Role of the adherence-promoting receptors, CR3, LFA-1, and p150,95, in binding of Histoplasma capsulatum by human macrophages.

Abstract

Histoplasma capsulatum is a dimorphic fungal zoopathogen of worldwide distribution that produces a broad spectrum of disease activity . In most cases the portal of entry is the lung, where inhaled spores and mycelial fragments of the fungus lodge within the terminal bronchioles and alveoli. Here, transition from the mycelial phase to the yeast phase ensues, presumably over a period of hours to days. The mycelial to yeast phase conversion is critical since it is the yeast form of H. capsulatum (Hc)' that is responsible for the pathogenesis of histoplasmosis in nearly all of its clinical manifestations (1) .The earliest pulmonary lesions induced by He yeasts in man and experimental animals are patches of pneumonitis consisting largely of parasitized macrophages (MO) (2-4) . He yeasts are thought to be phagocytized by resident pulmonary Mo within which they multiply with a generation time of -9-11 h (5) . Host Mep appear to be destroyed by the multiplying yeast forms that in turn, are phagocytosed by other Mo attracted to the infected site . The multiplication cycle is repeated within these cells and He yeasts are disseminated from the lung to other organs by the lympho-hematogenous route. In most cases, the primary lesions in lung and those at peripheral sites begin to resolve after development of measurable delayed-type hypersensitivity to antigens of He at 10-20 d after inoculation.During an early phase of infection, MO bind to and phagocytose He yeasts, thereby providing a highly permissive intracellular environment for multiplication of the organism. Later, however, after the activation of cell-mediated immune defenses, He yeasts that are bound and ingested by Mo appear to be inhibited or killed . To better understand the crucial process of initial recognition and attachment of He yeasts by phagocytic cells, we have studied the receptorligand interactions between unopsonized He yeasts and human MO derived from peripheral blood monocytes (PBM) of nommmune donors .

Histoplasma capsulatumYeasts Are Phagocytosed Via Very Late Antigen-5, Killed, and Processed for Antigen Presentation by Human Dendritic Cells

“…A surprising finding was that binding of Hc yeasts to DC was mediated by the fibronectin receptor, VLA-5, rather than the CD18 receptors as was found for M (28,29). This difference in receptor usage between these cells may account for the ability of DC to inhibit the intracellular growth of Hc, whereas M are permissive for intracellular growth.…”

“…Human M bind and internalize Hc yeasts and conidia via the CD18 family of integrin receptors (28,29). As human DC also express high levels of CD18 receptors on their surface, we hypothesized that immature DC might phagocytose Hc yeasts through CD18 and subsequently kill and degrade the organism, process Hc-specific Ags, and stimulate lymphocyte proliferation.…”

Phagocytosis of Histoplasma capsulatum yeasts and microconidia by human cultured macrophages and alveolar macrophages. Cellular cytoskeleton requirement for attachment and ingestion.

“…As was found for cultured Mo (14), AM also bind Hc yeasts via the CD1 8 receptor complex. Thus, MAbs specific for the a-chains of each member of the CD18 family all partially blocked the binding of Hc yeasts to AM, and maximum inhibition was obtained with a MAb specific for the A-chain.…”

“…As proposed previously (14), Hc might bind independently to each of the a-chains of the CD1 8 family, or the binding site for Hc might be located on the common p-chain. In our original experiments (14), OKM …”

Protective and Memory Immunity toHistoplasma capsulatumin the Absence of IL-10

“…The failure to observe a difference in fungal burden between wild-type and IL-10 Ϫ/Ϫ mice implies that the putative modulatory effect of IL-10 on effector molecules from phagocytes was not crucial to early elimination of Hc. One explanation for this result is that Hc yeast thrive intracellularly despite robust generation of toxic oxygen radicals by phagocytes (33). NO also is important in host control of Hc, especially within the first 7 days of infection (2).…”