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Histoplasma Capsulatum Secretes Cyst...

Azimova, Dinara.

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Histoplasma Capsulatum Secretes Cysteine-Rich Protein Virulence Factors to Lyse Host Macrophages.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Histoplasma Capsulatum Secretes Cysteine-Rich Protein Virulence Factors to Lyse Host Macrophages./
作者:	Azimova, Dinara.
出版者:	Ann Arbor : ProQuest Dissertations & Theses, : 2021,
面頁冊數:	116 p.
附註:	Source: Dissertations Abstracts International, Volume: 83-01, Section: B.
Contained By:	Dissertations Abstracts International83-01B.
標題:	Biochemistry. -
電子資源:	https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=28543522
ISBN:	9798516944635

Histoplasma Capsulatum Secretes Cysteine-Rich Protein Virulence Factors to Lyse Host Macrophages.
Azimova, Dinara.

Histoplasma Capsulatum Secretes Cysteine-Rich Protein Virulence Factors to Lyse Host Macrophages. - Ann Arbor : ProQuest Dissertations & Theses, 2021 - 116 p.

Source: Dissertations Abstracts International, Volume: 83-01, Section: B.

Thesis (Ph.D.)--University of California, San Francisco, 2021.

This item must not be sold to any third party vendors.

Intracellular pathogens secrete effectors to manipulate their host cells. Histoplasma capsulatum (Hc) is a fungal intracellular pathogen of humans that grows in a yeast form in the host. Hc yeasts are phagocytosed by macrophages, where fungal intracellular replication is followed by macrophage lysis. The most abundant virulence factor secreted by Hc yeast cells is Calcium Binding Protein 1 (Cbp1), which is absolutely required for macrophage lysis. Here in Chapter 2, we take an evolutionary, structural, and cell biological approach to understand Cbp1 function. We find that Cbp1 is present only in the genomes of closely related dimorphic fungal species of the Ajellomycetaceae family that lead primarily intracellular lifestyles in their mammalian hosts (Histoplasma, Paracoccidioides, and Emergomyces), but not conserved in the closely related extracellular fungal pathogen Blastomyces dermatitidis. We determine the de novo structures of Cbp1 from Hc H88 Cbp1 and the Paracoccidioides americana (Pb03) Cbp1, revealing a novel "binocular" fold, consisting of a helical dimer arrangement where two helices from each monomer contribute to a four-helix bundle. In contrast to Pb03 Cbp1, we show that Emergomyces Cbp1 orthologs are unable to stimulate macrophage lysis when expressed in the Hc cbp1 mutant. Consistent with this result, we find that wild-type E. africanus yeast are able to grow within primary macrophages but are incapable of lysing them. Finally, we use subcellular fractionation of infected macrophages and indirect immunofluorescence to show that Cbp1 localizes to the macrophage cytosol during Hc infection, making this the first instance of a primary intracellular human fungal pathogen directing an effector into the cytosol of the host cell. We additionally show that Cbp1 forms a complex with Yps-3, another known Hc virulence factor. Taken together, these data imply that Cbp1 is a rapidly evolving fungal virulence factor that localizes to the cytosol to trigger host cell lysis.We also show that Cbp1 is not the only virulence factor that enters the macrophage cytosol. In Chapter 3, we identify other virulence factors including a Cerato-platanin domain containing protein (Scp1) and Yps-3, are also found in the macrophage cytosol and contribute to optimal lysis.In Chapter 4, we identify a family of putative cysteine-knot containing proteins that are specifically expanded in Hc species using a new, unbiased algorithm known as KNOTTIN Finder. One putative cysteine-knot, Rockstar10, contributes to optimal lysis of macrophages during infection. Taken together, these data demonstrate that Hc relies on a strategy of secreting cysteine-rich proteins into the macrophage cytosol in order to potentiate the lysis of its host cell to further dissemination.

ISBN: 9798516944635Subjects--Topical Terms:

518028
Biochemistry.
Subjects--Index Terms:

Cysteine knot

Histoplasma Capsulatum Secretes Cysteine-Rich Protein Virulence Factors to Lyse Host Macrophages.
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500 $a Source: Dissertations Abstracts International, Volume: 83-01, Section: B.
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502 $a Thesis (Ph.D.)--University of California, San Francisco, 2021.
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520 $a Intracellular pathogens secrete effectors to manipulate their host cells. Histoplasma capsulatum (Hc) is a fungal intracellular pathogen of humans that grows in a yeast form in the host. Hc yeasts are phagocytosed by macrophages, where fungal intracellular replication is followed by macrophage lysis. The most abundant virulence factor secreted by Hc yeast cells is Calcium Binding Protein 1 (Cbp1), which is absolutely required for macrophage lysis. Here in Chapter 2, we take an evolutionary, structural, and cell biological approach to understand Cbp1 function. We find that Cbp1 is present only in the genomes of closely related dimorphic fungal species of the Ajellomycetaceae family that lead primarily intracellular lifestyles in their mammalian hosts (Histoplasma, Paracoccidioides, and Emergomyces), but not conserved in the closely related extracellular fungal pathogen Blastomyces dermatitidis. We determine the de novo structures of Cbp1 from Hc H88 Cbp1 and the Paracoccidioides americana (Pb03) Cbp1, revealing a novel "binocular" fold, consisting of a helical dimer arrangement where two helices from each monomer contribute to a four-helix bundle. In contrast to Pb03 Cbp1, we show that Emergomyces Cbp1 orthologs are unable to stimulate macrophage lysis when expressed in the Hc cbp1 mutant. Consistent with this result, we find that wild-type E. africanus yeast are able to grow within primary macrophages but are incapable of lysing them. Finally, we use subcellular fractionation of infected macrophages and indirect immunofluorescence to show that Cbp1 localizes to the macrophage cytosol during Hc infection, making this the first instance of a primary intracellular human fungal pathogen directing an effector into the cytosol of the host cell. We additionally show that Cbp1 forms a complex with Yps-3, another known Hc virulence factor. Taken together, these data imply that Cbp1 is a rapidly evolving fungal virulence factor that localizes to the cytosol to trigger host cell lysis.We also show that Cbp1 is not the only virulence factor that enters the macrophage cytosol. In Chapter 3, we identify other virulence factors including a Cerato-platanin domain containing protein (Scp1) and Yps-3, are also found in the macrophage cytosol and contribute to optimal lysis.In Chapter 4, we identify a family of putative cysteine-knot containing proteins that are specifically expanded in Hc species using a new, unbiased algorithm known as KNOTTIN Finder. One putative cysteine-knot, Rockstar10, contributes to optimal lysis of macrophages during infection. Taken together, these data demonstrate that Hc relies on a strategy of secreting cysteine-rich proteins into the macrophage cytosol in order to potentiate the lysis of its host cell to further dissemination.
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650 4 $a Cellular biology. $3 3172791
650 4 $a Microbiology. $3 536250
653 $a Cysteine knot
653 $a Fungus
653 $a Macrophage
653 $a Pathogen
653 $a Protein effector
653 $a Virulence factor
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