Long-lasting, specific immunologic unresponsiveness associated with cryptococcal meningitis.

Henderson, David K.; Bennett, John E.; Huber, Marion

doi:10.1172/jci110555

Cited by 56 publications

(29 citation statements)

References 28 publications

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“…The signals responsible for downmodulating MCP-1 production during the later stages of infection remain to be determined. Down modulation of various elements of the immune response have been described previously in association with cryptococcal infection, including antibody responsiveness (16), lymphoproliferative responses (28), and macrophage activation (26). Interestingly, we found that MCP-1 production by PuM from older rats was diminished in comparison to the response of PuM from younger rats.…”

Section: Discussionsupporting

confidence: 69%

Phagocytic Activity and Monocyte Chemotactic Protein Expression by Pulmonary Macrophages in Persistent Pulmonary Cryptococcosis

He¹,

Casadevall

Lee

et al. 2003

Infect Immun

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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.

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Section: Discussionsupporting

confidence: 69%

Phagocytic Activity and Monocyte Chemotactic Protein Expression by Pulmonary Macrophages in Persistent Pulmonary Cryptococcosis

He¹,

Casadevall

Lee

et al. 2003

Infect Immun

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“…Another study reported a high percentage of individuals with pre-existing anti-CPS antibodies. However, tolerance to immunization with cryptococcal polysaccharide was noted in patients that survive CM [21]. In the AIDS era, an ELISAbased sero-prevalence study [22] Method 2.…”

Section: Aids Immunoglobulin Isotypementioning

confidence: 99%

Antibodies to theCryptococcus neoformanscapsular glucuronoxylomannan are ubiquitous in serum from HIV+ and HIV− individuals

DeShaw

Pirofski

1995

Clinical and Experimental Immunology

103

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SUMMARYMurine MoAbs to the Cryptococcus neoformans capsular glucuronoxylomannan (GXM) polysaccharide are protective in mice in vivo and in vitro. The prevalence of protective anti-GXM antibodies in human serum is unknown. To provide further insight into the human antibody response to C. neoformans we determined the prevalence, isotype, and IgG subclass utilization of human anti-GXM antibodies in HIV+ and HIV-sera by a sensitive antigen capture ELISA assay. One hundred and twenty-three sera from the Bronx Municipal Hospital Centre serum bank were studied retrospectively. Seventy were from HIV+ individuals, 10 with a history of cryptococcal meningitis (CM), and 53 were from HIV-individuals. Serum GXM determinations were also performed on 61 HIV+ sera. Our results demonstrated that anti-GXM IgG, IgA, and IgM are ubiquitous in both HIV+ (including those with CM), and HIV-sera. Anti-GXM IgA titres and total serum IgA concentration were elevated in HIV+ sera. Anti-GXM IgG antibodies were almost exclusively isotype-restricted to the IgG2 subclass. Our data also demonstrated elevations of antibovine serum albumin (BSA) titres in HIV+ sera. Taken together, our findings confirm hypergammaglobulinaemia and expansion of anti-protein (BSA) antibodies in HIV+ individuals and isotype restriction of human anti-carbohydrate (GXM) antibodies to the IgG2 subclass. Our report of ubiquitous anti-GXM antibodies of the IgG and IgA isotypes suggests that anti-GXM antibodies exist before HIV infection.

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“…The organism is distributed worldwide, and most individuals have protective immunity and evidence of prior exposure (21,29). The incidence of cryptococcal meningitis has increased because of immunosuppression as a result of AIDS, cancer chemotherapy, steroid treatment, and organ transplantation.…”

mentioning

confidence: 99%

Cyclic AMP-Dependent Protein Kinase Controls Virulence of the Fungal Pathogen Cryptococcus neoformans

D’Souza¹,

Alspaugh²,

Yue³

et al. 2001

Molecular and Cellular Biology

315

392

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Cryptococcus neoformans is an opportunistic fungal pathogen that infects the human central nervous system. This pathogen elaborates two specialized virulence factors: the antioxidant melanin and an antiphagocytic immunosuppressive polysaccharide capsule. A signaling cascade controlling mating and virulence was identified. The PKA1 gene encoding the major cyclic AMP (cAMP)-dependent protein kinase catalytic subunit was identified and disrupted. pka1 mutant strains were sterile, failed to produce melanin or capsule, and were avirulent. The PKR1 gene encoding the protein kinase A (PKA) regulatory subunit was also identified and disrupted. pkr1 mutant strains overproduced capsule and were hypervirulent in animal models of cryptococcosis. pkr1 pka1 double mutant strains exhibited phenotypes similar to that of pka1 mutants, providing epistasis evidence that the Pka1 catalytic subunit functions downstream of the Pkr1 regulatory subunit. The PKA pathway was also shown to function downstream of the G␣ protein Gpa1 and to regulate cAMP production by feedback inhibition. These findings define a G␣ protein-cAMP-PKA signaling pathway regulating differentiation and virulence of a human fungal pathogen.

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Long-lasting, specific immunologic unresponsiveness associated with cryptococcal meningitis.

Cited by 56 publications

References 28 publications

Phagocytic Activity and Monocyte Chemotactic Protein Expression by Pulmonary Macrophages in Persistent Pulmonary Cryptococcosis

Phagocytic Activity and Monocyte Chemotactic Protein Expression by Pulmonary Macrophages in Persistent Pulmonary Cryptococcosis

Antibodies to theCryptococcus neoformanscapsular glucuronoxylomannan are ubiquitous in serum from HIV+ and HIV− individuals

Cyclic AMP-Dependent Protein Kinase Controls Virulence of the Fungal Pathogen Cryptococcus neoformans

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