Biomedical subjects

David L Goldman

Publications and source records attributed to David L Goldman.

3 recordsLinked to original sources

PubMed2003

Phagocytic activity and monocyte chemotactic protein expression by pulmonary macrophages in persistent pulmonary cryptococcosis.

The mechanisms by which Cryptococcus neoformans persists in an immunocompetent host are not well understood. Using a rat model of persistent infection, we investigated the ability of pulmonary macrophages (PuM) to phagocytize C. neoformans and produce monocyte chemotactic protein 1 (MCP-1) as a function of the length of time of infection and opsonin. The ability of macrophages to affect serum-mediated phagocytosis varied over the course of infection and was dependent on CD11b/c and CD18 expression. Infection resulted in increased MCP-1 levels within the lung, though the actual amounts varied over the course of infection. Immunohistochemical studies localized MCP-1 expression to macrophages and epithelioid cells. Enhanced production of MCP-1 by PuM from infected rats was confirmed by ex vivo studies. Induction of MCP-1 following serum-mediated phagocytosis was observed for PuM from both infected and noninfected rats and depended on the interaction of C. neoformans with CD11b/c and CD18. Specific antibody was more efficient than serum in promoting phagocytosis and consistently elicited more MCP-1. The relative amount of MCP-1 produced in association with phagocytosis was similar for PuM at all lengths of time of infection. Decreased MCP-1 production was observed for PuM obtained from older rats, including long-term (8 to 10 months)-infected and age-matched controls, suggesting that aging may affect the production of MCP-1 by PuM in response to cryptococcal infection. In summary, our results show that macrophages are an important source of MCP-1 during pulmonary cryptococcosis and that MCP-1 production is actively regulated during infection. Furthermore, we find that phagocytosis of C. neoformans can serve as an important stimulus for MCP-1 production by PuM, though the efficiency of this process is dependent on the opsonin type and may be affected by aging.

Animals↗

PubMed2002

Phenotypic switching in Cryptococcus neoformans.

Cryptococcus neoformans strains exhibit considerable phenotype variability with regards to the capsular polysaccharide, sterol composition of the cell wall, and cell and colony morphology. Phenotypic changes can occur spontaneously during in vitro passage of strains or during chronic infection in vivo and may be associated with differences in virulence. Studies from our laboratory have demonstrated that phenotype variability can be the result of phenotypic switching. Phenotypic switching is defined as a reversible change of an observable colony phenotype that occurs at a frequency above the expected frequency for somatic mutations. This implies that phenotypic switching represents controlled and programmed changes in this pathogenic yeast rather than random mutations. We have shown that a phenotypic switch from a smooth colony phenotype to a mucoid colony phenotype occurs in vitro and in vivo during chronic infection of mice. More importantly we have now demonstrated that the switch is associated with an increase in virulence and a change in the host immune response. Implications of these findings for the pathogenesis of cryptococcosis are discussed.

Cryptococcosis↗

PubMed2002

Fcgamma receptor I- and III-mediated macrophage inflammatory protein 1alpha induction in primary human and murine microglia.

Microglial cell phagocytic receptors may play important roles in the pathogenesis and treatment of several neurological diseases. We studied microglial Fc receptor (FcR) activation with respect to the specific FcgammaR types involved and the downstream signaling events by using monoclonal antibody (MAb)-coated Cryptococcus neoformans immune complexes as the stimuli and macrophage inflammatory protein 1alpha (MIP-1alpha) production as the final outcome. C. neoformans complexed with murine immunoglobulin G (IgG) of gamma1, gamma2a, and gamma3, but not gamma2b isotype, was effective in inducing MIP-1alpha in human microglia. Since murine gamma2b binds to human FcgammaRII (but not FcgammaRI or FcgammaRIII), these results indicate that FcgammaRI and/or FcgammaRIII is involved in MIP-1alpha production. Consistent with this, an antibody that blocks FcgammaRII (IV.3) failed to inhibit MIP-1alpha production, while an antibody that blocks FcgammaRIII (3G8) did. An anti-C. neoformans MAb, 18B7 (IgG1), but not its F(ab')(2), induced extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase kinase phosphorylation, and MIP-1alpha release was suppressed by the ERK inhibitor U0126. C. neoformans plus 18B7 also induced degradation of I-kappaBalpha, and MIP-1alpha release was suppressed by the antioxidant NF-kappaB inhibitor pyrrolidine dithiocarbamate. To confirm the role of FcR more directly, we isolated microglia from wild-type and various FcR-deficient mice and then challenged them with C. neoformans plus 18B7. While FcgammaRII-deficient microglia showed little difference from the wild-type microglia, both FcgammaRI alpha-chain- and FcgammaRIII alpha-chain-deficient microglia produced less MIP-1alpha, and the common Fc gamma-chain-deficient microglia showed no MIP-1alpha release. Taken together, our results demonstrate a definitive role for FcgammaRI and FcgammaRIII in microglial chemokine induction and implicate ERK and NF-kappaB as the signaling components leading to MIP-1alpha expression. Our results delineate a new mechanism for microglial activation and may have implications for central nervous system inflammatory diseases.

Animals↗