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1.  Detection of BK virus DNA in nasopharyngeal aspirates from children with respiratory infections but not in saliva from immunodeficient and immunocompetent adult patients. 
Journal of Clinical Microbiology  1994;32(5):1390-1394.
Our understanding of important stages in the pathogenesis of the human polyomavirus BK virus (BKV) and JC virus (JCV) infections is limited. In this context, nasopharyngeal aspirates from 201 children with respiratory diseases and saliva from 60 human immunodeficiency virus type 1-infected adults and 10 healthy adult controls were collected and analyzed for the presence of BKV and JCV DNA by PCR. Neither BKV nor JCV DNA was detected in the saliva specimens. We demonstrated BKV DNA, but no infectious BKV, in 2 of 201 nasopharyngeal aspirates. Each sample contained one unique rearranged noncoding control region variant of BKV. The results indicate that (i) BKV and JCV are not regularly associated with respiratory infections in children requiring hospitalization, (ii) nasopharyngeal cells are not an important site for primary replication of human polyomavirus BKV and JCV, and (iii) the salivary glands and oropharyngeal cells seem not to be involved in BKV and JCV persistence. We propose that for the polyomaviruses BKV and JCV the alimentary tract should be considered as a portal of entrance to the human organism.
PMCID: PMC263712  PMID: 8051277
2.  Natural Killer Cells Regulate Murine Cytomegalovirus-Induced Sialadenitis and Salivary Gland Disease 
Journal of Virology  2012;86(4):2132-2142.
The transmission of herpesviruses depends on viral shedding at mucosal surfaces. The salivary gland represents a major site of persistent viral replication for many viruses, including cytomegalovirus. We established a mouse model of salivary gland dysfunction after acute viral infection and investigated the cellular requirements for the loss of secretion. Murine cytomegalovirus (MCMV) infection severely impaired saliva secretion independently of salivary gland virus levels. Lymphocytes or circulating monocytes/macrophages were not required for secretory dysfunction. Dysfunction occurred before glandular inflammation, suggesting that a soluble mediator initiated the disruption of acinar cell function. Despite genetic differences in innate resistance to MCMV, NK cells protected the host against acinar atrophy and the loss of secretions under conditions of an exceedingly low virus inoculum. NK cells also modulated the type of glandular inflammation after infection, as they prevented an influx of Siglec-F+ polymorphonuclear leukocytes (PMNs). Therefore, beyond their recognized role in controlling MCMV replication, NK cells preserve organ integrity and function and regulate the innate inflammatory response within the gland.
PMCID: PMC3302420  PMID: 22156514
3.  Transforming growth factor-beta-mediated regulation of BK virus gene expression 
Virology  2008;378(1):6-12.
The increasing prevalence of BK virus (BKV)-associated diseases in immunosuppressed patients has prompted an investigation of the immune response to BKV, especially the role of cytokines in regulating viral replication. We examined the effect of TGF-β, a cytokine that is stimulated by certain immunosuppressive therapies, on BKV gene expression during lytic infection of renal proximal tubule epithelial cells. Viral gene expression, and specifically the activity of the BKV early promoter, is regulated by TGF-β in a strain-dependent manner. Promoter activity is upregulated in the presence of TGF-β for the TU strain of BKV, and not for the Dik, Dunlop, or Proto-2 strains. Using site-directed mutagenesis, we have identified a small segment of the TU promoter that is required for stimulation in response to TGF-β. These results demonstrate that BKV strains can respond differently to cytokine treatment and suggest that TGF-β may play a role in the reactivation of BKV.
PMCID: PMC2569840  PMID: 18559281
polyomavirus; BK virus; TGF-β; Smad3
4.  Anatomy and Histology of Rodent and Human Major Salivary Glands 
Acta Histochemica et Cytochemica  2012;45(5):241-250.
Major salivary glands of both humans and rodents consist of three pairs of macroscopic glands: parotid, submandibular, and sublingual. These glands secrete serous, mucous or mixed saliva via the proper main excretory ducts connecting the glandular bodies with the oral cavity. A series of discoveries about the salivary ducts in the 17th century by Niels Stensen (1638–1686), Thomas Wharton (1614–1673), and Caspar Bartholin (1655–1738) established the concept of exocrine secretion as well as salivary glands. Recent investigations have revealed the endocrine functions of parotin and a variety of cell growth factors produced by salivary glands.
The present review aims to describe macroscopic findings on the major salivary glands of rodents and the microscopic differences between those of humans and rodents, which review should be of interest to those researchers studying salivary glands.
PMCID: PMC3496860  PMID: 23209333
salivary glands; mouse; rat; human; immunohistochemistry
5.  Multiple components contribute to ability of saliva to inhibit influenza viruses 
Saliva is a potentially important barrier against respiratory viral infection but its mechanism of action is not well studied.
We tested the antiviral activities of whole saliva, specific salivary gland secretions, and purified salivary proteins against strains of influenza A virus (IAV) in vitro.
Whole saliva or parotid or submandibular/sublingual secretions from healthy donors inhibited IAV based on hemagglutination inhibition and neutralization assays. This differs from human immunodeficiency virus (HIV), for which only submandibular/sublingual secretions are reported to be inhibitory. Among purified salivary proteins, MUC5B, scavenger receptor cysteine-rich glycoprotein 340 (salivary gp-340), histatins, and human neutrophil defensins (HNPs) inhibited IAV at the concentrations present in whole saliva. In contrast, some abundant salivary proteins (acidic proline-rich proteins and amylase) had no activity, nor did several other less abundant salivary proteins with known activity against HIV (e.g. thrombospondin or serum leukocyte protease inhibitor). Whole saliva and MUC5B did not inhibit neuraminidase activity of IAV and viral neutralizing and aggregating activity of MUC5B was potentiated by the neuraminidase inhibitor oseltamivir. Hence, MUC5B inhibits IAV by presenting a sialic acid ligand for the viral hemagglutinin. The mechanism of action of histatins requires further study.
These findings indicate that saliva represents an important initial barrier to IAV infection and underline the complexity of host defense activity of oral secretions. Of interest, antiviral activity of saliva against IAV and HIV differs in terms of specific glandular secretions and proteins that are inhibitory.
PMCID: PMC2848456  PMID: 19121065
histatins; innate immunity; MUC5B
6.  Evaluation of Therapeutic Effects of Astaxanthin on Impairments in Salivary Secretion 
The involvement of reactive oxygen species (ROS) in the pathophysiology of Sjögren’s syndrome (SS), an autoimmune disorder, and irradiation-induced impairments in salivary secretion has been reported. Meanwhile, the strong antioxidant astaxanthin (Ast) has been suggested to have therapeutic effects on various diseases. In the present study, we examined the ROS scavenging capacity of Ast using a human salivary gland epithelial cell line (HSY) and investigated the effects of Ast on salivary secretion in a mouse model of irradiation-induced salivary gland dysfunction. Furthermore, we performed a clinical study of Ast in six SS patients and six normal individuals, quantifying the volume of saliva secretion and the level of oxidative stress markers in the saliva. Ast partially suppressed hydrogen peroxide-induced ROS in HSY cells. The mouse model demonstrated that the pre-administration of Ast resulted in the suppression of irradiation-induced hyposalivation. Furthermore, the administration of Ast appeared to increase salivary output in both the SS and normal groups. The level of oxidative stress marker, hexanoyl-lysine, in the saliva was reduced after Ast intake. These results suggest that Ast might act as an ROS scavenger, providing benefits to SS patients with impaired salivary secretion.
PMCID: PMC2935153  PMID: 20838568
astaxanthin; sjögren’s syndrome; salivary secretion; reactive oxygen species
7.  Pictorial essay: Salivary gland imaging 
Salivary glands are the first organs of digestion secreting their digestive juices into the oral cavity. Parotid, submandibular, and sublingual glands are the major paired salivary glands in the decreasing order of their size. In addition, multiple small minor salivary glands are noted randomly distributed in the upper aerodigestive tract, including paranasal sinuses and parapharyngeal spaces. The imaging is directed to the major salivary glands. Commonly used imaging methods include plain radiography and conventional sialography. Recently, high-resolution ultrasonography (HRUS) is being increasingly used for targeted salivary gland imaging. However, the advent of cross-sectional imaging techniques such as computed tomography (CT) and magnetic resonance imaging (MRI) have revolutionized the imaging of salivary glands. This article illustrates the role of imaging in evaluating the variegated disease pattern of the major salivary glands.
PMCID: PMC3698896  PMID: 23833425
Computed tomography; imaging; magnetic resonance imaging; salivary glands
8.  Functional transplantation of salivary gland cells differentiated from mouse early ES cells in vitro 
Human Cell  2013;26(2):80-90.
Atrophy or hypofunction of the salivary gland because of aging or disease causes hyposalivation and has an effect on the quality of life of patients, for example not only dry mouth but deterioration in mastication/deglutition disorder and the status of oral hygiene. Currently conducted therapies for atrophy or hypofunction of the salivary gland in clinical practice are only symptomatic treatments with drugs and artificial saliva, and therefore it is preferable to establish a radical therapy. At this time, as a fundamental investigation, by co-culturing mouse early ES (mEES-6) cells with human salivary gland-derived fibroblasts (hSG-fibro), differentiation of mEES-6 cells to salivary gland cells has been attempted. Also, the possibility of cell engraftment was examined. After identifying the cells which were co-cultured with GFP-transfected mEES-6 cells and hSG-fibro, the cells were transplanted into the submandibular gland of SCID mice, and the degree of differentiation into tissues was examined. The possibility of tissue functional reconstitution from co-cultured cells in a three-dimensional culture system was examined. Our results confirmed that the co-cultured cells expressed salivary gland-related markers and had an ability to generate neo-tissues by transplantation in vivo. Moreover, the cells could reconstitute gland structures in a three-dimensional culture system. By co-culture with hSG-fibro, mEES-6 cells were successfully differentiated into salivary gland cells which were transplantable and have tissue neogenetic ability.
PMCID: PMC3676639  PMID: 23681939
Salivary gland; Cell-based therapy; Co-culture system; Cell differentiation; Regeneration
9.  A Focused Salivary Gland Infection with attenuated MCMV: An Animal Model with Prevention of Pathology Associated with Systemic MCMV Infection1, 2 
While the salivary gland has been recognized as an important effector site of the common mucosal immune system, a useful model for studying anti-viral salivary gland immune responses in vivo and for exploring the role of the salivary gland within the common mucosal system has been lacking. Murine cytomegalovirus (MCMV) is a beta-herpesvirus that displays a strong tropism for the salivary gland and produces significant morbidity in susceptible mice when introduced by intraperitoneal (i.p.) inoculation. This study tested the hypothesis that MCMV morbidity and pathology could be reduced by injecting the virus directly the submandibular salivary gland (intraglandular (i.g.)), using either in vivo derived MCMV or the less virulent, tissue culture-derived MCMV (tcMCMV). Peak salivary gland viral titers were completely unaffected by infection route (i.p vs. i.g.) after inoculation with either MCMV or tcMCMV. However, i.g. tcMCMV inoculation reduced viremia in all systemic tissues tested compared to i.p. inoculation. Further, systemic organ pathology observed in the liver and spleen after i.p. inoculation with either MCMV or tcMCMV was completely eliminated by i.g. inoculation with tcMCMV. Cellular infiltrates in the salivary glands, after i.p. or i.g. inoculation were composed of both B and T cells, indicating the potential for a local immune response to occur in the salivary gland. These results demonstrate that a focused MCMV infection of the salivary gland without systemic organ pathology is possible using i.g. delivery of tcMCMV.
PMCID: PMC3506192  PMID: 17320076
rodent; viral; MCMV; mucosa; spleen and lymph nodes; salivary gland; antibodies; mucosal immunity
10.  Major salivary gland flow rates in young and old, generally healthy African Americans and whites. 
Saliva is essential to maintain and preserve oral health. Previous studies of primarily white populations demonstrated that salivary gland flow rates are age-stable in healthy adults, but there are little data on African Americans of different ages. The purpose of this study was to determine if there is a relationship between age, gender, and race in unstimulated and stimulated parotid and submandibular salivary gland flow rates and to evaluate subjective responses to questions regarding salivary dysfunction. Sixty generally healthy, middle socioeconomic class African Americans and whites between the ages of 20 to 40 and 60 to 80 years were evaluated. The results indicate, in general, that objective and subjective measurements of major salivary gland flow rates are independent of age, gender, and race. Further studies are required using larger populations. These results suggest that signs and symptoms of dry mouth in the elderly regardless of race or gender should not be considered a normal sequela of aging.
PMCID: PMC2607773  PMID: 7897685
11.  Cytomegalovirus exploits IL-10–mediated immune regulation in the salivary glands 
The Journal of Experimental Medicine  2007;204(5):1217-1225.
The salivary glands represent a major site of cytomegalovirus replication and transmission to other hosts. Despite control of viral infection by strong T cell responses in visceral organs cytomegalovirus replication continues in the salivary glands of mice, suggesting that the virus exploits the mucosal microenvironment. Here, we show that T cell immunity in the salivary glands is limited by the induction of CD4 T cells expressing the regulatory cytokine interleukin (IL)-10. Blockade of IL-10 receptor (IL-10R) with an antagonist antibody dramatically reduced viral load in the salivary glands, but not in the spleen. The mucosa-specific protection afforded by IL-10R blockade was associated with an increased accumulation of CD4 T cells expressing interferon γ, suggesting that IL-10R signaling limits effector T cell differentiation. Consistent with this, an agonist antibody targeting the tumor necrosis factor receptor superfamily member OX40 (TNFRSF4) enhanced effector T cell differentiation and increased the number of interferon γ–producing T cells, thus limiting virus replication in the salivary glands. Collectively, the results indicate that modulating effector T cell differentiation can counteract pathogen exploitation of the mucosa, thus limiting persistent virus replication and transmission.
PMCID: PMC2118568  PMID: 17485516
12.  PrPSc in Salivary Glands of Scrapie-Affected Sheep▿  
Journal of Virology  2007;81(9):4872-4876.
The salivary glands of scrapie-affected sheep and healthy controls were investigated for the presence of the pathological prion protein (PrPSc). PrPSc was detected in major (parotid and mandibular) and minor (buccal, labial, and palatine) salivary glands of naturally and experimentally infected sheep. Using Western blotting, the PrPSc concentration in glands was estimated to be 0.02 to 0.005% of that in brain. Immunohistochemistry revealed intracellular depositions of PrPSc in ductal and acinar epithelia and occasional labeling in the lumina of salivary ducts. The presence of PrPSc in salivary glands highlights the possible role of saliva in the horizontal transmission of scrapie.
PMCID: PMC1900156  PMID: 17301130
13.  Functional salivary gland regeneration by transplantation of a bioengineered organ germ 
Nature Communications  2013;4:2498.
Salivary gland hypofunction, also known as xerostomia, occurs as a result of radiation therapy for head cancer, Sjögren’s syndrome or aging, and can cause a variety of critical oral health issues, including dental decay, bacterial infection, mastication dysfunction, swallowing dysfunction and reduced quality of life. Here we demonstrate the full functional regeneration of a salivary gland that reproduces the morphogenesis induced by reciprocal epithelial and mesenchymal interactions through the orthotopic transplantation of a bioengineered salivary gland germ as a regenerative organ replacement therapy. The bioengineered germ develops into a mature gland through acinar formations with a myoepithelium and innervation. The bioengineered submandibular gland produces saliva in response to the administration of pilocarpine and gustatory stimulation by citrate, protects against oral bacterial infection and restores normal swallowing in a salivary gland-defective mouse model. This study thus provides a proof-of-concept for bioengineered salivary gland regeneration as a potential treatment of xerostomia.
Salivary gland dysfunction as a result of diseases or ageing reduces the quality of life and causes various oral health problems. Here the authors show that the salivary gland function of mice can be recovered by orthotopic transplantation of a bioengineered salivary gland germ.
PMCID: PMC3806330  PMID: 24084982
14.  Human herpesvirus 6: An emerging pathogen. 
Emerging Infectious Diseases  1999;5(3):353-366.
Infections with human herpesvirus 6 (HHV-6), a beta-herpesvirus of which two variant groups (A and B) are recognized, is very common, approaching 100% in seroprevalence. Primary infection with HHV-6B causes roseola infantum or exanthem subitum, a common childhood disease that resolves spontaneously. After primary infection, the virus replicates in the salivary glands and is shed in saliva, the recognized route of transmission for variant B strains; it remains latent in lymphocytes and monocytes and persists at low levels in cells and tissues. Not usually associated with disease in the immunocompetent, HHV-6 infection is a major cause of opportunistic viral infections in the immunosuppressed, typically AIDS patients and transplant recipients, in whom HHV-6 infection/reactivation may culminate in rejection of transplanted organs and death. Other opportunistic viruses, human cytomegalovirus and HHV-7, also infect or reactivate in persons at risk. Another disease whose pathogenesis may be correlated with HHV-6 is multiple sclerosis. Data in favor of and against the correlation are discussed.
PMCID: PMC2640789  PMID: 10341172
Recent studies have demonstrated the expression of Toll-like receptor 3 (TLR3) in salivary glands and epithelial cell lines derived from Sjögren’s syndrome (SS) patients. Since viral infections are considered to be a trigger for SS, in this study we investigated whether in vivo engagement of TLR3 affects salivary gland function.
Female NZB/WF1 mice were repeatedly injected with polyinosinic:polycytidylic acid (poly(I:C)). TLR3 expression within submandibular glands was studied by immunohistochemistry. RNA levels of inflammatory cytokines in the submandibular glands were determined by real time PCR. Pilocarpine induced saliva volume was used as an index of glandular function.
Immunohistochemical analysis of submandibular glands showed TLR3 expression in epithelium of serous and mucous acini, granular convoluted tubules and ducts. Poly(I:C) treatment rapidly upregulated the mRNA levels of type I IFN and inflammatory cytokines in the submandibular glands. By one week after treatment, the saliva volumes in poly(I:C) treated mice were significantly reduced in comparison with the PBS treated mice. Hematoxylin and eosin staining showed that salivary gland histology was normal and lymphocytic foci were not detected. Glandular function recovered after poly(I:C) treatment was stopped.
Our results demonstrate that engagement of TLR3 within the salivary glands results in a rapid loss of glandular function. This phenomenon is associated with the production of type I IFN and inflammatory cytokines in the salivary glands. Restoration of glandular function suggests that for viral etiology of SS, a chronic infection of salivary glands might be necessary.
PMCID: PMC2763314  PMID: 19192049
Inflammatory Cytokines; Poly(I:C); Salivary Gland; Sjögren’s Syndrome TLR3
16.  Estimation and Comparison of Salivary Secretory Leukocyte Protease Inhibitor in Human Immunodeficiency Virus Patients and Healthy Individuals 
Transmission of human immunodeficiency virus (HIV) in the oral cavity is a rare event, despite detectable virus in saliva and oropharyngeal tissues of infected persons, unlike other mucosal sites. Secretory leukocyte protease inhibitor (SLPI) has been suggested as the main soluble factor responsible for the HIV inhibitory effect of saliva. The study was designed to estimate and compare the salivary SLPI levels in HIV patients and healthy controls. Furthermore, the relationship between salivary SLPI levels and disease severity was also investigated.
Materials and Methods:
Unstimulated whole saliva specimens were collected from 60 HIV-infected and 20 healthy subjects. Disease severity was determined by CD4 count in HIV subjects, who were divided into two groups: ≥200 cells/μL (n = 30) and < 200 cells/μL n = 30. Salivary SLPI levels were determined by enzyme-linked immunosorbent assay.
Numerically higher SLPI levels were observed in HIV subjects 193.342 ng/mL vs. 190.587 ng/mL; P = 0.517. A nonsignificant negative correlation was noted between CD4 counts and SLPI levels r = −0.037, P = 0.781.
The salivary anti-HIV factor, SLPI, is not only preserved in HIV infection but its concentration may even get enhanced in the infection. However, the clinical significance of SLPI levels and disease severity should be investigated further with a larger sample of patients.
PMCID: PMC3931238  PMID: 24600179
CD4 count; Human immunodeficiency virus; Saliva; Secretory leukocyte protease inhibitor
17.  Recombinant AAV9-TLK1B Administration Ameliorates Fractionated Radiation-Induced Xerostomia 
Human Gene Therapy  2013;24(6):604-612.
Salivary glands are highly susceptible to radiation, and patients with head and neck cancer treated with radiotherapy invariably suffer from its distressing side effect, salivary hypofunction. The reduction in saliva disrupts oral functions, and significantly impairs oral health. Previously, we demonstrated that adenoviral-mediated expression of Tousled-like kinase 1B (TLK1B) in rat submandibular glands preserves salivary function after single-dose ionizing radiation. To achieve long-term transgene expression for protection of salivary gland function against fractionated radiation, this study examines the usefulness of recombinant adeno-associated viral vector for TLK1B delivery. Lactated Ringers or AAV2/9 with either TLK1B or GFP expression cassette were retroductally delivered to rat submandibular salivary glands (1011 vg/gland), and animals were exposed, or not, to 20 Gy in eight fractions of 2.5 Gy/day. AAV2/9 transduced predominantly the ductal cells, including the convoluted granular tubules of the submandibular glands. Transgene expression after virus delivery could be detected within 5 weeks, and stable gene expression was observed till the end of study. Pilocarpine-stimulated saliva output measured at 8 weeks after completion of radiation demonstrated >10-fold reduction in salivary flow in saline- and AAV2/9-GFP-treated animals compared with the respective nonirradiated groups (90.8% and 92.5% reduction in salivary flow, respectively). Importantly, there was no decrease in stimulated salivary output after irradiation in animals that were pretreated with AAV2/9-TLK1B (121.5% increase in salivary flow; p<0.01). Salivary gland histology was better preserved after irradiation in TLK1B-treated group, though not significantly, compared with control groups. Single preemptive delivery of AAV2/9-TLK1B averts salivary dysfunction resulting from fractionated radiation. Although AAV2/9 transduces mostly the ductal cells of the gland, their protection against radiation assists in preserving submandibular gland function. AAV2/9-TLK1B treatment could prove beneficial in attenuating xerostomia in patients with head and neck cancer undergoing radiotherapy.
Shanmugam and colleagues demonstrate that a single instillation of recombinant AAV9 encoding Tousled-like kinase 1B (TLK1B) in rat submandibular glands leads to a complete amelioration of salivary dysfunction caused by fractionated radiation. They suggest that this treatment modality may be beneficial in attenuating xerostomia in headand-neck cancer patients undergoing radiotherapy.
PMCID: PMC3689188  PMID: 23614651
18.  Permeability of Oral Tissues to Blood-borne Coxsackievirus B-1 
Applied Microbiology  1967;15(2):296-299.
The ability of coxsackievirus B-1 to pass the barriers of the circulatory system into whole saliva has been shown previously. In this investigation, the major salivary glands and the oral mucosa were studied, and their role as participants in the excretion of coxsackievirus B-1 during viremia was evaluated. The effect of the salivary-gland stimulant pilocarpine nitrate on both the salivary flow rate and the recovery of virus during viremia was determined. A comparison was made between the amount of virus recovered from whole saliva during viremia in animals deficient in one or both of the major salivary-gland pairs and animals with a complete complement of salivary glands. The salivary glands in other animals were cannulated, and pure glandular secretions were collected during viremia and assayed for the presence of virus The amount of virus passing from the capillaries of the oral mucosa to the surface was also determined to evaluate this route as a possible site for the excretion of virus into saliva during viremia. The major salivary glands did not excrete appreciable quantities of virus during viremia. The submaxillary-gland secretions did not contain virus, and the parotid-gland secretions showed virus only at extremely high blood virus levels. Either removal of the major salivary glands or decreased salivary flow rates increased the concentration of virus in whole saliva. This observation suggested that the production of saliva by the major salivary glands tends to dilute the virus in the oral cavity. A 0.88-cm2 sample of the oral mucosa excreted significantly large amounts of virus during viremia and suggested that the passage of virus through the oral mucosa was the major route for the excretion of virus into saliva during viremia.
PMCID: PMC546894  PMID: 6029830
19.  Proteome of Human Minor Salivary Gland Secretion 
Journal of dental research  2008;87(5):445-450.
Recent research efforts in oral biology have resulted in elucidation of the proteomes of major human salivary secretions and whole saliva. One might hypothesize that the proteome of minor gland secretions may show significantly different characteristics when compared with the proteomes of parotid or submandibular/sublingual secretions. To test this hypothesis, we conducted the first exploration into the proteome of minor salivary gland secretion. Minor gland secretion was obtained from healthy volunteers, and its components were subjected to liquid-chromatography-electrospray-ionization-tandemmass-spectrometry. This led to the identification of 56 proteins, 12 of which had never been identified in any salivary secretion. The unique characteristics of the minor salivary gland secretion proteome are related to the types as well as the numbers of components present. The differences between salivary proteomes may be important with respect to specific oral functions.
PMCID: PMC2857507  PMID: 18434574
minor salivary gland secretion; proteomics; oral; protein; saliva
20.  Functional Reorganization of Promyelocytic Leukemia Nuclear Bodies during BK Virus Infection 
mBio  2011;2(1):e00281-10.
BK virus (BKV) is the causative agent for polyomavirus-associated nephropathy, a severe disease found in renal transplant patients due to reactivation of a persistent BKV infection. BKV replication relies on the interactions of BKV with many nuclear components, and subnuclear structures such as promyelocytic leukemia nuclear bodies (PML-NBs) are known to play regulatory roles during a number of DNA virus infections. In this study, we investigated the relationship between PML-NBs and BKV during infection of primary human renal proximal tubule epithelial (RPTE) cells. While the levels of the major PML-NB protein components remained unchanged, BKV infection of RPTE cells resulted in dramatic alterations in both the number and the size of PML-NBs. Furthermore, two normally constitutive components of PML-NBs, Sp100 and hDaxx, became dispersed from PML-NBs. To define the viral factors responsible for this reorganization, we examined the cellular localization of the BKV large tumor antigen (TAg) and viral DNA. TAg colocalized with PML-NBs during early infection, while a number of BKV chromosomes were adjacent to PML-NBs during late infection. We demonstrated that TAg alone was not sufficient to reorganize PML-NBs and that active viral DNA replication is required. Knockdown of PML protein did not dramatically affect BKV growth in culture. BKV infection, however, was able to rescue the growth of an ICP0-null herpes simplex virus 1 mutant whose growth defect was partially due to its inability to disrupt PML-NBs. We hypothesize that the antiviral functions of PML-NBs are inactivated through reorganization during normal BKV infection.
BK virus (BKV) is a human pathogen that causes severe diseases, including polyomavirus-associated nephropathy in kidney transplant patients and hemorrhagic cystitis in bone marrow transplant recipients. How BKV replication is regulated and the effects of a lytic BKV infection on host cells at the molecular level are not well understood. Currently, there is no specific antiviral treatment for BKV-associated disease, and a better understanding of the complete life cycle of the virus is necessary. Here, we report the interplay between BKV and one of the regulatory structures in the host cell nucleus, promyelocytic leukemia nuclear bodies (PML-NBs). Our results show that BKV infection reorganizes PML-NBs as a strategy to inactivate the negative functions of PML-NBs.
PMCID: PMC3039439  PMID: 21304169
21.  Detection of human herpesvirus 6 and human herpesvirus 7 in the submandibular gland, parotid gland, and lip salivary gland by PCR. 
Journal of Clinical Microbiology  1996;34(9):2320-2321.
In order to define the major sites of persistence of human herpesvirus 6 (HHV-6) and HHV-7, PCR with DNAs from more than 100 specimens of 3 different salivary glands was performed. HHV-6 DNA was detected in 52 (88.1%) of 59 submandibular gland, 17 (63.0%) of 27 parotid gland, and 9 (52.9%) of 17 lip salivary gland specimens. On the other hand, HHV-7 DNA was detected in 59 (100%) of 59 submandibular gland, 23 (85.2%) of 27 parotid gland, and 10 (58.8%) of 17 lip salivary gland specimens. These findings demonstrate that salivary glands are a site of persistent infection of both HHV-6 and HHV-7 and that among the three types of salivary gland examined, the submandibular gland is the primary one in which these herpesviruses, especially HHV-7, persist.
PMCID: PMC229244  PMID: 8862611
22.  Restriction of Human Polyomavirus BK Virus DNA Replication in Murine Cells and Extracts▿  
Journal of Virology  2009;83(11):5708-5717.
BK virus (BKV) causes persistent and asymptomatic infections in most humans and is the etiologic agent of polyomavirus-associated nephropathy (PVAN) and other pathologies. Unfortunately, there are no animal models with which to study activation of BKV replication in the human kidney and the accompanying PVAN. Here we report studies of the restriction of BKV replication in murine cells and extracts and the cause(s) of this restriction. Upon infection of murine cells, BKV expressed large T antigen (TAg), but viral DNA replication and progeny were not detected. Transfection of murine cells with BKV TAg expression vectors also caused TAg expression without accompanying DNA replication. Analysis of the replication of DNAs containing chimeric BKV and murine polyomavirus origins revealed the importance of BKV core origin sequences and TAg for DNA replication. A sensitive assay was developed with purified BKV TAg that supported TAg-dependent BKV DNA replication with human but not with murine cell extracts. Addition of human replication proteins, DNA polymerase α-primase, replication protein A, or topoisomerase I to the murine extracts with BKV TAg did not rescue viral DNA replication. Notably, addition of murine extracts to human extracts inhibited BKV TAg-dependent DNA replication at a step prior to or during unwinding of the viral origin. These findings and differences in replication specificity between BKV TAg and the TAgs of simian virus 40 (SV40) and JC virus (JCV) and their respective origins implicate features of the BKV TAg and origin distinct from SV40 and JCV in restriction of BKV replication in murine cells.
PMCID: PMC2681987  PMID: 19297467
23.  Functional similarity between the early antigens of simian virus 40 and human papovavirus BK. 
Journal of Virology  1979;30(1):141-147.
The functional properties of the early antigens of simian virus 40 (SV40) and human papovavirus BK (BKV) were investigated. Infection of African green monkey kidney cells with BKV permitted the bidirectional replication of an early temperature-sensitive mutant (tsA) at a nonpermissive temperature. Conceivably, an early gene product (T-antigen) of BKV can substitute functionally for the defective SV40 T-antigen. On the other hand, SV40 DNA replication remained undetectable in human embryonic kidney cells preinfected with BKV, suggesting that BKV early antigens alone are not sufficient to provide for the replication of SV40. Preinfection of African green monkey kidney cells with BKV restored the normal pattern of late lytic SV40 transcription, suppressing the overproduction of early RNA by an SV40 tsA mutant at the nonpermissive temperature. Furthermore, preinfection of African green monkey kidney cells with BKV supported the growth of adenovirus type 2, providing a "helper function" similar to that provided by SV40 for the growth of human adenovirus in monkey kidney cells.
PMCID: PMC353308  PMID: 225512
24.  Common T cell receptor clonotype in lacrimal glands and labial salivary glands from patients with Sjögren's syndrome. 
Journal of Clinical Investigation  1996;97(8):1969-1977.
Sjogren's syndrome (SS) is an autoimmune disease characterized by lymphocytic infiltration into lacrimal and salivary glands leading to symptomatic dry eyes and mouth. Immunohistological studies have clarified that the majority of infiltrating lymphocytes around the lacrimal glands and labial salivary glands are CD4 positive alphabeta T cells. To analyze the pathogenesis of T cells infiltrating into lacrimal and labial salivary glands, we examined T cell clonotype of these cells in both glands from four SS patients using PCR-single-strand conformation polymorphism (SSCP) and a sequencing method. SSCP analysis showed that some infiltrating T cells in both glands expand clonally, suggesting that the cells proliferate by antigen-driven stimulation. Intriguingly, six to sixteen identical T cell receptor (TCR) Vbeta genes were commonly found in lacrimal glands and labial salivary glands from individual patients. This indicates that some T cells infiltrating into both glands recognize the shared epitopes on autoantigens. Moreover, highly conserved amino acid sequence motifs were found in the TCR CDR3 region bearing the same TCR Vbeta family gene from four SS patients, supporting the notion that the shared epitopes on antigens are limited. In conclusion, these findings suggest that some autoreactive T cells infiltrating into the lips and eyes recognized restricted epitopes of a common autoantigen in patients with SS.
PMCID: PMC507267  PMID: 8621782
25.  Salivary secretion and connective tissue disease in man. 
Parotid and submandibular gland secretions collected from patients with rheumatoid arthritis or systemic sclerosis have been analysed and the results compared with those obtained from a matched group of healthy individuals. Flow rates were measured and the saliva samples assayed for amylase, kallikrein, protein, and salivary IgA concentration. The results showed that only patients with rheumatoid arthritis had a reduced salivary flow, especially parotid flow, with a significantly increased concentration of salivary IgA in both parotid and submandibular saliva. Patients with systemic sclerosis did not show significantly altered salivary flow rates, but there was a marked depletion of salivary IgA content in both parotid and submandibular saliva. Neither disease states appeared to alter the kallikrein or amylase content of saliva. The possible clinical value of these findings is discussed.
PMCID: PMC1001561  PMID: 2578776

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