Anaplasma phagocytophilum Manipulates Host Cell Apoptosis by Different Mechanisms to Establish Infection.

Pilar Alberdi,Alejandro Cabezas-Cruz,Pedro Espinosa,José De La Fuente

doi:10.3390/vetsci3030015

Abstract

Anaplasma phagocytophilum is an emerging zoonotic pathogen that causes human and animal granulocytic anaplasmosis and tick-borne fever of ruminants. This obligate intracellular bacterium evolved to use common strategies to establish infection in both vertebrate hosts and tick vectors. Herein, we discuss the different strategies used by the pathogen to modulate cell apoptosis and establish infection in host cells. In vertebrate neutrophils and human promyelocytic cells HL-60, both pro-apoptotic and anti-apoptotic factors have been reported. Tissue-specific differences in tick response to infection and differential regulation of apoptosis pathways have been observed in adult female midguts and salivary glands in response to infection with A. phagocytophilum. In tick midguts, pathogen inhibits apoptosis through the Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway, while in salivary glands, the intrinsic apoptosis pathways is inhibited but tick cells respond with the activation of the extrinsic apoptosis pathway. In Ixodes scapularis ISE6 cells, bacterial infection down-regulates mitochondrial porin and manipulates protein processing in the endoplasmic reticulum and cell glucose metabolism to inhibit apoptosis and facilitate infection, whereas in IRE/CTVM20 tick cells, inhibition of apoptosis appears to be regulated by lower caspase levels. These results suggest that A. phagocytophilum uses different mechanisms to inhibit apoptosis for infection of both vertebrate and invertebrate hosts.

Highlights

IntroductionAnaplasma phagocytophilum is an obligate intracellular bacterium transmitted primarily by Ixodes spp. ticks with a great impact on both human health and animal production worldwide [1,2]
Anaplasma phagocytophilum is an obligate intracellular bacterium transmitted primarily by Ixodes spp. ticks with a great impact on both human health and animal production worldwide [1,2].A. phagocytophilum is a cocoid, gram negative bacterium that infects host immune cells, mainly neutrophils, and endothelial cells of vertebrate hosts
We focused on the effect of A. phagocytophilum infection on the inhibition of cell apoptosis, which appears to be a key adaptation mechanism to facilitate infection and survival of

Summary

Introduction

Anaplasma phagocytophilum is an obligate intracellular bacterium transmitted primarily by Ixodes spp. ticks with a great impact on both human health and animal production worldwide [1,2]. The nucleolar protein 3 (NOL3)—an apoptosis repressor with a caspase recruitment domain—is up-regulated in HL-60 infected cells, whereas anti-apoptotic factors Bcl-2 and Bcl-2-like proteins are down-regulated in infected cells [38], suggesting that control mechanisms of cell growth induced by A. phagocytophilum infection are quite complex and operate at different levels depending on the host cell type [15] (Figure 1). Gene expression profile analysis in naturally-infected pigs did not show an effect on caspases 3 and 8 and the PI3K/AKT pathway, which have been linked to A. phagocytophilum-induced apoptosis inhibition in human neutrophils [34,35,46]. Reactive oxygen species (ROS)-mediated damage to midgut epithelial cells results in activation of the JAK/STAT pathway, which in turn inhibits apoptosis that facilitates infection of tick salivary glands [24,52]. Midguts and salivary glands in response to A. phagocytophilum infection [24] (Figure 3)

Effect

Conclusions