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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Glycoprotein C of herpes simplex virus type 1 is required to cause keratitis at low infectious doses in intact rabbit corneas

Current Eye Research (2004)

Barbara S. Drolet Kevin R. Mott Andrew M. Lippa Steven L. Wechsler Guey‐Chuen Perng

To determine whether the herpes simplex virus type 1 (HSV-1) viral glycoprotein C (gC) plays a role in induction of keratitis in unscarified and scarified rabbit eyes.A gC deletion mutant (DeltagC) was constructed and then rescued back to wild type (wt) for use as a control. Following ocular infection with each virus in rabbit eyes, with or without prior corneal scarification, keratitis was compared.At low infection doses of 2 x 10(3) and 2 x 10(4) plaque-forming units (PFU)/eye, in unscarified cornea, DeltagC produced significantly less keratitis than did wt virus (p = 0.007 and 0.03, respectively). In contrast, the keratitis induced by DeltagC was similar to that induced by the wt virus (p > 0.60) in scarified cornea. At high infection dose (2 x 10(5) PFU/eye), keratitis induced by DeltagC was similar in scarified and unscarified cornea, and the severity of disease was similar to that seen in scarified eyes at the low-dose DeltagC infections. Interestingly, although DeltagC induced keratitis with or without corneal scarification at high infection doses, the severity of disease was significantly less than that induced by wt infection. At all infection doses, keratitis induced by wt infection was similar in scarified and unscarified eyes.These results suggest that (1) at low infection doses, in unscarified corneas, gC is required for HSV-1 induced keratitis; (2) corneal scarification prior to infection can circumvent the need for gC at low doses, but (3) at higher doses, gC is required for wild-type levels of keratitis even in scarified cornea.

Scarification

Corneal Diseases

Corneal ulceration

10.1080/02713680490504542

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Citations (8)

Herpes simplex virus type 1 immediate-early protein ICP0 diffuses out of infected rabbit corneas

Journal of General Virology (2005)

Julie Naito Kevin R. Mott Nelson Osorio Ling Jin Guey‐Chuen Perng

Herpes stromal keratitis (HSK) results from infection of herpes simplex virus (HSV) in the cornea. Recurrent HSV infection is a leading cause of corneal scarring and visual loss. Although it is generally thought that HSK is the result of an immune response to one or more viral proteins, no viral proteins have been detected in HSK corneas. Thus, the viral proteins involved in HSK, if any, remain undetermined. In contrast, it is reported here that when HSK corneal buttons from latently infected rabbits were fixed using standard procedures, the important immediate-early HSV-1 protein ICP0 was readily detected in the fixative by Western blotting. Similarly, when HSK corneal buttons were soaked in buffer (rather than fixative), ICP0 was readily detected in the soaking buffer. Other HSV-1 proteins were not detected either in the fixative or in the soaking buffer. It is also reported here that ICP0 was consistently detected in virus-free tears from the eyes of rabbits acutely infected with HSV-1. These results suggest that ICP0 rapidly diffuses out of the cornea and may explain why ICP0 was detected in the fixative of HSK corneas and in the soaking buffer of acutely infected corneas.

Fixative

10.1099/vir.0.81246-0

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Citations (11)

Interrelationship of primary virus replication in the eye, level of latency and time to reactivate in the trigeminal ganglia (TG) of latently infected mice

Homayon Ghiasi Kevin R. Mott Sariah J. Allen Yasamin N. Ghiasi Terrence Town

Replication

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A Recombinant Herpes Simplex Virus Type 1 Expressing Two Additional Copies of gK Is More Pathogenic than Wild-Type Virus in Two Different Strains of Mice

Journal of Virology (2007)

Kevin R. Mott Guey‐Chuen Perng Yanira Osorio Konstantin G. Kousoulas Homayon Ghiasi

ABSTRACT The effect of glycoprotein K (gK) overexpression on herpes simplex virus type 1 (HSV-1) infection in two different strains of mice was evaluated using a recombinant HSV-1 virus that expresses two additional copies of the gK gene in place of the latency-associated transcript (LAT). This mutant virus (HSV-gK 3 ) expressed higher levels of gK than either the wild-type McKrae virus or the parental dLAT2903 virus both in vitro (in cultured cells) and in vivo (in infected mouse corneas and trigeminal ganglia [TG] of BALB/c and C57BL/6 mice). gK transcripts were detected in the TG of both HSV-gK 3 -infected mouse strains on day 30 postinfection (p.i.), while gB transcripts were detected only in the TG of the HSV-gK 3 -infected C57BL/6 mice, a finding that suggests that increased gK levels promote chronic infection. C57BL/6 mice infected with HSV-gK 3 also contained free virus in their TG on day 30 p.i. Both HSV-gK 3 -infected mouse strains had significantly higher corneal scarring (CS) than did McKrae-infected mice. T-cell depletion studies in C57BL/6 mice suggested that this CS enhancement in the HSV-gK 3 -infected mice was mediated by a CD8 + T-cell response. Taken together, these results strongly suggest that increased gK levels promote eye disease and chronic infection in infected mice.

Virus latency

Recombinant virus

Wild type

10.1128/jvi.01442-07

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Citations (68)

The MMTV-Wnt1 murine model produces two phenotypically distinct subtypes of mammary tumors with unique therapeutic responses to an EGFR inhibitor

Disease Models & Mechanisms (2019)

Adam D. Pfefferle David B. Darr Benjamin C. Calhoun Kevin R. Mott Jeffrey M. Rosen

The Wnt gene family encodes an evolutionarily conserved group of proteins that regulate cell growth, differentiation and stem cell self-renewal. Aberrant Wnt signaling in human breast tumors has been proposed as a driver of tumorigenesis, especially in the basal-like tumor subtype where canonical Wnt signaling is both enriched and predictive of poor clinical outcomes. The development of effective Wnt-based therapeutics, however, has been slowed in part by a limited understanding of the context-dependent nature with which these aberrations influence breast tumorigenesis. We previously reported that MMTV-Wnt1 mice, an established model for studying Wnt signaling in breast tumors, develop two subtypes of tumors by gene expression classification: Wnt1-EarlyEx and Wnt1-LateEx Here, we extend this initial observation and show that Wnt1-EarlyEx tumors exhibit high expression of canonical Wnt, non-canonical Wnt, and EGFR signaling pathway signatures. Therapeutically, Wnt1-EarlyEx tumors showed a dynamic reduction in tumor volume when treated with an EGFR inhibitor. Wnt1-EarlyEx tumors had primarily Cd49fpos/Epcamneg FACS profiles, but it was not possible to serially transplant these tumors into wild-type FVB female mice. Conversely, Wnt1-LateEx tumors had a bloody gross pathology, which was highlighted by the presence of 'blood lakes' identified by H&E staining. These tumors had primarily Cd49fpos/Epcampos FACS profiles, but also contained a secondary Cd49fpos/Epcamneg subpopulation. Wnt1-LateEx tumors were enriched for activating Hras1 mutations and were capable of reproducing tumors when serially transplanted into wild-type FVB female mice. This study definitively shows that the MMTV-Wnt1 mouse model produces two phenotypically distinct subtypes of mammary tumors that differ in multiple biological aspects including sensitivity to an EGFR inhibitor.

Mammary tumor

10.1242/dmm.037192

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The absense of DHHC3 affects primary and latent HSV-1 infection

Investigative Ophthalmology & Visual Science (2018)

Shaohui Wang Kevin R. Mott Marianne Cilluffo Casey L. Kilpatrick Shoko Murakami

Primary (astronomy)

HSL and HSV

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Supplementary Table from Integrated Metabolic Profiling and Transcriptional Analysis Reveals Therapeutic Modalities for Targeting Rapidly Proliferating Breast Cancers

Chengheng Liao Cherise Ryan Glodowski Cheng Fan Juan Liu Kevin R. Mott

Supplementary Table from Integrated Metabolic Profiling and Transcriptional Analysis Reveals Therapeutic Modalities for Targeting Rapidly Proliferating Breast Cancers

Profiling (computer programming)

Modalities

10.1158/0008-5472.22431228

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The Latency-Associated Transcript Inhibits Apoptosis via Downregulation of Components of the Type I Interferon Pathway during Latent Herpes Simplex Virus 1 Ocular Infection

Journal of Virology (2019)

Kati Tormanen Sariah J. Allen Kevin R. Mott Homayon Ghiasi

The HSV-1 latency reactivation cycle is the cause of significant human pathology. The HSV-1 latency-associated transcript (LAT) functions by regulating latency and reactivation, in part by inhibiting apoptosis. However, the mechanism of this process is unknown. Here we show that LAT likely controls apoptosis via downregulation of several components in the JAK-STAT pathway. Furthermore, we provide evidence that immune exhaustion is not caused by the antiapoptotic activity of the LAT.

Virus latency

Interferon type I

Simplexvirus

10.1128/jvi.00103-19

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Citations (27)

Leukocyte Involvement in CNS Demyelination After Ocular Infection With Recombinant HSV-1 Expressing IL-2

Investigative Ophthalmology & Visual Science (2010)

Jane Kuo Mandana Zandian Kevin R. Mott David Gate Terrence Town

HSL and HSV

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Immunization with Different Viral Antigens Alters the Pattern of T Cell Exhaustion and Latency in Herpes Simplex Virus Type 1-Infected Mice

Journal of Virology (2010)

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

We have shown previously that immunization with herpes simplex virus type 1 (HSV-1) glycoprotein K (gK) exacerbated corneal scarring (CS) in ocularly infected mice. In this study, we investigated whether higher levels of CS were correlated with higher levels of latency and T cell exhaustion in gK-immunized mice. BALB/c mice were vaccinated with baculovirus-expressed gK or gD or mock immunized. Twenty-one days after the third immunization, mice were ocularly infected with 2 × 10(4) PFU/eye of virulent HSV-1 strain McKrae. On day 5 postinfection, virus replication in the eye was measured, and on day 30 postinfection, infiltration of the trigeminal ganglia (TG) by CD4, CD8, programmed death 1 (PD-1), and T cell immunoglobulin and mucin domain-containing protein 3 (Tim-3) was monitored by immunohistochemistry and quantitative real-time PCR (qRT-PCR). This study demonstrated that higher levels of CS were correlated with higher levels of latency, and this was associated with the presence of significantly higher numbers of CD4(+)PD-1(+) and CD8(+)PD-1(+) cells in the TG of the gK-immunized group than in both the gD- and mock-immunized groups. Levels of exhaustion associated with Tim-3 were the same among gK- and mock-vaccinated groups but higher than levels in the gD-vaccinated group. In this study, we have shown for the first time that both PD-1 and Tim-3 contribute to T cell exhaustion and an increase of latency in the TG of latently infected mice.

10.1128/jvi.01600-10

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Citations (20)