A dual to the death: using novel host-directed antivirals to promote death of HCMV-infected myeloid cells through apoptosis and necroptosis
Human cytomegalovirus (HCMV) is a ubiquitous member of the betaherpesvirus family, with seroprevalence rates ranging from 40-100% worldwide. Although primary infection is asymptomatic in most immunocompetent patients, HCMV is a significant cause of morbidity and mortality in the immunosuppressed and immunonaїve, including transplant recipients, patients with AIDS, and developing fetuses in utero. The diverse clinical presentations of HCMV are attributable to the pervasive systemic dissemination and extensive cellular tropism of the virus. Peripheral blood monocytes are believed to be the key cells responsible for HCMV dissemination from the initial site of infection to distant organ systems. Monocytes are normally short-lived, surviving for only 48 h in circulation before undergoing apoptosis. Previous work from our lab has shown that HCMV circumvents the short lifespan of monocytes by inducing a noncanonical activation of Akt to upregulate the expression of antiapoptotic proteins, thereby prolonging survival of infected monocytes. HCMV promotes survival in the absence of viral replication and lytic gene expression, rendering current direct-acting antivirals ineffective against quiescently infected monocytes. There are currently no antivirals that target quiescent or latent HCMV infection. We hypothesize that targeting host proteins that are essential for HCMV's induction of monocyte survival mechanisms will reduce viability of infected monocytes, ultimately reducing systemic viral dissemination. The studies in this thesis investigate novel host-directed antivirals targeted at two different cellular factors and their efficacy against quiescent HCMV infection in monocytes. The first host protein under scrutiny as an antiviral target is Sirtuin 2 (Sirt2), an NAD+-dependent deacetylase. Treatment with novel Sirt2 inhibitors promoted death of HCMV-infected monocytes as a cellular antiviral defense response through two concurrent regulated death pathways: apoptosis and necroptosis. HCMV has developed mechanisms to ....
| Medienart: |
E-Book |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
Erscheinungsort nicht ermittelbar: [Verlag nicht ermittelbar] ; 2022 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Cheung, Jennifer [VerfasserIn] |
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| Hochschulschrift: |
| Links: |
hdl.handle.net [kostenfrei] |
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| Weitere IDs: |
20.500.12648/7331 |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
1828024546 |
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| 245 | 1 | 0 | |a A dual to the death: using novel host-directed antivirals to promote death of HCMV-infected myeloid cells through apoptosis and necroptosis |
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| 520 | |a Human cytomegalovirus (HCMV) is a ubiquitous member of the betaherpesvirus family, with seroprevalence rates ranging from 40-100% worldwide. Although primary infection is asymptomatic in most immunocompetent patients, HCMV is a significant cause of morbidity and mortality in the immunosuppressed and immunonaїve, including transplant recipients, patients with AIDS, and developing fetuses in utero. The diverse clinical presentations of HCMV are attributable to the pervasive systemic dissemination and extensive cellular tropism of the virus. Peripheral blood monocytes are believed to be the key cells responsible for HCMV dissemination from the initial site of infection to distant organ systems. Monocytes are normally short-lived, surviving for only 48 h in circulation before undergoing apoptosis. Previous work from our lab has shown that HCMV circumvents the short lifespan of monocytes by inducing a noncanonical activation of Akt to upregulate the expression of antiapoptotic proteins, thereby prolonging survival of infected monocytes. HCMV promotes survival in the absence of viral replication and lytic gene expression, rendering current direct-acting antivirals ineffective against quiescently infected monocytes. There are currently no antivirals that target quiescent or latent HCMV infection. We hypothesize that targeting host proteins that are essential for HCMV's induction of monocyte survival mechanisms will reduce viability of infected monocytes, ultimately reducing systemic viral dissemination. The studies in this thesis investigate novel host-directed antivirals targeted at two different cellular factors and their efficacy against quiescent HCMV infection in monocytes. The first host protein under scrutiny as an antiviral target is Sirtuin 2 (Sirt2), an NAD+-dependent deacetylase. Treatment with novel Sirt2 inhibitors promoted death of HCMV-infected monocytes as a cellular antiviral defense response through two concurrent regulated death pathways: apoptosis and necroptosis. HCMV has developed mechanisms to ... | ||
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