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Current insights into the biology and pathogenesis of Pneumocystis pneumonia

Nature Reviews Microbiology volume 5, pages 298–308 (2007)Cite this article

Key Points

  • Pneumocystis pneumonia (PCP) remains the most prevalent opportunistic infection in patients with AIDS and is a significant cause of severe pneumonia in immunocompromised patients with cancer, organ transplant recipients or those receiving immunosuppressant medications.

  • Pneumocystis is an intractable fungal pathogen classified phylogenetically with the Ascomycetes. Pneumocystis has pathways involved in cell-cycle control, signal transduction and metabolism that are analogous to the pathways in these yeast.

  • Pneumocystis has a unique life cycle alternating between small trophic forms and cysts, which contain 2, 4 or 8 intracystic bodies. The airborne route of transmission is currently the favoured model for the spread of infection.

  • Pneumocystis interacts with the lung epithelium and immune cells of the lower respiratory tract, resulting in inflammation, which is hazardous to the host. This is a complex interaction involving surface antigens of the organism and host surfactant proteins, adhesion molecules, macrophages, neutrophils, lymphocytes, and cytokine and chemokine responses.

  • Drug targets for the treatment of PCP include metabolic pathways for dihydropteroate synthase (DHPS) and dihydrofolate reductase (DHFR), DNA and protein synthesis inhibition, sterol metabolism, cytochrome b complex and cell-wall construction through inhibition of the GSC1 glucan synthetase.

  • Mutations in DHPS, DHFR, and cytochrome b have raised the concern of emerging resistance to the medications currently in use. The efforts of the Pneumocystis research community have contributed substantially to the current understanding of the complex biology of Pneumocystis and the intricate association with the host. Continued research is essential to continue investigating the biology of this organism in the hope of developing novel treatment strategies for PCP.

Abstract

The fungal infection Pneumocystis pneumonia is the most prevalent opportunistic infection in patients with AIDS. Although the analysis of this opportunistic fungal pathogen has been hindered by the inability to isolate it in pure culture, the use of molecular techniques and genomic analysis have brought insights into its complex cell biology. Analysis of the intricate relationship between Pneumocystis and the host lung during infection has revealed that the attachment of Pneumocystis to the alveolar epithelium promotes the transition of the organism from the trophic to the cyst form. It also revealed that Pneumocystis infection elicits the production of inflammatory mediators, culminating in lung injury and impaired gas exchange. Here we discuss these and other recent findings relating to the biology and pathogenesis of this intractable fungus.

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Figure 1: Pneumocystis life cycle.
Figure 2: The Pneumocystis cell surface and cell-surface proteins.
Figure 3: Fungal mitogen-activated protein kinase (MAPK) pathways.
Figure 4: Interactions between Pneumocystis and alveolar macrophages.

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Acknowledgements

C.F.T. and A.H.L. have National Institutes of Health funding. We appreciate the many helpful discussions of P. K. Vohra, B. Sanyal, R. Vassallo, Z. Vuk-Pavlovic and T. J. Kottom. We apologize to our colleagues whose work we could not reference owing to space limitations.

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Authors and Affiliations

  1. Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Thoracic Diseases Research Unit, Rochester, 55905, Minnesota, USA

    Charles F. Thomas Jr

  2. Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, 55905, Minnesota, USA

    Andrew H. Limper

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  1. Charles F. Thomas Jr
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Correspondence to Charles F. Thomas Jr.

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Supplementary information

Supplementary information S1 (table)

Selected characterized Pneumocystis genes* (PDF 106 kb)

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DATABASES

Entrez Genome

HIV

Entrez Genome Project

Kluyveromyces lactis

Neurospora crassa

Pneumocystis carinii

Pneumocystis muris

Saccharomyces cerevisiae

Schizosaccharomyces pombe

FURTHER INFORMATION

Charles F. Thomas's homepage

Andrew H. Limper's homepage

Broad Institute status of Fungal Genome Initiative projects

Pneumocystis genome project

Wellcome Trust Sanger Institute Pneumocystis carinii telomeric clone sequencing project

Glossary

Surfactant

A surface-active lipoprotein produced by type II alveolar epithelial cells that results in a reduction of surface tension in the alveoli.

Donor consensus site

The recognition sequence at the 5′-end of the intron required for intron splicing.

Acceptor consensus site

The recognition sequence at the 3′-end of the intron required for intron splicing.

Branch-site sequence

An internal recognition sequence in an intron that is necessary for intron splicing.

Chitin

A long-chain polymeric polysaccharide that is a component of the fungal cell wall.

Degenerate PCR

A PCR technique to clone genes based on protein-domain homology. The PCR primer sequence is called degenerate if some of its positions (typically encoding the third codon) have several possible bases.

Cell-division cycle (Cdc) molecules

A conserved family of molecules in eukaryotes that include cyclins and cyclin-dependent kinases.

Cyclin

A cell-cycle protein that has a fluctuating (or cycling) concentration during growth. It interacts with a cyclin-dependent kinase to promote cell-cycle progression.

DNA damage checkpoint

A DNA damage checkpoint is an essential control point in the cell cycle ensuring effective damage repair. When cells have DNA damage that needs to be repaired, cells activate DNA damage checkpoints that arrest the cell cycle.

DNA replication checkpoint

When DNA replication is disrupted, cells activate DNA replication checkpoints that arrest the cell cycle at the G2/M transition until DNA replication is complete. The loss of checkpoint functions leads to loss of genomic integrity and allows accumulation of genetic damage in the daughter cells.

Ascus

The spore-containing structure of the fungi Ascomycota.

Opsonic protein

A protein that functions as a binding enhancer for a cell.

RAG−/−

(RAG−/− mice). A genetic strain of mice that lack the recombination activation gene and are severely immunodeficient owing to a lack of functional B cells and T cells.

Alveolar type I epithelial cell

The most distal portion of the lung, the alveoli, participate in gas exchange and metabolic functions. The alveolar structure includes long, flat, type I pneumocytes, which encompass approximately 95% of the surface area of the alveoli.

Alveolar type II epithelial cell

The alveolar structure also includes cuboidal type II pneumocytes. Type II pneumocytes secrete surfactant proteins and are believed to be regenerative cells involved in alveolar repair.

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Thomas, C., Limper, A. Current insights into the biology and pathogenesis of Pneumocystis pneumonia. Nat Rev Microbiol 5, 298–308 (2007). https://doi.org/10.1038/nrmicro1621

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