Ehrlichia

Ehrlichiae are small, obligately intracellular, gram-negative, tick-transmitted bacteria responsible for life-threatening emerging human zoonoses and diseases of veterinary importance, and one species is recognized as a significant agricultural biothreat. Organisms in the genus Ehrlichia were first described in the early 20th century, and the contemporary genus Ehrlichia consists of six named species that have regional or global distribution. The emergence of Ehrlichia chaffeensis and Ehrlichia ewingii as human pathogens is attributed to a combination of ecologic and demographic factors that have converged to establish these new human zoonoses in North America. Conversely, Ehrlichia ruminantium, an established pathogen of agricultural importance, is confined to Africa and a few eastern Caribbean islands, causes high mortality in ruminants, and can be efficiently transmitted by Ambloymma vectors native to North America. Thus, E. ruminantium is considered a potential agricultural biothreat to the United States agricultural industry. Ehrlichiae have small genomes but have evolved complex mechanisms that allow intracellular survival in arthropod hosts and persistent infections in vertebrate hosts, by evading the innate and adaptive immune responses. Ehrlichiae enter the host cell by receptor-mediated endocytosis that requires cellular signaling events and calcium influx. They reside in cytoplasmic vacuoles that do not fuse with lysosomes, and they alter transcription of host cell genes involved in apoptosis, cell cyclins, membrane trafficking, and various cytokines, by inhibiting MAK phosphorylation and potentially by translocation of ehrlichial proteins to the host cell nucleus that modulate gene expression. Ehrlichiae have a small group of major immunoreactive proteins that include multigene families of paralogous proteins potentially involved in immune evasion and serine/threonine-rich proteins with tandem repeats that elicit vigorous antibody responses. Ehrlichiae elicit an innate immune response dominated by inflammatory chemokines, but the pattern recognition receptors and pathogen-associated molecular patterns involved in innate immune recognition are unknown. Natural killer cells play a role in innate immune recognition of ehrlichiae, and antibodies and cell-mediated immune responses both play a role in ehrlichial clearance. The pathophysiology of the disease appears to involve overproduction of cytokines associated with toxic shock by cytotoxic T cells. Live, attenuated, killed, nucleic acid, and recombinant vaccines have been developed against Ehrlichia spp. However, development of new-generation vaccines that are effective and practical will be facilitated by the availability of the genome sequence of several ehrlichial pathogens, recent characterization of many of the major immunoreactive proteins and pathogenic mechanisms, and a more comprehensive understanding of protective and pathologic immune mechanisms.