Abstract
Understanding what influences the ability of some arthropods to harbor and transmit pathogens may be key for controlling the spread of vector-borne diseases. Arthropod immunity has a central role in dictating vector competence for pathogen acquisition and transmission. Microbial infection elicits immune responses and imparts stress on the host by causing physical damage and nutrient deprivation, which triggers evolutionarily conserved stress response pathways aimed at restoring cellular homeostasis. Recent studies increasingly recognize that eukaryotic stress responses and innate immunity are closely intertwined. Herein, we describe two well-characterized and evolutionarily conserved mechanisms, the Unfolded Protein Response (UPR) and the Integrated Stress Response (ISR), and examine evidence that these stress responses impact immune signaling. We then describe how multiple pathogens, including vector-borne microbes, interface with stress responses in mammals. Owing to the well-conserved nature of the UPR and ISR, we speculate that similar mechanisms may be occurring in arthropod vectors and ultimately impacting vector competence. We conclude this Perspective by positing that novel insights into vector competence will emerge when considering that stress-signaling pathways may be influencing the arthropod immune network.
Highlights
Among arthropods, the adaptation to blood-feeding is a life history trait that evolved independently at least 20 times [1]
Vector-borne pathogens selectively interface with the Unfolded Protein Response (UPR) and the Integrated Stress Response (ISR) to promote survival and infection in mammals
Given the well-conserved nature of both the UPR and the ISR between evolutionarily distant species (Table 1), it is reasonable to speculate that vectored microbes may be modulating the stress responses in their arthropod vectors
Summary
The adaptation to blood-feeding is a life history trait that evolved independently at least 20 times [1]. While inhibiting the translation of most mRNAs, eIF2a selectively induces the expression of some proteins including ATF4 (activating transcription factor 4). As previously discussed in reference to PERK signaling, ATF4 is activated downstream of eIF2a phosphorylation and can act as TABLE 1 | Distribution of Unfolded Protein Response (UPR) and Integrated Stress Response (ISR) genes across arthropod vectors. CHIKV activates BiP and the ATF6 and IRE1a branches of the UPR, but blocks PERK signaling by suppressing eIF2a phosphorylation through the nonstructural viral protein nsP4 [160, 161]. Epithelial cell infection with Shigella flexneri disrupts host cell membranes, causing GCN2-mediated eIF2a phosphorylation This halts global protein translation, leading to stress granule formation and autophagy that eliminates bacteria [170]. These studies illustrate that vectored pathogens evade ISR signaling to facilitate replication and survival
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