Abstract
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.IMPORTANCEPneumocystis continues to be a major cause of disease in humans with immunodeficiency, especially those with HIV/AIDS and organ transplants, and is being seen with increasing frequency worldwide in patients treated with immunodepleting monoclonal antibodies. Annual health care associated with Pneumocystis pneumonia costs ∼$475 million dollars in the United States alone. In addition to causing overt disease in immunodeficient individuals, Pneumocystis can cause subclinical infection or colonization in healthy individuals, which may play an important role in species preservation and disease transmission. Our work sheds new light on the diversity and complexity of the msg superfamily and strongly suggests that the versatility of this superfamily reflects multiple functions, including antigenic variation to allow immune evasion and optimal adaptation to host environmental conditions to promote efficient infection and transmission. These findings are essential to consider in developing new diagnostic and therapeutic strategies.
Highlights
This is a work of the U.S Government and is not subject to copyright protection in the United States
Sources of Pneumocystis msg sequences. msg sequences for P. murina, P. carinii, and P. jirovecii were obtained primarily from our previous msg and genome sequencing studies [1, 15, 16]. The accuracy of these sequences was maximized by integrating Illumina high-throughput sequencing of genomic DNA, PacBio long-read sequencing of msg repertoire amplicons, and Sanger sequencing of cloned msg genes
We mbio.asm.org present an in-depth analysis of the msg domain structure and the characteristics of each individual msg family or subfamily, including new msg genes identified from P. oryctolagi, Pneumocystis sp. “macacae,” Pneumocystis sp. “canis,” P. wakefieldiae, and P. carinii infecting wild rats
Summary
This is a work of the U.S Government and is not subject to copyright protection in the United States. Our work sheds new light on the diversity and complexity of the msg superfamily and strongly suggests that the versatility of this superfamily reflects multiple functions, including antigenic variation to allow immune evasion and optimal adaptation to host environmental conditions to promote efficient infection and transmission. These findings are essential to consider in developing new diagnostic and therapeutic strategies. Pneumocystis continues to be a major cause of disease in humans with immunodeficiencies, especially those with HIV/AIDS and organ transplants, and is being seen with increasing frequency in patients treated with immunodepleting monoclonal antibodies. While there is no apparent variation in the msg repertoire among laboratory-bred P. murina or P. carinii isolates, extensive variation is present among P. jirovecii isolates [14]
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