Anaplasma Phagocytophilum

Maiara S Severo; Kimberly D Stephens; Michail Kotsyfakis; Joao HF Pedra


Future Microbiol. 2012;7(6):719-731. 

In This Article

The Tick Interface: So Close but Yet So Far

Tick-borne pathogens have evolved an intimate relationship with their vectors. Nonetheless, the precise coevolutionary history of Ixodes spp. and A. phagocytophilum remains unclear. Once acquired via blood meal, A. phagocytophilum reaches the gut and later migrates to the salivary glands allowing transmission and continuity of its life cycle. This is only possible owing to an orchestrated pattern of gene expression regulating pathogen development and vector physiology. In order to survive and perpetuate this cycle, A. phagocytophilum not only has to control expression of its own genes, but it must also alter gene expression in ticks. Transcription profiling of A. phagocytophilum during tick infection shows a possible role for virB2 genes. These genes code for a surface-exposed pilus and are part of the A. phagocytophilum T4SS. By using tiling arrays, Munderloh and colleagues have found that virB2 genes show human or tick cell-dependent differential transcription.[19] Moreover, A. phagocytophilum has human- and tick-specific operons and paralogs, such as for the major surface proteins p44/msp2.[19]

A recent postgenomic approach revealed that A. phagocytophilum transcription and translation are more active than replication during tick transmission.[40] Cell surface proteins and the virulence factors AnkA and AptA also appear to be highly induced in tick salivary glands during A. phagocytophilum transmission.[40] Another study analyzed the A. phagocytophilum expression profile during infection of ISE6 cells and found that this pathogen clearly modulates tick gene expression.[74]A. phagocytophilum morulae can be individually detected in HL-60, but not in ISE6 cells, in which A. phagocytophilum appears enlarged and pleomorphic.[74] These findings underscore the existence of specific adaptations to divergent hosts and suggest that this bacterium uses different strategies to colonize tick and mammalian cells. The P11 protein was recently shown to be required for A. phagocytophilum migration from hemocytes to the salivary glands in ticks (Figure 3).[75] Another molecule affected by A. phagocytophilum infection of ticks is the salivary gland protein SALP16. A. phagocytophilum upregulates salp16 to survive within the tick vector[76] and alters the monomeric:filamentous actin ratio leading to translocation of phosphorylated/G-actin to the nucleus.[77] This selectively regulates salp16 gene transcription in association with RNAPII and the TATA-binding protein. Strikingly, A. phagocytophilum failed to induce actin phosphorylation in primary cultures of human neutrophils, suggesting that this phenomenon is specific for the arthropod vector.

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.

When in nature, ticks often have to survive extreme conditions, such as low humidity and temperatures. Fikrig and colleagues demonstrated that A. phagocytophilum appears to increase the ability of I. scapularis to survive in cold temperatures by upregulating an antifreeze glycoprotein.[78] α1,3-fucosyltransferases are also upregulated in ticks during A. phagocytophilum infection. When α1,3-fucosyltransferases are silenced in vivo, A. phagocytophilum is less efficient at colonizing ticks as demonstrated by a decrease in pathogen acquisition during feeding. However, pathogen transmission was unaffected, indicating that A. phagocytophilum uses α1,3-fucose specifically upon acquisition.[79] On the other hand, the tick salivary protein subolesin was downregulated during A. phagocytophilum infection of I. scapularis nymphs, but the same was not observed in ISE6 cells. Additionally, vaccination against subolesin was protective against tick infection.[80] The mechanism by which subolesin contributes to A. phagocytophilum pathogenesis is still unresolved.


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