Derek J. Royer

Bio: Derek J. Royer is an academic researcher from University of Oklahoma Health Sciences Center. The author has contributed to research in topics: Immune system & Innate immune system. The author has an hindex of 10, co-authored 17 publications receiving 317 citations. Previous affiliations of Derek J. Royer include University of Oklahoma.

Microglia and a Functional Type I IFN Pathway Are Required To Counter HSV-1–Driven Brain Lateral Ventricle Enlargement and Encephalitis

Abstract: HSV-1 is the leading cause of sporadic viral encephalitis, with mortality rates approaching 30% despite treatment with the antiviral drug of choice, acyclovir. Permanent neurologic deficits are common in patients that survive, but the mechanism leading to this pathology is poorly understood, impeding clinical advancements in treatment to reduce CNS morbidity. Using magnetic resonance imaging and type I IFN receptor-deficient mouse chimeras, we demonstrate HSV-1 gains access to the murine brain stem and subsequently brain ependymal cells, leading to enlargement of the cerebral lateral ventricle and infection of the brain parenchyma. A similar enlargement in the lateral ventricles is found in a subpopulation of herpes simplex encephalitic patients. Associated with encephalitis is an increase in CXCL1 and CXCL10 levels in the cerebral spinal fluid, TNF-α expression in the ependymal region, and the influx of neutrophils of encephalitic mouse brains. Reduction in lateral ventricle enlargement using anti-secretory factor peptide 16 reduces mortality significantly in HSV-1-infected mice without any effect on expression of inflammatory mediators, infiltration of leukocytes, or changes in viral titer. Microglial cells but not infiltrating leukocytes or other resident glial cells or neurons are the principal source of resistance in the CNS during the first 5 d postinfection through a Toll/IL-1R domain-containing adapter inducing IFN-β-dependent, type I IFN pathway. Our results implicate lateral ventricle enlargement as a major cause of mortality in mice and speculate such an event transpires in a subpopulation of human HSV encephalitic patients.

Granulocytes in Ocular HSV-1 Infection: Opposing Roles of Mast Cells and Neutrophils.

Abstract: Herpes simplex virus type-1 (HSV-1) is a neurotropic double-stranded DNA virus with significant clinical interest due to its endemic nature, life-long persistence, and status as the leading cause of infectious corneal blindness.1,2 The global burden of corneal HSV-1 infection is estimated to be 1.5 million annual occurrences including 40,000 new cases of severe monocular visual impairment or blindness.3 More than 60% of the human population is infected with and harbors latent HSV-1 in neuronal ganglia.2,4,5 Periodic reactivation of HSV-1 facilitates shedding of infectious progeny in external mucosae innervated by infected neurons, often resulting in herpes labialis (i.e., cold sores) or ocular herpes keratitis.2,6 Farooq et al.7 have reviewed the mechanisms of HSV-1 cell entry and spread in the eye. Intermittent but recurrent HSV-1 reactivation in the cornea contributes to the development of herpes stromal keratitis (HSK), a blinding immunopathology characterized by inflammation, scarring, and neovascularization.2,3 Investigating processes of immune surveillance and innate countermeasures during the earliest stages of infection is important to better understand HSV-1 pathogenesis, focus development of novel therapeutics, and ultimately prevent HSK. The innate immune response to HSV-1 infection in the cornea is multifactorial. It is abundantly clear that type-1 IFN-α/β signaling in both resident cells and infiltrating leukocytes is required for control of HSV-1.8 Due to the avascular nature of the normal cornea, circulating leukocytes must extravasate from blood vessels surrounding the cornea in the limbus and migrate through the tissue in accordance with the local milieu of inflammatory mediators (i.e., cytokines, chemokines, eicosanoids, etc.) following injury or pathogenic insult.9–12 Acute corneal HSV-1 infection provokes a potent influx of innate leukocytes including inflammatory monocytes, macrophages, natural killer (NK) cells, and neutrophils (PMNs). Of these responders, inflammatory monocytes contribute to virus clearance during the first 48 hours post infection (pi).8 Conversely, current evidence suggests that PMNs are not responsible for HSV-1 clearance.13,14 Resident and perhaps infiltrating dendritic cells also respond to HSV-1 infection or regulate the activity of other leukocytes in the cornea.15 In addition to resident dendritic cells, an often overlooked bone marrow–derived cell residing in the mucosa of the external eye is the mast cell (MC).16 Mast cells are long-lived radioresistant granulocytes strategically localized in tissues exposed to the external environment to facilitate pathogen surveillance.17,18 Mast cells express an armament of innate sensors to accommodate this protective role.18 Upon stimulation, MCs undergo rapid degranulation of cytoplasmic granules containing preformed proteases and potent vasoactive mediators including histamine and TNFα . Following degranulation, MCs produce many soluble factors de novo to fine-tune subsequent innate and adaptive responses.17,18 The scope and functional diversity of immunomodulatory mast cell granule products have recently been reviewed by Wernersson and Pejler.19 Though the activities attributed to MCs in general are broad, it is recognized that the MC phenotype and products are regulated in a niche- and stimulus-specific manner.19,20 Mast cells have been implicated in the maintenance of immune privilege and contribute to pathogen surveillance and defense in various anatomic sites including the skin, lung, bladder, and gut.18,19,21,22 In the human host, MCs reside in an organized fashion within the eye-associated lymphoid tissue including the lacrimal gland, limbus, and conjunctiva.23–25 Whereas the contributions of ocular MCs are appreciated in IgE-mediated allergic conjunctivitis, they have not been investigated with respect to pathogen defense in the eye. In the present article, we hypothesized MCs are involved in the innate immune response to ocular HSV-1 infection due to their proximity to the cornea and immunomodulatory potential. Mice deficient in MCs were found to be more sensitive to HSV-1 infection, but counterintuitively exhibited greater corneal edema. Collectively, our results underscore a novel role for MCs in the eye as an innate sentinel against acute HSV-1 infection by promoting virus clearance and limiting inflammation to preserve the visual axis. We also found that MCs serve as a type of gatekeeper in the corneal vasculature. Imbalances in eicosanoid mediators are implicated in increased corneal PMN infiltration and inflammation in KitW-sh mice. Neutrophils were identified as surrogates for HSV-1 replication using in vivo, in vitro, and adoptive cell transfer approaches. Lastly, we establish that myeloid-derived suppressor cells (MDSC) do not compromise the use of KitW-sh mice in our model investigating the impact of MCs on the innate and early adaptive immune response to acute HSV-1 infection.

Thrombocytopenia as an adverse effect of complementary and alternative medicines, herbal remedies, nutritional supplements, foods, and beverages

Abstract: Background: Thrombocytopenia is a well-recognized adverse effect of many drugs. However, the association of thrombocytopenia with complementary ⁄alternative medicines, herbal remedies, nutritional supplements, foods, and beverages has been rarely described, except for reports of thrombocytopenia caused by quinine-containing beverages. Objectives: To systematically identify all published reports of thrombocytopenia associated with these substances and to assess the evidence supporting their causal association with thrombocytopenia. Methods: Eleven databases were searched to identify relevant published reports. A priori criteria were defined for article selection and assessment. Each selected article was independently assessed by the three authors to document the presence of the criteria and determine the level of evidence for a causal association of the reported substance with thrombocytopenia. Results: Twenty-seven articles were identified that reported the occurrence of thrombocytopenia with 25 substances (other than quinine). However, only six articles describing five substances (cow’s milk, cranberry juice, Jui [Chinese herbal tea], Lupinus termis bean, and tahini [pulped sesame seeds]) reported clinical data supporting definite evidence of a causal association with thrombocytopenia. Four articles provided probable evidence for four additional substances, and five articles provided possible evidence for five additional substances. In the remaining articles, the association with thrombocytopenia was unlikely or the articles were excluded from review. Conclusions: Reports of thrombocytopenia describing definite or probable evidence for an association of a complementary ⁄alternative medicines, herbal remedies, nutritional supplements, foods, and beverages are rare. Whether the occurrence of thrombocytopenia with these substances is uncommon or unrecognized is unknown.

A Highly Efficacious Herpes Simplex Virus 1 Vaccine Blocks Viral Pathogenesis and Prevents Corneal Immunopathology via Humoral Immunity

Abstract: Correlates of immunologic protection requisite for an efficacious herpes simplex virus 1 (HSV-1) vaccine remain unclear with respect to viral pathogenesis and clinical disease. In the present study, mice were vaccinated with a novel avirulent, live attenuated virus (0ΔNLS) or an adjuvanted glycoprotein D subunit (gD-2) similar to that used in several human clinical trials. Mice vaccinated with 0ΔNLS showed superior protection against early viral replication, neuroinvasion, latency, and mortality compared to that of gD-2-vaccinated or naive mice following ocular challenge with a neurovirulent clinical isolate of HSV-1. Moreover, 0ΔNLS-vaccinated mice exhibited protection against ocular immunopathology and maintained corneal mechanosensory function. Vaccinated mice also showed suppressed T cell activation in the draining lymph nodes following challenge. Vaccine efficacy correlated with serum neutralizing antibody titers. Humoral immunity was identified as the correlate of protection against corneal neovascularization, HSV-1 shedding, and latency through passive immunization. Overall, 0ΔNLS affords remarkable protection against HSV-1-associated ocular sequelae by impeding viral replication, dissemination, and establishment of latency. IMPORTANCE HSV-1 manifests in a variety of clinical presentations ranging from a rather benign “cold sore” to more severe forms of infection, including necrotizing stromal keratitis and herpes simplex encephalitis. The present study was undertaken to evaluate a novel vaccine to ocular HSV-1 infection not only for resistance to viral replication and spread but also for maintenance of the visual axis. The results underscore the necessity to reconsider strategies that utilize attenuated live virus as opposed to subunit vaccines against ocular HSV-1 infection.

Sensing of HSV-1 by the cGAS-STING pathway in microglia orchestrates antiviral defence in the CNS

Abstract: Herpes simplex encephalitis (HSE) is the most common form of acute viral encephalitis in industrialized countries. Type I interferon (IFN) is important for control of herpes simplex virus (HSV-1) in the central nervous system (CNS). Here we show that microglia are the main source of HSV-induced type I IFN expression in CNS cells and these cytokines are induced in a cGAS-STING-dependent manner. Consistently, mice defective in cGAS or STING are highly susceptible to acute HSE. Although STING is redundant for cell-autonomous antiviral resistance in astrocytes and neurons, viral replication is strongly increased in neurons in STING-deficient mice. Interestingly, HSV-infected microglia confer STING-dependent antiviral activities in neurons and prime type I IFN production in astrocytes through the TLR3 pathway. Thus, sensing of HSV-1 infection in the CNS by microglia through the cGAS-STING pathway orchestrates an antiviral program that includes type I IFNs and immune-priming of other cell types.

Adverse hematological effects of hexavalent chromium: an overview

Abstract: Workers of tanneries, welding industries, factories manufacturing chromate containing paints are exposed to hexavalent chromium that increases the risk of developing serious adverse health effects. This review elucidates the mode of action of hexavalent chromium on blood and its adverse effects. Both leukocyte and erythrocyte counts of blood sharply decreased in Swiss mice after two weeks of intraperitoneal treatment with Cr (VI), with the erythrocytes transforming into echinocytes. The hexavalent chromium in the blood is readily reduced to trivalent form and the reductive capacity of erythrocytes is much greater than that of plasma. Excess Cr (VI), not reduced in plasma, may enter erythrocytes and lymphocytes and in rodents it induces microcytic anemia. The toxic effects of chromium (VI) include mitochondrial injury and DNA damage of blood cells that leads to carcinogenicity. Excess Cr (VI) increases cytosolic Ca2+ activity and ATP depletion thereby inducing eryptosis. Se, vitamin C, and quercetin are assumed to have some protective effect against hexavalent chromium induced hematological disorders.