Leukocyte candidacidal activity and resistance to systemic candidiasis in patients with cancer

Lehrer, Robert I.; Cline, Martin J.

doi:10.1002/1097-0142(197105)27:5<1211::aid-cncr2820270528>3.0.co;2-3

Cited by 85 publications

(34 citation statements)

References 38 publications

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“…Mouse Strains and Procedures-Host neutrophil function is the most important determinant in the outcome of human systemic infections (20), and so the virulence of C. albicans was measured in DBA/2N mice, which are deficient in complement component 5 and impaired in their ability to recruit neutrophils to foci of fungal growth (21). The DBA/2N mouse model therefore highlights damage due to direct effects of the fungus while minimizing the contribution from host inflammatory cells.…”

Section: Albicans Strains and Growthmentioning

confidence: 99%

Inactivation of Kex2p Diminishes the Virulence of Candida albicans

Newport¹,

Kuo²,

Flattery³

et al. 2003

Journal of Biological Chemistry

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Deletion of the kexin gene (KEX2) in Candida albicanshas a pleiotropic effect on phenotype and virulence due partly to a defect in the expression of two major virulence factors: the secretion of active aspartyl proteinases and the formation of hyphae. kex2/kex2 mutants are highly attenuated in a mouse systemic infection model and persist within cultured macrophages for at least 24 h without causing damage. Pathology is modest, with little disruption of kidney matrix. The infecting mutant cells are largely confined to glomeruli, and are aberrant in morphology. The complex phenotype of the deletion mutants reflects a role for kexin in a wide range of cellular processes. Taking advantage of the specificity of Kex2p cleavage, an algorithm we developed to scan the 9168 open reading frames in Assembly 6 of the C. albicans genome identified 147 potential substrates of Kex2p. These include all previously identified substrates, including eight secreted aspartyl proteinases, the exoglucanase Xog1p, the immunodominant antigen Mp65, and the adhesin Hwp1p. Other putative Kex2p substrates identified include several adhesins, cell wall proteins, and hydrolases previously not implicated in pathogenesis. Kexins also process fungal mating pheromones; a modification of the algorithm identified a putative mating pheromone with structural similarities to Saccharomyces cerevisiae ␣-factor.Serine proteinases of the kexin/subtilisin superfamily activate precursor forms of many exported eukaryotic proteins by specific endoproteolytic cleavage adjacent and C-terminal to dibasic residues. Members of the superfamily play a crucial role in a large and varied set of biological processes in animals, plants, and fungi. In metazoan cells, kexins participate in both the constitutive and regulated secretory pathways, with substrates including hormones, serum proteins, neuropeptides, cell surface receptors, components of the extracellular matrix (ECM), 1 and proteinases, which modify the ECM (1). Furin, a member of the mammalian kexin family, processes several ECM metalloproteinases requisite for the dissemination of cancer cells (2). Kexins have also been suborned to mediate the maturation of viral proteins and bacterial toxins (3). In fungi, kexins cycle between the outer face of the Golgi and the prevacuolar compartment where they process proteins involved in maintenance and remodeling of the cell wall (4, 5), proteins associated with the formation of aerial hyphae (6), ␣-type mating prepropheromones (7), killer toxins (7) , zymogens of secreted proteinases (8 -10), lipases (11), polysaccharide-degrading enzymes (12, 13), and themselves (14). Deleting the kexin of the yeast Yarrowia lipolytica abolishes the formation of hyphae (15). kex2-null mutants of the yeast Saccharomyces cerevisiae are viable but exhibit conditional morphological abnormalities (16), defective vacuolar proton-translocating V-ATPase activity (17), cold-sensitive growth (16), and a partial defect in meiosis (genome-www.stanford.edu/Saccharomyces). Genetic data indicate that ...

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Section: Albicans Strains and Growthmentioning

confidence: 99%

Inactivation of Kex2p Diminishes the Virulence of Candida albicans

Newport¹,

Kuo²,

Flattery³

et al. 2003

Journal of Biological Chemistry

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“…There are many papers reports on the increased susceptibility of tumor-bearing hosts to systemic fungal infections. [2][3][4][5][6] The protective activity of allogeneic sarcoma 180 tumor-bearing mice against Candida albicans and Aspergillus fumigatus infections has been reported in our previous papers. [7][8][9][10][11] It has also been reported that there is a significant delay in the lethal response to C. albicans in mice bearing Lewis lung carcinoma.…”

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confidence: 99%

Role of Polymorphonuclear Leukocytes in the Resistance of Tumor-Bearing Mice against Candida albicans Infection

Okawa

Kobayashi

Sakai

et al. 2004

Biological & Pharmaceutical Bulletin

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Opportunistic fungal infection occurring frequently in a compromised host is one of the most important problems in modern medicine, because of the difficulty of treatment and the frequency with which such infections progress to a lifethreatening condition. There are many papers reports on the increased susceptibility of tumor-bearing hosts to systemic fungal infections. [2][3][4][5][6] The protective activity of allogeneic sarcoma 180 tumor-bearing mice against Candida albicans and Aspergillus fumigatus infections has been reported in our previous papers. [7][8][9][10][11] It has also been reported that there is a significant delay in the lethal response to C. albicans in mice bearing Lewis lung carcinoma. 12) However, the mechanisms of such an effect have yet to be fully elucidated. We reported that the number of peripheral blood polymorphonuclear leukocytes (PMNs) dramatically increased in sarcoma 180 tumor-bearing mice. [7][8][9] We also investigated the producibility of the granulocyte-macrophage colony-stimulating factor from the tumor cells. 9,10) We thought that this phenomenon should be investigated not only in allogeneic tumor-bearing mice but also in syngeneic tumor-bearing mice. In the present study, to demonstrate further the importance of PMNs in the resistance of tumor-bearing mice against C. albicans, we conducted a protection assay against the infection using allogeneic (sarcoma 180) and syngeneic (Meth A fibrosarcoma [Meth A] and MM 46 mammary carcinoma [MM46]) solid tumor-bearing mice over the course of 3 weeks after tumor cell transplantation. Furthermore, we investigated in detail the involvement of PMNs from tumor-bearing mice as the likely mechanism of such protection. MATERIALS AND METHODS Mice and TumorsMale 6-to 8-week-old ddY, BALB/c, and C3H/He mice were obtained from the Shizuoka Laboratory Animal Center, Hamamatsu, Japan. Sarcoma 180 (1ϫ10 6 ), 3-methylcholanthrene-induced Meth A fibrosarcoma (Meth A, 1ϫ10 6 ), and MM 46 mammary carcinoma (MM46, 3ϫ10 6 ) were transplanted subcutaneously in the ddY, BALB/c, and C3H/He mice, respectively. Cyclophosphamide (CY)-treated mice were prepared as follows: 16 d after tumor transplantation, the mice were injected intraperitoneally with a single dose of 15, 50, or 200 mg/kg of CY (Cytoxan, Shionogi Co., Ltd., Osaka, Japan).Fungus The C. albicans NIH A-207 strain was kindly donated by Dr. T. Shinoda, Department of Microbiology, Meiji College of Pharmacy, Tokyo, Japan, and was maintained on Sabouraud agar slants. For this study, the fungus was cultured in a Sabouraud liquid medium which was shaken at 27°C for 48 h.Infection-Protection Assay One, 2, and 3 weeks after tumor cell transplantation, the mice were inoculated intravenously with 2ϫ10 6 viable C. albicans cells. The mice bearing only the solid tumor began dying by week 4; therefore reliable data could not be obtained beyond 3 weeks. In the CY experiment, 4 d after CY administration, the mice were infected intravenously with the fungal cells. The mortality rate of the mice was recorded for...

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“…It is not known whether the plasma effects are due to the presence of factors which inhibit phagocytosis or to absence of stimulating factors. On the other hand Lehrer & Cline (1971) found neutrophil phagocytosis to be normal in patients with HD on chemotherapy, but they used a lower Candida/cell ratio, which may have presented a lesser phagocytic challenge. Davies et al (1976) have shown that cytotoxic agents can impair neutrophil phagocytosis in vitro and in patients on treatment.…”

Section: Idiscussionmentioning

confidence: 99%

“…disease and of treatment. Results have therefore been conflicting; neutrophil microbial-killing activity for example being reported as depressed (Lehrer & Cline, 1971) or normal (Steigbigel et al, 1976;Hancock et al, 1976).…”

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confidence: 99%

Neutrophil function during chemotherapy for Hodgkin's disease

Gandossini¹,

Souhami²,

Babbage³

et al. 1981

Br J Cancer

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Summary.-Simultaneous measurement of neutrophil migration, phagocytic activity, candidacidal and bactericidal activity were made during quadruple chemotherapy of advanced Hodgkin's disease (HD). Measurements were also made in normal individuals, hospital patients not on chemotherapy, untreated patients with advanced HD and patients off chemotherapy for over a year.Neutrophil migratory activity was usually normal in untreated HD patients and those on chemotherapy, but > 200O of all tests showed depressed values, some of which were corrected by plasma. Similar results were found with neutrophil phagocytosis. Abnormalities in these functions were found in both early and late cycles, but there was a tendency for migration to deteriorate during later chemotherapy cycles. Neutrophil candidacidal and bactericidal activity were frequently depressed in patients on treatment and there was deterioration in candidacidal activity during the chemotherapy cycle. These abnormalities of killing activity were frequently corrected in control plasma.Neutrophil function is normal in most patients with advanced HD and in patients in remission. In a minority of patients on treatment there are marked functional defects, especially in killing activity. These defects are partly cell-associated and partly plasma-related. Susceptibility to infection during chemotherapy of HD may be partly due to defective neutrophil function.

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Leukocyte candidacidal activity and resistance to systemic candidiasis in patients with cancer

Cited by 85 publications

References 38 publications

Inactivation of Kex2p Diminishes the Virulence of Candida albicans

Inactivation of Kex2p Diminishes the Virulence of Candida albicans

Role of Polymorphonuclear Leukocytes in the Resistance of Tumor-Bearing Mice against Candida albicans Infection

Neutrophil function during chemotherapy for Hodgkin's disease

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