Publications by authors named "Allen Jankeel"

16 Publications

  • Page 1 of 1

Phenotypic and Epigenetic Adaptations of Cord Blood CD4+ T Cells to Maternal Obesity.

Front Immunol 2021 12;12:617592. Epub 2021 Apr 12.

Department of Molecular Biology and Biochemistry, School of Biological Sciences, University of California Irvine, Irvine, CA, United States.

Pregravid obesity has been shown to disrupt the development of the offspring's immune system and increase susceptibility to infection. While the mechanisms underlying the impact of maternal obesity on fetal myeloid cells are emerging, the consequences for T cells remain poorly defined. In this study, we collected umbilical cord blood samples from infants born to lean mothers and mothers with obesity and profiled CD4 T cells using flow cytometry and single cell RNA sequencing at resting and following polyclonal stimulation. We report that maternal obesity is associated with higher frequencies of memory CD4 T cells suggestive of activation. Moreover, single cell RNA sequencing revealed expansion of an activated subset of memory T cells with maternal obesity. However, stimulation of purified CD4 T cells resulted in poor cytokine responses, suggesting functional defects. These phenotypic and functional aberrations correlated with methylation and chromatin accessibility changes in loci associated with lymphocyte activation and T cell receptor signaling, suggesting a possible link between maternal obesogenic environment and fetal immune reprogramming. These observations offer a potential explanation for the increased susceptibility to microbial infection in babies born to mothers with obesity.
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http://dx.doi.org/10.3389/fimmu.2021.617592DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8071865PMC
April 2021

SARS-CoV-2 Acquisition and Immune Pathogenesis Among School-Aged Learners in Four K-12 Schools.

medRxiv 2021 Mar 26. Epub 2021 Mar 26.

Objectives: To directly measure SARS-CoV-2 infection in diverse schools with either remote or onsite learning.

Methods: 4 schools participated. Schools A and B served low-income Hispanic learners, school C special needs, and all three provided predominantly remote instruction. School D served middle and upper-middle income, White learners, with predominantly onsite instruction. 320 learners [10.5±2.1(SD); 7-17 y.o.]; 86% had phlebotomy. Testing occurred early in the fall (2020), at lower levels of COVID-19, and 6-8 weeks later during the fall-winter surge (tenfold increase in COVID-19 cases).

Results: Nasal RT-qPCR for SARS-CoV-2 and 21 respiratory pathogens was performed. Phlebotomy was obtained for circulating immunity. Face covering and physical distancing fidelity was measured by direct observation. 17 learners were SARS-CoV-2 positive during the surge. School A (97% remote) had the highest infection rate (9/70, 12.9%, p<0.01) and IgG positivity rate (13/70, 18.6%). School D had the lowest infection and IgG positive rate (1/86, 1.2%). Mitigation compliance [physical distancing (mean 87.4%) and face covering (91.3%)] was high at all schools. Learners with documented SARS-CoV-2 infection had neutralizing antibodies (94.7%), broad and robust IFN-γ+ T cell responses, reduced frequencies of monocytes, and lower levels of circulating inflammatory mediators.

Conclusions: Infection in the schools reflected regional rates rather than remote or onsite learning modalities. Schools can implement successful mitigation strategies across a wide range of income, school-type, and student diversity. Reduced monocyte and immune mediator concentrations coupled with robust humoral and cellular immunity may explain the generally milder symptoms in school-aged children.

Table Of Contents Summary: SARS-CoV-2 infection and immunobiology was measured in children at 4 diverse schools with varying degrees of onsite and remote learning.

What’s Known On This Subject: At the start of the COVID-19 pandemic, schools were reflexively closed as there were fears that agreggation of school-aged children would lead to increased infection. Infectivity and immunobiology of SARS-CoV-2 in children attending schools not understood.

What This Study Adds: School-associated infections reflected regional rates rather than remote or onsite learning. Successful mitigation was implemented across a diverse range of schools. Reduced immune mediator concentrations coupled with robust humoral and cellular immunity may explain the milder symptoms in school-aged children.
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http://dx.doi.org/10.1101/2021.03.20.21254035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010744PMC
March 2021

Rapid protection from COVID-19 in nonhuman primates vaccinated intramuscularly but not intranasally with a single dose of a recombinant vaccine.

bioRxiv 2021 Jan 19. Epub 2021 Jan 19.

The ongoing pandemic of Coronavirus disease 2019 (COVID-19) continues to exert a significant burden on health care systems worldwide. With limited treatments available, vaccination remains an effective strategy to counter transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Recent discussions concerning vaccination strategies have focused on identifying vaccine platforms, number of doses, route of administration, and time to reach peak immunity against SARS-CoV-2. Here, we generated a single dose, fast-acting vesicular stomatitis virus-based vaccine derived from the licensed Ebola virus (EBOV) vaccine rVSV-ZEBOV, expressing the SARS-CoV-2 spike protein and the EBOV glycoprotein (VSV-SARS2-EBOV). Rhesus macaques vaccinated intramuscularly (IM) with a single dose of VSV-SARS2-EBOV were protected within 10 days and did not show signs of COVID-19 pneumonia. In contrast, intranasal (IN) vaccination resulted in limited immunogenicity and enhanced COVID-19 pneumonia compared to control animals. While IM and IN vaccination both induced neutralizing antibody titers, only IM vaccination resulted in a significant cellular immune response. RNA sequencing data bolstered these results by revealing robust activation of the innate and adaptive immune transcriptional signatures in the lungs of IM-vaccinated animals only. Overall, the data demonstrates that VSV-SARS2-EBOV is a potent single-dose COVID-19 vaccine candidate that offers rapid protection based on the protective efficacy observed in our study.

One Sentence Summary: VSV vaccine protects NHPs from COVID-19 in 10 days.
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http://dx.doi.org/10.1101/2021.01.19.426885DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7836117PMC
January 2021

Toxoplasma gondii Extends the Life Span of Infected Human Neutrophils by Inducing Cytosolic PCNA and Blocking Activation of Apoptotic Caspases.

mBio 2021 01 26;12(1). Epub 2021 Jan 26.

Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, California, USA

is an intracellular protozoan parasite that has the remarkable ability to infect and replicate in neutrophils, immune cells with an arsenal of antimicrobial effector mechanisms. We report that infection extends the life span of primary human peripheral blood neutrophils by delaying spontaneous apoptosis, serum starvation-induced apoptosis, and tumor necrosis alpha (TNF-α)-mediated apoptosis. blockade of apoptosis was associated with an inhibition of processing and activation of the apoptotic caspases caspase-8 and -3, decreased phosphatidylserine exposure on the plasma membrane, and reduced cell death. We performed a global transcriptome analysis of -infected peripheral blood neutrophils using RNA sequencing (RNA-Seq) and identified gene expression changes associated with DNA replication and DNA repair pathways, which in mature neutrophils are indicative of changes in regulators of cell survival. Consistent with the RNA-Seq data, infection upregulated transcript and protein expression of PCNA, which is found in the cytosol of human neutrophils, where it functions as a key inhibitor of apoptotic pro-caspases. Infection of neutrophils resulted in increased interaction of PCNA with pro-caspase-3. Inhibition of this interaction with an AlkB homologue 2 PCNA-interacting motif (APIM) peptide reversed the infection-induced delay in cell death. Taken together, these findings indicate a novel strategy by which manipulates cell life span in primary human neutrophils, which may allow the parasite to maintain an intracellular replicative niche and avoid immune clearance. is an obligate intracellular parasite that can cause life-threatening disease in immunocompromised individuals and in the developing fetus. Interestingly, has evolved strategies to successfully manipulate the host immune system to establish a productive infection and evade host defense mechanisms. Although it is well documented that neutrophils are mobilized during acute infection and infiltrate the site of infection, these cells can also be actively infected by and serve as a replicative niche for the parasite. However, there is a limited understanding of the molecular processes occurring within infected neutrophils. This study reveals that extends the life span of human neutrophils by inducing the expression of PCNA, which prevents activation of apoptotic caspases, thus delaying apoptosis. This strategy may allow the parasite to preserve its replicative intracellular niche.
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http://dx.doi.org/10.1128/mBio.02031-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7858050PMC
January 2021

Transcriptional Analysis of Lymphoid Tissues from Infected Nonhuman Primates Reveals the Basis for Attenuation and Immunogenicity of an Ebola Virus Encoding a Mutant VP35 Protein.

J Virol 2021 02 24;95(6). Epub 2021 Feb 24.

Department of Molecular Biology and Biochemistry, College of Biological Sciences, University of California, Irvine, Irvine, California, USA

Infection with (EBOV), a member of the family, causes a disease characterized by high levels of viremia, aberrant inflammation, coagulopathy, and lymphopenia. EBOV initially replicates in lymphoid tissues and disseminates via dendritic cells (DCs) and monocytes to liver, spleen, adrenal gland, and other secondary organs. EBOV protein VP35 is a critical immune evasion factor that inhibits type I interferon signaling and DC maturation. Nonhuman primates (NHPs) immunized with a high dose (5 × 10 PFU) of recombinant EBOV containing a mutated VP35 (VP35m) are protected from challenge with wild-type EBOV (wtEBOV). This protection is accompanied by a transcriptional response in the peripheral blood reflecting a regulated innate immune response and a robust induction of adaptive immune genes. However, the host transcriptional response to VP35m in lymphoid tissues has not been evaluated. Therefore, we conducted a transcriptional analysis of axillary and inguinal lymph nodes and spleen tissues of NHPs infected with a low dose (2 × 10 PFU) of VP35m and then back-challenged with a lethal dose of wtEBOV. VP35m induced early transcriptional responses in lymphoid tissues that are distinct from those observed in wtEBOV challenge. Specifically, we detected robust antiviral innate and adaptive responses and fewer transcriptional changes in genes with roles in angiogenesis, apoptosis, and inflammation. Two of three macaques survived wtEBOV back-challenge, with only the nonsurvivor displaying a transcriptional response reflecting Ebola virus disease. These data suggest that VP35 is a key modulator of early host responses in lymphoid tissues, thereby regulating disease progression and severity following EBOV challenge. Zaire Ebola virus (EBOV) infection causes a severe and often fatal disease characterized by inflammation, coagulation defects, and organ failure driven by a defective host immune response. Lymphoid tissues are key sites of EBOV pathogenesis and the generation of an effective immune response to infection. A recent study demonstrated that infection with an EBOV encoding a mutant VP35, a viral protein that antagonizes host immunity, can protect nonhuman primates (NHPs) against lethal EBOV challenge. However, no studies have examined the response to this mutant EBOV in lymphoid tissues. Here, we characterize gene expression in lymphoid tissues from NHPs challenged with the mutant EBOV and subsequently with wild-type EBOV to identify signatures of a protective host response. Our findings are critical for elucidating viral pathogenesis, mechanisms of host antagonism, and the role of lymphoid organs in protective responses to EBOV to improve the development of antivirals and vaccines against EBOV.
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http://dx.doi.org/10.1128/JVI.01995-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8094945PMC
February 2021

Unique molecular signatures of antiviral memory CD8 T cells associated with asymptomatic recurrent ocular herpes.

Sci Rep 2020 08 14;10(1):13843. Epub 2020 Aug 14.

Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, School of Medicine, University of California Irvine, Hewitt Hall, Room 2032; 843 Health Sciences Rd, Irvine, CA, 92697, USA.

The nature of antiviral CD8 T cells associated with protective and pathogenic herpes simplex virus type 1 (HSV-1) infections remains unclear. We compared the transcriptome, phenotype, and function of memory CD8 T cells, sharing the same HSV-1 epitope-specificities, from infected HLA-A*0201 positive symptomatic (SYMP) vs. asymptomatic (ASYMP) individuals and HLA-A*0201 transgenic rabbits. Compared to higher frequencies of multifunctional effector memory CD8 T cells in ASYMP individuals, the SYMP individuals presented dysfunctional CD8 T cells, expressing major exhaustion pathways. Compared to protected ASYMP HLA transgenic rabbits, the trigeminal ganglia of non-protected SYMP HLA transgenic rabbits had higher frequencies of dysfunctional tissue-resident CD8 T cells. Moreover, blockade of T cell exhaustion pathways restored the function of CD8 T cells, reduced virus reactivation, and diminished recurrent disease in HLA transgenic rabbits. These findings reveal unique molecular signatures of protective CD8 T cells and pave the way for T-cell-based immunotherapy to combat recurrent ocular herpes.
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http://dx.doi.org/10.1038/s41598-020-70673-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7427992PMC
August 2020

Early Transcriptional Changes within Liver, Adrenal Gland, and Lymphoid Tissues Significantly Contribute to Ebola Virus Pathogenesis in Cynomolgus Macaques.

J Virol 2020 05 18;94(11). Epub 2020 May 18.

Department of Molecular Biology and Biochemistry, School of Biological Sciences, University of California, Irvine, Irvine, California, USA

Ebola virus (EBOV) continues to pose a significant threat to human health, as evidenced by the 2013-2016 epidemic in West Africa and the ongoing outbreak in the Democratic Republic of the Congo. EBOV causes hemorrhagic fever, organ damage, and shock culminating in death, with case fatality rates as high as 90%. This high lethality combined with the paucity of licensed medical countermeasures makes EBOV a critical human pathogen. Although EBOV infection results in significant damage to the liver and the adrenal glands, little is known about the molecular signatures of injury in these organs. Moreover, while changes in peripheral blood cells are becoming increasingly understood, the host responses within organs and lymphoid tissues remain poorly characterized. To address this knowledge gap, we tracked longitudinal transcriptional changes in tissues collected from EBOV-Makona-infected cynomolgus macaques. Following infection, both liver and adrenal glands exhibited significant and early downregulation of genes involved in metabolism, coagulation, hormone synthesis, and angiogenesis; upregulated genes were associated with inflammation. Analysis of lymphoid tissues showed early upregulation of genes that play a role in innate immunity and inflammation and downregulation of genes associated with cell cycle and adaptive immunity. Moreover, transient activation of innate immune responses and downregulation of humoral immune responses in lymphoid tissues were confirmed with flow cytometry. Together, these data suggest that the liver, adrenal gland, and lymphatic organs are important sites of EBOV infection and that dysregulating the function of these vital organs contributes to the development of Ebola virus disease. Ebola virus (EBOV) remains a high-priority pathogen since it continues to cause outbreaks with high case fatality rates. Although it is well established that EBOV results in severe organ damage, our understanding of tissue injury in the liver, adrenal glands, and lymphoid tissues remains limited. We begin to address this knowledge gap by conducting longitudinal gene expression studies in these tissues, which were collected from EBOV-infected cynomolgus macaques. We report robust and early gene expression changes within these tissues, indicating they are primary sites of EBOV infection. Furthermore, genes involved in metabolism, coagulation, and adaptive immunity were downregulated, while inflammation-related genes were upregulated. These results indicate significant tissue damage consistent with the development of hemorrhagic fever and lymphopenia. Our study provides novel insight into EBOV-host interactions and elucidates how host responses within the liver, adrenal glands, and lymphoid tissues contribute to EBOV pathogenesis.
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http://dx.doi.org/10.1128/JVI.00250-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7269430PMC
May 2020

Short-Term Caloric Restriction Attenuates Obesity-Induced Pro-Inflammatory Response in Male Rhesus Macaques.

Nutrients 2020 Feb 18;12(2). Epub 2020 Feb 18.

Division of Cardiometabolic Health, Oregon National Primate Center, Beaverton, OR 97006, USA.

White adipose tissue (WAT) hypertrophy is an essential hallmark of obesity and is associated with the activation of resident immune cells. While the benefits of caloric restriction (CR) on health span are generally accepted, its effects on WAT physiology are not well understood. We previously demonstrated that short-term CR reverses obesity in male rhesus macaques exposed to a high-fat Western-style diet (WSD). Here, we analyzed subcutaneous WAT biopsies collected from this cohort of animals before and after WSD and following CR. This analysis showed that WSD induced adipocyte hypertrophy and inhibited β-adrenergic-simulated lipolysis. CR reversed adipocyte hypertrophy, but WAT remained insensitive to β-adrenergic agonist stimulation. Whole-genome transcriptional analysis revealed that β3-adrenergic receptor and de novo lipogenesis genes were downregulated by WSD and remained downregulated after CR. In contrast, WSD-induced pro-inflammatory gene expression was effectively reversed by CR. Furthermore, peripheral blood monocytes isolated during the CR period exhibited a significant reduction in the production of pro-inflammatory cytokines compared to those obtained after WSD. Collectively, this study demonstrates that short-term CR eliminates an obesity-induced pro-inflammatory response in WAT and peripheral monocytes.
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http://dx.doi.org/10.3390/nu12020511DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7071433PMC
February 2020

Immune correlates of postexposure vaccine protection against Marburg virus.

Sci Rep 2020 02 20;10(1):3071. Epub 2020 Feb 20.

Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, 77555, USA.

Postexposure immunization can prevent disease and reduce transmission following pathogen exposure. The rapid immunostimulatory properties of recombinant vesicular stomatitis virus (rVSV)-based vaccines make them suitable postexposure treatments against the filoviruses Ebola virus and Marburg virus (MARV); however, the mechanisms that drive this protection are undefined. Previously, we reported 60-75% survival of rhesus macaques treated with rVSV vectors expressing MARV glycoprotein (GP) 20-30 minutes after a low dose exposure to the most pathogenic variant of MARV, Angola. Survival in this model was linked to production of GP-specific antibodies and lower viral load. To confirm these results and potentially identify novel correlates of postexposure protection, we performed a similar experiment, but analyzed plasma cytokine levels, frequencies of immune cell subsets, and the transcriptional response to infection in peripheral blood. In surviving macaques (80-89%), we observed induction of genes mapping to antiviral and interferon-related pathways early after treatment and a higher percentage of T helper 1 (Th1) and NK cells. In contrast, the response of non-surviving macaques was characterized by hypercytokinemia; a T helper 2 signature; recruitment of low HLA-DR expressing monocytes and regulatory T-cells; and transcription of immune checkpoint (e.g., PD-1, LAG3) genes. These results suggest dysregulated immunoregulation is associated with poor prognosis, whereas early innate signaling and Th1-skewed immunity are important for survival.
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http://dx.doi.org/10.1038/s41598-020-59976-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7033120PMC
February 2020

Toxoplasma gondii Dysregulates Barrier Function and Mechanotransduction Signaling in Human Endothelial Cells.

mSphere 2020 Jan 29;5(1). Epub 2020 Jan 29.

Department of Molecular Biology & Biochemistry, University of California, Irvine, California, USA

can infect and replicate in vascular endothelial cells prior to entering host tissues. However, little is known about the molecular interactions at the parasite-endothelial cell interface. We demonstrate that infection of primary human umbilical vein endothelial cells (HUVEC) altered cell morphology and dysregulated barrier function, increasing permeability to low-molecular-weight polymers. disrupted vascular endothelial cadherin (VE-cadherin) and β-catenin localization to the cell periphery and reduced VE-cadherin protein expression. Notably, infection led to reorganization of the host cytoskeleton by reducing filamentous actin (F-actin) stress fiber abundance under static and microfluidic shear stress conditions and by reducing planar cell polarity. RNA sequencing (RNA-Seq) comparing genome-wide transcriptional profiles of infected to uninfected endothelial cells revealed changes in gene expression associated with cell-cell adhesion, extracellular matrix reorganization, and cytokine-mediated signaling. In particular, genes downstream of Hippo signaling and the biomechanical sensor and transcriptional coactivator Yes-associated protein (YAP) were downregulated in infected endothelial cells. Interestingly, infection activated Hippo signaling by increasing phosphorylation of LATS1, leading to cytoplasmic retention of YAP, and reducing YAP target gene expression. These findings suggest that infection triggers Hippo signaling and YAP nuclear export, leading to an altered transcriptional profile of infected endothelial cells. is a foodborne parasite that infects virtually all warm-blooded animals and can cause severe disease in individuals with compromised or weakened immune systems. During dissemination in its infected hosts, breaches endothelial barriers to enter tissues and establish the chronic infections underlying the most severe manifestations of toxoplasmosis. The research presented here examines how infection of primary human endothelial cells induces changes in cell morphology, barrier function, gene expression, and mechanotransduction signaling under static conditions and under the physiological conditions of shear stress found in the bloodstream. Understanding the molecular interactions occurring at the interface between endothelial cells and may provide insights into processes linked to parasite dissemination and pathogenesis.
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http://dx.doi.org/10.1128/mSphere.00550-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6992369PMC
January 2020

A VP35 Mutant Ebola Virus Lacks Virulence but Can Elicit Protective Immunity to Wild-Type Virus Challenge.

Cell Rep 2019 09;28(12):3032-3046.e6

Center for Microbial Pathogenesis, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA 30303, USA. Electronic address:

Zaire ebolavirus (EBOV) VP35 protein is a suppressor of type I interferon (IFN) production, an inhibitor of dendritic cell maturation, and a putative virulence determinant. Here, a recombinant EBOV encoding a mutant VP35 virus (VP35m) is demonstrated to activate RIG-I-like receptor signaling and innate antiviral pathways. When inoculated into cynomolgus macaques, VP35m exhibits dramatic attenuation as compared to wild-type EBOV (wtEBOV), with 20 or 300 times the standard 100% lethal challenge dose not causing EBOV disease (EVD). Further, VP35m infection, despite limited replication in vivo, activates antigen presentation and innate immunity pathways and elicits increased frequencies of proliferating memory T cells and B cells and production of anti-EBOV antibodies. Upon wtEBOV challenge, VP35m-immunized animals survive, exhibiting host responses consistent with an orderly immune response and the absence of excessive inflammation. These data demonstrate that VP35 is a critical EBOV immune evasion factor and provide insights into immune mechanisms of EBOV control.
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http://dx.doi.org/10.1016/j.celrep.2019.08.047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6886687PMC
September 2019

Antiviral Innate Responses Induced by VSV-EBOV Vaccination Contribute to Rapid Protection.

mBio 2019 05 28;10(3). Epub 2019 May 28.

Department of Molecular Biology and Biochemistry, University of California-Irvine, Irvine, California, USA

Ebola virus (EBOV) is a single-stranded RNA virus that causes Ebola virus disease (EVD), characterized by excessive inflammation, lymphocyte apoptosis, hemorrhage, and coagulation defects leading to multiorgan failure and shock. Recombinant vesicular stomatitis virus expressing the EBOV glycoprotein (VSV-EBOV), which is highly efficacious against lethal challenge in nonhuman primates, is the only vaccine that successfully completed a phase III clinical trial. Additional studies showed VSV-EBOV provides complete and partial protection to macaques immunized 7 and 3 days before EBOV challenge, respectively. However, the mechanisms by which this live-attenuated vaccine elicits rapid protection are only partially understood. To address this, we carried out a longitudinal transcriptome analysis of host responses in whole-blood samples collected from cynomolgus macaques vaccinated with VSV-EBOV 28, 21, 14, 7, and 3 days before EBOV challenge. Our findings indicate the transcriptional response to the vaccine peaks 7 days following vaccination and contains signatures of both innate antiviral immunity as well as B-cell activation. EBOV challenge 1 week after vaccination resulted in large gene expression changes suggestive of a recall adaptive immune response 14 days postchallenge. Lastly, the timing and magnitude of innate immunity and interferon-stimulated gene expression correlated with viral burden and disease outcome in animals vaccinated 3 days before challenge. Ebola virus (EBOV) is the causative agent of Ebola virus disease (EVD), a deadly disease and major public health threat worldwide. A safe and highly efficacious vesicular stomatitis virus-based vaccine against EBOV is the only platform that has successfully completed phase III clinical trials and has been used in recent and ongoing outbreaks. Earlier studies showed that antibodies are the main mode of protection when this vaccine is administered 28 days before EBOV challenge. Recently, we showed this vaccine can provide protection when administered as early as 3 days before challenge and before antibodies are detected. This study seeks to identify the mechanisms of rapid protection, which in turn will pave the way for improved vaccines and therapeutics. Additionally, this study provides insight into host gene expression signatures that could provide early biomarkers to identify infected individuals who are at highest risk of poor outcomes.
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http://dx.doi.org/10.1128/mBio.00597-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6538780PMC
May 2019

Dose-dependent effects of chronic alcohol drinking on peripheral immune responses.

Sci Rep 2019 05 24;9(1):7847. Epub 2019 May 24.

Department of Molecular Biology and Biochemistry, University of California-Irvine, Irvine, CA, 92697, USA.

It is well established that chronic heavy alcohol drinking (CHD) results in significant organ damage, increased susceptibility to infections, and poor outcomes following injury. In contrast, chronic moderate drinking (CMD) has been associated with improved cardiovascular health and immunity. These differential outcomes have been linked to alterations in both innate and adaptive branches of the immune system; however, the mechanisms remain poorly understood. To address this question, we determined the impact of chronic drinking on the transcriptional and functional responses of peripheral blood mononuclear cells (PBMC) collected from male rhesus macaques classified as CMD or CHD after 12 months of voluntary ethanol self-administration. Our analysis suggests that chronic alcohol drinking, regardless of dose alters resting transcriptomes of PBMC, with the largest impact seen in innate immune cells. These transcriptional changes are partially explained by alterations in microRNA profiles. Additionally, chronic alcohol drinking is associated with a dose dependent heightened inflammatory profiled at resting and following LPS stimulation. Moreover, we observed a dose-dependent shift in the kinetics of transcriptional responses to LPS. These findings may explain the dichotomy in clinical and immunological outcomes observed with moderate versus heavy alcohol drinking.
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http://dx.doi.org/10.1038/s41598-019-44302-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6534547PMC
May 2019

Altered Immunity and Microbial Dysbiosis in Aged Individuals With Long-Term Controlled HIV Infection.

Front Immunol 2019 12;10:463. Epub 2019 Mar 12.

Molecular Biology and Biochemistry, University of California Irvine, Irvine, CA, United States.

The introduction of highly active antiretroviral therapy (HAART) resulted in a significant increase in life expectancy for HIV patients. Indeed, in 2015, 45% of the HIV+ individuals in the United States were ≥55 years of age. Despite improvements in diagnosis and treatment of HIV infection, geriatric HIV+ patients suffer from higher incidence of comorbidities compared to age-matched HIV- individuals. Both chronic inflammation and dysbiosis of the gut microbiome are believed to be major contributors to this phenomenon, however carefully controlled studies investigating the impact of long-term (>10 years) controlled HIV (LTC-HIV) infection are lacking. To address this question, we profiled circulating immune cells, immune mediators, and the gut microbiome from elderly (≥55 years old) LTC-HIV+ and HIV- gay men living in the Palm Springs area. LTC-HIV+ individuals had lower frequency of circulating monocytes and CD4+ T-cells, and increased frequency CD8+ T-cells. Moreover, levels of systemic INFγ and several growth factors were increased while levels of IL-2 and several chemokines were reduced. Upon stimulation, immune cells from LTC-HIV+ individuals produced higher levels of pro-inflammatory cytokines. Last but not least, the gut microbiome of LTC-HIV+ individuals was enriched in bacterial taxa typically found in the oral cavity suggestive of loss of compartmentalization, while levels of beneficial butyrate producing taxa were reduced. Additionally, prevalence of negatively correlated with CD4+ T-cells numbers in LTC-HIV+ individuals. These results indicate that despite long-term adherence and undetectable viral loads, LTC-HIV infection results in significant shifts in immune cell frequencies and gut microbial communities.
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http://dx.doi.org/10.3389/fimmu.2019.00463DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6423162PMC
September 2020

Protection Against Marburg Virus Using a Recombinant VSV-Vaccine Depends on T and B Cell Activation.

Front Immunol 2018 22;9:3071. Epub 2019 Jan 22.

Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, CA, United States.

Marburg virus (MARV) is the causative agent of hemorrhagic fever outbreaks with high case fatality rates. Closely related to Ebola virus, MARV is a filamentous virus with a negative-sense, single-stranded RNA genome. Although extensive studies on filovirus countermeasures have been conducted, there are no licensed treatments against MARV infections. An experimental vaccine based on the recombinant vesicular stomatitis virus (VSV) expressing the MARV-Musoke glycoprotein demonstrated complete protection when a single dose was administered 28 days and up to 14 months prior to MARV challenge. Here, we analyzed the protective efficacy of an updated vaccine expressing the MARV-Angola glycoprotein (VSV-MARV). A single dose of VSV-MARV given 5 weeks before challenge provided uniform protection with no detectable viremia. The vaccine induced B and T cell proliferation and, importantly, antigen-specific IgG production. Transcriptomic signatures confirm these findings and suggest innate immunity engendered by VSV-MARV may direct the development of protective humoral immunity.
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http://dx.doi.org/10.3389/fimmu.2018.03071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6350103PMC
October 2019

Transcriptome Analysis of Circulating Immune Cell Subsets Highlight the Role of Monocytes in Zaire Ebola Virus Makona Pathogenesis.

Front Immunol 2017 26;8:1372. Epub 2017 Oct 26.

Department of Molecular Biology and Biochemistry, College of Biological Sciences, University of California, Irvine, Irvine, CA, United States.

Existing models of Ebola virus disease (EVD) suggest antigen-presenting cells are initial targets of (ZEBOV). studies have shown that ZEBOV infection of monocytes and macrophages results in the production of inflammatory mediators, which may cause lymphocyte apoptosis. However, these findings have not been corroborated by studies. In this study, we report the first longitudinal analysis of transcriptional changes in purified monocytes, T-cells, and B-cells isolated from cynomolgus macaques following infection with ZEBOV-Makona. Our data reveal monocytes as one of the major immune cell subsets that supports ZEBOV replication . In addition, we report a marked increase in the transcription of genes involved in inflammation, coagulation, and vascular disease within monocytes, suggesting that monocytes contribute to EVD manifestations. Further, genes important for antigen presentation and regulation of immunity were downregulated, potentially subverting development of adaptive immunity. In contrast, lymphocytes, which do not support ZEBOV replication, showed transcriptional changes limited to a small number of interferon-stimulated genes (ISGs) and a failure to upregulate genes associated with an antiviral effector immune response. Collectively, these data suggest that ZEBOV-infected monocytes play a significant role in ZEBOV-Makona pathogenesis and strategies to suppress virus replication or modify innate responses to infection in these cells should be a priority for therapeutic intervention.
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http://dx.doi.org/10.3389/fimmu.2017.01372DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5662559PMC
October 2017