Structural Investigation of Bacterial Pathogenesis and Host Immune Response

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2023

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Abstract

Bacterial infection is a persistent threat to public health and agriculture. In nature, pathogenic bacteria utilize various mechanisms to invade the host and cause a variety of diseases in human, animals, and plants. Ongoing research is focused on revealing how several essential proteins manipulate the host immunity to cause disease. It’s necessary to understand the host-bacterial interactions as it is also a potential strategic hotspot for developing the novel therapeutic interventions against infectious diseases (Rana et al., 2015).

Many animal and plant pathogenic bacteria utilize the type III secretion system to deliver effector proteins into host cells, modulate host cellular functions, and cause infectious diseases (Bogdanove et al., 1996; Ruano-Gallego et al., 2021). The AvrE/DspE-family effectors are one of the widely conserved Type III effector proteins, which play a central role in the pathogenesis of diverse pytopathogenic bacteria (Degrave et al., 2015).

In the past three decades, the study of the function of type III secreted effector proteins has been hampered by the lack of structural information. By means of cryo-electron microscopy, we report the structure and function of DspE from Erwinia Amylovora, a representative of the AvrE/DspE-family type III effectors. Our structural information complemented the AlphaFold predictions, and our in vitro activity assays indicate that the EaDspE protein could function as a channel, mediating the interplay between the bacteria and the host. This offers an alternative mechanism of action for the AvrE/DspE-family effectors in the development of the plant disease. Furthermore, we propose the AvrE/DspE-family effectors might act as a novel class of pathogenic channels creating osmotic/water potential perturbation during bacterial infection.

Due to the lack of mobile defender cells and an adaptive immune system, plants have relied exclusively on the innate immunity of individual cells and on systemic signals emanating from the infection sites (Dodds & Rathjen, 2010). NPR1 (NONEXPRESSOR OF PATHOGENESIS-RELATED GENES 1) is a master immune regulator in plants. It orchestrates systemic acquired resistance (SAR) by activating PATHOGENESIS-RELATED(PR) genes in response to induction of salicylic acid (SA) during the plant response to pathogenic challenges. In contrast, NPR3 and NPR4, paralogs of NPR1, have been reported to serve as negative regulators of the SAR in Arabidopsis (Ding et al., 2018). Despite the important role of NPR proteins, the understanding of their regulatory mechanism is hindered by a lack of structural information. Here, we performed the X-crystallographic structural analysis of AtNPR1, AtNPR3 and its complex with the transcription factor TGA3. The disclosed high-resolution structures surprisingly uncover an unexpected palmitic acid at the interface of dimeric TGA3 NID. This new discovery of a lipid substrate of TGA3 opens a new venue of research in the role of lipid substrate in plant immunity.

In summary, we demonstrate successful structural characterization and functional studies of proteins essential in bacterial-host interactions and plant immunity. These studies have significant implications in understanding the fundamentals in pathogen-host interactions and in developing therapeutics to treat diseases both in plants and human.

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Cheng, Jie (2023). Structural Investigation of Bacterial Pathogenesis and Host Immune Response. Dissertation, Duke University. Retrieved from https://hdl.handle.net/10161/29128.

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