Interferon α Has Varied Effects On CD34+ Cells From Patients With Polycythemia Vera

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2840-2840
Author(s):  
Min Lu ◽  
Seungyeul Yoo ◽  
Lijuan Xia ◽  
Xiaoli Wang ◽  
Yan Li ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stem Cells ◽  
Immune Response ◽  
Colony Formation ◽  
Cellular Response ◽  
P Value ◽  
Type I ◽  
Signature Genes ◽  
Cd34 Cells ◽  
Ifn Γ

Abstract Prolonged therapy with pegylated interferon a (Peg-IFNα 2a) leads to hematological and complete molecular remissions in 70% and 17% of patients with polycythemia vera (PV) , respectively (Quintas-Cardama et al, Blood 2013). We have previously shown that PV CD34+ cells are more responsive to Peg-IFNα 2a than normal CD34+ cell. The type I IFN receptor 1 and 2 were shown to be expressed by a greater number of by PV CD34+ cells than normal(N) CD34+ cells (p=0.01 and p=0.002, respectively). The effects of Peg-IFNα 2a on PV hematopoietic stem cells(HSCs) was next evaluated by incubating PV CD34+ cell for 7 days with Peg-IFNα 2a (200ng/ml) followed by their transplantation into NSG mice. The degree of human cell chimerism following the transplantation of MPN CD 34+ cells was reduced by 50 -90% and the JAK2V617F allele burden by 40 -80%. Treatment of N CD34+ cells with Peg-IFNα 2a reduced donor chimerism by only 20%. We next examined the effects of increasing doses of Peg-IFNα 2a on CD34+ cells from 11 PV patients and 5 N controls. In 4 out of 10 PV cases the IC50 of Peg-IFNα 2a was less than 200ng/ml while in the remainder of cases the IC50 was greater. Low doses of IFNa were capable of eliminating JAK2V617F+ hematopoietic colonies in these IFNα sensitive patients while higher doses of IFNα were required to achieve the same effect in the other patients. PV and N CD34+ cells were then profiled using Illumina Gene expression arrays. In total, 32 intensity data files were generated, each containing 47,231 features, corresponding to 12,388 unique genes. At p-value <0.05 386 genes were down-regulated in PV; these genes were enriched for biological processes related to immune response including the IFN-γ-mediated signaling pathway (p=0.0002), the response to IFN-gamma (p=0.004), and the cellular response to IFN-γ (p=0.0004). The 715 up-regulated genes in PV were enriched for pathways involving glycolysis (p=9.4×10-05), cellular response to stress (p=0.006), and catabolic processes. The gene expression patterns of CD34+ cells incubated with and without INFα were next analyzed. At pairwise t-test p-value <0.001, 315 genes were differentially expressed (223 up-regulated and 92 down-regulated by INFα). Up-regulated genes were enriched for INFα functions and immune response including: response to type I IFN (p=9.0×10-49), innate immune response (2.6×10-45), response to virus (7.5×10-40). Among the 223 up-regulated genes, half were previously known as IFN regulated genes (IRGs). The individual response (IR) of genes to IFN was then defined as: IRi=log (exp ressioni @IFN/exp ressioni@control) IR patterns were remarkably consistent within N samples while large inter-patient variations were observed within the PV samples. Significantly positive IRs were observed for 75 genes and negative IRs for 117 genes within PV as compared to N samples (p value<0.01). The 75 positively responsive genes to IFNa overlapped with 16 down-regulated PV signature genes (p=1.1×10-10) while the negatively responsive of genes overlapped with 41 up-regulated PV signature genes (p=2.2×10-24).These data indicate that the action of IFNa is associated with the alteration of the expression of specific PV signature genes. The varied inhibitory effect of Peg-IFNα 2a on PV colony formation was then correlated with the IR of individual genes. The IRs of OAS2 and RPS24 showed particularly high variance and were related to colony formation. OAS2 (2'-5'-oligoadenylate synthetase 2) is an INF-induced, dsRNA-activated antiviral enzyme which plays a critical role in cellular innate antiviral response but also influences apoptosis, cell growth, differentiation and gene regulation. The IR of this gene was directly related to the inhibitory actions of IFNa (p=0.0011). By contrast, the IR of RPS24 (40S ribosomal protein S24), was inversely correlated to the IFNα response (p=0.0038). Mutations in RPS24 are associated with Diamond-Blackfan anemia. The strong correlation between the IR of these 2 genes with the inhibitory effects of IFNα suggests that their response ratio might be useful as therapeutic biomarker. These data indicate that the IFNα receptor is up-regulated in PV CD34+ cells and that IFNα treatment eliminates PV stem cells and its sensitivity against individual patient PV HSC/HPC varies. The patterns of differentially expressed genes following IFNα treatment may prove useful in determining its mechanism of action and predicting IFNα patient response. Disclosures: No relevant conflicts of interest to declare.

scholarly journals IFN-I Independent Antiviral Immune Response to Vesicular Stomatitis Virus Challenge in Mouse Brain

Vaccines ◽  
2020 ◽  
Vol 8 (2) ◽  
pp. 326
Author(s):  
Anurag R. Mishra ◽  
Siddappa N. Byrareddy ◽  
Debasis Nayak
Keyword(s):  
Gene Expression ◽  
Immune Response ◽  
Vesicular Stomatitis Virus ◽  
Antiviral Response ◽  
Type I ◽  
Immune Gene ◽  
Antiviral Immune Response ◽  
Virus Challenge ◽  
Vesicular Stomatitis ◽  
Ifn Γ

Type I interferon (IFN-I) plays a pivotal role during viral infection response in the central nervous system (CNS). The IFN-I can orchestrate and regulate most of the innate immune gene expression and myeloid cell dynamics following a noncytopathic virus infection. However, the role of IFN-I in the CNS against viral encephalitis is not entirely clear. Here we have implemented the combination of global differential gene expression profiling followed by bioinformatics analysis to decipher the CNS immune response in the presence and absence of the IFN-I signaling. We observed that vesicular stomatitis virus (VSV) infection induced 281 gene changes in wild-type (WT) mice primarily associated with IFN-I signaling. This was accompanied by an increase in antiviral response through leukocyte vascular patrolling and leukocyte influx along with the expression of potent antiviral factors. Surprisingly, in the absence of the IFN-I signaling (IFNAR−/− mice), a significantly higher (1357) number of genes showed differential expression compared to the WT mice. Critical candidates such as IFN-γ, CCL5, CXCL10, and IRF1, which are responsible for the recruitment of the patrolling leukocytes, are also upregulated in the absence of IFN-I signaling. The computational network analysis suggests the presence of the IFN-I independent pathway that compensates for the lack of IFN-I signaling in the brain. The analysis shows that TNF-α is connected maximally to the networked candidates, thus emerging as a key regulator of gene expression and recruitment of myeloid cells to mount antiviral action. This pathway could potentiate IFN-γ release; thereby, synergistically activating IRF1-dependent ISG expression and antiviral response.

scholarly journals Epstein-Barr Virus miR-BART6-3p Inhibits the RIG-I Pathway

2017 ◽  
Vol 9 (6) ◽  
pp. 574-586 ◽  
Author(s):  
Yuanjun Lu ◽  
Zailong Qin ◽  
Jia Wang ◽  
Xiang Zheng ◽  
Jianhong Lu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Immune Response ◽  
Epstein Barr Virus ◽  
Type I ◽  
Receptor Signaling ◽  
Viral Pathogen ◽  
Infection Period ◽  
Barr Virus ◽  
Ebv Infection ◽  
Epstein Barr

Recognition of viral pathogen-associated molecular patterns by pattern recognition receptors (PRRs) is the first step in the initiation of a host innate immune response. As a PRR, RIG-I detects either viral RNA or replication transcripts. Avoiding RIG-I recognition is a strategy employed by viruses for immune evasion. Epstein-Barr virus (EBV) infects the majority of the human population worldwide. During the latent infection period there are only a few EBV proteins expressed, whereas EBV-encoded microRNAs, such as BART microRNAs, are highly expressed. BART microRNAs regulate both EBV and the host's gene expression, modulating virus proliferation and the immune response. Here, through gene expression profiling, we found that EBV miR-BART6-3ps inhibited genes of RIG-I-like receptor signaling and the type I interferon (IFN) response. We demonstrated that miR-BART6-3p rather than other BARTs specifically suppressed RIG-I-like receptor signaling-mediated IFN-β production. RNA-seq was used to analyze the global transcriptome change upon EBV infection and miR-BART6-3p mimics transfection, which revealed that EBV infection-triggered immune response signaling can be repressed by miR-BART6-3p overexpression. Furthermore, miR-BART6-3p inhibited the EBV-triggered IFN-β response and facilitated EBV infection through targeting the 3′UTR of RIG-I mRNA. These findings provide new insights into the mechanism underlying the strategies employed by EBV to evade immune surveillance.

scholarly journals Early Response of CD8+ T Cells in COVID-19 Patients

2021 ◽  
Vol 11 (12) ◽  
pp. 1291
Author(s):  
Deni Ramljak ◽  
Martina Vukoja ◽  
Marina Curlin ◽  
Katarina Vukojevic ◽  
Maja Barbaric ◽  
...  
Keyword(s):  
Gene Expression ◽  
Immune Response ◽  
T Cells ◽  
Mrna Expression ◽  
Cd8 T Cells ◽  
Expression Profiles ◽  
Expression Patterns ◽  
Effector Memory ◽  
Healthy Controls ◽  
Ifn Γ

Healthy and controlled immune response in COVID-19 is crucial for mild forms of the disease. Although CD8+ T cells play important role in this response, there is still a lack of studies showing the gene expression profiles in those cells at the beginning of the disease as potential predictors of more severe forms after the first week. We investigated a proportion of different subpopulations of CD8+ T cells and their gene expression patterns for cytotoxic proteins (perforin-1 (PRF1), granulysin (GNLY), granzyme B (GZMB), granzyme A (GZMA), granzyme K (GZMK)), cytokine interferon-γ (IFN-γ), and apoptotic protein Fas ligand (FASL) in CD8+ T cells from peripheral blood in first weeks of SARS-CoV-2 infection. Sixteen COVID-19 patients and nine healthy controls were included. The absolute counts of total lymphocytes (p = 0.007), CD3+ (p = 0.05), and CD8+ T cells (p = 0.01) in COVID-19 patients were significantly decreased compared to healthy controls. In COVID-19 patients in CD8+ T cell compartment, we observed lower frequency effector memory 1 (EM1) (p = 0.06) and effector memory 4 (EM4) (p < 0.001) CD8+ T cells. Higher mRNA expression of PRF1 (p = 0.05) and lower mRNA expression of FASL (p = 0.05) at the fifth day of the disease were found in COVID-19 patients compared to healthy controls. mRNA expression of PRF1 (p < 0.001) and IFN-γ (p < 0.001) was significantly downregulated in the first week of disease in COVID-19 patients who progressed to moderate and severe forms after the first week, compared to patients with mild symptoms during the entire disease course. GZMK (p < 0.01) and FASL (p < 0.01) mRNA expression was downregulated in all COVID-19 patients compared to healthy controls. Our results can lead to a better understanding of the inappropriate immune response of CD8+ T cells in SARS-CoV2 with the faster progression of the disease.

scholarly journals High-Density Blood Transcriptomics Reveals Precision Immune Signatures of SARS-CoV-2 Infection in Hospitalized Individuals

2021 ◽  
Vol 12 ◽  
Author(s):  
Jeremy W. Prokop ◽  
Nicholas L. Hartog ◽  
Dave Chesla ◽  
William Faber ◽  
Chanise P. Love ◽  
...  
Keyword(s):  
Gene Expression ◽  
Immune Response ◽  
Viral Infections ◽  
Secretory Granules ◽  
Mitotic Cell ◽  
Hospitalized Patients ◽  
High Density ◽  
Type I ◽  
Secondary Infections ◽  
Blood Transcriptomics

The immune response to COVID-19 infection is variable. How COVID-19 influences clinical outcomes in hospitalized patients needs to be understood through readily obtainable biological materials, such as blood. We hypothesized that a high-density analysis of host (and pathogen) blood RNA in hospitalized patients with SARS-CoV-2 would provide mechanistic insights into the heterogeneity of response amongst COVID-19 patients when combined with advanced multidimensional bioinformatics for RNA. We enrolled 36 hospitalized COVID-19 patients (11 died) and 15 controls, collecting 74 blood PAXgene RNA tubes at multiple timepoints, one early and in 23 patients after treatment with various therapies. Total RNAseq was performed at high-density, with &gt;160 million paired-end, 150 base pair reads per sample, representing the most sequenced bases per sample for any publicly deposited blood PAXgene tube study. There are 770 genes significantly altered in the blood of COVID-19 patients associated with antiviral defense, mitotic cell cycle, type I interferon signaling, and severe viral infections. Immune genes activated include those associated with neutrophil mechanisms, secretory granules, and neutrophil extracellular traps (NETs), along with decreased gene expression in lymphocytes and clonal expansion of the acquired immune response. Therapies such as convalescent serum and dexamethasone reduced many of the blood expression signatures of COVID-19. Severely ill or deceased patients are marked by various secondary infections, unique gene patterns, dysregulated innate response, and peripheral organ damage not otherwise found in the cohort. High-density transcriptomic data offers shared gene expression signatures, providing unique insights into the immune system and individualized signatures of patients that could be used to understand the patient’s clinical condition. Whole blood transcriptomics provides patient-level insights for immune activation, immune repertoire, and secondary infections that can further guide precision treatment.

Abstract 256: Paracrine miRNA-Crosstalk Between Human CD34+ Stem Cells and Selective Myocardial Cells Via Therapeutic Exosomes Promotes Repair of the Ischemic Heart

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Susmita Sahoo ◽  
David Kim ◽  
Sol Misener ◽  
Christine E Kamide ◽  
Douglas E Vaughan ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stem Cells ◽  
Endothelial Cells ◽  
Ischemic Myocardium ◽  
Ischemic Heart ◽  
Target Cells ◽  
Myocardial Repair ◽  
Human Cd34 ◽  
Therapeutic Benefits ◽  
Cd34 Cells

Introduction: Earlier, in a first study of its kind, we have demonstrated a novel mechanism that therapeutically significant human CD34+ stem cells secrete membrane bound nano-vesicles called exosomes (CD34Exo). CD34Exo are angiogenic and constitute a critical component of the pro-angiogenic paracrine activity of the cells. Further, when transplanted locally, cell-free CD34Exo induce ischemic tissue repair in a murine hindlimb ischemia model. Here, we hypothesize that exosomes released via paracrine secretion from human CD34+ cells mediate myocardial repair by direct transfer of microRNAs to target cells in the heart. Methods and Results: When injected into mouse ischemic myocardium, cell-free CD34Exo replicated the therapeutic activity of human CD34+ cells by significantly improving ischemia (ejection fraction, 42±4 v 22±6%; capillary density, 113±7 v 66±6/HPF; fibrosis, 27±2 v 48±7%; p<0.05, n=7-12) compared with PBS control. Interestingly, confocal imaging and flow cytometry analyses of the exosomes-injected ischemic myocardial tissue revealed that CD34Exo was selectively internalized into endothelial cells and cardiomyocytes. CD34Exo, which is enriched with miR126, induced the expression of miR126 and several pro-angiogenic mRNAs in the exosomes-treated ischemic myocardium, but did not affect the endogenous synthesis of miR126. CD34Exo lacking miR126 had decreased angiogenic activity in vitro and decreased proangiogenic gene expression in vivo indicating that miR126 is important for CD34Exo function. Imaging using fluorescent miR126 confirms that CD34Exo directly transferred miR126 and possibly other yet to be identified moieties from its cargo, selectively to endothelial cells and cardiomyocytes in the ischemic heart. Conclusion: Our results reveal a novel molecular and trafficking mechanism of CD34Exo that may be responsible for intercellular transfer of genetic information such as miRNAs from human CD34+ stem cells, selectively to endothelial cells and cardiomyocytes inducing changes in gene expression, angiogenesis and myocardial recovery. Exosomes-shuttled miRNAs may signify amplification of stem cell function and may explain the therapeutic benefits associated with human CD34+ cell therapy.

Abstract 361: Neuregulin Transcriptional Programming of Embryonic Endothelial Progenitor Cells and Embryonic Stem Cells

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Jijun Hao ◽  
Cristi L Galindo ◽  
Radwan N Safa ◽  
Truc-Linh Tran ◽  
Douglas B Sawyer
Keyword(s):  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Heart Development ◽  
Progenitor Cell ◽  
Critical Role ◽  
Embryonic Stem ◽  
Mapk Signaling ◽  
P Value ◽  
Type I ◽  
Endothelial Progenitor

Jijun Hao, Cristi L. Galindo, Radwan N. Safa, Truc-Linh Tran, Douglas B. Sawyer Neuregulin-1 (NRG-1) plays a critical role in heart development by signaling through type I receptor tyrosine kinases in the erbB family (erbB2, erbB3 and erbB4). Mice with disrupted expression of NRG-1, ErbB2, ErbB3 or ErbB4 die in utero with failure of cardiac development. We have previously shown that NRG-1 has distinct effects on two embryonic progenitor cell populations that express ErbB2 and ErbB3 receptors. In an embryonic endothelial progenitor cell line (eEPCs) NRG-1 treatment induces phosphorylation of Akt, GSK-3β, and Erk1/2, and protects eEPCs against serum deprivation-induced apoptosis. In embryonic stem cells (ESCs) we find that NRG-1 treatment from day 0∼2 induces cardiomyocyte formation by day 8 in culture, and when ErbB3 is knocked down in the ESCs, NRG-1 fails to promote cardiomyogenesis. To understand early molecular events that might regulate these distinct effects, we analyzed global transcriptional changes induced by NRG-1 in both eEPCs and ESCs using microarrays. There were only 244 significantly differential (p value < 0.05, fold-change > 1.5) genes detected in NRG-1-treated ESCs, while NRG-1 induced differential expression of 1,547 transcripts in eEPCs. Based on functional analysis, the most significantly over-represented function (Fishers Exact Test, p value with FDR < 0.05) in ESCs was “cell morphogenesis during differentiation”. In eEPCs, genes regulated via Ras/MAPK signaling were altered, as were those downstream of the Akt-PI3K pathway and calcium signaling. For both cell lines, the most statistically significant transcription factor identified as a regulator of the genes altered in response to NRG-1 was SRF, consistent with a role for NRG-1 in heart development and regeneration. Based on the results of this study, we constructed a putative signaling pathway whereby NRG mediates cardiomyogenesis in pluripotent stem cells that correlates with phenotypic observations.

scholarly journals Cell-Free Demineralized Bone Matrix for Mesenchymal Stem Cells Survival and Colonization

Materials ◽  
2019 ◽  
Vol 12 (9) ◽  
pp. 1360 ◽  
Author(s):  
Monica Mattioli-Belmonte ◽  
Francesca Montemurro ◽  
Caterina Licini ◽  
Iolanda Iezzi ◽  
Manuela Dicarlo ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Tissue Regeneration ◽  
Demineralized Bone Matrix ◽  
Bone Matrix ◽  
Morphological Observation ◽  
Type I ◽  
Demineralized Bone

Decellularized bone matrix is receiving much attention as biological scaffolds and implantable biomaterials for bone tissue regeneration. Here, we evaluated the efficacy of a cell-free demineralized bone matrix on mesenchymal stem cells (MSCs) survival and differentiation in vitro. The seeding of human umbilical cord-derived MSCs (hUC-SCs) on decellularized bone matrices up to 14 days was exploited, assessing their capability of scaffold colonization and evaluating gene expression of bone markers. Light and Scanning Electron Microscopies were used. The obtained cell-free decalcified structures showed elastic moduli attributable to both topology and biochemical composition. Morphological observation evidenced an almost complete colonization of the scaffolds after 14 days of culture. Moreover, in hUC-SCs cultured on decalcified scaffolds, without the addition of any osteoinductive media, there was an upregulation of Collagen Type I (COL1) and osteonectin (ON) gene expression, especially on day 14. Modifications in the expression of genes engaged in stemness were also detected. In conclusion, the proposed decellularized bone matrix can induce the in vitro hUC-SCs differentiation and has the potential to be tested for in in vivo tissue regeneration.

Transient membrane recruitment of IRAK-1 in response to LPS and IL-1β requires TNF R1

2008 ◽  
Vol 295 (2) ◽  
pp. C313-C323 ◽  
Author(s):  
Angelia Lockett ◽  
Mark G. Goebl ◽  
Maureen A. Harrington
Keyword(s):  
Gene Expression ◽  
Immune Response ◽  
Plasma Membrane ◽  
Innate Immune Response ◽  
Cellular Response ◽  
Interleukin 1 ◽  
Innate Immune ◽  
Variable Response ◽  
Membrane Recruitment ◽  
Tnf Α

The transcription factor NF-κB is an essential regulator of the innate immune response that functions as the first line of defense against infections. Activation of the innate immune response by bacterial lipopolysaccharide (LPS) triggers production of tumor necrosis factor-α (TNF-α) followed by interleukin-1 (IL-1). The IL-1 receptor associated kinase-1 (IRAK-1) is an integral component of the LPS, TNF-α, and IL-1 signaling pathways that regulate NF-κB. Thus we hypothesized that IRAK-1 coordinates cellular NF-κB responses to LPS, TNF-α, and IL-1. In contrast to TNF-α where IRAK-1 subcellular localization does not change, treatment with LPS or IL-1 leads to a loss in cytoplasmic IRAK-1 with a coordinate increase in plasma membrane associated modified IRAK-1. In fibroblasts lacking the type 1 TNF-α receptor (TNF R1), IRAK-1 turnover is altered and modification of IRAK-1 in the plasma membrane is decreased in response to LPS and IL-1, respectively. When NF-κB controlled gene expression is measured, fibroblasts lacking TNF R1 are hyperresponsive to LPS, whereas a more variable response to IL-1 is seen. Further analysis of the LPS response revealed that plasma membrane-associated IRAK-1 is found in Toll 4, IL-1, and TNF R1-containing complexes. The data presented herein suggest a model whereby the TNF R1-IRAK-1 interaction integrates the cellular response to LPS, TNF-α, and IL-1, culminating in a cell poised to activate TNF-α-dependent NF-κB controlled gene expression. In the absence of TNF R1-dependent events, exposure to LPS or IL-1 leads to hyperactivation of the inflammatory response.

scholarly journals Tolerization of a Type I Allergic Immune Response through Transplantation of Genetically Modified Hematopoietic Stem Cells

2008 ◽  
Vol 180 (12) ◽  
pp. 8168-8175 ◽  
Author(s):  
Ulrike Baranyi ◽  
Birgit Linhart ◽  
Nina Pilat ◽  
Martina Gattringer ◽  
Jessamyn Bagley ◽  
...  
Keyword(s):  
Stem Cells ◽  
Immune Response ◽  
Hematopoietic Stem Cells ◽  
Genetically Modified ◽  
Type I ◽  
Hematopoietic Stem ◽  
Allergic Immune Response

scholarly journals Interleukin-12- and Gamma Interferon-Dependent Innate Immunity Are Essential and Sufficient for Long-Term Survival of Passively Immunized Mice Infected with Herpes Simplex Virus Type 1

2001 ◽  
Vol 75 (20) ◽  
pp. 9596-9600 ◽  
Author(s):  
Sabine Vollstedt ◽  
Marco Franchini ◽  
Gottfried Alber ◽  
Mathias Ackermann ◽  
Mark Suter
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Herpes Simplex Virus Type ◽  
Interleukin 12 ◽  
Type I ◽  
Ifn Γ ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACT Interferon (IFN) type I (alpha/beta IFN [IFN-α/β]) is very important in directly controlling herpes simplex virus type I (HSV-1) replication as well as in guiding and upregulating specific immunity against this virus. By contrast, the roles of IFN type II (IFN-γ) and antibodies in the defense against HSV-1 are not clear. Mice without a functional IFN system and no mature B and T cells (AGR mice) did not survive HSV-1 infection in the presence or absence of neutralizing antibodies to the virus. Mice without a functional IFN type I system and with no mature B and T cells (AR129 mice) were unable to control infection with as little as 10 PFU of HSV-1 strain F. By contrast, in the presence of passively administered neutralizing murine antibodies to HSV-1, some AR129 mice survived infection with up to104PFU of HSV-1. This acute immune response was dependent on the presence of interleukin-12 (IL-12) p75. Interestingly, some virus-infected mice stayed healthy for several months, at which time antibody to HSV-1 was no longer detectable. Treatment of these virus-exposed mice with dexamethasone led to death in approximately 40% of the mice. HSV-1 was found in brains of mice that did not survive dexamethasone treatment, whereas HSV-1 was absent in those that survived the treatment. We conclude that in the presence of passively administered HSV-1-specific antibodies, the IL-12-induced IFN-γ-dependent innate immune response is able to control low doses of virus infection. Surprisingly, in a significant proportion of these mice, HSV-1 appears to persist in the absence of antibodies and specific immunity.

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