Pathogenesis of Rickettsial Diseases: Pathogenic and Immune Mechanisms of an Endotheliotropic Infection

Abstract

Obligately intracytosolic rickettsiae that cycle between arthropod and vertebrate hosts cause human diseases with a spectrum of severity, primarily by targeting microvascular endothelial cells, resulting in endothelial dysfunction. Endothelial cells and mononuclear phagocytes have important roles in the intracellular killing of rickettsiae upon activation by the effector molecules of innate and adaptive immunity. In overwhelming infection, immunosuppressive effects contribute to the severity of illness. Rickettsia-host cell interactions involve host cell receptors for rickettsial ligands that mediate cell adhesion and, in some instances, trigger induced phagocytosis. Rickettsiae interact with host cell actin to effect both cellular entry and intracellular actin-based mobility. The interaction of rickettsiae with the host cell also involves rickettsial evasion of host defense mechanisms and exploitation of the intracellular environment. Signal transduction events exemplify these effects. An intriguing frontier is the array of rickettsial noncoding RNA molecules and their potential effects on the pathogenesis and transmission of rickettsial diseases.

Keywords: endothelium; immunosuppression; innate immune signaling; noncoding RNA; vascular permeability; –host cell interactions.

Figure 1.

A schematic diagram of interactions of spotted fever group rickettsiae with different components of the host immune system. After tick bite, the inoculated rickettsiae initially target mononuclear phagocytes (MNPs) and then activate dendritic cells (DCs). Rickettsial antigen is presented by DCs and subsequently activates natural killer (NK) cells, CD4 T cells and CD8 T cells. Simultaneously, IL-10-producing inducible CD4⁺CD25⁺ T regulatory (T Reg) cells are generated, leading to immunosuppressive T cell response.

Figure 2:

A model of rickettsial invasion into host cells. The mammalian receptors interact with rickettsial outer membrane proteins, resulting in the internalization of rickettsiae into the cells via endocytosis and/or induced phagocytosis. Internalized rickettsiae quickly escape from the phagosomes using membranolytic activities to establish free, i.e., non-vacuole bound parasites in the cytosol.