Characteristics of Histoplasma capsulatum and its antigens

The pathogenic fungus, Histoplasma capsulatum, exists in nature as a filamentous organism that produces two asexual spores, microconidia and tubercu-late macroconidia. The natural habitat of the organism is soil enriched by bird droppings. Chromosomal mapping studies of this fungus have revealed substantial variability in the genomic organization of H. capsulatum strains. The Downs strain, which is ther-mointolerant, possesses seven chromosomes, whereas two thermotolerant strains, G217B and G186B, contain three and four chromosomes, respectively. Thus, a small number of chromosomes regulate a considerable number of biological events.

Infection is acquired via inhalation of microconidia or small mycelial fragments that settle in terminal bronchioles and alveoli of lungs. Within a period of hours to days, these fungal elements convert into yeasts which represent the tissue-specific phase. The transformation of mycelia to yeasts is accompanied by an orderly sequence of biochemical events that can be divided into three stages. Initially, there is a reduction in the intracellular levels of adenosine triphosphate and a decrease in the respiratory rate of mycelia. In the second stage, the cells enter a dormant phase for 4-6 days. Subsequently, the rate of respiration returns to normal, and there is an induction of a yeast phase-specific cysteine oxidase. At this time, the morphological switch to yeasts is completed.

Phase transition is also associated with several alterations in gene expression. One to three hours after a temperature shift from 25 to 37°C, there is a marked increase in the expression of the genes encoding heat shock protein 70 and cdc2, which is a regulator of cell division. On the other hand, conversion of mycelia to yeasts produces a 2-3-fold reduction in expression of a-tubulin and (3-tubulin mRNAs. A yeast phase-specific gene, yps3, is expressed only by strains that arc thermotolerant and virulent. The avi-rulent Downs strain contains a 287 bp insertion that disrupts the open reading frame of yps3. A precise function for this gene and its protein product has not been defined. It is likely that it regulates, at least partially, the morphological conversion of H. capsulation.

Infection of humans with H. capsulatum is usually asymptomatic or it produces an influenze-like illness. A small percentage of individuals will develop a cavitary pulmonary disease or a disseminated infection that extensively involves the reticuloendothelial system. Although cases of histoplasmosis have been reported worldwide, the endemic areas are the Ohio and Mississippi river valleys in North America, and Central and South America. It is estimated that 200000-500 000 new infections occur annually. Disseminated histoplasmosis has become a prominent cause of morbidity and mortality in patients with acquired immune deficiency syndrome or in those receiving potent immunosuppressive agents.

The originally described H. capsulatum antigens consisted of the culture filtrate of aged mycelia, otherwise known as histoplasmin, and yeasts treated with formalin. Histoplasmin is currently the principal antigenic mixture that is employed for analysis of both humoral and cell-mediated immune responses in humans and experimental animals infected with H. capsulatum. This preparation contains two glycoprotein antigens, M and H, which elicit both cell-mediated and antibody responses and a carbohydrate moiety, termed C antigen, which is recognized by circulating antibody from infected humans. The gene encoding H antigen has been cloned, and the deduced amino acid sequence indicates that the protein is homologous to extracellular P-glucosidase. M antigen appears to be a member of the catalase family. The carbohydrate portions of M and H antigens and the C antigen are rich in man-nose and galactose. In vitro studies have shown that deglycosylation of M and H sharply reduces the capacity of these antigens to stimulate Histoplasma-reactive T cell clones. Antibody to C antigen can cross-react with antigens from heterologous fungi including Blastomyces dermatitidis and Coccidio-ides immitis.

Numerous other preparations of antigens have been isolated from disrupted mycelia and yeasts or from supernatants of actively growing organisms. Because much of this effort has been applied to improving serologic diagnosis of histoplasmosis, biochemical characterization of antigens has centered on identifying determinants that are recognized by circulating antibody. Polysaccharide determinants that contain galactomannan or glucomannan often react with sera from patients infected with H. capsulatum. More recently, several antigens that stimulate a cell-

mediated immune response have been identified. Heat shock protein 60, an 80 kDa protein with homology to heat shock protein 70, and yps3 stimulate proliferation of lymphocytes by H. capsulatum-exposed mice or humans.

The organism does not secrete any known virulence factors. However, the a-(l,3)-glucan content in the cell wall of yeasts appears to correlate directly with virulence. Thus, avirulent variants contain up to 1000-fold less a-glucan than virulent parental strains.

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