<p>We are studying two hemoglobin-induced genes <I>HBR1</I>and <I>HMX1</I>, a Candida heme oxygenase. Heme oxygenase converts heme to biliverdin and carbon monoxide. Biliverdin is increasing used to inhibit inflammatory responses associated with organ transplantation, but sources for this compound are limited. We developed a method to efficiently produce biliverdin using the heme oxygenase activity in <I>C. albicans</I>and obtained a patent for this method. We also found that a <I>HMX1</I>null strain of <I>C. albicans</I>has decreased virulence in a murine model of disseminated candidiasis. Reconstitution of one or both deleted alleles restores virulence to the level of wild type. Initial organ burdens in infected mice are not decreased for the null strain, indicating that early growth in the host is not impaired due to loss of this pathway for scavenging iron. In contrast, levels of several regulatory cytokines and chemokines are decreased in mice infected with null cells, and initial lesions in the kidney caused by the null mutant are more rapidly cleared following PMN infiltration. Collectively, these results show that <I>C. albicans</I>Hmx1 expression limits the host immune response to candidemia and contributes to disease progression.</P><p>We are studying two hemoglobin-induced genes <I>HBR1</I>and <I>HMX1</I>, a Candida heme oxygenase. Heme oxygenase converts heme to biliverdin and carbon monoxide. Biliverdin is increasing used to inhibit inflammatory responses associated with organ transplantation, but sources for this compound are limited. We developed a method to efficiently produce biliverdin using the heme oxygenase activity in <I>C. albicans</I>and obtained a patent for this method. We also found that a <I>HMX1</I>null strain of <I>C. albicans</I>has decreased virulence in a murine model of disseminated candidiasis. Reconstitution of one or both deleted alleles restores virulence to the level of wild type. Initial organ burdens in infected mice are not decreased for the null strain, indicating that early growth in the host is not impaired due to loss of this pathway for scavenging iron. In contrast, levels of several regulatory cytokines and chemokines are decreased in mice infected with null cells, and initial lesions in the kidney caused by the null mutant are more rapidly cleared following PMN infiltration. Collectively, these results show that <I>C. albicans</I>Hmx1 expression limits the host immune response to candidemia and contributes to disease progression.</P>

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIASC009173-21
Application #
7969793
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
21
Fiscal Year
2009
Total Cost
$439,914
Indirect Cost
Name
National Cancer Institute Division of Clinical Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
Navarathna, Dhammika H M L P; Pathirana, Ruvini U; Lionakis, Michail S et al. (2016) Candida albicans ISW2 Regulates Chlamydospore Suspensor Cell Formation and Virulence In Vivo in a Mouse Model of Disseminated Candidiasis. PLoS One 11:e0164449
Navarathna, Dhammika H; Roberts, David D; Munasinghe, Jeeva et al. (2016) Imaging Candida Infections in the Host. Methods Mol Biol 1356:69-78
Navarathna, Dhammika H M L P; Stein, Erica V; Lessey-Morillon, Elizabeth C et al. (2015) CD47 Promotes Protective Innate and Adaptive Immunity in a Mouse Model of Disseminated Candidiasis. PLoS One 10:e0128220
Pendrak, Michael L; Roberts, David D (2015) Hbr1 Activates and Represses Hyphal Growth in Candida albicans and Regulates Fungal Morphogenesis under Embedded Conditions. PLoS One 10:e0126919
Navarathna, Dhammika H M L P; Munasinghe, Jeeva; Lizak, Martin J et al. (2013) MRI confirms loss of blood-brain barrier integrity in a mouse model of disseminated candidiasis. NMR Biomed 26:1125-34
Martin-Manso, Gema; Navarathna, Dhammika H M L P; Galli, Susana et al. (2012) Endogenous thrombospondin-1 regulates leukocyte recruitment and activation and accelerates death from systemic candidiasis. PLoS One 7:e48775
Navarathna, Dhammika H M L P; Lionakis, Michail S; Lizak, Martin J et al. (2012) Urea amidolyase (DUR1,2) contributes to virulence and kidney pathogenesis of Candida albicans. PLoS One 7:e48475
Peterson, Alexander W; Pendrak, Michael L; Roberts, David D (2011) ATP binding to hemoglobin response gene 1 protein is necessary for regulation of the mating type locus in Candida albicans. J Biol Chem 286:13914-24
Navarathna, Dhammika H M L P; Das, Aditi; Morschhauser, Joachim et al. (2011) Dur3 is the major urea transporter in Candida albicans and is co-regulated with the urea amidolyase Dur1,2. Microbiology 157:270-9
Pendrak, Michael L; Roberts, David D (2011) Ribosomal RNA processing in Candida albicans. RNA 17:2235-48

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