scholarly journals MAVS Expressed by Hematopoietic Cells Is Critical for Control of West Nile Virus Infection and Pathogenesis

2016 ◽  
Vol 90 (16) ◽  
pp. 7098-7108 ◽  
Author(s):  
Jincun Zhao ◽  
Rahul Vijay ◽  
Jingxian Zhao ◽  
Michael Gale ◽  
Michael S. Diamond ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
West Nile Virus ◽  
Hematopoietic Cells ◽  
The United States ◽  
Innate Immune ◽  
Target Cells ◽  
West Nile ◽  
Adaptor Molecule ◽  
The Brain

ABSTRACTWest Nile virus (WNV) is the most important cause of epidemic encephalitis in North America. Innate immune responses, which are critical for control of WNV infection, are initiated by signaling through pathogen recognition receptors, RIG-I and MDA5, and their downstream adaptor molecule, MAVS. Here, we show that a deficiency of MAVS in hematopoietic cells resulted in increased mortality and delayed WNV clearance from the brain. InMavs−/−mice, a dysregulated immune response was detected, characterized by a massive influx of macrophages and virus-specific T cells into the infected brain. These T cells were polyfunctional and lysed peptide-pulsed target cellsin vitro. However, virus-specific T cells in the brains of infectedMavs−/−mice exhibited lower functional avidity than those in wild-type animals, and even virus-specific memory T cells generated by prior immunization could not protectMavs−/−mice from WNV-induced lethal disease. Concomitant with ineffective virus clearance, macrophage numbers were increased in theMavs−/−brain, and both macrophages and microglia exhibited an activated phenotype. Microarray analyses of leukocytes in the infectedMavs−/−brain showed a preferential expression of genes associated with activation and inflammation. Together, these results demonstrate a critical role for MAVS in hematopoietic cells in augmenting the kinetics of WNV clearance and thereby preventing a dysregulated and pathogenic immune response.IMPORTANCEWest Nile virus (WNV) is the most important cause of mosquito-transmitted encephalitis in the United States. The innate immune response is known to be critical for protection in infected mice. Here, we show that expression of MAVS, a key adaptor molecule in the RIG-I-like receptor RNA-sensing pathway, in hematopoietic cells is critical for protection from lethal WNV infection. In the absence of MAVS, there is a massive infiltration of myeloid cells and virus-specific T cells into the brain and overexuberant production of proinflammatory cytokines. These results demonstrate the important role that MAVS expression in hematopoietic cells has in regulating the inflammatory response in the WNV-infected brain.

scholarly journals Usutu virus uses langerin as a receptor to productively infect Langerhans cells more efficiently than West Nile virus

2021 ◽  
Author(s):  
Marie-France Martin ◽  
Ghizlane Maarifi ◽  
Hervé Abiven ◽  
Marine Seffals ◽  
Nicolas Mouchet ◽  
...  
Keyword(s):  
Immune Response ◽  
West Nile Virus ◽  
Human Skin ◽  
Langerhans Cells ◽  
Ectopic Expression ◽  
Target Cells ◽  
Global Public Health ◽  
West Nile ◽  
Lectin Receptors ◽  
Usutu Virus

AbstractUsutu virus (USUV) and West Nile virus (WNV) are emerging flaviviruses transmitted by mosquitoes. Although they differ in their endemicity, with WNV present throughout much of the world and USUV currently limited to Africa and Europe, both constitute a global public health threat. Since they are directly inoculated in the epidermis and the dermis during mosquito bites, the skin constitutes the initial site of viral replication and immune response. The skin is equipped with a unique network of dendritic cells, which represent an essential outpost of immune defenses. These skin-resident DCs comprise Langerhans cells (LCs) in the epidermis and dermal DCs in the dermis, which capture pathogens through the C-type lectin receptors (CLR) langerin and DC-SIGN, respectively. Despite the key role of these cells in the body’s antiviral defenses, their implication in the immune control and replication of WNV and USUV is not known.Using human skin explants, we show that while both viruses can replicate in keratinocytes, they can also infect resident DCs with distinct tropism, since WNV preferentially infects DCs in the dermis, whereas USUV has a greater propensity to infect LCs. Using both purified human epidermal LCs (eLCs) and monocyte derived LCs (MoLCs), we confirm that LCs sustain a faster and more efficient replication of USUV compared with WNV and that this correlates with a more intense innate immune response to USUV compared with WNV.Next, we show that ectopic expression of langerin in non-permissive cells rendered them permissive to USUV, but not to WNV. Conversely, blocking or silencing langerin in MoLCs or eLCs made them resistant to USUV infection, thus demonstrating that this specific CLR allows USUV to enter and productively infect LCs.Altogether, our results demonstrate that LCs constitute privileged target cells for USUV in human skin, because langerin favors its entry and replication. Intriguingly, this suggests that USUV efficiently escapes the antiviral functions of langerin, which normally safeguards LCs from most viral infections.

scholarly journals Vaccinia virus protein K7 is a virulence factor that alters the acute immune response to infection

2013 ◽  
Vol 94 (7) ◽  
pp. 1647-1657 ◽  
Author(s):  
Camilla T. O. Benfield ◽  
Hongwei Ren ◽  
Stuart J. Lucas ◽  
Basma Bahsoun ◽  
Geoffrey L. Smith
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Vaccinia Virus ◽  
Nk Cells ◽  
Virulence Factor ◽  
B Cell Lymphoma ◽  
Innate Immune ◽  
Virus Protein ◽  
Target Cells ◽  
Translational Initiation

Vaccinia virus (VACV) encodes many proteins that antagonize the innate immune system including a family of intracellular proteins with a B-cell lymphoma (Bcl)-2-like structure. One of these Bcl-2 proteins called K7 binds Toll-like receptor-adaptor proteins and the DEAD-box RNA helicase DDX3 and thereby inhibits the activation of NF-κB and interferon regulatory factor 3. However, the contribution of K7 to virus virulence is not known. Here a VACV lacking the K7R gene (vΔK7) was constructed and compared with control viruses that included a plaque purified wt (vK7), a revertant with the K7R gene reinserted (vK7-rev) and a frame-shifted virus in which the translational initiation codon was mutated to prevent K7 protein expression (vK7-fs). Data presented show that loss of K7 does not affect virus replication in cell culture or in vivo; however, viruses lacking the K7 protein were less virulent than controls in murine intradermal (i.d.) and intranasal (i.n.) infection models and there was an altered acute immune response to infection. In the i.d. model, vΔK7 induced smaller lesions than controls, and after i.n. infection vΔK7 induced a reduced weight loss and signs of illness, and more rapid clearance of virus from infected tissue. Concomitantly, the intrapulmonary innate immune response to infection with vΔK7 showed increased infiltration of NK cells and CD8+ T-cells, enhanced MHC class II expression by macrophages, and enhanced cytolysis of target cells by NK cells and VACV-specific CD8+ T-cells. Thus protein K7 is a virulence factor that affects the acute immune response to infection.

scholarly journals The Interferon-Stimulated GeneIfitm3Restricts West Nile Virus Infection and Pathogenesis

2016 ◽  
Vol 90 (18) ◽  
pp. 8212-8225 ◽  
Author(s):  
Matthew J. Gorman ◽  
Subhajit Poddar ◽  
Michael Farzan ◽  
Michael S. Diamond
Keyword(s):  
Central Nervous System ◽  
Cell Culture ◽  
T Cells ◽  
Nervous System ◽  
West Nile Virus ◽  
Transmembrane Protein ◽  
Viral Pathogenesis ◽  
West Nile ◽  
The Brain

ABSTRACTThe interferon-induced transmembrane protein (IFITM) family of proteins inhibit infection of several different enveloped viruses in cell culture by virtue of their ability to restrict entry and fusion from late endosomes. As few studies have evaluated the importance ofIfitm3 in vivoin restricting viral pathogenesis, we investigated its significance as an antiviral gene against West Nile virus (WNV), an encephalitic flavivirus, in cells and mice.Ifitm3−/−mice were more vulnerable to lethal WNV infection, and this was associated with greater virus accumulation in peripheral organs and central nervous system tissues. As no difference in viral burden in the brain or spinal cord was observed after direct intracranial inoculation, Ifitm3 likely functions as an antiviral protein in nonneuronal cells. Consistent with this,Ifitm3−/−fibroblasts but not dendritic cells resulted in higher yields of WNV in multistep growth analyses. Moreover, transcomplementation experiments showed that Ifitm3 inhibited WNV infection independently of Ifitm1, Ifitm2, Ifitm5, and Ifitm6. Beyond a direct effect on viral infection in cells, analysis of the immune response in WNV-infectedIfitm3−/−mice showed decreases in the total number of B cells, CD4+T cells, and antigen-specific CD8+T cells. Finally, bone marrow chimera experiments demonstrated that Ifitm3 functioned in both radioresistant and radiosensitive cells, as higher levels of WNV were observed in the brain only when Ifitm3 was absent from both compartments. Our analyses suggest that Ifitm3 restricts WNV pathogenesis likely through multiple mechanisms, including the direct control of infection in subsets of cells.IMPORTANCEAs part of the mammalian host response to viral infections, hundreds of interferon-stimulated genes (ISGs) are induced. The inhibitory activity of individual ISGs varies depending on the specific cell type and viral pathogen. Among ISGs, the genes encoding interferon-induced transmembrane protein (IFITM) have been reported to inhibit multiple families of viruses in cell culture. However, few reports have evaluated the impact ofIFITMgenes on viral pathogenesisin vivo. In this study, we characterized the antiviral activity of Ifitm3 against West Nile virus (WNV), an encephalitic flavivirus, using mice with a targeted gene deletion ofIfitm3. Based on extensive virological and immunological analyses, we determined that Ifitm3 protects mice from WNV-induced mortality by restricting virus accumulation in peripheral organs and, subsequently, in central nervous system tissues. Our data suggest that Ifitm3 restricts WNV pathogenesis by multiple mechanisms and functions in part by controlling infection in different cell types.

scholarly journals Role of CD8+ T Cells in Control of West Nile Virus Infection

2004 ◽  
Vol 78 (15) ◽  
pp. 8312-8321 ◽  
Author(s):  
Bimmi Shrestha ◽  
Michael S. Diamond
Keyword(s):  
Central Nervous System ◽  
T Cells ◽  
Nervous System ◽  
West Nile Virus ◽  
Immunoglobulin M ◽  
Target Cells ◽  
West Nile ◽  
Class I Mhc ◽  
Increased Risk

ABSTRACT Infection with West Nile virus (WNV) causes fatal encephalitis more frequently in immunocompromised humans than in those with a healthy immune system. Although a complete understanding of this increased risk remains unclear, experiments with mice have begun to define how different components of the adaptive and innate immune response function to limit infection. Previously, we demonstrated that components of humoral immunity, particularly immunoglobulin M (IgM) and IgG, have critical roles in preventing dissemination of WNV infection to the central nervous system. In this study, we addressed the function of CD8+ T cells in controlling WNV infection. Mice that lacked CD8+ T cells or classical class Ia major histocompatibility complex (MHC) antigens had higher central nervous system viral burdens and increased mortality rates after infection with a low-passage-number WNV isolate. In contrast, an absence of CD8+ T cells had no effect on the qualitative or quantitative antibody response and did not alter the kinetics or magnitude of viremia. In the subset of CD8+-T-cell-deficient mice that survived initial WNV challenge, infectious virus was recovered from central nervous system compartments for several weeks. Primary or memory CD8+ T cells that were generated in vivo efficiently killed target cells that displayed WNV antigens in a class I MHC-restricted manner. Collectively, our experiments suggest that, while specific antibody is responsible for terminating viremia, CD8+ T cells have an important function in clearing infection from tissues and preventing viral persistence.

scholarly journals Vγ4+T cells regulate host immune response to West Nile virus infection

2011 ◽  
Vol 63 (2) ◽  
pp. 183-192 ◽  
Author(s):  
Thomas Welte ◽  
Judith Aronson ◽  
Bin Gong ◽  
Aparna Rachamallu ◽  
Nicole Mendell ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
West Nile Virus ◽  
Virus Infection ◽  
West Nile Virus Infection ◽  
Host Immune Response ◽  
West Nile

scholarly journals Dynamics of Tissue-Specific CD8+ T Cell Responses during West Nile Virus Infection

2018 ◽  
Vol 92 (10) ◽  
pp. e00014-18 ◽  
Author(s):  
Renan Aguilar-Valenzuela ◽  
Jason Netland ◽  
Young-Jin Seo ◽  
Michael J. Bevan ◽  
Arash Grakoui ◽  
...  
Keyword(s):  
T Cells ◽  
West Nile Virus ◽  
T Cell ◽  
Immunodominant Epitope ◽  
West Nile ◽  
Cell Responses ◽  
Immunological Mechanisms ◽  
The Brain ◽  
Ns4b Protein

ABSTRACT The mouse model of West Nile virus (WNV), which is a leading cause of mosquito-borne encephalitis worldwide, has provided fundamental insights into the host and viral factors that regulate viral pathogenesis and infection outcome. In particular, CD8+ T cells are critical for controlling WNV replication and promoting protection against infection. Here, we present the characterization of a T cell receptor (TCR)-transgenic mouse with specificity for the immunodominant epitope in the WNV NS4B protein (here referred to as transgenic WNV-I mice). Using an adoptive-transfer model, we found that WNV-I CD8+ T cells behave similarly to endogenous CD8+ T cell responses, with an expansion phase in the periphery beginning around day 7 postinfection (p.i.) followed by a contraction phase through day 15 p.i. Through the use of in vivo intravascular immune cell staining, we determined the kinetics, expansion, and differentiation into effector and memory subsets of WNV-I CD8+ T cells within the spleen and brain. We found that red-pulp WNV-I CD8+ T cells were more effector-like than white-pulp WNV-I CD8+ T cells, which displayed increased differentiation into memory precursor cells. Within the central nervous system (CNS), we found that WNV-I CD8+ T cells were polyfunctional (gamma interferon [IFN-γ] and tumor necrosis factor alpha [TNF-α]), displayed tissue-resident characteristics (CD69+ and CD103+), persisted in the brain through day 15 p.i., and reduced the viral burden within the brain. The use of these TCR-transgenic WNV-I mice provides a new resource to dissect the immunological mechanisms of CD8+ T cell-mediated protection during WNV infection. IMPORTANCE West Nile Virus (WNV) is the leading cause of mosquito-borne encephalitis worldwide. There are currently no approved therapeutics or vaccines for use in humans to treat or prevent WNV infection. CD8+ T cells are critical for controlling WNV replication and protecting against infection. Here, we present a comprehensive characterization of a novel TCR-transgenic mouse with specificity for the immunodominant epitope in the WNV NS4B protein. In this study, we determine the kinetics, proliferation, differentiation into effector and memory subsets, homing, and clearance of WNV in the CNS. Our findings provide a new resource to dissect the immunological mechanisms of CD8+ T cell-mediated protection during WNV infection.

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