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Subversion of Monocyte Functions by Coxiella burnetii: Impairment of the Cross-Talk Between _vß₃ Integrin and CR3¹

Christian Capo^*, Frederik P. Lindberg, Sonia Meconi^*, Yona Zaffran^*, Gratiela Tardei^*, Eric J. Brown, Didier Raoult^* and Jean-Louis Mege^2,*

^* Université de la Méditerranée, Unité des Rickettsies, Centre National de la Recherche Scientifique, Unité Propre de Recherche de l’Enseignement Supérieur Associée 6020, Faculté de Médecine, Marseille, France; and Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110

Several intracellular pathogens exploit macrophages as a niche for survival and replication. The success of this strategy requires the subversion or the avoidance of microbicidal functions of macrophages. Coxiella burnetii, the agent of Q fever, is a strictly intracellular bacterium that multiplies in myeloid cells. The survival of C. burnetii may depend on the selective use of macrophage receptors. Virulent C. burnetii organisms were poorly internalized but survived successfully in human monocytes, whereas avirulent variants were efficiently phagocytosed but were also rapidly eliminated. The uptake of avirulent organisms was mediated by leukocyte response integrin (_vß₃ integrin) and CR3 (_Mß₂ integrin), as demonstrated by using specific Abs and RGD sequence-containing peptides. The phagocytic efficiency of CR3 depends on its activation via _vß₃ integrin and integrin-associated protein. Indeed, CR3-mediated phagocytosis of avirulent C. burnetii was abrogated in macrophages from integrin-associated protein^-/- mice. In contrast, the internalization of virulent C. burnetii organisms involved the engagement of _vß₃ integrin but not that of CR3. The pretreatment of monocytes with virulent C. burnetii organisms prevented the CR3-mediated phagocytosis of zymosan particles and CR3 activation assessed by the expression of the 24 neo-epitope. We conclude that the virulence of C. burnetii is associated with the engagement of _vß₃ integrin and the impairment of CR3 activity, which probably results from uncoupling _vß₃ integrin from integrin-associated protein. This study describes a strategy not previously reported of phagocytosis modulation by intracellular pathogens.

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