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Chapter 25 : Pathogenesis of Pneumocystis
Category: Fungi and Fungal Pathogenesis
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Pneumocystis can be detected in small numbers in hosts with intact immune systems, although the precise kinetics of this host-pathogen relationship are only now being systematically studied. Recent studies have detected Pneumocystis DNA in neonatal human and rat populations, but an assessment of potential reservoirs in the general population is only in its infancy. The sheer number of Pneumocystis-seropositive immunocompetent individuals argues against the fulminant Pneumocystis pneumonia (PCP)-infected host as the primary source of infection, since these patients are rare (in relation to the general public) and are often hospitalized or have limited access to the general population. Studies now being conducted with human populations, both immunosuppressed and non-immunsuppressed, point to certain reservoirs of infection in the general population, including patients with underlying disease states besides human immunodeficiency virus infection (HIV) or overt immunosuppression, neonates, and possibly pregnant women. This is an active and concerted area of research, and basic epidemiological principles for Pneumocystis infection should emerge within the next few years. Immunoblotting studies identified the major immunoglobulin G-reactive antigens of Pneumocystis from humans and animal models to be present at two regions with distinct molecular masses. Pneumocystis life cycle stages form tightly bound aggregates within the lung alveoli, presumably mediated by major surface glycoproteins (MSGs)-MSG interactions. A lack of clonal populations and of the ability to manipulate the genetics of Pneumocystis has prevented the demonstration of specific virulence factors.
Key Concept Ranking
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Morphological forms of Pneumocystis. Transmission electron micrographs of developmental forms of P. carinii are shown. (A) Trophic forms (T) in the alveolar lumen; most of these are attached to type I pneumocytes (arrow). The large cell at the top of the photograph is a macrophage (not fully shown). (B) A cyst/ascus (C) containing three ascospores (S). The single arrow indicates the double membrane and expanded periplasmic space; the double arrows indicate an area of increased periplasmic space often seen in this stage. A large trophic form is visible at the bottom right. (C) A cluster of trophic forms (T) adhered to one another and anchored by attachment to the type I pneumocytes extend into the alveolar lumen. The trophic form (T*) may be undergoing binary fission. Magnification, ×10,000. Courtesy of M. T. C and Susan G. Langreth, Uniformed Services University of the Health Sciences, Bethesda, Md.
Proposed life cycle of Pneumocystis in the alveolar lumen (pictured in left panel as a rectangle). (A) Asexual binary fission. A trophic form replicates its nuclear content, separates by binary fission, and produces two genetically identical progeny. (B) Sexual replication. The two proposed mating types of P. carinii are represented by the light gray and dark gray cytoplasms. The two mating types fuse and undergo karyogamy to produce a diploid zygote or “pre-cyst.” Meiosis proceeds with a reduction division followed by a mitotic replication, resulting in four nuclei. An additional mitotic replication of the haploid nuclei results in eight nuclei, which are then sequestered into eight individual spores or daughter forms. It is assumed that the spores are released from the mature cyst (ascus) and become new vegetative trophic forms. Figure created with SmartDraw v.7.0.
Proposed mechanism of MSG expression. Genes encoding MSG are arranged in arrays in a subtelomeric location on the ends of each chromosome. The arrays also contain genes encoding the MSG-related protein (MSR) and protease (PRT). One MSG gene present at an expression site (UCS locus) on chromosome 9 is actively transcribed. MSG gene translocation to the expression site may involve sequence-specific recombination, homologous crossover, or gene conversion. All transcribed MSG mRNAs contain the UCS sequence and result in the production of a preproprotein, which is postulated to be processed through the endoplasmic reticulum (ER). Cleavage of a signal peptide would result in a proprotein which undergoes posttranslational modification including attachment of a glycosyl phosphatidylinositol (GPI) anchor. PRT1 proteases may be involved in the cleavage of the UCS sequence from the proMSG protein to result in the surface expression of the mature MSG protein. (Adapted from reference 98 .)
Taxonomic hierarchy of Pneumocystisa
Underlying conditions leading to development of PCP