Role and Function of the Type IV Secretion System in Anaplasma and Ehrlichia Species

The obligatory intracellular pathogens Anaplasma phagocytophilum and Ehrlichia chaffeensis proliferate within membrane-bound vacuoles of human leukocytes and cause potentially fatal emerging infectious diseases. Despite the reductive genome evolution in this group of bacteria, genes encoding the type IV secretion system (T4SS), which is homologous to the VirB/VirD4 system of the plant pathogen Agrobacterium tumefaciens, have been expanded and are highly expressed in A. phagocytophilum and E. chaffeensis in human cells. Of six T4SS effector proteins identified in them, roles and functions have been described so far only for ankyrin repeat domain-containing protein A (AnkA), Anaplasma translocated substrate 1 (Ats-1), and Ehrlichia translocated factor 1 (Etf-1, ECH0825). These effectors are abundantly produced and secreted into the host cytoplasm during infection, but not toxic to host cells. They contain eukaryotic protein motifs or organelle localization signals and have distinct subcellular localization, target to specific host cell molecules to promote infection. Ats-1 and Etf-1 are orthologous proteins, subvert two important innate immune mechanisms against intracellular infection, cellular apoptosis and autophagy, and manipulate autophagy to gain nutrients from host cells. Although Ats-1 and Etf-1 have similar functions and roles in obligatory intracellular infection, they are specifically adapted to the distinct membrane-bound intracellular niche of A. phagocytophilum and E. chaffeensis, respectively. Ectopic expression of these effectors enhances respective bacterial infection, whereas intracellular delivery of antibodies against these effectors or targeted knockdown of the effector with antisense peptide nucleic acid significantly impairs bacterial infection. Thus, both T4SSs have evolved as important survival and nutritional virulence mechanism in these obligatory intracellular bacteria. Future studies on the functions of Anaplasma and Ehrlichia T4SS effector molecules and signaling pathways will undoubtedly advance our understanding of the complex interplay between obligatory intracellular pathogens and their hosts. Such data can be applied toward the treatment and control of anaplasmosis and ehrlichiosis.