scholarly journals SARS-CoV-2 infection, neuropathogenesis and transmission among deer mice: Implications for spillback to New World rodents

2021 ◽  
Vol 17 (5) ◽  
pp. e1009585
Author(s):  
Anna Fagre ◽  
Juliette Lewis ◽  
Miles Eckley ◽  
Shijun Zhan ◽  
Savannah M. Rocha ◽  
...  
Keyword(s):  
Immune Response ◽  
Deer Mouse ◽  
Purifying Selection ◽  
Deer Mice ◽  
Type I ◽  
Upper Respiratory Tract ◽  
Suitable Animal Model ◽  
Contact Transmission ◽  
Reservoir Hosts

Coronavirus disease-19 (COVID-19) emerged in late 2019 in China and rapidly became pandemic. As with other coronaviruses, a preponderance of evidence suggests the virus originated in horseshoe bats (Rhinolophus spp.) and may have infected an intermediate host prior to spillover into humans. A significant concern is that SARS-CoV-2 could become established in secondary reservoir hosts outside of Asia. To assess this potential, we challenged deer mice (Peromyscus maniculatus) with SARS-CoV-2 and found robust virus replication in the upper respiratory tract, lungs and intestines, with detectable viral RNA for up to 21 days in oral swabs and 6 days in lungs. Virus entry into the brain also occurred, likely via gustatory-olfactory-trigeminal pathway with eventual compromise to the blood-brain barrier. Despite this, no conspicuous signs of disease were observed, and no deer mice succumbed to infection. Expression of several innate immune response genes were elevated in the lungs, including IFNα, IFNβ, Cxcl10, Oas2, Tbk1 and Pycard. Elevated CD4 and CD8β expression in the lungs was concomitant with Tbx21, IFNγ and IL-21 expression, suggesting a type I inflammatory immune response. Contact transmission occurred from infected to naive deer mice through two passages, showing sustained natural transmission and localization into the olfactory bulb, recapitulating human neuropathology. In the second deer mouse passage, an insertion of 4 amino acids occurred to fixation in the N-terminal domain of the spike protein that is predicted to form a solvent-accessible loop. Subsequent examination of the source virus from BEI Resources determined the mutation was present at very low levels, demonstrating potent purifying selection for the insert during in vivo passage. Collectively, this work has determined that deer mice are a suitable animal model for the study of SARS-CoV-2 respiratory disease and neuropathogenesis, and that they have the potential to serve as secondary reservoir hosts in North America.

scholarly journals SARS-CoV-2 infection, neuropathogenesis and transmission among deer mice: Implications for reverse zoonosis to New World rodents

2020 ◽  
Author(s):  
Anna Fagre ◽  
Juliette Lewis ◽  
Miles Eckley ◽  
Shijun Zhan ◽  
Savannah M Rocha ◽  
...  
Keyword(s):  
Immune Response ◽  
Deer Mouse ◽  
Purifying Selection ◽  
Deer Mice ◽  
Human Populations ◽  
Type I ◽  
Upper Respiratory Tract ◽  
Contact Transmission ◽  
Reservoir Hosts

AbstractCoronavirus disease-19 (COVID-19) emerged in November, 2019 in China and rapidly became pandemic. As with other coronaviruses, a preponderance of evidence suggests the virus originated in horseshoe bats (Rhinolophus spp.) and likely underwent a recombination event in an intermediate host prior to entry into human populations. A significant concern is that SARS-CoV-2 could become established in secondary reservoir hosts outside of Asia. To assess this potential, we challenged deer mice (Peromyscus maniculatus) with SARS-CoV-2 and found robust virus replication in the upper respiratory tract, lungs and intestines, with detectable viral RNA for up to 21 days in oral swabs and 14 days in lungs. Virus entry into the brain also occurred, likely via gustatory-olfactory-trigeminal pathway with eventual compromise to the blood brain barrier. Despite this, no conspicuous signs of disease were observed and no deer mice succumbed to infection. Expression of several innate immune response genes were elevated in the lungs, notably IFNα, Cxcl10, Oas2, Tbk1 and Pycard. Elevated CD4 and CD8β expression in the lungs was concomitant with Tbx21, IFNγ and IL-21 expression, suggesting a type I inflammatory immune response. Contact transmission occurred from infected to naive deer mice through two passages, showing sustained natural transmission. In the second deer mouse passage, an insertion of 4 amino acids occurred to fixation in the N-terminal domain of the spike protein that is predicted to form a solvent-accessible loop. Subsequent examination of the source virus from BEI Resources indicated the mutation was present at very low levels, demonstrating potent purifying selection for the insert during in vivo passage. Collectively, this work has determined that deer mice are a suitable animal model for the study of SARS-CoV-2 pathogenesis, and that they have the potential to serve as secondary reservoir hosts that could lead to periodic outbreaks of COVID-19 in North America.

scholarly journals Rhesus Macaque Rhadinovirus Encodes a Viral Interferon Regulatory Factor To Disrupt Promyelocytic Leukemia Nuclear Bodies and Antagonize Type I Interferon Signaling

2019 ◽  
Vol 93 (6) ◽  
Author(s):  
Laura K. Springgay ◽  
Kristin Fitzpatrick ◽  
Byung Park ◽  
Ryan D. Estep ◽  
Scott W. Wong
Keyword(s):  
Immune Response ◽  
Rhesus Macaque ◽  
Promyelocytic Leukemia ◽  
Nuclear Bodies ◽  
Type I ◽  
Type I Ifn ◽  
Regulatory Factors ◽  
Successful Infection ◽  
Promyelocytic Leukemia Nuclear Bodies

ABSTRACTInterferon (IFN) production and the subsequent induction of IFN-stimulated genes (ISGs) are highly effective innate strategies utilized by cells to protect against invading pathogens, including viruses. Critical components involved in this innate process are promyelocytic leukemia nuclear bodies (PML-NBs), which are subnuclear structures required for the development of a robust IFN response. As such, PML-NBs serve as an important hurdle for viruses to overcome to successfully establish an infection. Both Kaposi’s sarcoma-associated herpesvirus (KSHV) and the closely related rhesus macaque rhadinovirus (RRV) are unique for encoding viral homologs of IFN regulatory factors (termed vIRFs) that can manipulate the host immune response by multiple mechanisms. All four KSHV vIRFs inhibit the induction of IFN, while vIRF1 and vIRF2 can inhibit ISG induction downstream of the IFN receptor. Less is known about the RRV vIRFs. RRV vIRF R6 can inhibit the induction of IFN by IRF3; however, it is not known whether any RRV vIRFs inhibit ISG induction following IFN receptor signaling. In our present study, we demonstrate that the RRV vIRF R12 aids viral replication in the presence of the type I IFN response. This is achieved in part through the disruption of PML-NBs and the inhibition of robust ISG transcription.IMPORTANCEKSHV and RRV encode a unique set of homologs of cellular IFN regulatory factors, termed vIRFs, which are hypothesized to help these viruses evade the innate immune response and establish infections in their respective hosts. Our work elucidates the role of one RRV vIRF, R12, and demonstrates that RRV can dampen the type I IFN response downstream of IFN signaling, which would be important for establishing a successful infectionin vivo.

scholarly journals Development and Characterization of a Sin Nombre Virus Transmission Model in Peromyscus maniculatus

Viruses ◽  
2019 ◽  
Vol 11 (2) ◽  
pp. 183 ◽  
Author(s):  
Bryce Warner ◽  
Derek Stein ◽  
Bryan Griffin ◽  
Kevin Tierney ◽  
Anders Leung ◽  
...  
Keyword(s):  
Peromyscus Maniculatus ◽  
Deer Mouse ◽  
Virus Transmission ◽  
Transmission Model ◽  
Deer Mice ◽  
Sin Nombre Virus ◽  
Infection Model ◽  
Main Driver ◽  
Heat Shock Responses

In North America, Sin Nombre virus (SNV) is the main cause of hantavirus cardiopulmonary syndrome (HCPS), a severe respiratory disease with a fatality rate of 35–40%. SNV is a zoonotic pathogen carried by deer mice (Peromyscus maniculatus), and few studies have been performed examining its transmission in deer mouse populations. Studying SNV and other hantaviruses can be difficult due to the need to propagate the virus in vivo for subsequent experiments. We show that when compared with standard intramuscular infection, the intraperitoneal infection of deer mice can be as effective in producing SNV stocks with a high viral RNA copy number, and this method of infection provides a more reproducible infection model. Furthermore, the age and sex of the infected deer mice have little effect on viral replication and shedding. We also describe a reliable model of direct experimental SNV transmission. We examined the transmission of SNV between deer mice and found that direct contact between deer mice is the main driver of SNV transmission rather than exposure to contaminated excreta/secreta, which is thought to be the main driver of transmission of the virus to humans. Furthermore, increases in heat shock responses or testosterone levels in SNV-infected deer mice do not increase the replication, shedding, or rate of transmission. Here, we have demonstrated a model for the transmission of SNV between deer mice, the natural rodent reservoir for the virus. The use of this model will have important implications for further examining SNV transmission and in developing strategies for the prevention of SNV infection in deer mouse populations.

scholarly journals Angiostatic activity of the antitumor cytokine interleukin-21

Blood ◽  
2008 ◽  
Vol 112 (13) ◽  
pp. 4940-4947 ◽  
Author(s):  
Karolien Castermans ◽  
Sebastien P. Tabruyn ◽  
Rong Zeng ◽  
Judy R. van Beijnum ◽  
Cheryl Eppolito ◽  
...  
Keyword(s):  
Immune Response ◽  
Tumor Angiogenesis ◽  
Chorioallantoic Membrane ◽  
Antitumor Immune Response ◽  
In Vivo Studies ◽  
Type I ◽  
Stat3 Phosphorylation ◽  
Interleukin 21

Abstract Interleukin-21 (IL-21) is a recently described immunoregulatory cytokine. It has been identified as a very potent immunotherapeutic agent in several cancer types in animal models, and clinical studies are ongoing. IL-21 belongs to the type I cytokine family of which other members, ie, IL-2, IL-15, and IL-4, have been shown to exert activities on vascular endothelial cells (ECs). We hypothesized that IL-21, in addition to inducing the antitumor immune response, also inhibits tumor angiogenesis. In vitro experiments showed a decrease of proliferation and sprouting of activated ECs after IL-21 treatment. We found that the IL-21 receptor is expressed on vascular ECs. Furthermore, in vivo studies in the chorioallantoic membrane of the chick embryo and in mouse tumors demonstrated that IL-21 treatment disturbs vessel architecture and negatively affects vessel outgrowth. Our results also confirm the earlier suggested angiostatic potential of IL-2 in vitro and in vivo. The angiostatic effect of IL-21 is confirmed by the decrease in expression of angiogenesis-related genes. Interestingly, IL-21 treatment of ECs leads to a decrease of Stat3 phosphorylation. Our research shows that IL-21 is a very powerful antitumor compound that combines the induction of an effective antitumor immune response with inhibition of tumor angiogenesis.

scholarly journals Temporal and Spatial Analysis of Sin Nombre Virus Quasispecies in Naturally Infected Rodents

1999 ◽  
Vol 73 (11) ◽  
pp. 9544-9554 ◽  
Author(s):  
Ralph Feuer ◽  
John D. Boone ◽  
Dale Netski ◽  
Sergey P. Morzunov ◽  
Stephen C. St. Jeor
Keyword(s):  
Neutralizing Antibodies ◽  
Immune Escape ◽  
Deer Mouse ◽  
Viral Rna ◽  
Deer Mice ◽  
Sin Nombre Virus ◽  
Viral Diversity ◽  
Host Immune System ◽  
Natural Setting

ABSTRACT Sin Nombre virus (SNV) is thought to establish a persistent infection in its natural reservoir, the deer mouse (Peromyscus maniculatus), despite a strong host immune response. SNV-specific neutralizing antibodies were routinely detected in deer mice which maintained virus RNA in the blood and lungs. To determine whether viral diversity played a role in SNV persistence and immune escape in deer mice, we measured the prevalence of virus quasispecies in infected rodents over time in a natural setting. Mark-recapture studies provided serial blood samples from naturally infected deer mice, which were sequentially analyzed for SNV diversity. Viral RNA was detected over a period of months in these rodents in the presence of circulating antibodies specific for SNV. Nucleotide and amino acid substitutions were observed in viral clones from all time points analyzed, including changes in the immunodominant domain of glycoprotein 1 and the 3′ small segment noncoding region of the genome. Viral RNA was also detected in seven different organs of sacrificed deer mice. Analysis of organ-specific viral clones revealed major disparities in the level of viral diversity between organs, specifically between the spleen (high diversity) and the lung and liver (low diversity). These results demonstrate the ability of SNV to mutate and generate quasispecies in vivo, which may have implications for viral persistence and possible escape from the host immune system.

scholarly journals Integrated Transcriptomic and Proteomic Analysis of Red Blood Cells from Rainbow Trout Challenged with VHSV Point Towards Novel Immunomodulant Targets

Vaccines ◽  
2019 ◽  
Vol 7 (3) ◽  
pp. 63 ◽  
Author(s):  
Nombela ◽  
Lopez-Lorigados ◽  
Salvador-Mira ◽  
Puente-Marin ◽  
Chico ◽  
...  
Keyword(s):  
Immune Response ◽  
Rainbow Trout ◽  
Red Blood Cells ◽  
Blood Cells ◽  
Antigen Processing ◽  
Head Kidney ◽  
Interferon Response ◽  
Type I ◽  
Fish Viruses

Teleost red blood cells (RBCs) are nucleated and therefore can propagate cellular responses to exogenous stimuli. RBCs can mount an immune response against a variety of fish viruses, including the viral septicemia hemorrhagic virus (VHSV), which is one of the most prevalent fish viruses resulting in aquaculture losses. In this work, RBCs from blood and head kidney samples of rainbow trout challenged with VHSV were analyzed via transcriptomic and proteomic analyses. We detected an overrepresentation of differentially expressed genes (DEGs) related to the type I interferon response and signaling in RBCs from the head kidney and related to complement activation in RBCs from blood. Antigen processing and presentation of peptide antigen was overrepresented in RBCs from both tissues. DEGs shared by both tissues showed an opposite expression profile. In summary, this work has demonstrated that teleost RBCs can modulate the immune response during an in vivo viral infection, thus implicating RBCs as cell targets for the development of novel immunomodulants.

scholarly journals Systems Biology behind immunoprotection of both Sheep and Goats after Sungri/96 PPRV vaccination

2020 ◽  
Author(s):  
Sajad Ahmad Wani ◽  
Manas Ranjan Praharaj ◽  
Amit R Sahu ◽  
Raja Ishaq Nabi Khan ◽  
Kaushal Kishor Rajak ◽  
...  
Keyword(s):  
Immune Response ◽  
Systems Biology ◽  
B Lymphocytes ◽  
Adaptive Immune Response ◽  
Small Ruminants ◽  
Type I ◽  
Peste Des Petits Ruminants ◽  
Sheep And Goats ◽  
Adaptive Immune

AbstractImmune response is a highly coordinated cascade involving all the subsets of PBMCs. In this study, RNA-Seq analysis of PBMC subsets - CD4+, CD8+, CD14+, CD21+ and CD335+ cells from day 0 and day 5 of Sungri/96 Peste des Petits Ruminants vaccinated sheep and goats was done to delineate the systems biology behind immune - protection of the vaccine in sheep and goats. Assessment of the immune response processes enriched by the differentially expressed genes in all the subsets suggested a strong dysregulation towards development of early inflammatory microenvironment, which is very much required for differentiation of monocytes to macrophages, and for activation and migration of dendritic cells into the draining lymph nodes. The protein - protein interaction networks among the antiviral molecules (IFIT3, ISG15, MX1, MX2, RSAD2, ISG20, IFIT5 and IFIT1) and common DEGs across PBMCs subsets in both the species identified ISG15 to be an ubiquitous hub, that helps in orchestrating antiviral host response against PPRV. IRF7 was found to be the key master regulator activated in most of the subsets in sheep and goats. Most of the pathways were found to be inactivated in B - lymphocytes of both the species indicating that 5 dpv is too early a time point for the B - lymphocytes to react. The cell mediated immune response and humoral immune response pathways were found more enriched in goats than in sheep. Though, animals from both the species survived the challenge, a contrast in pathway activation was observed in CD335+ cells.ImportancePeste des petits ruminants (PPR) by PPRV is an OIE listed acute, contagious transboundary viral disease of small ruminants. Attenuated Sungri/96 PPRV vaccine used all over India against this PPR, provides long-lasting robust innate and adaptive immune response. The early antiviral response was found mediated through type I interferon independent ISGs expression. However, systems biology behind this immune response is unknown. In this study, in vivo transcriptome profiling of PBMC subsets (CD4+, CD8+, CD14+, CD21+ and CD335+) in vaccinated goats and sheep (at 5 days of post vaccination) was done to understand this systems biology. Though there are a few differences in the systems biology across cells (specially the NK cells) between sheep and goats, the co-ordinated response that is inclusive of all the cell subsets was found to be towards induction of strong innate immune response, which is needed for an appropriate adaptive immune response.

scholarly journals Non-Pathogenic Mopeia Virus Induces More Robust Activation of Plasmacytoid Dendritic Cells than Lassa Virus

Viruses ◽  
2019 ◽  
Vol 11 (3) ◽  
pp. 287 ◽  
Author(s):  
Justine Schaeffer ◽  
Stéphanie Reynard ◽  
Xavier Carnec ◽  
Natalia Pietrosemoli ◽  
Marie-Agnès Dillies ◽  
...  
Keyword(s):  
Immune Response ◽  
Dendritic Cells ◽  
T Cell Activation ◽  
Cell Activation ◽  
Plasmacytoid Dendritic Cells ◽  
Health Concern ◽  
Lassa Virus ◽  
Type I ◽  
Viral Haemorrhagic Fever

Lassa virus (LASV) causes a viral haemorrhagic fever in humans and is a major public health concern in West Africa. An efficient immune response to LASV appears to rely on type I interferon (IFN-I) production and T-cell activation. We evaluated the response of plasmacytoid dendritic cells (pDC) to LASV, as they are an important and early source of IFN-I. We compared the response of primary human pDCs to LASV and Mopeia virus (MOPV), which is very closely related to LASV, but non-pathogenic. We showed that pDCs are not productively infected by either MOPV or LASV, but produce IFN-I. However, the activation of pDCs was more robust in response to MOPV than LASV. In vivo, pDC activation may support the control of viral replication through IFN-I production, but also improve the induction of a global immune response. Therefore, pDC activation could play a role in the control of LASV infection.

scholarly journals Lactococcus lactis Expressing Type I Interferon From Atlantic Salmon Enhances the Innate Antiviral Immune Response In Vivo and In Vitro

2021 ◽  
Vol 12 ◽  
Author(s):  
Carlos Muñoz ◽  
Josue González-Lorca ◽  
Mick Parra ◽  
Sarita Soto ◽  
Natalia Valdes ◽  
...  
Keyword(s):  
Immune Response ◽  
Viral Load ◽  
Atlantic Salmon ◽  
Oral Administration ◽  
Lactococcus Lactis ◽  
Type I Interferon ◽  
Type I ◽  
Antiviral Immune Response

In salmon farming, viruses are responsible for outbreaks that produce significant economic losses for which there is a lack of control tools other than vaccines. Type I interferon has been successfully used for treating some chronic viral infections in humans. However, its application in salmonids depends on the proper design of a vehicle that allows its massive administration, ideally orally. In mammals, administration of recombinant probiotics capable of expressing cytokines has shown local and systemic therapeutic effects. In this work, we evaluate the use of Lactococcus lactis as a type I Interferon expression system in Atlantic salmon, and we analyze its ability to stimulate the antiviral immune response against IPNV, in vivo and in vitro. The interferon expressed in L. lactis, even though it was located mainly in the bacterial cytoplasm, was functional, stimulating Mx and PKR expression in CHSE-214 cells, and reducing the IPNV viral load in SHK-1 cells. In vivo, the oral administration of this L. lactis producer of Interferon I increases Mx and PKR expression, mainly in the spleen, and to a lesser extent, in the head kidney. The oral administration of this strain also reduces the IPNV viral load in Atlantic salmon specimens challenged with this pathogen. Our results show that oral administration of L. lactis producing Interferon I induces systemic effects in Atlantic salmon, allowing to stimulate the antiviral immune response. This probiotic could have effects against a wide variety of viruses that infect Atlantic salmon and also be effective in other salmonids due to the high identity among their type I interferons.

scholarly journals Statins act as transient type I interferon inhibitors to enable the antitumor activity of modified vaccinia Ankara viral vectors

2021 ◽  
Vol 9 (7) ◽  
pp. e001587
Author(s):  
Shirley Tenesaca ◽  
Marcos Vasquez ◽  
Maite Alvarez ◽  
Itziar Otano ◽  
Myriam Fernandez-Sendin ◽  
...  
Keyword(s):  
Immune Response ◽  
Antitumor Activity ◽  
Viral Vectors ◽  
Type I Interferon ◽  
In Vitro Assays ◽  
Type I ◽  
Antitumor Effects ◽  
Transcriptomic Response ◽  
Β Receptor

BackgroundModified vaccinia virus Ankara (MVA) are genetically engineered non-replicating viral vectors. Intratumoral administration of MVA induces a cyclic GMP-AMP synthase-mediated type I interferon (IFN) response and the production of high levels of the transgenes engineered into the viral genome such as tumor antigens to construct cancer vaccines. Although type I IFNs are essential for establishing CD8-mediated antitumor responses, this cytokine family may also give rise to immunosuppressive mechanisms.MethodsIn vitro assays were performed to evaluate the activity of simvastatin and atorvastatin on type I IFN signaling and on antigen presentation. Surface levels of IFN α/β receptor 1, endocytosis of bovine serum albumin-fluorescein 5 (6)-isothiocyanate, signal transducer and activator of transcription (STAT) phosphorylation, and real-time PCR of IFN-stimulated genes were assessed in the murine fibroblast cell line L929. In vivo experiments were performed to characterize the effect of simvastatin on the MVA-induced innate immune response and on the antitumor effect of MVA-based antitumor vaccines in B16 melanoma expressing ovalbumin (OVA) and Lewis lung carcinoma (LLC)-OVA tumor models. RNAseq analysis, depleting monoclonal antibodies, and flow cytometry were used to evaluate the MVA-mediated immune response.ResultsIn this work, we identified commonly prescribed statins as potent IFNα pharmacological inhibitors due to their ability to reduce surface expression levels of IFN-α/β receptor 1 and to reduce clathrin-mediated endocytosis. Simvastatin and atorvastatin efficiently abrogated for 8 hours the transcriptomic response to IFNα and enhanced the number of dendritic cells presenting an OVA-derived peptide bound to major histocompatibility complex (MHC) class I. In vivo, intraperitoneal or intramuscular administration of simvastatin reduced the inflammatory response mediated by peritumoral administration of MVA and enhanced the antitumor activity of MVA encoding tumor-associated antigens. The synergistic antitumor effects critically depend on CD8+ cells, whereas they were markedly improved by depletion of CD4+ lymphocytes, T regulatory cells, or NK cells. Either MVA-OVA alone or combined with simvastatin augmented B cells, CD4+ lymphocytes, CD8+ lymphocytes, and tumor-specific CD8+ in the tumor-draining lymph nodes. However, only the treatment combination increased the numbers of these lymphocyte populations in the tumor microenvironment and in the spleen.ConclusionIn conclusion, blockade of IFNα functions by simvastatin markedly enhances lymphocyte infiltration and the antitumor activity of MVA, prompting a feasible drug repurposing.

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