Conserved natural IgM antibodies mediate innate and adaptive immunity against the opportunistic fungus <i>Pneumocystis murina</i>

Rapaka, Rekha R.; Ricks, David M.; Alcorn, John F.; Chen, Kong; Khader, Shabaana A.; Zheng, Mingquan; Plevy, Scott E.; Bengtén, Eva; Kolls, Jay K.

doi:10.1084/jem.20100034

Cited by 106 publications

(111 citation statements)

References 76 publications

(92 reference statements)

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“…In addition to the role of class-switched anti-Pneumocystis antibodies in protection, recent studies have explored the role of natural immunoglobulin in control of Pneumocystis infection (251). Natural antibodies, predominantly IgM, are produce by the B-1 subset of B cells and are generated without exogenous antigenic stimulation; thus, they are thought to contribute to an early defense system against a wide range of common pathogens.…”

Section: B Cellsmentioning

confidence: 99%

“…The specific role of natural IgM antibodies that recognize common fungal cell wall carbohydrate antigens was recently examined in murine models of Pneumocystis infection (251). Rapaka and colleagues showed that these antibodies are conserved across many species and contribute to early host defense against Pneumocystis infection (251). Natural IgM antibodies influence recognition of fungal antigens by dendritic cells (DC), enhancing DC maturation and migration to the draining lymph nodes.…”

Section: B Cellsmentioning

confidence: 99%

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Colonization by Pneumocystis jirovecii and Its Role in Disease

2012

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SUMMARY Although the incidence of Pneumocystis pneumonia (PCP) has decreased since the introduction of combination antiretroviral therapy, it remains an important cause of disease in both HIV-infected and non-HIV-infected immunosuppressed populations. The epidemiology of PCP has shifted over the course of the HIV epidemic both from changes in HIV and PCP treatment and prevention and from changes in critical care medicine. Although less common in non-HIV-infected immunosuppressed patients, PCP is now more frequently seen due to the increasing numbers of organ transplants and development of novel immunotherapies. New diagnostic and treatment modalities are under investigation. The immune response is critical in preventing this disease but also results in lung damage, and future work may offer potential areas for vaccine development or immunomodulatory therapy. Colonization with Pneumocystis is an area of increasing clinical and research interest and may be important in development of lung diseases such as chronic obstructive pulmonary disease. In this review, we discuss current clinical and research topics in the study of Pneumocystis and highlight areas for future research.

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Section: B Cellsmentioning

confidence: 99%

Section: B Cellsmentioning

confidence: 99%

Colonization by Pneumocystis jirovecii and Its Role in Disease

2012

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“…Antibody-mediated immunity to fungal pathogens has been extensively reported in the literature (107). For example, natural fungal polysaccharide-targeting IgM antibodies enhance DC-mediated recognition of fungal antigen, the development of Th2 and Th17 responses, and B cell isotype class-switch recombination during murine pneumocystosis (108). In a model of X-linked agammaglobulinemia, pulmonary and CNS cryptococcal disease progressed rapidly, in part due to IgM-dependent defects in macrophage phagocytosis (109).…”

Section: Il-17mentioning

confidence: 99%

Immunity against fungi

Lionakis¹,

Iliev²,

Hohl³

2017

JCI Insight

106

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“…These included classic biochemical methods for determination of this moiety in the organism via GlcNAc-binding/-labeling experiments using antibody staining techniques, as well as incorporation of 3 H-glucosamine into the P. carinii (Pc) cell walls, supportive of GlcNAc deposition (12)(13)(14). 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).…”

mentioning

confidence: 99%

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

Kottom

Hebrink

Jenson

et al. 2017

Am J Respir Cell Mol Biol

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N-acetylglucosamine (GlcNAc) serves as an essential structural sugar on the cell surface of organisms. For example, GlcNAc is a major component of bacterial peptidoglycan, it is an important building block of fungal cell walls, including a major constituent of chitin and mannoproteins, and it is also required for extracellular matrix generation by animal cells. Herein, we provide evidence for a uridine diphospho (UDP)-GlcNAc pathway in Pneumocystis species. Using an in silico search of the Pneumocystis jirovecii and P. murina (Pm) genomic databases, we determined the presence of at least four proteins implicated in the Saccharomyces cerevisiae UDP-GlcNAc biosynthetic pathway. These genes, termed GFA1, GNA1, AGM1, and UDP-GlcNAc pyrophosphorylase (UAP1), were either confirmed to be present in the Pneumocystis genomes by PCR, or, in the case of Pm uap1 (Pmuap1), functionally confirmed by direct enzymatic activity assay. Expression analysis using quantitative PCR of Pneumocystis pneumonia in mice demonstrated abundant expression of the Pm uap1 transcript. A GlcNAc-binding recombinant protein and a novel GlcNAc-binding immune detection method both verified the presence of GlcNAc in P. carinii (Pc) lysates. Studies of Pc cell wall fractions using highperformance gas chromatography/mass spectrometry documented the presence of GlcNAc glycosyl residues. Pc was shown to synthesize GlcNAc in vitro. The competitive UDP-GlcNAc substrate synthetic inhibitor, nikkomycin Z, suppressed incorporation of GlcNAc by Pc preparations. Finally, treatment of rats with Pneumocystis pneumonia using nikkomycin Z significantly reduced organism burdens. Taken together, these data support an important role for GlcNAc generation in the cell surface of Pneumocystis organisms.

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Conserved natural IgM antibodies mediate innate and adaptive immunity against the opportunistic fungus Pneumocystis murina

Abstract: Natural IgM antibodies in diverse species recognize conserved carbohydrates in fungal cell walls and influence early host defense against Pneumocystis in mice.

Cited by 106 publications

References 76 publications

Colonization by Pneumocystis jirovecii and Its Role in Disease

Colonization by Pneumocystis jirovecii and Its Role in Disease

Immunity against fungi

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

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