramphenicol have been obtained in the laboratory and would be easy to develop by genetic manipulation. A terrorist could obtain a rickettsia from nature, propagate it by using readily available materials and limited skills, and maintain it in a form with stable infectivity. If R. rickettsii or R. prowazekii were made resistant to antirickettsial drugs, a very low dose inhaled as an aerosol would have a case fatality rate of 25 percent, similar to that of pathogens classified as category A by the National Institute of Allergy and Infectious Diseases.
New treatment tools could range from antibodies to OmpB, which have been demonstrated to be effective in laboratory animals,5 to inhibiting the functions of the host-cell proteins that are necessary for rickettsiae to survive (although this strategy could be tricky if it proved deleterious to the patient). Although inhibiting protein synthesis by R. rickettsii and inhibiting rickettsial growth benefit the patient, such brutal foes as the bacteria that cause Rocky Mountain spotted fever and typhus warrant a quiver of many therapeutic arrows.
No potential conflict of interest relevant to this article was reported.
Source Information
From the Center for Biodefense and Emerging Infectious Diseases, University of Texas Medical Branch, Galveston.
References
Martinez JJ, Seveau S, Veiga E, Matsuyama S, Cossart P. Ku70, a component of DNA-dependent protein kinase, is a mammalian receptor for Rickettsia conorii. Cell 2005;123:1013-1023.
Martinez JJ, Cossart P. Early signaling events involved in the entry of Rickettsia conorii into mammalian cells. J Cell Sci 2004;117:5097-5106.
Whitworth T, Popov VL, Yu XJ, Walker DH, Bouyer DH. Expression of the Rickettsia prowazekii pld or tlyC gene in Salmonella enterica serovar Typhimurium mediates phagosomal escape. Infect Immun 2005;73:6668-6673.
Gouin E, Egile C, Dehoux P, et al. The RickA protein of Rickettsia conorii activates the Arp2/3 complex. Nature 2004;427:457-461.
Feng H-M, Whitworth T, Olano JP, Popov VL, Walker DH. Fc-dependent polyclonal antibodies and antibodies to outer membrane proteins A and B, but not to lipopolysaccharide, protect SCID mice against fatal Rickettsia conorii infection. Infect Immun 2004;72:2222-2228.(David H. Walker, M.D.)