Periodic Reporting for period 1 - MsInfection (Mechanistic basis of host infection and intracellular development in microsporidia)
Période du rapport: 2021-11-01 au 2023-10-31
Microsporidia are spore-forming eukaryotic obligate intracellular parasites that infect hosts ranging from protists to humans, including economically important honeybees, silkworms, fish, and livestock. Given their widespread prevalence and acute zoonotic potential coupled with their threat to public health and global food chains, the US NIH has classified microsporidia as emerging pathogens of high priority. These parasites pose a particular risk to the elderly, children, and patients of organ transplants, HIV, and diabetes. However, no specific drugs or vaccines have been designed against microsporidia. This problem stems from the lack of mechanistic knowledge about the mechanisms by which these parasites infect their host cells and their methods of undermining host cell defensive strategies. Towards this, this project aimed to understand the unique host cell invasion organelle of microsporidia parasites and identify genes contributing to establishing infection. Collectively, insights from this project will help identify molecular mechanisms that drive infection and identification of drug targets.
Through this IF action, we contributed to the structural and molecular insights into microsporidia infection biology. Using the novel cryo-ET technology combined with proteomic and transcriptomic approaches, we visualized the ultrafast process of host cell invasion by microsporidia parasites and discovered proteins that assist infection. The application of cryo-ET to study polar tube germination is a major advancement in microsporidia infection biology as it provides the first instances of natively capturing the host cell invasion process. Further, the elastic remodeling of polar tubes establishes that both the polar tube and the cytoplasmic material undergo large-scale ultrastructure changes to invade the host cells. Additionally, we believe that these extensive remodeling events will also be of great interest to the protein biophysics community. Next, we also deliver the first reference transcriptome of the organism Vairimorpha necatrix along with identifying genes whose expression correlated with establishing infection. Results from this work have been discussed with experts at conferences and meetings through oral presentations and posters along with publications on preprint servers and peer-review at open-access compatible journals. All data generated in this action has been deposited to open-access servers like the EMDB, NCBI, and PRIDE.
We report the first cryo-electron tomography-based insights into the host cell invasion process. These results capture how the microsporidia infection apparatus manages to inject host cells with infectious material and initiate pathogenesis. We show novel structural and compositional insights into this process using microscopic and mass spectrometry. Further using transcriptomics, we also show the regulation of genes that may have a role in sustaining pathogenesis after the parasite has entered the host cell.