Bulk and single-cell transcriptome profiling revealed dynamic immune response of Granulomatous Amebic Encephalitis caused by Balamuthia mandrillaris, a cohort study

Jingjia Zhang^1*Xinmiao Jia¹Bin Yang²Ying Ge¹Wei Jiang¹Yang Cong¹Huanwen Wu¹Liu Huifang¹Jingjing Tian¹Ying-Chun Xu¹Qiwen Yang^1*

• ¹Peking Union Medical College Hospital (CAMS), Beijing, China
• ²Vision Medicals Center for Infection Diseases, Guangzhou, China

Balamuthia mandrillaris infection in humans is rare and usually has a fatal outcome. It has become clear that B. mandrillaris can cause Granulomatous Amebic Encephalitis (GAE) in humans. But little is known about the factors that determine B. mandrillaris pathogenicity and its host-specific factors. In this study, we carried out a cohort study comprising five patients with B. mandrillaris GAE, and analyzed immune pathway alterations, differentially expressed genes (DEGs), and immune cell composition changes to delineate the immune response in this rare infectious disease by bulk transcriptome. Notably, we conducted bulk and single-cell transcriptome sequencing on paired CSF and blood samples from a single patient across three distinct infection stages. The bulk transcriptome of 7 CSF specimens revealed that as the infection progressed, a total of 5,177 DEGs were identified in the CSF after infection. The most enriched pathway among the upregulated DEGs was the "PI3K-Akt signaling pathway". Moreover, its upstream pathways, namely the "Toll-like receptor (TLR) signaling pathway" and "JAK/STAT signaling pathway" were also upregulated. Among these, TLR2, TLR9, and IFN-I/III related genes played a crucial role in activating these pathways. The results of single-cell transcriptome served to validate the above findings. Overall, we sought to elucidate the pathogenic mechanisms underlying B. mandrillaris GAE, thereby providing novel insights into the disease-associated immune responses.