scholarly journals Mast Cell Responses to Viruses and Pathogen Products

2019 ◽  
Vol 20 (17) ◽  
pp. 4241 ◽  
Author(s):  
Jean S. Marshall ◽  
Liliana Portales-Cervantes ◽  
Edwin Leong
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Immune Responses ◽  
Viral Infection ◽  
Viral Infections ◽  
Inflammatory Responses ◽  
Local Source ◽  
Type I ◽  
Viral Challenge ◽  
Cell Responses

Mast cells are well accepted as important sentinel cells for host defence against selected pathogens. Their location at mucosal surfaces and ability to mobilize multiple aspects of early immune responses makes them critical contributors to effective immunity in several experimental settings. However, the interactions of mast cells with viruses and pathogen products are complex and can have both detrimental and positive impacts. There is substantial evidence for mast cell mobilization and activation of effector cells and mobilization of dendritic cells following viral challenge. These cells are a major and under-appreciated local source of type I and III interferons following viral challenge. However, mast cells have also been implicated in inappropriate inflammatory responses, long term fibrosis, and vascular leakage associated with viral infections. Progress in combating infection and boosting effective immunity requires a better understanding of mast cell responses to viral infection and the pathogen products and receptors we can employ to modify such responses. In this review, we outline some of the key known responses of mast cells to viral infection and their major responses to pathogen products. We have placed an emphasis on data obtained from human mast cells and aim to provide a framework for considering the complex interactions between mast cells and pathogens with a view to exploiting this knowledge therapeutically. Long-lived resident mast cells and their responses to viruses and pathogen products provide excellent opportunities to modify local immune responses that remain to be fully exploited in cancer immunotherapy, vaccination, and treatment of infectious diseases.

Pulmonary immunity to viruses

2017 ◽  
Vol 131 (14) ◽  
pp. 1737-1762 ◽  
Author(s):  
S. Rameeza Allie ◽  
Troy D. Randall
Keyword(s):  
Immune Responses ◽  
Respiratory Tract ◽  
Viral Infection ◽  
Viral Infections ◽  
Inflammatory Responses ◽  
Lung Damage ◽  
Immune Memory ◽  
Chronic Obstructive ◽  
Adaptive Immune ◽  
Respiratory Viral Infections

Mucosal surfaces, such as the respiratory epithelium, are directly exposed to the external environment and therefore, are highly susceptible to viral infection. As a result, the respiratory tract has evolved a variety of innate and adaptive immune defenses in order to prevent viral infection or promote the rapid destruction of infected cells and facilitate the clearance of the infecting virus. Successful adaptive immune responses often lead to a functional state of immune memory, in which memory lymphocytes and circulating antibodies entirely prevent or lessen the severity of subsequent infections with the same virus. This is also the goal of vaccination, although it is difficult to vaccinate in a way that mimics respiratory infection. Consequently, some vaccines lead to robust systemic immune responses, but relatively poor mucosal immune responses that protect the respiratory tract. In addition, adaptive immunity is not without its drawbacks, as overly robust inflammatory responses may lead to lung damage and impair gas exchange or exacerbate other conditions, such as asthma or chronic obstructive pulmonary disease (COPD). Thus, immune responses to respiratory viral infections must be strong enough to eliminate infection, but also have mechanisms to limit damage and promote tissue repair in order to maintain pulmonary homeostasis. Here, we will discuss the components of the adaptive immune system that defend the host against respiratory viral infections.

scholarly journals Mast Cells Modulate Antigen-Specific CD8+ T Cell Activation During LCMV Infection

2021 ◽  
Vol 12 ◽  
Author(s):  
Yana Hackler ◽  
Frank Siebenhaar ◽  
Max Löhning ◽  
Marcus Maurer ◽  
Melba Muñoz
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mast Cells ◽  
Immune Responses ◽  
Cytokine Production ◽  
T Cell Responses ◽  
Type I ◽  
Cell Responses ◽  
Deficient Mice ◽  
Lcmv Infection

Mast cells (MCs), strategically localized at mucosal surfaces, provide first-line defense against pathogens and shape innate and adaptive immune responses. Recent studies have shown that MCs are involved in pathogenic responses to several viruses including herpes simplex viruses, dengue virus, vaccinia virus and influenza virus. However, the underlying mechanisms of MCs in the activation of CD8+ T cells during viral infections are not fully understood. Therefore, we investigate the role of MCs in the development of virus-specific CD8+ T cell responses using the well-characterized murine lymphocytic choriomeningitis virus (LCMV) model and the transgenic MasTRECK mice that contain the human diphtheria toxin receptor as an inducible MC-deficient model. Here, we report that MCs are essential for the activation and expansion of virus-specific CD8+ T cells. After MC depletion and subsequent intradermal LCMV infection, the CD8+ T cell effector phenotype and antiviral cytokine production were impaired at the peak of infection (day 8 p.i.). Importantly, MC-deficient mice were unable to control the infection and exhibited significantly higher viral loads in the spleen and in the ear draining lymph nodes compared to that of wild type control mice. In the absence of MCs, dendritic cell (DC) activation was impaired upon LCMV infection. In addition, type-I interferon (IFN) levels in the serum and in the spleen of MC-deficient mice were reduced during the first days of infection. Interestingly, depletion of MCs after intradermal LCMV infection did not impair virus-specific CD8+ T cell expansion, activation or antiviral cytokine production. In summary, our results indicate that MCs play a pivotal role in the activation and antiviral functions of CD8+ T cells through proper DC activation. A better understanding of the impact of MCs on CD8+ T cell responses is mandatory to improve antiviral immune responses.

scholarly journals SAMHD1 suppresses innate immune responses to viral infections and inflammatory stimuli by inhibiting the NF-κB and interferon pathways

2018 ◽  
Vol 115 (16) ◽  
pp. E3798-E3807 ◽  
Author(s):  
Shuliang Chen ◽  
Serena Bonifati ◽  
Zhihua Qin ◽  
Corine St. Gelais ◽  
Karthik M. Kodigepalli ◽  
...  
Keyword(s):  
Immune Responses ◽  
Viral Infections ◽  
Inflammatory Responses ◽  
Sendai Virus ◽  
Innate Immune ◽  
Type I ◽  
Innate Immune Responses ◽  
Monocytic Cells ◽  
Intracellular Dntp ◽  
Inflammatory Stimuli

Sterile alpha motif and HD-domain–containing protein 1 (SAMHD1) blocks replication of retroviruses and certain DNA viruses by reducing the intracellular dNTP pool. SAMHD1 has been suggested to down-regulate IFN and inflammatory responses to viral infections, although the functions and mechanisms of SAMHD1 in modulating innate immunity remain unclear. Here, we show that SAMHD1 suppresses the innate immune responses to viral infections and inflammatory stimuli by inhibiting nuclear factor-κB (NF-κB) activation and type I interferon (IFN-I) induction. Compared with control cells, infection of SAMHD1-silenced human monocytic cells or primary macrophages with Sendai virus (SeV) or HIV-1, or treatment with inflammatory stimuli, induces significantly higher levels of NF-κB activation and IFN-I induction. Exogenous SAMHD1 expression in cells or SAMHD1 reconstitution in knockout cells suppresses NF-κB activation and IFN-I induction by SeV infection or inflammatory stimuli. Mechanistically, SAMHD1 inhibits NF-κB activation by interacting with NF-κB1/2 and reducing phosphorylation of the NF-κB inhibitory protein IκBα. SAMHD1 also interacts with the inhibitor-κB kinase ε (IKKε) and IFN regulatory factor 7 (IRF7), leading to the suppression of the IFN-I induction pathway by reducing IKKε-mediated IRF7 phosphorylation. Interactions of endogenous SAMHD1 with NF-κB and IFN-I pathway proteins were validated in human monocytic cells and primary macrophages. Comparing splenocytes from SAMHD1 knockout and heterozygous mice, we further confirmed SAMHD1-mediated suppression of NF-κB activation, suggesting an evolutionarily conserved property of SAMHD1. Our findings reveal functions of SAMHD1 in down-regulating innate immune responses to viral infections and inflammatory stimuli, highlighting the importance of SAMHD1 in modulating antiviral immunity.

Mast cells release cytokines in response to mediators produced by virus-infected epithelial cellss

2007 ◽  
Vol 30 (4) ◽  
pp. 96
Author(s):  
Candy Tsang ◽  
A. D. Befus
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Epithelial Cells ◽  
Viral Infections ◽  
Allergic Diseases ◽  
Type I Interferons ◽  
Human Mast Cell ◽  
Type I ◽  
Dependent Manner ◽  
Tlr Agonists

Background: Mast cells have long been recognized for their involvement in allergic diseases. In the last decade, the importance of mast cells in innate responses against bacteria has been established, but little is known about their contribution in viral infections. Mast cells are abundant at mucosal surfaces such as the lungs in close proximity to the epithelium. In the lung, the epithelium is a primary target for viral infections. Mast cells are secondarily exposed to newly formed virions released from epithelial cells. Mast cells have toll-like receptors (TLRs) that detect various pathogen components. Our first hypothesis is that viral TLR agonists will induce mast cells to release cytokines thought to be involved in viral infections. Both the pro-inflammatory cytokine IL-6 and the chemokine IL-8 are produced during viral infections. TGF-β is an immunoregulatory cytokine that modulates the activity of various immune cells and could also play a role in viral infections. Methods: We used polyI:C, a synthetic double-stranded RNA (dsRNA), as a TLR3 agonist, loxoribine as a TLR7 agonist, and unmethylated CpG DNA as a TLR9 agonist. We treated mast cells from the cell line HMC-1 (Human Mast cell-1) for 0.5 – 24hr with the TLR agonists and performed dose response studies for all stimuli. Supernatants from treated mast cells were measured for IL-6, IL-8, and TGF-β by ELISA. Results: Cytokine release was highest at the 24hr time point. Mast cells released IL-6, IL-8, and TGF-β in response to the TLR3 agonist polyI:C in a dose-dependent manner, but not to the other viral TLR agonists. PolyI:C (10μg/mL) versus unstimulated controls significantly increased mast cell release of IL-6 (224.7±57.4 vs. 39.0±5.7, p≤0.001) and TGF-β (240.2±28.9 vs. 116.1±16.7, p≤0.05). PolyI:C induced release of IL-8 from mast cells was increased but not significant. Viral exposure also induces epithelial cells to produce type I interferons, IFNα and β. These interferons have potent antiviral activity, but also have effects on mast cells, decreasing mast cell adhesion to extracellular matrix and reducing co-stimulatory activity on T cells. Our second hypothesis is that IFNα and β will induce mast cells to release cytokines similar to stimulation with polyI:C. Our preliminary data showed that IFNα, IFNβ , and IFNα and β in combination induced a low level of IL-8 and TGF-β release from mast cells, but had no effect on IL-6 release. Conclusion: HMC-1 responds to dsRNA, a TLR3 agonist produced in epithelial cells during viral replication, by releasing IL-6 and TGF-β. HMC-1 also responds to IFNα and β by releasing IL-8 and TGF-β, indicating that human mast cells respond to epithelial mediators produced during viral infections. Our results show that mast cells contribute to the innate response against viruses by responding to mediators released by virus-infected epithelial cells.

scholarly journals Systems analysis of immune responses to attenuated P. falciparum malaria sporozoite vaccination reveals excessive inflammatory signatures correlating with impaired immunity

2021 ◽  
Author(s):  
Ying Du ◽  
Nina Hertoghs ◽  
Jason Carnes ◽  
Suzanne M. McDermott ◽  
Maxwell L. Neal ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
Malaria Infection ◽  
Vaccine Development ◽  
Inflammatory Responses ◽  
T Cell Responses ◽  
Type I ◽  
Cell Responses ◽  
Controlled Human Malaria Infection ◽  
Interferon Responses

Immunization with radiation-attenuated sporozoites (RAS) can confer sterilizing protection against malaria, although the mechanisms behind this protection are incompletely understood. We performed a systems biology analysis of samples from the Immunization by Mosquito with Radiation Attenuated Sporozoites IMRAS) trial, which comprised P. falciparum RAS-immunized (PfRAS), malaria-naive participants whose protection from malaria infection was subsequently assessed by controlled human malaria infection (CHMI). Blood samples collected after initial PfRAS immunization were analyzed to compare immune responses between protected and non-protected volunteers leveraging integrative analysis of whole blood RNA-seq, high parameter flow cytometry, and single cell CITEseq of PBMCs. This analysis revealed differences in early innate immune responses indicating divergent paths associated with protection. In particular, elevated levels of inflammatory responses early after the initial immunization were detrimental for the development of protective adaptive immunity. Specifically, non-classical monocytes and early type I interferon responses induced within 1 day of PfRAS vaccination correlated with impaired immunity. Non-protected individuals also showed an increase in Th2 polarized T cell responses whereas we observed a trend towards increased Th1 and T-bet+ CD8 T cell responses in protected individuals. Temporal differences in genes associated with natural killer cells suggest an important role in immune regulation by these cells. These findings give insight into the immune responses that confer protection against malaria and may guide further malaria vaccine development.

scholarly journals Role of Alternative Splicing in Regulating Host Response to Viral Infection

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1720
Author(s):  
Kuo-Chieh Liao ◽  
Mariano A. Garcia-Blanco
Keyword(s):  
Innate Immunity ◽  
Alternative Splicing ◽  
Immune Responses ◽  
Viral Infection ◽  
Rna Splicing ◽  
Type I ◽  
Host Immune Responses ◽  
Transcriptional Regulatory Mechanisms ◽  
Host Virus Interactions

The importance of transcriptional regulation of host genes in innate immunity against viral infection has been widely recognized. More recently, post-transcriptional regulatory mechanisms have gained appreciation as an additional and important layer of regulation to fine-tune host immune responses. Here, we review the functional significance of alternative splicing in innate immune responses to viral infection. We describe how several central components of the Type I and III interferon pathways encode spliced isoforms to regulate IFN activation and function. Additionally, the functional roles of splicing factors and modulators in antiviral immunity are discussed. Lastly, we discuss how cell death pathways are regulated by alternative splicing as well as the potential role of this regulation on host immunity and viral infection. Altogether, these studies highlight the importance of RNA splicing in regulating host–virus interactions and suggest a role in downregulating antiviral innate immunity; this may be critical to prevent pathological inflammation.

scholarly journals Innate cell microenvironments in lymph nodes shape the generation of T cell responses during type I inflammation

2021 ◽  
Vol 6 (56) ◽  
pp. eabb9435
Author(s):  
Joseph M. Leal ◽  
Jessica Y. Huang ◽  
Karan Kohli ◽  
Caleb Stoltzfus ◽  
Miranda R. Lyons-Cohen ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
Lymph Nodes ◽  
Critical Role ◽  
Myeloid Cell ◽  
T Cell Responses ◽  
Type I ◽  
Cell Responses ◽  
Inflammatory Monocytes ◽  
Cell Effector

Microanatomical organization of innate immune cells within lymph nodes (LNs) is critical for the generation of adaptive responses. In particular, steady-state LN-resident dendritic cells (Res cDCs) are strategically localized to intercept lymph-draining antigens. Whether myeloid cell organization changes during inflammation and how that might affect the generation of immune responses are unknown. Here, we report that during type I, but not type II, inflammation after adjuvant immunization or viral infection, antigen-presenting Res cDCs undergo CCR7-dependent intranodal repositioning from the LN periphery into the T cell zone (TZ) to elicit T cell priming. Concurrently, inflammatory monocytes infiltrate the LNs via local blood vessels, enter the TZ, and cooperate with Res cDCs by providing polarizing cytokines to optimize T cell effector differentiation. Monocyte infiltration is nonuniform across LNs, generating distinct microenvironments with varied local innate cell composition. These spatial microdomains are associated with divergent early T cell effector programming, indicating that innate microenvironments within LNs play a critical role in regulating the quality and heterogeneity of T cell responses. Together, our findings reveal that dynamic modulation of innate cell microenvironments during type I inflammation leads to optimized generation of adaptive immune responses to vaccines and infections.

scholarly journals Type I interferons act directly on nociceptors to produce pain sensitization: Implications for viral infection-induced pain

2019 ◽  
Author(s):  
Paulino Barragan-Iglesias ◽  
Úrzula Franco-Enzástiga ◽  
Vivekanand Jeevakumar ◽  
Andi Wangzhou ◽  
Vinicio Granados-Soto ◽  
...  
Keyword(s):  
Viral Infection ◽  
Viral Infections ◽  
Mrna Translation ◽  
Type I Interferons ◽  
Poly I:C ◽  
Type I ◽  
Drg Neurons ◽  
Pain Hypersensitivity ◽  
Type I Ifns ◽  
Pain Sensitization

ABSTRACTOne of the first signs of viral infection is body-wide aches and pain. While this type of pain usually subsides, at the extreme, viral infections can induce painful neuropathies that can last for decades. Neither of these types of pain sensitization are well understood. A key part of the response to viral infection is production of interferons (IFNs), which then activate their specific receptors (IFNRs) resulting in downstream activation of cellular signaling and a variety of physiological responses. We sought to understand how type I IFNs (IFN-α and IFN-β) might act directly on nociceptors in the dorsal root ganglion (DRG) to cause pain sensitization. We demonstrate that type I IFNRs are expressed in small/medium DRG neurons and that their activation produces neuronal hyper-excitability and mechanical pain in mice. Type I IFNs stimulate JAK/STAT signaling in DRG neurons but this does not apparently result in PKR-eIF2α activation that normally induces an anti-viral response by limiting mRNA translation. Rather, type I interferons stimulate MNK-mediated eIF4E phosphorylation in DRG neurons to promote pain hypersensitivity. Endogenous release of type I IFNs with the double stranded RNA mimetic poly(I:C) likewise produces pain hypersensitivity that is blunted in mice lacking MNK-eIF4E signaling. Our findings reveal mechanisms through which type I IFNs cause nociceptor sensitization with implications for understanding how viral infections promote pain and can lead to neuropathies.SIGNIFICANCE STATEMENTIt is increasingly understood that pathogens interact with nociceptors to alert organisms to infection as well as to mount early host defenses. While specific mechanisms have been discovered for diverse bacteria and fungal pathogens, mechanisms engaged by viruses have remained elusive. Here we show that type 1 interferons, one of the first mediators produced by viral infection, act directly on nociceptors to produce pain sensitization. Type I interferons act via a specific signaling pathway (MNK-eIF4E signaling) that is known to produce nociceptor sensitization in inflammatory and neuropathic pain conditions. Our work reveals a mechanism through which viral infections cause heightened pain sensitivity

scholarly journals Substance P and IL-33 administered together stimulate a marked secretion of IL-1β from human mast cells, inhibited by methoxyluteolin

2018 ◽  
Vol 115 (40) ◽  
pp. E9381-E9390 ◽  
Author(s):  
Alexandra Taracanova ◽  
Irene Tsilioni ◽  
Pio Conti ◽  
Errol R. Norwitz ◽  
Susan E. Leeman ◽  
...  
Keyword(s):  
Gene Expression ◽  
Mast Cell ◽  
Mast Cells ◽  
Substance P ◽  
Proinflammatory Cytokine ◽  
Inflammatory Responses ◽  
Human Umbilical Cord Blood ◽  
Human Umbilical Cord ◽  
Cell Secretion ◽  
Active Caspase

Mast cells are critical for allergic and inflammatory responses in which the peptide substance P (SP) and the cytokine IL-33 are involved. SP (0.01–1 μM) administered together with IL-33 (30 ng/mL) to human cultured LAD2 mast cells stimulates a marked increase (P< 0.0001) in secretion of the proinflammatory cytokine IL-1β. Preincubation of LAD2 (30 min) with the SP receptor (NK-1) antagonists L-733,060 (10 μM) or CP-96345 (10 µM) inhibits (P< 0.001) secretion of IL-1β stimulated by either SP (1 μM) or SP together with IL-33 (30 ng/mL). Surprisingly, secretion of IL-1β stimulated by IL-33 is inhibited (P< 0.001) by each NK-1 antagonist. Preincubation with an antibody against the IL-33 receptor ST2 inhibits (P< 0.0001) secretion of IL-1β stimulated either by IL-33 or together with SP. The combination of SP (1 μM) with IL-33 (30 ng/mL) increases IL-1β gene expression by 90-fold in LAD2 cells and by 200-fold in primary cultured mast cells from human umbilical cord blood. The combination of SP and IL-33 increases intracellular levels of IL-1β in LAD2 by 100-fold and gene expression of IL-1β and procaspase-1 by fivefold and pro-IL-1β by twofold. Active caspase-1 is present even in unstimulated cells and is detected extracellularly. Preincubation of LAD2 cells with the natural flavonoid methoxyluteolin (1–100 mM) inhibits (P< 0.0001) secretion and gene expression of IL-1β, procaspase-1, and pro-IL-1β. Mast cell secretion of IL-1β in response to SP and IL-33 reveals targets for the development of antiinflammatory therapies.

scholarly journals Beyond IgE: Alternative Mast Cell Activation Across Different Disease States

2020 ◽  
Vol 21 (4) ◽  
pp. 1498 ◽  
Author(s):  
David O. Lyons ◽  
Nicholas A. Pullen
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Cell Activation ◽  
Autoimmune Disorders ◽  
Receptor Expression ◽  
Mast Cell Activation ◽  
Food Allergies ◽  
Type I ◽  
Disease States ◽  
Ige Mediated

Mast cells are often regarded through the lens of IgE-dependent reactions as a cell specialized only for anti-parasitic and type I hypersensitive responses. However, recently many researchers have begun to appreciate the expansive repertoire of stimuli that mast cells can respond to. After the characterization of the interleukin (IL)-33/suppression of tumorigenicity 2 (ST2) axis of mast cell activation—a pathway that is independent of the adaptive immune system—researchers are revisiting other stimuli to induce mast cell activation and/or subsequent degranulation independent of IgE. This discovery also underscores that mast cells act as important mediators in maintaining body wide homeostasis, especially through barrier defense, and can thus be the source of disease as well. Particularly in the gut, inflammatory bowel diseases (Crohn’s disease, ulcerative colitis, etc.) are characterized with enhanced mast cell activity in the context of autoimmune disease. Mast cells show phenotypic differences based on tissue residency, which could manifest as different receptor expression profiles, allowing for unique mast cell responses (both IgE and non-IgE mediated) across varying tissues as well. This variety in receptor expression suggests mast cells respond differently, such as in the gut where immunosuppressive IL-10 stimulates the development of food allergy or in the lungs where transforming growth factor-β1 (TGF-β1) can enhance mast cell IL-6 production. Such differences in receptor expression illustrate the truly diverse effector capabilities of mast cells, and careful consideration must be given toward the phenotype of mast cells observed in vitro. Given mast cells’ ubiquitous tissue presence and their capability to respond to a broad spectrum of non-IgE stimuli, it is expected that mast cells may also contribute to the progression of autoimmune disorders and other disease states such as metastatic cancer through promoting chronic inflammation in the local tissue microenvironment and ultimately polarizing toward a unique Th17 immune response. Furthermore, these interconnected, atypical activation pathways may crosstalk with IgE-mediated signaling differently across disorders such as parasitism, food allergies, and autoimmune disorders of the gut. In this review, we summarize recent research into familiar and novel pathways of mast cells activation and draw connections to clinical human disease.

Sign in / Sign up

Export Citation Format

Share Document