Transcriptional Profiling Confirms the Therapeutic Effects of Mast Cell Stabilization in a Dengue Disease Model

Morrison, Juliet; Rathore, Abhay P. S.; Mantri, Chinmay K.; Aman, Siti A B; Nishida, Andrew; John, Ashley L. St.

doi:10.1128/jvi.00617-17

Cited by 37 publications

(35 citation statements)

References 77 publications

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“…70 Hence inhibition of MC degranulation induces improvement of clinical symptoms. 71 Because DENV-specific IgE titers were increased in patients with Dengue hemorrhagic fever or shock syndrome, 72 FcεRI-mediated MC activation could result in increased MC reactivity, which is in line with observed increased IL-9 and IL-17 levels. 70 Being sentinel cells in human lungs, MCs get in contact with human respiratory pathogens, such as influenza A virus (IAV) and rhinoviruses.…”

Section: Multifaceted Roles Of Mcs In Host Defense Against Infectionmentioning

confidence: 62%

Mast cells as protectors of health

Dudeck

Köberle

Goldmann

et al. 2019

Journal of Allergy and Clinical Immunology

108

106

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Mast cells (MCs), which are well known for their effector functions in T H 2-skewed allergic and also autoimmune inflammation, have become increasingly acknowledged for their role in protection of health. It is now clear that they are also key modulators of immune responses at interface organs, such as the skin or gut. MCs can prime tissues for adequate inflammatory responses and cooperate with dendritic cells in T-cell activation. They also regulate harmful immune responses in trauma and help to successfully orchestrate pregnancy. This review focuses on the beneficial effects of MCs on tissue homeostasis and elimination of toxins or venoms. MCs can enhance pathogen clearance in many bacterial, viral, and parasitic infections, such as through Toll-like receptor 2-triggered degranulation, secretion of antimicrobial cathelicidins, neutrophil recruitment, or provision of extracellular DNA traps. The role of MCs in tumors is more ambiguous; however, encouraging new findings show they can change the tumor microenvironment toward antitumor immunity when adequately triggered. Uterine tissue remodeling by a-chymase (mast cell protease [MCP] 5) is crucial for successful embryo implantation. MCP-4 and the tryptase MCP-6 emerge to be protective in central nervous system trauma by reducing inflammatory damage and excessive scar formation, thereby protecting axon growth. Last but not least, proteases, such as carboxypeptidase A, released by FcεRIactivated MCs detoxify an increasing number of venoms and endogenous toxins. A better understanding of the plasticity of MCs will help improve these advantageous effects and hint at ways to cut down detrimental MC actions.

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Section: Multifaceted Roles Of Mcs In Host Defense Against Infectionmentioning

confidence: 62%

Mast cells as protectors of health

Dudeck

Köberle

Goldmann

et al. 2019

Journal of Allergy and Clinical Immunology

108

106

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“…The involvement of mast cells in dengue pathogenesis suggests they may be potential therapeutic targets. The mast cell-stabilizing drug, ketotifen, not only improves DENV-induced vasculopathy [ 83 ] but also reverses the DENV-induced host response without suppressing memory T cell formation [ 108 ]. Furthermore, antibodies against DENV NS1 provide protection in mice against DENV challenge and reduce mast cell degranulation and macrophage infiltration as well as the production of chemokines including CCL2, CCL5, and CXCL10 (IP-10) at local skin DENV infection sites [ 109 ].…”

Section: Introductionmentioning

confidence: 99%

The monocyte-macrophage-mast cell axis in dengue pathogenesis

et al. 2018

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Dengue virus, the causative agent of dengue disease which may have hemorrhagic complications, poses a global health threat. Among the numerous target cells for dengue virus in humans are monocytes, macrophages and mast cells which are important regulators of vascular integrity and which undergo dramatic cellular responses after infection by dengue virus. The strategic locations of these three cell types, inside blood vessels (monocytes) or outside blood vessels (macrophages and mast cells) allow them to respond to dengue virus infection with the production of both intracellular and secretory factors which affect virus replication, vascular permeability and/or leukocyte extravasation. Moreover, the expression of Fc receptors on the surface of monocytes, macrophages and mast cells makes them important target cells for antibody-enhanced dengue virus infection which is a major risk factor for severe dengue disease, involving hemorrhage. Collectively, these features of monocytes, macrophages and mast cells contribute to both beneficial and harmful responses of importance to understanding and controlling dengue infection and disease.

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“…However, in adult mice, we did not detect any ZIKV RNA in 24 the brain (Figure 1g), which is consistent with our understanding that ZIKV causes only a mild 25 febrile illness in the majority of adult human patients 4 . Our data showing that ZIKV RNA could 12 that induces Flavivirus cross-reactive antibodies 26,27 . Pregnant dams were either naïve (to both 13 ZIKV and DENV), immune to DENV2 after clearing infection that preceded pregnancy by 3 14 weeks, or adoptively transferred monoclonal antibody 4G2, which was raised against DENV2 15 but is Flavivirus cross-reactive 28 .…”

mentioning

confidence: 66%

Maternal immunity and antibodies to dengue promote Zika virus-induced microcephaly in fetuses

Rathore

Saron

Lim

et al. 2018

Preprint

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2Zika virus (ZIKV), a recently emerged flaviviral pathogen, has been linked to 3 microcephaly in neonates 1 . Yet, it is not understood why some fetuses develop severe 4 microcephaly due to maternal ZIKV infection while others do not. The risk for ZIKV-5 induced microcephaly is greatest during the first trimester of pregnancy in humans 2,3 , yet 6 this alone cannot account for the varied presentation of microcephaly observed. Given 7 the antigenic similarity between ZIKV and closely related dengue virus (DENV) 4 , 8 combined with the substantial immunity to DENV in ZIKV target populations in recent 9 outbreaks, we hypothesized that maternal antibodies against DENV could promote ZIKV-10 induced microcephaly. Here, using immune-competent mice, we show that maternal to 11 fetal transmission of ZIKV occurs, leading to fetal infection and disproportionate 12 microcephaly. DENV-specific antibodies in pregnant female mice enhance vertical 13 transmission of infection and result in a severe microcephaly like-syndrome during ZIKV 14 infection. Furthermore, fetal infection was promoted by the neonatal Fc receptor (FcRN).15 Our results identify a novel immune-mediated mechanism of vertical transmission of 16 viral infection and raise caution since ZIKV epidemic regions are also endemic to DENV. 17 18 19 Zika virus (ZIKV) belongs to the family of Flaviviridae, which includes other arboviruses, 21 such as dengue virus (DENV), Japanese encephalitis virus (JEV) and West Nile virus 4 . ZIKV 22unexpectedly surfaced recently as a major public health concern due to the ongoing and 23 spreading epidemic in South and Central America and the realization that it could cause birth 24 defects and neurological complications 3,5 . In a recent study the rate of neurologic and ocular 25 defects in fetuses born to ZIKV infected mothers were calculated to be ~7% 6 . Rarely, adults 26 experience ZIKV-induced Guillain Barré syndrome 7 , but the congenital ZIka syndrome in infants 27 that includes a spectrum of neurological defects, including microcephaly, is the most 28 devastating and pressing aspect of ZIKV infection 8 . It is suggested that the risk of microcephaly 29 is higher in the fetus when mothers are exposed to ZIKV during first trimester of pregnancy 3,6 . 30Some studies have reported the direct effects of ZIKV infection on neuronal tissue damage 9,10 . 31However, not all ZIKV infections during pregnancy appear to result in brain abnormality during 32 embryonic development and the mechanisms that lead to microcephaly in some fetuses but not 33 others are not yet understood.Interestingly, ZIKV epidemic regions are often endemic for other Flavivirus infections, 1 particularly DENV. Due to the structural similarities between ZIKV and DENV 11,12 , antibodies 2 raised against one of the viruses are able to cross react with the others 12,13 . It is thought that 3 DENV antibodies can potentially lead to antibody-dependent enhanced replication (ADE) of 4 ZIKV in infected patients 14 , which has been shown through in vitro assays 13 . The res...

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Transcriptional Profiling Confirms the Therapeutic Effects of Mast Cell Stabilization in a Dengue Disease Model

Cited by 37 publications

References 77 publications

Mast cells as protectors of health

Mast cells as protectors of health

The monocyte-macrophage-mast cell axis in dengue pathogenesis

Maternal immunity and antibodies to dengue promote Zika virus-induced microcephaly in fetuses

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