Cytomegalovirus-induced salivary gland pathology: resistance to kinase inhibitors of the upregulated host cell EGFR/ERK pathway is associated with CMV-dependent stromal overexpression of IL-6 and fibronectin

AbstractIntroduction:Salivary gland pathology in the paediatric population is rare and can present management challenges regarding both investigation and treatment.Method:Case report and review of available literature.Results:A seven-year-old, fit, well girl presented with a two-month history of a painless mass over the left parotid area. Ultrasonography confirmed the presence of a well-defined, 1.5 × 2 cm, predominantly solid lesion with minor internal cystic spaces arising from the superficial part of the gland. Magnetic resonance imaging showed no invasion of the deep lobe or skeletal erosion. Superficial parotidectomy was performed via a facelift incision. Histopathology confirmed a diagnosis of pleomorphic adenoma. Review of the literature emphasised important differences in managing this pathology in the paediatric population when compared with adults.Conclusion:We present the youngest reported case of a pleomorphic adenoma of the parotid gland, detail its management, and discuss the general approach to parotid pathology management in the paediatric population.

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Salivary Gland Pathology

10.1002/9781118949139 ◽

2015 ◽

Cited By ~ 1

Keyword(s):

Salivary Gland ◽

Salivary Gland Pathology

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Lassa Virus Cell Entry via Dystroglycan Involves an Unusual Pathway of Macropinocytosis

Journal of Virology ◽

10.1128/jvi.00257-16 ◽

2016 ◽

Vol 90 (14) ◽

pp. 6412-6429 ◽

Cited By ~ 44

Author(s):

Joel Oppliger ◽

Giulia Torriani ◽

Antonio Herrador ◽

Stefan Kunz

Keyword(s):

Antiviral Activity ◽

Host Cell ◽

Therapeutic Intervention ◽

Kinase Inhibitors ◽

Hemorrhagic Fever ◽

Human Cells ◽

New Drugs ◽

High Rate ◽

Actin Dynamics ◽

Lassa Virus

ABSTRACTThe pathogenic Old World arenavirus Lassa virus (LASV) causes a severe hemorrhagic fever with a high rate of mortality in humans. Several LASV receptors, including dystroglycan (DG), TAM receptor tyrosine kinases, and C-type lectins, have been identified, suggesting complex receptor use. Upon receptor binding, LASV enters the host cell via an unknown clathrin- and dynamin-independent pathway that delivers the virus to late endosomes, where fusion occurs. Here we investigated the mechanisms underlying LASV endocytosis in human cells in the context of productive arenavirus infection, using recombinant lymphocytic choriomeningitis virus (rLCMV) expressing the LASV glycoprotein (rLCMV-LASVGP). We found that rLCMV-LASVGP entered human epithelial cells via DG using a macropinocytosis-related pathway independently of alternative receptors. Dystroglycan-mediated entry of rLCMV-LASVGP required sodium hydrogen exchangers, actin, and the GTPase Cdc42 and its downstream targets, p21-activating kinase-1 (PAK1) and Wiskott-Aldrich syndrome protein (N-Wasp). Unlike other viruses that enter cells via macropinocytosis, rLCMV-LASVGP entry did not induce overt changes in cellular morphology and hardly affected actin dynamics or fluid uptake. Screening of kinase inhibitors identified protein kinase C, phosphoinositide 3-kinase, and the receptor tyrosine kinase human hepatocyte growth factor receptor (HGFR) to be regulators of rLCMV-LASVGP entry. The HGFR inhibitor EMD 1214063, a candidate anticancer drug, showed antiviral activity against rLCMV-LASVGP at the level of entry. When combined with ribavirin, which is currently used to treat human arenavirus infection, EMD 1214063 showed additive antiviral effects. In sum, our study reveals that DG can link LASV to an unusual pathway of macropinocytosis that causes only minimal perturbation of the host cell and identifies cellular kinases to be possible novel targets for therapeutic intervention.IMPORTANCELassa virus (LASV) causes several hundred thousand infections per year in Western Africa, with the mortality rate among hospitalized patients being high. The current lack of a vaccine and the limited therapeutic options at hand make the development of new drugs against LASV a high priority. In the present study, we uncover that LASV entry into human cells via its major receptor, dystroglycan, involves an unusual pathway of macropinocytosis and define a set of cellular factors implicated in the regulation of LASV entry. A screen of kinase inhibitors revealed HGFR to be a possible candidate target for antiviral drugs against LASV. An HGFR candidate inhibitor currently being evaluated for cancer treatment showed potent antiviral activity and additive drug effects with ribavirin, which is used in the clinic to treat human LASV infection. In sum, our study reveals novel fundamental aspects of the LASV-host cell interaction and highlights a possible candidate drug target for therapeutic intervention.

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Human Immunodeficiency Virus Type 1 Vpr-Dependent Cell Cycle Arrest through a Mitogen-Activated Protein Kinase Signal Transduction Pathway

Journal of Virology ◽

10.1128/jvi.79.17.11366-11381.2005 ◽

2005 ◽

Vol 79 (17) ◽

pp. 11366-11381 ◽

Cited By ~ 27

Author(s):

Naoto Yoshizuka ◽

Yuko Yoshizuka-Chadani ◽

Vyjayanthi Krishnan ◽

Steven L. Zeichner

Keyword(s):

Gene Expression ◽

Cell Cycle ◽

Human Immunodeficiency Virus ◽

Cell Cycle Arrest ◽

Host Cell ◽

Human Immunodeficiency Virus Type ◽

Erk Pathway ◽

Cycle Arrest ◽

Immunodeficiency Virus

ABSTRACT The human immunodeficiency virus type 1 (HIV-1) Vpr protein has important functions in advancing HIV pathogenesis via several effects on the host cell. Vpr mediates nuclear import of the preintegration complex, induces host cell apoptosis, and inhibits cell cycle progression at G2, which increases HIV gene expression. Some of Vpr's activities have been well described, but some functions, such as cell cycle arrest, are not yet completely characterized, although components of the ATR DNA damage repair pathway and the Cdc25C and Cdc2 cell cycle control mechanisms clearly play important roles. We investigated the mechanisms underlying Vpr-mediated cell cycle arrest by examining global cellular gene expression profiles in cell lines that inducibly express wild-type and mutant Vpr proteins. We found that Vpr expression is associated with the down-regulation of genes in the MEK2-ERK pathway and with decreased phosphorylation of the MEK2 effector protein ERK. Exogenous provision of excess MEK2 reverses the cell cycle arrest associated with Vpr, confirming the involvement of the MEK2-ERK pathway in Vpr-mediated cell cycle arrest. Vpr therefore appears to arrest the cell cycle at G2/M through two different mechanisms, the ATR mechanism and a newly described MEK2 mechanism. This redundancy suggests that Vpr-mediated cell cycle arrest is important for HIV replication and pathogenesis. Our findings additionally reinforce the idea that HIV can optimize the host cell environment for viral replication.

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Salivary gland pathology in HIV patients

Diagnostic Histopathology ◽

10.1016/j.mpdhp.2012.08.001 ◽

2012 ◽

Vol 18 (9) ◽

pp. 366-372 ◽

Cited By ~ 5

Author(s):

Nadim M. Islam ◽

Indraneel Bhattacharyya ◽

Donald M. Cohen

Keyword(s):

Salivary Gland ◽

Hiv Patients ◽

Salivary Gland Pathology

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A Focused Small-Molecule Screen Identifies 14 Compounds with Distinct Effects on Toxoplasma gondii

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00868-12 ◽

2012 ◽

Vol 56 (11) ◽

pp. 5581-5590 ◽

Cited By ~ 24

Author(s):

Edwin T. Kamau ◽

Ananth R. Srinivasan ◽

Mark J. Brown ◽

Matthew G. Fair ◽

Erin J. Caraher ◽

...

Keyword(s):

Toxoplasma Gondii ◽

Host Cell ◽

Kinase Inhibitors ◽

Severe Disease ◽

Content Type ◽

Cellular Target ◽

Small Molecule Screen ◽

Parasite Motility ◽

Future Work

ABSTRACTToxoplasma gondiiis a globally ubiquitous pathogen that can cause severe disease in immunocompromised humans and the developing fetus. Given the proven role ofToxoplasma-secreted kinases in the interaction ofToxoplasmawith its host cell, identification of novel kinase inhibitors could precipitate the development of new anti-Toxoplasmadrugs and define new pathways important for parasite survival. We selected a small (n= 527) but diverse set of putative kinase inhibitors and screened them for effects on the growth ofToxoplasmain vitro. We identified and validated 14 noncytotoxic compounds, all of which had 50% effective concentrations in the nanomolar to micromolar range. We further characterized eight of these compounds, four inhibitors and four enhancers, by determining their effects on parasite motility, invasion, and the likely cellular target (parasite or host cell). Only two compounds had an effect on parasite motility and invasion. All the inhibitors appeared to target the parasite, and interestingly, two of the enhancers appeared to rather target the host cell, suggesting modulation of host cell pathways beneficial for parasite growth. For the four inhibitors, we also tested their efficacy in a mouse model, where one compound proved potent. Overall, these 14 compounds represent a new and diverse set of small molecules that are likely targeting distinct parasite and host cell pathways. Future work will aim to characterize their molecular targets in both the host and parasite.

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