Genome analysis of three Pneumocystis species reveals adaptation mechanisms to life exclusively in mammalian hosts

Abstract

Pneumocystis jirovecii is a major cause of life-threatening pneumonia in immunosuppressed patients including transplant recipients and those with HIV/AIDS, yet surprisingly little is known about the biology of this fungal pathogen. Here we report near complete genome assemblies for three Pneumocystis species that infect humans, rats and mice. Pneumocystis genomes are highly compact relative to other fungi, with substantial reductions of ribosomal RNA genes, transporters, transcription factors and many metabolic pathways, but contain expansions of surface proteins, especially a unique and complex surface glycoprotein superfamily, as well as proteases and RNA processing proteins. Unexpectedly, the key fungal cell wall components chitin and outer chain N-mannans are absent, based on genome content and experimental validation. Our findings suggest that Pneumocystis has developed unique mechanisms of adaptation to life exclusively in mammalian hosts, including dependence on the lungs for gas and nutrients and highly efficient strategies to escape both host innate and acquired immune defenses.

Characterization of N-Acetylglucosamine Biosynthesis in Pneumocystis species. A New Potential Target for Therapy

“…More recently, an intriguing study by Rapaka and colleagues (15) suggested that mice infected with P. murina (Pm) could generate increased levels of IgM antibodies against fungal carbohydrates, including GlcNAc-containing carbohydrates. Recently, however, it has been shown that, although Pneumocystis species contain chitin chaperone proteins implicated in proper transportation of major chitin synthases to the cell membrane in yeast, the genomes of Pneumocystis species lack major chitin synthase or chitin-degrading chitinase enzymes (5). In this light, we initiated a comprehensive analysis of the various enzymes potentially leading to the synthesis of GlcNAc in Pneumocystis organisms.…”

“…The cell surface of the pathogenic fungal species represented by Pneumocystis organisms have not been fully elucidated, but are known to contain b-1,3 and b-1,6 glucans, and the major surface mannoserich glycoproteins, variously termed major surface glycoprotein (MSG) or glycoprotein A (gpA) (3)(4)(5). We and others have shown that the Pneumocystis species contain b-glucan synthetases that can be inhibited by specific b-glucan inhibitors, such as the echinocandins, pneumocandins, and newly generated compounds (3,4,6,7).…”

The Life Cycle Stages of Pneumocystis murina Have Opposing Effects on the Immune Response to This Opportunistic Fungal Pathogen

“…Both stages express surface glycoproteins and mannoproteins, which may serve as pathogen-associated molecular patterns (PAMPs) that could interact with receptors on phagocytic cells (17)(18)(19). Neither life form expresses chitin or ␣-glucans (20).…”

Kinetics of Genetic Variation of the Mycoplasma genitalium MG192 Gene in Experimentally Infected Chimpanzees

“…A total of 14 and 16 MG192 variants, with 1 to 8 variants per time point, were identified from each of the two animals. It is likely that the MG192 variants detected may not represent all variants in each isolate studied and that additional variants could be detected if a larger number of plasmid clones were stud- ied or using the newly developed high-throughput long-read PacBio SMRT sequencing technology (19), though currently this technology is not widely available or affordable (20,24). Using average numbers of nucleotide and predicted amino acid changes at each time point, we observed a significant increase of sequence changes over time during an 11-to 13-week period of infection in both animals ( Table 1).…”