Kevin R. Mott

University of North Carolina at Chapel Hill

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Homayon Ghiasi

Cedars-Sinai Medical Center

Sariah J. Allen

St. Jude Children's Research Hospital

Steven L. Wechsler

University of California, Irvine

Charles M. Perou

University of North Carolina at Chapel Hill

Cherise Ryan Glodowski

University of North Carolina at Chapel Hill

Guey‐Chuen Perng

National Cheng Kung University

Juan Liu

Southwest University

Qing Zhang

Nanjing Drum Tower Hospital

Jason W. Locasale

Duke University

Chengheng Liao

The University of Texas Southwestern Medical Center

Cooperative Institutions

University of North Carolina at Chapel Hill

Cedars-Sinai Medical Center

UNC Lineberger Comprehensive Cancer Center

University of California, Irvine

University of California, Los Angeles

University of North Carolina Health Care

Harvard University

Segeberger Kliniken

GEICAM – Spanish Breast Cancer Group

Pediatrics and Genetics

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Role of Interleukin-2 and Herpes Simplex Virus 1 in Central Nervous System Demyelination in Mice

Journal of Virology (2013)

Kevin R. Mott Mandana Zandian Sariah J. Allen Homayon Ghiasi

ABSTRACT We have reported previously that ocular infection of different strains of mice with recombinant herpes simplex virus 1 (HSV-1) constitutively expressing interleukin-2 (IL-2) provokes central nervous system (CNS) demyelination and optic neuropathy, as determined by changes in visual evoked cortical potentials and pathological changes in the optic nerve and CNS, whereas recombinant viruses expressing IL-4, gamma interferon, IL-12p35, IL-12p40, or IL-12p70 do not induce this neuropathy. The goal of this study was to dissect the mechanism underlying the interplay between the immune system (elevation of IL-2) and an environmental factor (infection with HSV-1) that elicits this pathology. Similar results were obtained upon delivery of IL-2 into the mouse brain using osmotic minipumps or injection of mice with recombinant IL-2 protein, IL-2 DNA, or IL-2 synthetic peptides prior to infection with wild-type (wt) HSV-1 strains McKrae and KOS. The critical role of IL-2 is further supported by our data, indicating that a single mutation at position T27A in IL-2 completely blocks the HSV-1-induced pathology. This study shows a novel model of autoimmunity in which viral infection and enhanced IL-2 cause CNS demyelination.

10.1128/jvi.02241-13

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Citations (16)

Coregulatory Interactions among CD8α Dendritic Cells, the Latency-Associated Transcript, and Programmed Death 1 Contribute to Higher Levels of Herpes Simplex Virus 1 Latency

Journal of Virology (2014)

Kevin R. Mott Sariah J. Allen Mandana Zandian Homayon Ghiasi

ABSTRACT The latency-associated transcript (LAT) of herpes simplex virus 1 (HSV-1), CD8α + dendritic cells (DCs), and programmed death 1 (PD-1) have all been implicated in the HSV-1 latency-reactivation cycle. It is not known, however, whether an interaction between LAT and CD8α + DCs regulates latency and T-cell exhaustion. To address this question, we used LAT-expressing [LAT(+)] and LAT-negative [LAT(−)] viruses. Depletion of DCs in mice ocularly infected with LAT(+) virus resulted in a reduction in the number of T cells expressing PD-1 in the trigeminal ganglia (TG), whereas depletion of DCs in mice similarly infected with LAT(−) virus did not alter PD-1 expression. CD8α + DCs, but not CD4 + DCs, infected with LAT(+) virus had higher levels of ICP0, ICP4, thymidine kinase (TK), and PD-1 ligand 1 (PD-L1) transcripts than those infected with LAT(−) virus. Coculture of infected bone marrow (BM)-derived DCs from wild-type (WT) mice, but not infected DCs from CD8α −/− mice, with WT naive T cells contributed to an increase in PD-1 expression. Transfer of bone marrow from WT mice but not CD8α −/− mice to recipient Rag1 −/− mice increased the number of latent viral genomes in reconstituted mice infected with the LAT(+) virus. Collectively, these data indicated that a reduction in latency correlated with a decline in the levels of CD8α + DCs and PD-1 expression. In summary, our results demonstrate an interaction among LAT, PD-1, and CD11c CD8α + cells that regulates latency in the TG of HSV-1-infected mice. IMPORTANCE Very little is known regarding the interrelationship of LAT, PD-1, and CD8α + DCs and how such interactions might contribute to relative numbers of latent viral genomes. We show here that (i) in both in vivo and in vitro studies, deficiency of CD8α + DCs significantly reduced T-cell exhaustion in the presence of LAT(+) virus but not LAT(−) virus; (ii) HSV-1 infectivity was significantly lower in LAT(−)-infected DCs than in their LAT(+)-infected counterparts; and (iii) adoptive transfer of bone marrow (BM) from WT but not CD8α −/− mice to recipient Rag1 −/− mice restored latency to the level in WT mice following infection with LAT(+) virus. These studies point to a key role for CD8α + DCs in T-cell exhaustion in the presence of LAT, which leads to larger numbers of latent viral genomes. Thus, altering this negative function of CD8α + DCs can potentially be used to generate a more effective vaccine against HSV infection.

Virus latency

CD11c

10.1128/jvi.00590-14

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Citations (21)

Binding of HSV-1 UL20 to Golgi-specific Zinc-finger protein affect virus infectivity and latency-reactivation

Investigative Ophthalmology & Visual Science (2017)

Shaohui Wang Kevin R. Mott Kolja Wawrowsky Bernhard Lüscher Homayon Ghiasi

Infectivity

Affect

HSL and HSV

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Adaptive and Innate Transforming Growth Factor β Signaling Impact Herpes Simplex Virus 1 Latency and Reactivation

Journal of Virology (2011)

Sariah J. Allen Kevin R. Mott Steven L. Wechsler Richard A. Flavell Terrence Town

Innate and adaptive immunity play important protective roles by combating herpes simplex virus 1 (HSV-1) infection. Transforming growth factor β (TGF-β) is a key negative cytokine regulator of both innate and adaptive immune responses. Yet, it is unknown whether TGF-β signaling in either immune compartment impacts HSV-1 replication and latency. We undertook genetic approaches to address these issues by infecting two different dominant negative TGF-β receptor type II transgenic mouse lines. These mice have specific TGF-β signaling blockades in either T cells or innate cells. Mice were ocularly infected with HSV-1 to evaluate the effects of restricted innate or adaptive TGF-β signaling during acute and latent infections. Limiting innate cell but not T cell TGF-β signaling reduced virus replication in the eyes of infected mice. On the other hand, blocking TGF-β signaling in either innate cells or T cells resulted in decreased latency in the trigeminal ganglia of infected mice. Furthermore, inhibiting TGF-β signaling in T cells reduced cell lysis and leukocyte infiltration in corneas and trigeminal ganglia during primary HSV-1 infection of mice. These findings strongly suggest that TGF-β signaling, which generally functions to dampen immune responses, results in increased HSV-1 latency.

10.1128/jvi.00678-11

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Citations (21)

Involvement of STAT4 in IgG subtype switching and ocular HSV-1 replication in mice.

PubMed (2010)

Sariah J. Allen Kevin R. Mott Homayon Ghiasi

To assess the relative impact of elevated T-helper 2 (T(H)2)- and reduced T-Helper 1 (T(H)1)-dependent immune responses on ocular herpes simplex virus type 1 (HSV-1) infection.Signal transducer and activator of transcription protein 4 knockout mice (BALB/c-STAT4(-/-)) and wild-type BALB/c control mice were immunized with avirulent HSV-1 strain KOS or were mock-immunized. Three weeks after the third immunization, neutralizing antibody titers were determined by plaque reduction assays. Following ocular infection with virulent HSV-1 strain McKrae, viral replication in the eye, blepharitis, corneal scarring (CS), survival, and immunoglobulin (Ig) isotypes in sera were determined.Vaccinated STAT4(-/-) and BALB/c mice contained significant and similar neutralizing antibody titers and were completely protected against HSV-1-induced death and CS. In contrast to vaccinated STAT4(-/-) mice, mock-vaccinated STAT4(-/-) mice had higher ocular HSV-1 titers than mock-vaccinated BALB/c mice on days 2-3 post-ocular infection. There were also significant differences in the levels of IgG2a, IgG2b, and IgG3 in the sera of STAT4(-/-) mice when compared to the control BALB/c mice.These results suggest that the absence of T(H)1 cytokine responses did alter protection against viral replication and IgG isotypes but not eye disease or survival.

STAT4

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CD8 ⁺ T Cells Play a Bystander Role in Mice Latently Infected with Herpes Simplex Virus 1

Journal of Virology (2016)

Kevin R. Mott David Gate Harry H. Matundan Yasamin N. Ghiasi Terrence Town

Based on an explant reactivation model, it has been proposed that CD8(+) T cells maintain latency in trigeminal ganglia (TG) of mice latently infected with herpes simplex virus 1 (HSV-1) [T. Liu, K. M. Khanna, X. Chen, D. J. Fink, and R. L. Hendricks, J Exp Med 191:1459-1466, 2000, doi:10.1084/jem.191.9.1459; K. M. Khanna, R. H. Bonneau, P. R. Kinchington, and R. L. Hendricks, Immunity 18:593-603, 2003, doi:10.1016/S1074-7613(03)00112-2]. In those studies, BALB/c mice were ocularly infected with an avirulent HSV-1 strain (RE) after corneal scarification. However, in our studies, we typically infect mice with a virulent HSV-1 strain (McKrae) that does not require corneal scarification. Using a combination of knockout mice, adoptive transfers, and depletion studies, we recently found that CD8α(+) dendritic cells (DCs) contribute to HSV-1 latency and reactivation in TG of ocularly infected mice (K. R. Mott, S. J. Allen, M. Zandian, B. Konda, B. G. Sharifi, C. Jones, S. L. Wechsler, T. Town, and H. Ghiasi, PLoS One 9:e93444, 2014, doi:10.1371/journal.pone.0093444). This suggested that CD8(+) T cells might not be the major regulators of HSV-1 latency in the mouse TG. To investigate this iconoclastic possibility, we used a blocking CD8 antibody and CD8(+) T cells in reactivated TG explants from mice latently infected with (i) the avirulent HSV-1 strain RE following corneal scarification or (ii) the virulent HSV-1 strain McKrae without corneal scarification. Independently of the strain or approach, our results show that CD8α(+) DCs, not CD8(+) T cells, drive latency and reactivation. In addition, adoptive transfer of CD8(+) T cells from wild-type (wt) mice to CD8α(-/-) mice did not restore latency to the level for wt mice or wt virus. In the presence of latency-associated transcript (LAT((+)); wt virus), CD8(+) T cells seem to play a bystander role in the TG. These bystander T cells highly express PD-1, most likely due to the presence of CD8α(+) DCs. Collectively, these results support the notion that CD8(+) T cells do not play a major role in maintaining HSV-1 latency and reactivation.

Virus latency

10.1128/jvi.00255-16

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Citations (35)

Identification of Jun loss promotes resistance to histone deacetylase inhibitor entinostat through Myc signaling in luminal breast cancer

Carolina Digital Repository (University of North Carolina at Chapel Hill) (2018)

Maki Tanioka Kevin R. Mott Daniel P. Hollern Cheng Fan David B. Darr

Histone deacetylase inhibitor

Identification

10.17615/e90k-tz76

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High-dose paclitaxel and its combination with CSF1R inhibitor in polymeric micelles for chemoimmunotherapy of triple negative breast cancer

Nano Today (2023)

Chaemin Lim Duhyeong Hwang Mostafa Yazdimamaghani Hannah Marie Atkins Hyesun Hyun

Chemoimmunotherapy

Triple-negative breast cancer

10.1016/j.nantod.2023.101884

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FGFR4 regulates tumor subtype differentiation in luminal breast cancer and metastatic disease

Journal of Clinical Investigation (2020)

Susana García‐Recio Aatish Thennavan Michael P. East Joel S. Parker Juan Miguel Cejalvo

Mechanisms driving tumor progression from less aggressive subtypes to more aggressive states represent key targets for therapy. We identified a subset of luminal A primary breast tumors that give rise to HER2-enriched (HER2E) subtype metastases, but remain clinically HER2 negative (cHER2–). By testing the unique genetic and transcriptomic features of these cases, we developed the hypothesis that FGFR4 likely participates in this subtype switching. To evaluate this, we developed 2 FGFR4 genomic signatures using a patient-derived xenograft (PDX) model treated with an FGFR4 inhibitor, which inhibited PDX growth in vivo. Bulk tumor gene expression analysis and single-cell RNA sequencing demonstrated that the inhibition of FGFR4 signaling caused molecular switching. In the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) breast cancer cohort, FGFR4-induced and FGFR4-repressed signatures each predicted overall survival. Additionally, the FGFR4-induced signature was an independent prognostic factor beyond subtype and stage. Supervised analysis of 77 primary tumors with paired metastases revealed that the FGFR4-induced signature was significantly higher in luminal/ER+ tumor metastases compared with their primaries. Finally, multivariate analysis demonstrated that the FGFR4-induced signature also predicted site-specific metastasis for lung, liver, and brain, but not for bone or lymph nodes. These data identify a link between FGFR4-regulated genes and metastasis, suggesting treatment options for FGFR4-positive patients, whose high expression is not caused by mutation or amplification.

10.1172/jci130323

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Citations (69)

Role of CD8+ T cells versus CD8α+ DCs in HSV-1 latency-reactivation

Investigative Ophthalmology & Visual Science (2017)

Homayon Ghiasi Kevin R. Mott Sariah J. Allen Yasamin N. Ghiasi Harry H. Matundan

HSL and HSV

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