IFN-independent G0 arrest and SAMHD1 activation following TLR4 activation in macrophages

Mlčochová, Petra; Winstone, Helena; Zuliani-Alvarez, Lorena; Gupta, Ravindra

doi:10.1101/741124

Cited by 3 publications

(4 citation statements)

References 46 publications

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“…Intriguingly, SAMHD1 de-phosphorylation is part of the macrophage response to inflammatory stimuli. Thus, viruses, but also the TLR4 ligand LPS induce p21 upregulation, CDK1 depletion, G0 arrest and SAMHD1 dephosphorylation, thus enhancing the transcriptional activity of NF-kB and IRF7 [88,89] and the upregulation of type I IFNs in macrophages, while IL12/IL18 signaling in primary macrophages increased expression of SAMHD1 and SAMHD1-dependent HIV1 restriction [90] providing a link between inflammatory stimuli, cell cycle control and macrophage function, a link that may be required for macrophage genomic stability.…”

Section: Tlr Signaling and Genotoxic Stress Regulate Nucleic Acid Met...mentioning

confidence: 99%

Genotoxic stress signalling as a driver of macrophage diversity

Kasapi¹,

Triantafyllopoulou²

2022

CST

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Tissue macrophages arise from yolk sac, fetal liver and hematopoietic progenitors and adopt diverse transcriptional programs and phenotypes, instructed by their microenvironment. In chronic inflammation, such as in chronic infections, autoimmunity, or cancer, tissue microenvironments change dramatically thus imprinting new programs on tissue macrophages. While stress is a known driver of carcinogenesis in epithelial cells, emerging evidence suggests that macrophage responses to genotoxic stress are embedded in their ‘physiologic’ immune and tissue healing programs and in most cases do not lead to myeloid malignancies. The role of genotoxic stress as an instructor of macrophage-mediated immune defense and tissue remodeling is only beginning to be understood. Here, we review the evidence showing that genotoxic stress, which macrophages and their precursors face upon encountering inflammatory and/or growth signals, instructs their transcriptional programs, by activating non-canonical, cell-type specific DNA Damage Response (DDR)-driven signaling pathways. We propose that immune-cell specific, DDR-instructed programs are crucial for tissue homeostasis as well as for the maintenance and resolution of inflammatory responses in infection, cancer, autoinflammatory and autoimmune microenvironments.

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Section: Tlr Signaling and Genotoxic Stress Regulate Nucleic Acid Met...mentioning

confidence: 99%

Genotoxic stress signalling as a driver of macrophage diversity

Kasapi¹,

Triantafyllopoulou²

2022

CST

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“…This simple picture of non-dividing MDM being repair-deficient has been complicated by recent findings that these cells exist in two populations: (i) a major G0 population where the dNTP pool is depleted, the DNA repair activity is low and HIV proviruses are heavily uracilated [ 21 ], and (ii) a minor pseudo-G1 population characterized by a normal dNTP pool, DNA repair activity, and low levels of repair-associated DNA replication [ 5 , 10 , 37 , 38 ]. The pseudo-G1 state can be transiently and reversibly accessed from the G0-state, providing a mechanism for long-lived macrophages to repair genomic DNA, but also an increased chance of viral infection while in the pseudo-G1 state.…”

Section: Introductionmentioning

confidence: 99%

Replication-competent HIV-1 in human alveolar macrophages and monocytes despite nucleotide pools with elevated dUTP

et al. 2022

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Background Although CD4 + memory T cells are considered the primary latent reservoir for HIV-1, replication competent HIV has been detected in tissue macrophages in both animal and human studies. During in vitro HIV infection, the depleted nucleotide pool and high dUTP levels in monocyte derived macrophages (MDM) leads to proviruses with high levels of dUMP, which has been implicated in viral restriction or reduced transcription depending on the uracil base excision repair (UBER) competence of the macrophage. Incorporated dUMP has also been detected in viral DNA from circulating monocytes (MC) and alveolar macrophages (AM) of HIV infected patients on antiretroviral therapy (ART), establishing the biological relevance of this phenotype but not the replicative capacity of dUMP-containing proviruses. Results As compared to in vitro differentiated MDM, AM from normal donors had sixfold lower levels of dTTP and a sixfold increased dUTP/dTTP, indicating a highly restrictive dNTP pool for reverse transcription. Expression of uracil DNA glycosylase (UNG) was eightfold lower in AM compared to the already low levels in MDM. Accordingly, ~ 80% of HIV proviruses contained dUMP, which persisted for at least 14-days due to low UNG excision activity. Unlike MDM, AM expression levels of UNG and SAM and HD domain containing deoxynucleoside triphosphate triphosphohydrolase 1 (SAMHD1) increased over 14 days post-HIV infection, while dUTP nucleotidohydrolase (DUT) expression decreased. These AM-specific effects suggest a restriction response centered on excising uracil from viral DNA copies and increasing relative dUTP levels. Despite the restrictive nucleotide pools, we detected rare replication competent HIV in AM, peripheral MC, and CD4 + T cells from ART-treated donors. Conclusions These findings indicate that the potential integration block of incorporated dUMP is not realized during in vivo infection of AM and MC due to the near absence of UBER activity. In addition, the increased expression of UNG and SAMHD1 in AM post-infection is too slow to prevent integration. Accordingly, dUMP persists in integrated viruses, which based on in vitro studies, can lead to transcriptional silencing. This possible silencing outcome of persistent dUMP could promote viral latency until the repressive effects of viral dUMP are reversed. Supplementary Information The online version contains supplementary material available at 10.1186/s12977-022-00607-2.

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“…The presence of two populations with greatly different susceptibilities to infection complicates quantitative evaluation of the effects of depleted and imbalanced dNTP pools 9, 20 . The presence of G0 and pseudo-G1 populations is but one example of the malleable nature of the macrophage phenotype that is determined by the microenvironment of the tissue in which the cell resides 36 . Importantly, the nucleotide pool and DNA repair attributes of in vitro differentiated MDM have never been compared to in vivo differentiated tissue macrophages.…”

Section: Introductionmentioning

confidence: 99%

“…Further, because MDM have low expression levels of uracil base excision repair (UBER) enzymes 20,30,31 , dUMP can persist in proviral DNA and has been associated with transcriptional repression of viral genes 20,31,34,35 . This simple picture of non-dividing MDM being repair-deficient has been complicated by recent findings that these cells exist in two populations: (i) a major G0 population where the dNTP pool is depleted, the DNA repair activity is low and HIV proviruses are heavily uracilated 20 , and (ii) a minor pseudo-G1 population characterized by a normal dNTP pool, DNA repair activity, and low levels of repair-associated DNA replication 4,9,36 . The pseudo-G1 state can be transiently and reversibly accessed from the G0-state, providing a mechanism for long-lived macrophages to repair genomic DNA, but also an increased chance of viral infection while in the pseudo-G1 state.…”

Section: Introductionmentioning

confidence: 99%

Replication-competent HIV-1 in human alveolar macrophages and monocytes despite nucleotide pools with elevated dUTP

Cui¹,

Meshesha²,

Churgulia³

et al. 2022

Preprint

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Although CD4+ memory T cells are considered the primary latent reservoir for HIV-1, replication competent HIV has been detected in tissue macrophages in both animal and human studies. During in vitro HIV infection, the depleted nucleotide pool and high dUTP levels in monocyte derived macrophages (MDM) leads to proviruses with high levels of dUMP, which has been implicated in viral restriction or reduced transcription depending on the uracil base excision repair (UBER) competence of the macrophage. Incorporated dUMP has also been detected in viral DNA from circulating monocytes (MC) and alveolar macrophages (AM) of HIV infected patients on antiretroviral therapy (ART), establishing the biological relevance of this phenotype but not the replicative capacity of dUMP-containing proviruses. As compared to in vitro differentiated MDM, AM from normal donors had 6-fold lower levels of dTTP and a 6-fold increased dUTP/dTTP, indicating a highly restrictive dNTP pool for reverse transcription. Expression of uracil DNA glycosylase (UNG) was 8-fold lower in AM compared to the already low levels in MDM. Accordingly, ∼80% of HIV proviruses contained dUMP, which persisted for at least 14-days due to low UNG excision activity. Unlike MDM, AM expression levels of UNG and SAM and HD domain containing deoxynucleoside triphosphate triphosphohydrolase 1 (SAMHD1) increased over 14 days post-HIV infection, while dUTP nucleotidohydrolase expression decreased. These AM-specific effects suggest a restriction response centered on excising uracil from viral DNA copies and increasing relative dUTP levels. Despite the restrictive nucleotide pools, we detected rare replication competent HIV in AM, peripheral MC, and CD4+ T cells from ART-treated donors. These findings indicate that the potential integration block of incorporated dUMP is not realized during in vivo infection of AM and MC due to the near absence of UBER activity. In addition, the increased expression of UNG and SAMHD1 in AM post-infection is too slow to prevent integration. Accordingly, dUMP persists in integrated viruses, which based on in vitro studies, can lead to transcriptional silencing. This possible silencing outcome of persistent dUMP could promote viral latency until the repressive effects of viral dUMP are reversed.

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IFN-independent G0 arrest and SAMHD1 activation following TLR4 activation in macrophages

Abstract: 19Monocyte-derived macrophages mostly reside in a resting, G0 state, expressing high levels of 20 dephosphorylated, active SAMHD1. We have previously shown that macrophages can re-21 enter the cell cycle without division, into a G1-like state. This cell cycle re-entry is 22

Cited by 3 publications

References 46 publications

Genotoxic stress signalling as a driver of macrophage diversity

Genotoxic stress signalling as a driver of macrophage diversity

Replication-competent HIV-1 in human alveolar macrophages and monocytes despite nucleotide pools with elevated dUTP

Replication-competent HIV-1 in human alveolar macrophages and monocytes despite nucleotide pools with elevated dUTP

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