Apoptosis and Autophagy: Current Understanding in Tick-Pathogen Interactions

Abstract

Tick-borne diseases are a significant threat to human and animal health throughout the world. How tick-borne pathogens successfully infect and disseminate in both their vertebrate and invertebrate hosts is only partially understood. Pathogens have evolved several mechanisms to combat host defense systems, and to avoid and modulate host immunity during infection, therefore benefitting their survival and replication. In the host, pathogens trigger responses from innate and adaptive immune systems that recognize and eliminate invaders. Two important innate defenses against pathogens are the programmed cell death pathways of apoptosis and autophagy. This Mini Review surveys the current knowledge of apoptosis and autophagy pathways in tick-pathogen interactions, as well as the strategies evolved by pathogens for their benefit. We then assess the limitations to studying both pathways and discuss their participation in the network of the tick immune system, before highlighting future perspectives in this field. The knowledge gained would significantly enhance our understanding of the defense responses in vector ticks that regulate pathogen infection and burden, and form the foundation for future research to identify novel approaches to the control of tick-borne diseases.

Keywords: Anaplasma; Ehrlichia; Rickettsia; apoptosis; autophagy; cross-talk; intracellular pathogens; tick.

Figure 1

Global distribution of major tick-borne diseases by continent. Map created in ArcGIS online (ESRI, California) using open-source layers from Natural Earth (naturalearthdata.com).

Figure 2

Overview of apoptosis and autophagy research on tick-borne obligate intracellular pathogens. (A) Manipulation of apoptosis. In the vertebrate host (left) the C-terminal fragment of the Anaplasma phagocytophilum effector Ats-1 localizes to the host mitochondria where it inhibits apoptosis. A large number of kinases and pro-/anti-apoptotic factors (shown in pale blue box) also show changes in expression during A. phagocytophilum infection. Rickettsia rickettsii infection leads to NF-κB activation, inhibiting cytochrome c release from mitochondria resulting in downstream inhibition of apoptosis. In the tick vector (right), A. phagocytophilum uses multiple pathways to inhibit apoptosis, including activation of the JAK/STAT pathway, down-regulation of mitogen-activated protein kinase (MKK) and apoptosis signal-regulating kinase 1 (ASK1), decreasing FAS expression, and reducing porin expression to inhibit cytochrome c release from the mitochondria. Rickettsia rickettsii prevents caspase 3 activation in order to inhibit apoptosis. Rickettsia parkeri infection is associated with increased mitochondrial cytochrome c release, leading to increased activation of apoptosis, which is essential to its infection of tick cells. (B) Manipulation of autophagy. Experimental evidence only exists from mammalian systems. The N-terminal portion of the A. phagocytophilum effector Ats-1 localizes to the endoplasmic reticulum (ER) where it interacts with Beclin1 to initiate autophagosome formation. Autophagosomes are prevented from trafficking to the lysosome and instead fuse with the bacterial vacuole to deliver membrane and nutrients to A. phagocytophilum. The Etf-1 effector secreted by Erhlichia chaffeensis interacts with Beclin1, Rab5 and the PI3K complex to induce autophagosome formation. The autophagosomes fuse with the Erhlichia-containing vacuole and are prevented from fusing with the lysosome by bacterial interference with the Wnt signalling pathway. During R. parkeri infection of macrophages, ompB shields the rickettsial surface protein ompA from polyubiquitination, preventing its recognition by the autophagy adaptors p62 and NDP52. (C) Challenges and future directions in the research of interactions of intracellular tick-borne pathogens with apoptosis and autophagy pathways.