Professor Han Bing's group from the School of Basic Medical Sciences / Biomedical Sciences (BMS) of Shandong University has published new research in PNAS (SCI Q1, Impact Factor: 10.8), detailing how Encephalitozoon microsporidia regulate their host to enhance their survival. The paper, titled "Microsporidian EnP1 alters host cell H2B monoubiquitination and prevents ferroptosis facilitating microsporidia survival", explains the molecular interactions caused by the pathogen's effector protein EnP1, which targets the host cell nucleus to promote pathogen proliferation. PhD candidate Guan Jingyu is the first author. Professor Han Bing, Assistant Researcher Qu Hongnan, Professor Zhou Huaiyu from Shandong University, and Professor Louis Weiss from Albert Einstein College of Medicine are the corresponding authors of the paper. Shandong University is the first unit of completion.

Microsporidia are obligate intracellular eukaryotic pathogens comprising over 1,700 identified species that are prevalent across various natural environments. These pathogens are capable of infecting nearly all animal hosts, leading to microsporidiosis — a significant zoonotic disease. Historically considered a major threat primarily to immunocompromised individuals, microsporidia were known as common lethal pathogens in AIDS patients. Recent research, however, indicates that microsporidia can also infect healthy individuals, causing serious health issues such as encephalitis, meningitis, microsporidial keratoconjunctivitis (MKC), and potentially contributing to aseptic periprosthetic osteolysis, which can cause implant loosening. These findings underline the critical need to recognize microsporidia as a significant, yet underappreciated, pathogen. Infection typically begins when microsporidia inject sporoplasm into host cells through polar tube extrusion, resulting in rapid sporoplasm proliferation and disease progression. Given the current gaps in our understanding of microsporidial pathogenic mechanisms and the lack of effective prevention strategies, in-depth studies of microsporidia-host interactions are essential to better control microsporidiosis.

EnP1, initially recognized as a spore wall protein in microsporidia, plays a crucial role in spore adhesion to host cells. This study employed biotin labelling techniques to identify effector proteins secreted into the host cell nucleus during microsporidian infection and discovered that EnP1 targets the host cell nucleus. The entry of EnP1 into the nucleus was confirmed using highly specific antibodies. Further investigations revealed that EnP1 interacts with host histone H2B and inhibits its monoubiquitination. By modulating epigenetic regulation, EnP1 decreases the expression of downstream p53, reducing its inhibitory impact on the ferroptosis-regulating factor SLC7A11, thus enhancing host cell resistance to ferroptosis and benefiting microsporidia survival. This research elucidates the molecular mechanisms by which Encephalitozoon microsporidia epigenetically regulate their hosts through the effector protein EnP1, offering potential targets for microsporidiosis treatment.

Professor Han Bing's group has long been dedicated to studying the pathogenic mechanisms and control strategies of zoonotic parasitic diseases, such as microsporidiosis and toxoplasmosis. Their previous work includes elucidating the molecular dynamics of microsporidia's polar tube infection process and interactions between microsporidia sporoplasm and host mitochondria. Their findings have been published in journals like PNAS, PLoS Pathogens, mBio, Clinical Microbiology Reviews, and Parasites & Vectors. This study was supported by the National Natural Science Foundation of China and the Qilu Young Scholars Program at Shandong University.

Link: https://www.pnas.org/doi/10.1073/pnas.2400657121