Publications by authors named "Ilhem Messaoudi"

123 Publications

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 Feb 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
February 2021

Impaired hypothalamic feedback dysregulates brain glucocorticoid signaling in genetically-selected Marchigian Sardinian alcohol-preferring rats.

Addict Biol 2020 Nov 3:e12978. Epub 2020 Nov 3.

Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California, USA.

Genetically-selected Marchigian Sardinian alcohol-preferring (msP) rats display comorbid symptoms of increased alcohol preference and elevated anxiety-like behavior. Heightened stress sensitivity in msPs is influenced by genetic polymorphisms of the corticotropin-releasing factor receptor in the central nucleus of the amygdala (CeA), as well as reduced influence of anti-stress mechanisms that normally constrain the stress response. Given this propensity for stress dysregulation, in this study, we expand on the possibility that msPs may display differences in neuroendocrine processes that normally terminate the stress response. We utilized behavioral, biochemical, and molecular assays to compare basal and restraint stress-induced changes in the hypothalamic-pituitary-adrenal (HPA) axis of male and female msPs relative to their nonselected Wistar counterparts. The results showed that msPs display deficits in marble-burying behavior influenced by environmental factors and procedures that modulate arousal states in a sex-dependent manner. Whereas male msPs display evidence of dysregulated neuroendocrine function (higher adrenocorticotropic hormone levels and subthreshold reductions in corticosterone), females display restraint-induced elevations in corticosterone levels that were persistently higher in msPs. A dexamethasone challenge reduced the circulation of these stress hormones, although the reduction in corticosterone was generally attenuated in msP versus Wistar rats. Finally, we found evidence of diminished stress-induced glucocorticoid receptor (GR) phosphorylation in the hypothalamic paraventricular nucleus of msPs, as well as innate increases in phosphorylated GR levels in the CeA of male msPs. Collectively, these findings suggest that negative feedback processes regulating HPA responsiveness are diminished in msP rats, possibly underlying differences in the expression of anxiety-like behaviors.
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http://dx.doi.org/10.1111/adb.12978DOI Listing
November 2020

Importance of sex and trauma context on circulating cytokines and amygdalar GABAergic signaling in a comorbid model of posttraumatic stress and alcohol use disorders.

Mol Psychiatry 2020 Oct 21. Epub 2020 Oct 21.

Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, 92037, USA.

Alcohol use disorder (AUD) and anxiety disorders are frequently comorbid and share mechanisms that could be therapeutic targets. To facilitate mechanistic studies, we adapted an inhibitory avoidance-based "2-hit" rat model of posttraumatic stress disorder (PTSD) and identified predictors and biomarkers of comorbid alcohol (ethanol)/PTSD-like symptoms in these animals. Stressed Wistar rats received a single footshock on two occasions. The first footshock occurred when rats crossed into the dark chamber of a shuttle box. Forty-eight hours later, rats received the second footshock in a familiar (FAM) or novel (NOV) context. Rats then received 4 weeks of two-bottle choice (2BC) ethanol access. During subsequent abstinence, PTSD-like behavior responses, GABAergic synaptic transmission in the central amygdala (CeA), and circulating cytokine levels were measured. FAM and NOV stress more effectively increased 2BC drinking in males and females, respectively. Stressed male rats, especially drinking-vulnerable individuals (≥0.8 g/kg average 2-h ethanol intake with >50% ethanol preference), showed higher fear overgeneralization in novel contexts, increased GABAergic transmission in the CeA, and a profile of increased G-CSF, GM-CSF, IL-13, IL-6, IL-17a, leptin, and IL-4 that discriminated between stress context (NOV > FAM > Control). However, drinking-resilient males showed the highest G-CSF, IL-13, and leptin levels. Stressed females showed increased acoustic startle and decreased sleep maintenance, indicative of hyperarousal, with increased CeA GABAergic transmission in NOV females. This paradigm promotes key features of PTSD, including hyperarousal, fear generalization, avoidance, and sleep disturbance, with comorbid ethanol intake, in a sex-specific fashion that approximates clinical comorbidities better than existing models, and identifies increased CeA GABAergic signaling and a distinct pro-hematopoietic, proinflammatory, and pro-atopic cytokine profile that may aid in treatment.
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http://dx.doi.org/10.1038/s41380-020-00920-2DOI Listing
October 2020

Insights into the pathogenesis of varicella viruses.

Curr Clin Microbiol Rep 2019 Sep 6;6(3):156-165. Epub 2019 Jul 6.

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

Purpose Of Review: Varicella zoster virus (VZV) is a highly contagious, neurotropic alpha herpes virus that causes varicella (chickenpox). VZV establishes lifelong latency in the sensory ganglia from which it can reactivate to induce herpes zoster (HZ), a painful disease that primarily affects older individuals and those who are immune-suppressed. Given that VZV infection is highly specific to humans, developing a reliable model that recapitulates the hallmarks of VZV infection has been challenging. Simian Varicella Virus (SVV) infection in nonhuman primates reproduces the cardinal features of VZV infections in humans and allows the study of varicella virus pathogenesis in the natural host. In this review, we summarize our current knowledge about genomic and virion structure of varicelloviruses as well as viral pathogenesis and antiviral immune responses during acute infection, latency and reactivation. We also examine the immune evasion mechanisms developed by varicelloviruses to escape the host immune responses and the current vaccines available for protecting individuals against chickenpox and herpes zoster.

Recent Findings: Data from recent studies suggest that infected T cells are important for viral dissemination to the cutaneous sites of infection as well as site of latency and that a viral latency-associated transcript might play a role in the transition from lytic infection to latency and then reactivation.

Summary: Recent studies have provided exciting insights into mechanisms of varicelloviruses pathogenesis such as the critical role of T cells in VZV/SVV dissemination from the respiratory mucosa to the skin and the sensory ganglia; the ability of VZV/SVV to interfere with host defense; and the identification of VLT transcripts in latently infected ganglia. However, our understanding of these phenomena remains poorly understood. Therefore, it is critical that we continue to investigate host-pathogen interactions during varicelloviruses infection. These studies will lead to a deeper understanding of VZV biology as well as novel aspects of cell biology.
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http://dx.doi.org/10.1007/s40588-019-00119-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7523919PMC
September 2019

To B or Not to B: Mechanisms of Protection Conferred by rVSV-EBOV-GP and the Roles of Innate and Adaptive Immunity.

Microorganisms 2020 Sep 25;8(10). Epub 2020 Sep 25.

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

Zaire Ebola virus (EBOV) is a member of the family of negative sense, single-stranded RNA viruses. EBOV infection causes Ebola virus disease (EVD), characterized by coagulopathy, lymphopenia, and multi-organ failure, which can culminate in death. In 2019, the FDA approved the first vaccine against EBOV, a recombinant live-attenuated viral vector wherein the G protein of vesicular stomatitis virus is replaced with the glycoprotein (GP) of EBOV (rVSV-EBOV-GP, Ervebo by Merck). This vaccine demonstrates high efficacy in nonhuman primates by providing prophylactic, rapid, and post-exposure protection. In humans, rVSV-EBOV-GP demonstrated 100% protection in several phase III clinical trials in over 10,000 individuals during the 2013-2016 West Africa epidemic. As of 2020, over 218,000 doses of rVSV-EBOV-GP have been administered to individuals with high risk of EBOV exposure. Despite licensure and robust preclinical studies, the mechanisms of rVSV-EBOV-GP-mediated protection are not fully understood. Such knowledge is crucial for understanding vaccine-mediated correlates of protection from EVD and to aid the further design and development of therapeutics against filoviruses. Here, we summarize the current literature regarding the host response to vaccination and EBOV exposure, and evidence regarding innate and adaptive immune mechanisms involved in rVSV-EBOV-GP-mediated protection, with a focus on the host transcriptional response. Current data strongly suggest a protective synergy between rapid innate and humoral immunity.
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http://dx.doi.org/10.3390/microorganisms8101473DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7600878PMC
September 2020

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

Vaccine-mediated protection against -associated enteric disease.

Sci Adv 2020 Jun 24;6(26):eaba4511. Epub 2020 Jun 24.

Najít Technologies Inc., Beaverton, OR, USA.

and are responsible for 400 million to 500 million cases of enteric disease each year and represent the most common cause of bacterial gastroenteritis worldwide. Despite its global importance, vaccine development has been hampered by the lack of animal models that recapitulate human disease pathogenesis. Here, we describe a naturally occurring -associated diarrhea model in outdoor-housed rhesus macaques. Using this model, we developed novel next-generation HO-based vaccines that induced strong antibacterial antibodies to multiple proteins including flagellin and provided up to 83% protection against severe -associated diarrhea. Whole-genome sequencing of circulating strains revealed little to no homology within lipooligosaccharide or capsular polysaccharide loci with the vaccine strains used in these studies, indicating that vaccine-mediated immunity was not restricted to a single homologous serotype. Together, these results demonstrate an important advance in vaccine development and a new approach to reducing -associated enteric disease.
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http://dx.doi.org/10.1126/sciadv.aba4511DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7314533PMC
June 2020

Henipavirus W Proteins Interact with 14-3-3 To Modulate Host Gene Expression.

J Virol 2020 07 1;94(14). Epub 2020 Jul 1.

Center for Microbial Pathogenesis, Institute for Biomedical Sciences, Georgia State University, Atlanta, Georgia, USA

Nipah virus (NiV) and Hendra virus (HeV), members of the genus in the family, are recently emerged, highly lethal zoonotic pathogens. The NiV and HeV nonsegmented, negative-sense RNA genomes encode nine proteins, including the W protein. Expressed from the P gene through mRNA editing, W shares a common N-terminus with P and V but has a unique C-terminus. Expressed alone, W modulates innate immune responses by several mechanisms, and elimination of W from NiV alters the course of infection in experimentally infected ferrets. However, the specific host interactions that allow W to modulate innate immunity are incompletely understood. This study demonstrates that the NiV and HeV W proteins interact with all seven isoforms of the 14-3-3 family, regulatory molecules that preferentially bind phosphorylated target proteins to regulate a wide range of cellular functions. The interaction is dependent on the penultimate amino acid residue in the W sequence, a conserved, phosphorylated serine. The cocrystal structure of the W C-terminal binding motif with 14-3-3 provides only the second structure of a complex containing a mode III interactor, which is defined as a 14-3-3 interaction with a phosphoserine/phosphothreonine at the C-termini of the target protein. Transcriptomic analysis of inducible cell lines infected with an RNA virus and expressing either wild-type W or W lacking 14-3-3 binding, identifies new functions for W. These include the regulation of cellular metabolic processes, extracellular matrix organization, and apoptosis. Nipah virus (NiV) and Hendra virus (HeV), members of the genus, are recently emerged, highly lethal zoonotic pathogens that cause yearly outbreaks. NiV and HeV each encode a W protein that has roles in regulating host signaling pathways, including antagonism of the innate immune response. However, the mechanisms used by W to regulate these host responses are not clear. Here, characterization of the interaction of NiV and HeV W with 14-3-3 identifies modulation of 14-3-3-regulated host signaling pathways not previously associated with W, suggesting new avenues of research. The cocrystal structure of the NiV W:14-3-3 complex, as only the second structure of a 14-3-3 mode III interactor, provides further insight into this less-well-understood 14-3-3 binding motif.
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http://dx.doi.org/10.1128/JVI.00373-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7343215PMC
July 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

Vaccine-Induced Skewing of T Cell Responses Protects Against Chikungunya Virus Disease.

Front Immunol 2019 31;10:2563. Epub 2019 Oct 31.

Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, OR, United States.

Chikungunya virus (CHIKV) infections can cause severe and debilitating joint and muscular pain that can be long lasting. Current CHIKV vaccines under development rely on the generation of neutralizing antibodies for protection; however, the role of T cells in controlling CHIKV infection and disease is still unclear. Using an overlapping peptide library, we identified the CHIKV-specific T cell receptor epitopes recognized in C57BL/6 infected mice at 7 and 14 days post-infection. A fusion protein containing peptides 451, 416, a small region of nsP4, peptide 47, and an HA tag (CHKVf5) was expressed using adenovirus and cytomegalovirus-vectored vaccines. Mice vaccinated with CHKVf5 elicited robust T cell responses to higher levels than normally observed following CHIKV infection, but the vaccine vectors did not elicit neutralizing antibodies. CHKVf5-vaccinated mice had significantly reduced infectious viral load when challenged by intramuscular CHIKV injection. Depletion of both CD4 and CD8 T cells in vaccinated mice rendered them fully susceptible to intramuscular CHIKV challenge. Depletion of CD8 T cells alone reduced vaccine efficacy, albeit to a lesser extent, but depletion of only CD4 T cells did not reverse the protective phenotype. These data demonstrated a protective role for CD8 T cells in CHIKV infection. However, CHKVf5-vaccinated mice that were challenged by footpad inoculation demonstrated equal viral loads and increased footpad swelling at 3 dpi, which we attributed to the presence of CD4 T cell receptor epitopes present in the vaccine. Indeed, vaccination of mice with vectors expressing only CHIKV-specific CD8 T cell epitopes followed by CHIKV challenge in the footpad prevented footpad swelling and reduced proinflammatory cytokine and chemokines associated with disease, indicating that CHIKV-specific CD8 T cells prevent CHIKV disease. These results also indicate that a T cell-biased prophylactic vaccination approach is effective against CHIKV challenge and reduces CHIKV-induced disease in mice.
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http://dx.doi.org/10.3389/fimmu.2019.02563DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6834551PMC
October 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

Impact of pregravid obesity on maternal and fetal immunity: Fertile grounds for reprogramming.

J Leukoc Biol 2019 11 4;106(5):1035-1050. Epub 2019 Sep 4.

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

Maternal pregravid obesity results in several adverse health outcomes during pregnancy, including increased risk of gestational diabetes, preeclampsia, placental abruption, and complications at delivery. Additionally, pregravid obesity and in utero exposure to high fat diet have been shown to have detrimental effects on fetal programming, predisposing the offspring to adverse cardiometabolic, endocrine, and neurodevelopmental outcomes. More recently, a deeper appreciation for the modulation of offspring immunity and infectious disease-related outcomes by maternal pregravid obesity has emerged. This review will describe currently available animal models for studying the impact of maternal pregravid obesity on fetal immunity and review the data from clinical and animal model studies. We also examine the burden of pregravid obesity on the maternal-fetal interface and the link between placental and systemic inflammation. Finally, we discuss future studies needed to identify key mechanistic underpinnings that link maternal inflammatory changes and fetal cellular reprogramming events.
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http://dx.doi.org/10.1002/JLB.3RI0619-181RDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7443713PMC
November 2019

Maturation of the infant rhesus macaque gut microbiome and its role in the development of diarrheal disease.

Genome Biol 2019 08 26;20(1):173. Epub 2019 Aug 26.

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

Background: Diarrhea is the second leading cause of death in children under 5 years of age. Enhanced understanding of causal pathways, pathogenesis, and sequelae of diarrhea is urgently needed. Although the gut microbiota is believed to play a role in susceptibility to diarrheal diseases, our understanding of this association remains incomplete. Infant rhesus macaques (Macaca mulatta) are susceptible to diarrhea making them an ideal model to address this question.

Results: The maturation of the infant rhesus macaque gut microbiome throughout the first 8 months of life occurs in a similar pattern as that described for human infants. Moreover, the microbiome of the captive reared infant rhesus macaque more closely resembles that of human infants in the developing world than in the western world. Importantly, prior to disease onset, the gut microbiome of infants that later develop diarrhea is enriched in pathways of immunomodulatory metabolite synthesis, while those of infants that remain asymptomatic are enriched in pathways for short-chain fatty acid production. We identify Prevotella strains that are more abundant at 1 month in infants that later develop diarrhea. At 8 months, the microbiomes of animals that experience diarrhea show increased abundance of Campylobacter and a reduction in Helicobacter macacae.

Conclusion: The composition of the microbial community could provide a phenotypic marker of an infant's susceptibility to diarrheal disease. Given the significant physiological and immunological similarities between human and nonhuman primates, these findings provide potential markers of susceptibility to diarrhea that could be modulated to improve infant health, especially in the developing world.
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http://dx.doi.org/10.1186/s13059-019-1789-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6709555PMC
August 2019

A Multidimensional Assessment of Successful Aging Among Older People Living with HIV in Palm Springs, California.

AIDS Res Hum Retroviruses 2019 Nov/Dec;35(11-12):1174-1180. Epub 2019 Sep 25.

School of Medicine, University of California, Riverside, Riverside, California.

We assessed successful aging among older people living with HIV (PLWH) compared with older people without HIV. One hundred ten older men and women in Palm Springs, California completed a self-administered 28-question survey, which collected data on physiological and psychosocial factors related to successfully aging with HIV, including demographics, HIV status, sexual activity, health and well-being, experiences of stigma or discrimination, feelings of isolation, receipt of disability benefits, work and volunteer participation, and presence of comorbid infectious diseases, noninfectious diseases, and geriatric syndromes. Most participants were male (96.4%), non-Hispanic white (84.5%), college educated (61.7%), and ranged in age from 55 to 87 years (median = 64 years). Respondents with HIV were significantly older than those without HIV ( = .04). The overall prevalence of two or more comorbid conditions across the sample was 59.1%. PLWH were more likely to report depression ( = .008). PLWH were also significantly more likely to report having a current sex partner living with HIV ( < .001) and receiving disability benefits than people without HIV (41.9% vs. 6.3%). Among PLWH, there was a significant relationship between not working or volunteering and feelings of isolation ( = .005). For people without HIV, we found a significant relationship between feelings of isolation and not living with someone ( < .001), but there was no such relationship among PLWH-possibly reflecting the strength of the support network for PLWH in Palm Springs. Our findings suggest that older PLWH experience successful aging to a similar degree compared with their peers without HIV. However, depression and social isolation remain highly salient issues that threaten successful aging and with which PLWH must contend.
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http://dx.doi.org/10.1089/AID.2019.0048DOI Listing
September 2020

Current In Vivo Models of Varicella-Zoster Virus Neurotropism.

Viruses 2019 05 31;11(6). Epub 2019 May 31.

Division of Microbiology, Tulane University, Tulane National Primate Research Center, Covington, LA 70433, USA.

Varicella-zoster virus (VZV), an exclusively human herpesvirus, causes chickenpox and establishes a latent infection in ganglia, reactivating decades later to produce zoster and associated neurological complications. An understanding of VZV neurotropism in humans has long been hampered by the lack of an adequate animal model. For example, experimental inoculation of VZV in small animals including guinea pigs and cotton rats results in the infection of ganglia but not a rash. The severe combined immune deficient human (SCID-hu) model allows the study of VZV neurotropism for human neural sub-populations. Simian varicella virus (SVV) infection of rhesus macaques (RM) closely resembles both human primary VZV infection and reactivation, with analyses at early times after infection providing valuable information about the extent of viral replication and the host immune responses. Indeed, a critical role for CD4 T-cell immunity during acute SVV infection as well as reactivation has emerged based on studies using RM. Herein we discuss the results of efforts from different groups to establish an animal model of VZV neurotropism.
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http://dx.doi.org/10.3390/v11060502DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6631480PMC
May 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

Author Correction: Infection with the Makona variant results in a delayed and distinct host immune response compared to previous Ebola virus variants.

Sci Rep 2019 May 8;9(1):7329. Epub 2019 May 8.

Galveston National Laboratory, Galveston, TX, USA.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.
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http://dx.doi.org/10.1038/s41598-019-42949-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6505025PMC
May 2019

Chronic heavy drinking drives distinct transcriptional and epigenetic changes in splenic macrophages.

EBioMedicine 2019 May 18;43:594-606. Epub 2019 Apr 18.

Department of Molecular Biology and Biochemistry, University of California-Irvine, Irvine, CA 92697, USA; Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR 97006, USA. Electronic address:

Background: Chronic heavy alcohol drinking (CHD) leads to significant organ damage, increased susceptibility to infections, and delayed wound healing. These adverse outcomes are believed to be mediated by alterations in the function of myeloid cells; however, the mechanisms underlying these changes are poorly understood.

Methods: We determined the impact of CHD on the phenotype of splenic macrophages using flow cytometry. Changes in functional responses to LPS were measured using luminex and RNA-Seq. Finally, alterations in chromatin accessibility were uncovered using ATAC-Seq.

Findings: A history of CHD led to increased frequency of splenic macrophages that exhibited a heightened activation state at resting. Additionally, splenic macrophages from CHD animals generated a larger inflammatory response to LPS, both at protein and gene expression levels. Finally, CHD resulted in increased levels of H3K4me3, a histone mark of active promoters, as well as chromatin accessibility at promoters and intergenic regions that regulate inflammatory responses.

Interpretation: These findings suggest that a history of CHD alters the immune fitness of tissue-resident macrophages via epigenetic mechanisms. FUND: National Institute on Alcohol Abuse and Alcoholism (NIAAA), National Institutes of Health (NIH) - R24AA019431, U01 AA13641, U01 AA13510, R21AA021947, and R21AA025839.
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http://dx.doi.org/10.1016/j.ebiom.2019.04.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6557917PMC
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

Chronic ethanol consumption alters lamina propria leukocyte response to stimulation in a region-dependent manner.

FASEB J 2019 06 21;33(6):7767-7777. Epub 2019 Mar 21.

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

Chronic heavy alcohol consumption, also referred to as chronic heavy drinking (CHD), results in intestinal injury characterized by increased permeability, dysbiosis, nutrient malabsorption, potentially higher susceptibility to infection, and increased risk of colorectal cancer. However, our understanding of the mechanisms by which CHD results in intestinal damage remains incomplete. Here, we investigated the impact of chronic drinking on transcriptional and functional responses of lamina propria leukocytes (LPLs) isolated from the 4 major gut sections. Although no significant differences were detected between LPLs isolated from the ethanol and control groups at resting state within each major gut section, our analysis uncovered key regional differences in composition and function of LPLs independent of alcohol consumption. However, in response to phorbol myristate acetate and ionomycin, duodenal LPLs from ethanol-drinking animals generated a dampened response, whereas jejunal and ileal LPLs from ethanol-drinking animals produced a heightened response. Transcriptional responses following stimulation were pronounced in ileal and duodenal LPLs from the ethanol-drinking group but less evident in jejunal and colonic LPLs compared with controls, suggesting a more significant impact of alcohol on these gut regions. The altered intestinal LPL function detected in our study reveals remarkable region specificity and novel insight into potential mechanisms of intestinal injury associated with CHD.-Barr, T., Lewis, S. A., Sureshchandra, S., Doratt, B., Grant, K. A., Messaoudi, I. Chronic ethanol consumption alters lamina propria leukocyte response to stimulation in a region-dependent manner.
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http://dx.doi.org/10.1096/fj.201802780RDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6529332PMC
June 2019

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

Varicella Virus-Host Interactions During Latency and Reactivation: Lessons From Simian Varicella Virus.

Front Microbiol 2018 21;9:3170. Epub 2018 Dec 21.

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

Varicella zoster virus (VZV) is a neurotropic alphaherpesvirus and the causative agent of varicella (chickenpox) in humans. Following primary infection, VZV establishes latency in the sensory ganglia and can reactivate to cause herpes zoster, more commonly known as shingles, which causes significant morbidity, and on rare occasions mortality, in the elderly. Because VZV infection is highly restricted to humans, the development of a reliable animal model has been challenging, and our understanding of VZV pathogenesis remains incomplete. As an alternative, infection of rhesus macaques with the homologous simian varicella virus (SVV) recapitulates the hallmarks of VZV infection and thus constitutes a robust animal model to provide critical insights into VZV pathogenesis and the host antiviral response. In this model, SVV infection results in the development of varicella during primary infection, generation of an adaptive immune response, establishment of latency in the sensory ganglia, and viral reactivation upon immune suppression. In this review, we discuss our current knowledge about host and viral factors involved in the establishment of SVV latency and reactivation as well as the important role played by T cells in SVV pathogenesis and antiviral immunity.
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http://dx.doi.org/10.3389/fmicb.2018.03170DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6308120PMC
December 2018

Inflammatory Determinants of Pregravid Obesity in Placenta and Peripheral Blood.

Front Physiol 2018 7;9:1089. Epub 2018 Aug 7.

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

Pre-pregnancy (pregravid) obesity has been linked to several adverse health outcomes for both mother and offspring. Complications during pregnancy include increased risk for gestational diabetes, hypertension, preeclampsia, placental abruption, and difficulties during delivery. Several studies suggest that these negative outcomes are mediated by heightened systemic inflammation as well as changes in placental development and function. However, the molecular mechanisms by which pregravid obesity affects these processes are poorly understood. In this study, we aimed to address this question by carrying out a comprehensive analysis of the systemic maternal immune system coupled with placental gene expression and microbial profiling at term delivery (11 lean and 14 obese). Specifically, we examined the impact of pregravid obesity on circulating cytokines, chemokine, adipokines, and growth factors using multiplex Luminex assay. Innate and adaptive immune cell frequencies and their cytokine production in response to stimuli were measured using flow cytometry. Finally, changes in placental transcriptome and microbiome were profiled using RNA- and 16S-sequencing, respectively. Pregravid obesity is characterized by insulin and leptin resistance, high levels of circulating inflammatory markers IL-6 and CRP, in addition to chemokine IL-8 ( < 0.01). Moreover, pregravid obesity was associated with lower frequency of naïve CD4+ T-cells ( < 0.05), increased frequency of memory CD4+ T-cells ( < 0.01), and a shift towards Th2 cytokine production ( = 0.05). Myeloid cells from the obese cohort produced higher levels of pro-inflammatory cytokines but lower levels of chemokines following TLR stimulation ( < 0.05). Lastly, pregravid obesity is associated with increased abundance of Bacteroides and changes in the expression of genes important for nutrient transport and immunity (FDR < 0.05). Collectively, these data indicate that pregravid obesity is associated with heightened systemic inflammation and of dysregulated nutrient transport in the placenta and provide insight into the basis of fetal reprogramming.
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http://dx.doi.org/10.3389/fphys.2018.01089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6090296PMC
August 2018