The “Biological Weapons” of Ehrlichia chaffeensis: Novel Molecules and Mechanisms to Subjugate Host Cells

Abstract

Ehrlichia chaffeensis is an obligatory intracellular bacterium that causes human monocytic ehrlichiosis, an emerging, potentially fatal tick-borne infectious disease. The bacterium enters human cells via the binding of its unique outer-membrane invasin EtpE to the cognate receptor DNase X on the host-cell plasma membrane; this triggers actin polymerization and filopodia formation at the site of E. chaffeensis binding, and blocks activation of phagocyte NADPH oxidase that catalyzes the generation of microbicidal reactive oxygen species. Subsequently, the bacterium replicates by hijacking/dysregulating host-cell functions using Type IV secretion effectors. For example, the Ehrlichia translocated factor (Etf)-1 enters mitochondria and inhibits mitochondria-mediated apoptosis of host cells. Etf-1 also induces autophagy mediated by the small GTPase RAB5, the result being the liberation of catabolites for proliferation inside host cells. Moreover, Etf-2 competes with the RAB5 GTPase-activating protein, for binding to RAB5-GTP on the surface of E. chaffeensis inclusions, which blocks GTP hydrolysis and consequently prevents the fusion of inclusions with host-cell lysosomes. Etf-3 binds ferritin light chain to induce ferritinophagy to obtain intracellular iron. To enable E. chaffeensis to rapidly adapt to the host environment and proliferate, the bacterium must acquire host membrane cholesterol and glycerophospholipids for the purpose of producing large amounts of its own membrane. Future studies on the arsenal of unique Ehrlichia molecules and their interplay with host-cell components will undoubtedly advance our understanding of the molecular mechanisms of obligatory intracellular infection and may identify hitherto unrecognized signaling pathways of human hosts. Such data could be exploited for development of treatment and control measures for ehrlichiosis as well as other ailments that potentially could involve the same host-cell signaling pathways that are appropriated by E. chaffeensis.

Glutathione Synthesis Regulated by CtrA Protects Ehrlichia chaffeensis From Host Cell Oxidative Stress

“…After being released from infected macrophages, extracellular E. chaffeensis might encounter osmotic changes in blood or tissues, and GSH in E. chaffeensis might be involved in resisting environmental osmotic stress. After internalization, E. chaffeensis is confined within the early endosome-like membrane-bound compartments in macrophages, which retain the vacuolar type H + ATPase and are slightly acidic ( Barnewall et al, 1997 ; Rikihisa, 2015 , 2022 ). GSH in E. chaffeensis might also participate in bacterial resistance to acid stress.…”

Protective Immunity and Immunopathology in Ehrlichiosis

“…Ehrlichia membranes differ from other Gram-negative bacteria in that they lack LPS, including lipid A, peptidoglycan, and cholesterol-major PAMPS that trigger inflammasome activation during infection with these pathogens [125][126][127]. Although Ehrlichia lack genes for cholesterol biosynthesis in their cell walls, Ehrlichia hijack host membrane phospholipids from host cells and depend on host-derived cholesterol for survival and infection [128][129][130]. Genomic analysis has revealed that the E. Chaffeensis genome does not encode phosphatidylcholine or cholesterol, but encodes enzymes responsible for phosphatidylethanolamine biosynthesis.…”

“…This translocation of host-cell membranes and molecules to Ehrlichia inclusions is dependent on autophagy as well as host endocytosis, and is mediated by the effector protein Ehrlichia translocated factor-1 (Etf-1). This protein translocates from the phagosomal compartment where Ehrlichia reside to the host cytoplasm through a type IV secretion system [129,130,132]. Key components of the type IV secretion system include genes encoding VirB and VirD proteins, which are associated with the inner membrane channel and ATPase.…”

Metagenome diversity illuminates origins of pathogen effectors

“…The rvh T4SS is odd in its design 41,42 , with specialized duplications of some components hypothesized to autoregulate effector secretion 43,44 . Effectors have been characterized for species of Ehrlichia [45][46][47][48] , Anaplasma [49][50][51][52][53][54] , and Rickettsia [55][56][57] . Schön et al proposed that species of Mitibacteraceae and Athabascaceae utilize the rvh T4SS for killing congener microbes 28 , provided that these genomes harbor candidate rvh effectors with characteristics similar to effectors in other T4SS and T6SS killing machines 58,59 .…”