Browsing by Author "Ma, Liang"

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    Diversity and Complexity of the Large Surface Protein Family in the Compacted Genomes of Multiple Pneumocystis Species
    (American Society for Microbiology, 2020-03-03) Ma, Liang; Chen, Zehua; Huang, Da Wei; Cissé, Ousmane H.; Rothenburger, Jamie L.; Latinne, Alice; Bishop, Lisa; Blair, Robert; Brenchley, Jason M.; Chabé, Magali; Deng, Xilong; Hirsch, Vanessa; Keesler, Rebekah; Kutty, Geetha; Liu, Yueqin; Margolis, Daniel; Morand, Serge; Pahar, Bapi; Peng, Li; Van Rompay, Koen K.A.; Song, Xiaohong; Song, Jun; Sukura, Antti; Thapar, Sabrina; Wang, Honghui; Weissenbacher-Lang, Christiane; Xu, Jie; Lee, Chao-Hung; Jardine, Claire; Lempicki, Richard A.; Cushion, Melanie T.; Cuomo, Christina A.; Kovacs, Joseph A.; Pathology and Laboratory Medicine, School of Medicine
    Pneumocystis, a major opportunistic pathogen in patients with a broad range of immunodeficiencies, contains abundant surface proteins encoded by a multicopy gene family, termed the major surface glycoprotein (Msg) gene superfamily. This superfamily has been identified in all Pneumocystis species characterized to date, highlighting its important role in Pneumocystis biology. In this report, through a comprehensive and in-depth characterization of 459 msg genes from 7 Pneumocystis species, we demonstrate, for the first time, the phylogeny and evolution of conserved domains in Msg proteins and provide a detailed description of the classification, unique characteristics, and phylogenetic relatedness of five Msg families. We further describe, for the first time, the relative expression levels of individual msg families in two rodent Pneumocystis species, the substantial variability of the msg repertoires in P. carinii from laboratory and wild rats, and the distinct features of the expression site for the classic msg genes in Pneumocystis from 8 mammalian host species. Our analysis suggests multiple functions for this superfamily rather than just conferring antigenic variation to allow immune evasion as previously believed. This study provides a rich source of information that lays the foundation for the continued experimental exploration of the functions of the Msg superfamily in Pneumocystis biology.
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    Rational design of structure-based vaccines targeting misfolded alpha-synuclein conformers of Parkinson's disease and related disorders
    (Wiley, 2024-04-09) Flores-Fernandez, Jose Miguel; Pesch, Verena; Sriraman, Aishwarya; Chimal-Juarez, Enrique; Amidian, Sara; Wang, Xiongyao; Duckering, Caleb; Fang, Andrew; Reithofer, Sara; Ma, Liang; Cortez, Leonardo M.; Sim, Valerie L.; Tamgüney, Gültekin; Wille, Holger; Neurology, School of Medicine
    Synucleinopathies, including Parkinson's disease (PD), multiple system atrophy (MSA), and dementia with Lewy bodies (DLB), are neurodegenerative disorders caused by the accumulation of misfolded alpha-synuclein protein. Developing effective vaccines against synucleinopathies is challenging due to the difficulty of stimulating an immune-specific response against alpha-synuclein without causing harmful autoimmune reactions, selectively targeting only pathological forms of alpha-synuclein. Previous attempts using linear peptides and epitopes without control of the antigen structure failed in clinical trials. The immune system was unable to distinguish between native alpha-synuclein and its amyloid form. The prion domain of the fungal HET-s protein was selected as a scaffold to introduce select epitopes from the surface of alpha-synuclein fibrils. Four vaccine candidates were generated by introducing specific amino acid substitutions onto the surface of the scaffold protein. The approach successfully mimicked the stacking of the parallel in-register beta-sheet structure seen in alpha-synuclein fibrils. All vaccine candidates induced substantial levels of IgG antibodies that recognized pathological alpha-synuclein fibrils derived from a synucleinopathy mouse model. Furthermore, the antisera recognized pathological alpha-synuclein aggregates in brain lysates from patients who died from DLB, MSA, or PD, but did not recognize linear alpha-synuclein peptides. Our approach, based on the rational design of vaccines using the structure of alpha-synuclein amyloid fibrils and strict control over the exposed antigen structure used for immunization, as well as the ability to mimic aggregated alpha-synuclein, provides a promising avenue toward developing effective vaccines against alpha-synuclein fibrils.