Anaplasma phagocytophilum: deceptively simple or simply deceptive?

Abstract

Anaplasma phagocytophilum is an obligate intracellular rickettsial pathogen transmitted by ixodid ticks. This bacterium colonizes myeloid and nonmyeloid cells and causes human granulocytic anaplasmosis--an important immunopathological vector-borne disease in the USA, Europe and Asia. Recent studies uncovered novel insights into the mechanisms of A. phagocytophilum pathogenesis and immunity. Here, we provide an overview of the underlying events by which the immune system responds to A. phagocytophilum infection, how this pathogen counteracts host immunity and the contribution of the tick vector for microbial transmission. We also discuss current scientific gaps in the knowledge of A. phagocytophilum biology for the purpose of exchanging research perspectives.

Figure 1. Anaplasmataceae phylogenetic tree

The order Rickettsiales, family Anaplasmataceae includes bacteria such as Anaplasma spp., Ehrlichia spp., Wolbachia spp. and Neorickettsia spp. The Anaplasmataceae phylogenetic tree was built according to a maximum likelihood based on SEQBOOT alignment of 16S rRNA gene sequences utilizing POWER [101]. Accession numbers were obtained from GenBank [81].

Figure 2. Anaplasma phagocytophilum modulates the host machinery

Anaplasma phagocytophilum infection of human cells causes IL-8 secretion, which leads to the recruitment of neutrophils. Neutrophil apoptosis is inhibited through degradation of XIAP and dampening of apoptotic caspase function, such as CASP3 and CASP8. The p38 MAP kinase and the PI3K/AKT signaling pathways are involved in this process. ROS production is inhibited by modulating NADPH oxidase assembly and/or regulation of gene expression. The ERK pathway is also affected by this pathogen. PSGL-1 signaling is activated during infection leading to actin reorganization via the molecules Syk and ROCK1. A. phagocytophilum entry also requires lipid rafts, caveolin-1, GPI–GAP and flotillin 1. Recently, Ub was shown to decorate the A. phagocytophilum vacuole. GPI–GAP: Glycoinositol phospholipid anchored proteins; ROS: Reactive oxygen species; Ub: Monoubiquitination.

Figure 3. Anaplasma phagocytophilum manipulates the tick vector for its own benefit

The tick Ixodes scapularis pierces the skin using its hypostome. During feeding, Anaplasma phagocytophilum alters I. scapularis gene expression for colonization, enters the midgut and migrates to the salivary glands via hemocytes. Bioactive molecules, such as P11, bind to A. phagocytophilum during hemocyte colonization and facilitate pathogen trafficking to the salivary glands. A. phagocytophilum inhibits tick subolesin and modulates the expression of a tick salivary protein named SALP16 for its own survival. A. phagocytophilum also induces actin phosphorylation leading to the translocation of phosphorylated G-actin to the nucleus. Upregulation of antifreeze proteins favors tick survival in cold temperatures. When α1,3-fucosyltransferases are silenced by siRNA, I. scapularis acquisition of A. phagocytophilum is decreased, suggesting that α1,3-fucosylated structures are critical for pathogen colonization.