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  • 1.
    Barrenäs, Fredrik
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Green, Richard R.
    Thomas, Matthew J.
    Law, G. Lynn
    Proll, Sean C.
    Engelmann, Flora
    Messaoudi, Ilhem
    Marzi, Andrea
    Feldmann, Heinz
    Katze, Michael G.
    Next-Generation Sequencing Reveals a Controlled Immune Response to Zaire Ebola Virus Challenge in Cynomolgus Macaques Immunized with Vesicular Stomatitis Virus Expressing Zaire Ebola Virus Glycoprotein (VSV Delta G/EBOVgp)2015In: Clinical and Vaccine Immunology, ISSN 1556-6811, E-ISSN 1556-679X, Vol. 22, no 3, p. 354-356Article in journal (Refereed)
    Abstract [en]

    Vesicular stomatitis virus expressing Zaire Ebola virus (EBOV) glycoprotein (VSV Delta G/EBOVgp) could be used as a vaccine to meet the 2014 Ebola virus outbreak. To characterize the host response to this vaccine, we used mRNA sequencing to analyze peripheral blood mononuclear cells (PBMCs) from cynomolgus macaques after VSV Delta G/EBOVgp immunization and subsequent EBOV challenge. We found a controlled transcriptional response that transitioned to immune regulation as the EBOV was cleared. This observation supports the safety of the vaccine.

  • 2.
    Barrenäs, Fredrik
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Palermo, Robert E.
    Agricola, Brian
    Agy, Michael B.
    Aicher, Lauri
    Carter, Victoria
    Flanary, Leon
    Green, Richard R.
    McLain, Randy
    Li, Qingsheng
    Lu, Wuxun
    Murnane, Robert
    Peng, Xinxia
    Thomas, Matthew J.
    Weiss, Jeffrey M.
    Anderson, David M.
    Katze, Michael G.
    Deep Transcriptional Sequencing of Mucosal Challenge Compartment from Rhesus Macaques Acutely Infected with Simian Immunodeficiency Virus Implicates Loss of Cell Adhesion Preceding Immune Activation2014In: Journal of Virology, ISSN 0022-538X, E-ISSN 1098-5514, Vol. 88, no 14, p. 7962-7972Article in journal (Refereed)
    Abstract [en]

    Pathology resulting from human immunodeficiency virus (HIV) infection is driven by protracted inflammation; the primary loss of CD4(+) T cells is caused by activation-driven apoptosis. Recent studies of nonhuman primates (NHPs) have suggested that during the acute phase of infection, antiviral mucosal immunity restricts viral replication in the primary infection compartment. These studies imply that HIV achieves systemic infection as a consequence of a failure in host antiviral immunity. Here, we used high-dose intrarectal inoculation of rhesus macaques with simian immunodeficiency virus (SIV) SIVmac251 to examine how the mucosal immune system is overcome by SIV during acute infection. The host response in rectal mucosa was characterized by deep mRNA sequencing (mRNA-seq) at 3 and 12 days postinoculation (dpi) in 4 animals for each time point. While we observed a strong host transcriptional response at 3 dpi, functions relating to antiviral immunity were absent. Instead, we observed a significant number of differentially expressed genes relating to cell adhesion and reorganization of the cytoskeleton. We also observed downregulation of genes encoding members of the claudin family of cell adhesion molecules, which are coexpressed with genes associated with pathology in the colorectal mucosa, and a large number of noncoding transcripts. In contrast, at 12 dpi the differentially expressed genes were enriched in those involved with immune system functions, in particular, functions relating to T cells, B cells, and NK cells. Our findings indicate that host responses that negatively affect mucosal integrity occur before inflammation. Consequently, when inflammation is activated at peak viremia, mucosal integrity is already compromised, potentially enabling rapid tissue damage, driving further inflammation. IMPORTANCE The HIV pandemic is one of the major threats to human health, causing over a million deaths per year. Recent studies have suggested that mucosal antiviral immune responses play an important role in preventing systemic infection after exposure to the virus. Yet, despite their potential role in decreasing transmission rates between individuals, these antiviral mechanisms are poorly understood. Here, we carried out the first deep mRNA sequencing analysis of mucosal host responses in the primary infection compartment during acute SIV infection. We found that during acute infection, a significant host response was mounted in the mucosa before inflammation was triggered. Our analysis indicated that the response has a detrimental effect on tissue integrity, causing increased permeability, tissue damage, and recruitment of SIV target cells. These results emphasize the importance of mucosal host responses preceding immune activation in preventing systemic SIV infection.

  • 3.
    Barrenäs, Fredrik
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics. Univ Washington, Dept Microbiol, Seattle, WA 98195 USA.
    Raehtz, Kevin
    Univ Pittsburgh, Dept Med, Div Infect Dis, Pittsburgh, PA USA;Univ Pittsburgh, Sch Med, Dept Microbiol & Mol Genet, Pittsburgh, PA USA.
    Xu, Cuiling
    Univ Pittsburgh, Sch Med, Dept Pathol, Pittsburgh, PA USA.
    Law, Lynn
    Univ Washington, Dept Immunol, Seattle, WA 98195 USA;Univ Washington, Ctr Innate Immun & Immune Dis, Seattle, WA 98195 USA.
    Green, Richard R.
    Univ Washington, Dept Immunol, Seattle, WA 98195 USA;Univ Washington, Ctr Innate Immun & Immune Dis, Seattle, WA 98195 USA.
    Silvestri, Guido
    Emory Univ, Dept Pathol & Lab Med, Atlanta, GA 30322 USA;Emory Univ, Yerkes Natl Primate Res Ctr, Div Microbiol & Immunol, Atlanta, GA 30322 USA.
    Bosinger, Steven E.
    Emory Univ, Dept Pathol & Lab Med, Atlanta, GA 30322 USA;Emory Univ, Yerkes Natl Primate Res Ctr, Div Microbiol & Immunol, Atlanta, GA 30322 USA.
    Nishida, Andrew
    Univ Washington, Dept Microbiol, Seattle, WA 98195 USA.
    Li, Qingsheng
    Univ Nebraska, Sch Biol Sci, Nebraska Ctr Virol, Lincoln, NE USA.
    Lu, Wuxun
    Univ Nebraska, Sch Biol Sci, Nebraska Ctr Virol, Lincoln, NE USA.
    Zhang, Jianshui
    Univ Nebraska, Sch Biol Sci, Nebraska Ctr Virol, Lincoln, NE USA.
    Thomas, Matthew J.
    Univ Washington, Dept Immunol, Seattle, WA 98195 USA;Univ Washington, Washington Natl Primate Res Ctr, Seattle, WA 98195 USA.
    Chang, Jean
    Univ Washington, Dept Immunol, Seattle, WA 98195 USA;Univ Washington, Ctr Innate Immun & Immune Dis, Seattle, WA 98195 USA.
    Smith, Elise
    Univ Washington, Dept Immunol, Seattle, WA 98195 USA;Univ Washington, Ctr Innate Immun & Immune Dis, Seattle, WA 98195 USA.
    Weiss, Jeffrey M.
    Univ Washington, Dept Microbiol, Seattle, WA 98195 USA.
    Dawoud, Reem A.
    Emory Univ, Dept Pathol & Lab Med, Atlanta, GA 30322 USA.
    Richter, George H.
    Univ Pittsburgh, Sch Med, Dept Pathol, Pittsburgh, PA USA.
    Trichel, Anita
    Univ Pittsburgh, Div Lab Anim Resources, Pittsburgh, PA USA.
    Ma, Dongzhu
    Univ Pittsburgh, Dept Orthoped Surg, Pittsburgh, PA USA.
    Peng, Xinxia
    North Carolina State Univ, Dept Mol Biomed Sci, Raleigh, NC 27695 USA.
    Komorowski, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
    Apetrei, Cristian
    Univ Pittsburgh, Dept Med, Div Infect Dis, Pittsburgh, PA USA;Univ Pittsburgh, Sch Med, Dept Microbiol & Mol Genet, Pittsburgh, PA USA.
    Pandrea, Ivona
    Univ Pittsburgh, Sch Med, Dept Microbiol & Mol Genet, Pittsburgh, PA USA;Univ Pittsburgh, Sch Med, Dept Pathol, Pittsburgh, PA USA.
    Gale, Michael, Jr.
    Univ Washington, Dept Immunol, Seattle, WA 98195 USA;Univ Washington, Ctr Innate Immun & Immune Dis, Seattle, WA 98195 USA;Univ Washington, Washington Natl Primate Res Ctr, Seattle, WA 98195 USA.
    Macrophage-associated wound healing contributes to African green monkey SIV pathogenesis control2019In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 10, article id 5101Article in journal (Refereed)
    Abstract [en]

    Natural hosts of simian immunodeficiency virus (SIV) avoid AIDS despite lifelong infection. Here, we examined how this outcome is achieved by comparing a natural SIV host, African green monkey (AGM) to an AIDS susceptible species, rhesus macaque (RM). To asses gene expression profiles from acutely SIV infected AGMs and RMs, we developed a systems biology approach termed Conserved Gene Signature Analysis (CGSA), which compared RNA sequencing data from rectal AGM and RM tissues to various other species. We found that AGMs rapidly activate, and then maintain, evolutionarily conserved regenerative wound healing mechanisms in mucosal tissue. The wound healing protein fibronectin shows distinct tissue distribution and abundance kinetics in AGMs. Furthermore, AGM monocytes exhibit an embryonic development and repair/regeneration signature featuring TGF-beta and concomitant reduced expression of inflammatory genes compared to RMs. This regenerative wound healing process likely preserves mucosal integrity and prevents inflammatory insults that underlie immune exhaustion in RMs.

  • 4.
    Rajan, Meenu Rohini
    et al.
    Univ Gothenburg, Inst Med, Dept Mol & Clin Med, Wallenberg Lab, Gothenburg, Sweden; Univ Gothenburg, Wallenberg Ctr Mol & Translat Med, Gothenburg, Sweden.
    Sotak, Matus
    Univ Gothenburg, Inst Med, Dept Mol & Clin Med, Wallenberg Lab, Gothenburg, Sweden; Univ Gothenburg, Wallenberg Ctr Mol & Translat Med, Gothenburg, Sweden.
    Barrenäs, Fredrik
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics. Univ Gothenburg, Inst Med, Dept Mol & Clin Med, Wallenberg Lab, Gothenburg, Sweden; Univ Gothenburg, Wallenberg Ctr Mol & Translat Med, Gothenburg, Sweden.
    Shen, Tong
    Univ Calif Davis, NIH West Coast Metabol Ctr, Genome Ctr, Davis, CA 95616 USA.
    Borkowski, Kamil
    Univ Calif Davis, NIH West Coast Metabol Ctr, Genome Ctr, Davis, CA 95616 USA.
    Ashton, Nicholas J.
    Univ Gothenburg, Wallenberg Ctr Mol & Translat Med, Gothenburg, Sweden;Univ Gothenburg, Inst Physiol & Neurosci, Dept Psychiat & Neurochem, Gothenburg, Sweden;Kings Coll London, Inst Psychiat Psychol & Neurosci, Maurice Wohl Clin Neurosci Inst, London, England;NIHR Biomed Res Ctr Mental Hlth, London, England;Biomed Res Unit Dementia South London, London, England;Maudsley NHS Fdn, London, England.
    Biorserud, Christina
    Univ Gothenburg, Sahlgrenska Univ Hosp, Inst Clin Sci, Dept Gastrosurg Res & Educ, Gothenburg, Sweden.
    Lindahl, Tomas L.
    Linkoping Univ, Dept Clin Chem, Linkoping, Sweden;Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden.
    Ramstrom, Sofia
    Linkoping Univ, Dept Clin Chem, Linkoping, Sweden;Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden;Orebro Univ, Cardiovasc Res Ctr, Sch Med Sci, Orebro, Sweden.
    Scholl, Michael
    Univ Gothenburg, Wallenberg Ctr Mol & Translat Med, Gothenburg, Sweden;Univ Gothenburg, Inst Physiol & Neurosci, Dept Psychiat & Neurochem, Gothenburg, Sweden;UCL, Dementia Res Ctr, Inst Neurol, London, England.
    Lindahl, Per
    Univ Gothenburg, Inst Med, Dept Mol & Clin Med, Wallenberg Lab, Gothenburg, Sweden.
    Fiehn, Oliver
    Univ Calif Davis, NIH West Coast Metabol Ctr, Genome Ctr, Davis, CA 95616 USA.
    Newman, John W.
    Univ Calif Davis, NIH West Coast Metabol Ctr, Genome Ctr, Davis, CA 95616 USA;Univ Calif Davis, Dept Nutr, Davis, CA 95616 USA;ARS, USDA, Western Human Nutr Res Ctr, Davis, CA USA.
    Perkins, Rosie
    Univ Gothenburg, Inst Med, Dept Mol & Clin Med, Wallenberg Lab, Gothenburg, Sweden.
    Wallenius, Ville
    Univ Gothenburg, Sahlgrenska Univ Hosp, Inst Clin Sci, Dept Gastrosurg Res & Educ, Gothenburg, Sweden.
    Lange, Stephan
    Univ Gothenburg, Inst Med, Dept Mol & Clin Med, Wallenberg Lab, Gothenburg, Sweden;Univ Calif San Diego, Sch Med, Div Cardiol, San Diego, CA 92103 USA.
    Borgeson, Emma
    Univ Gothenburg, Inst Med, Dept Mol & Clin Med, Wallenberg Lab, Gothenburg, Sweden;Univ Gothenburg, Wallenberg Ctr Mol & Translat Med, Gothenburg, Sweden;Sahlgrens Univ Hosp, Dept Clin Physiol, Gothenburg, Sweden.
    Comparative analysis of obesity-related cardiometabolic and renal biomarkers in human plasma and serum2019In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 15385Article in journal (Refereed)
    Abstract [en]

    The search for biomarkers associated with obesity-related diseases is ongoing, but it is not clear whether plasma and serum can be used interchangeably in this process. Here we used high-throughput screening to analyze 358 proteins and 76 lipids, selected because of their relevance to obesity-associated diseases, in plasma and serum from age- and sex-matched lean and obese humans. Most of the proteins/lipids had similar concentrations in plasma and serum, but a subset showed significant differences. Notably, a key marker of cardiovascular disease PAI-1 showed a difference in concentration between the obese and lean groups only in plasma. Furthermore, some biomarkers showed poor correlations between plasma and serum, including PCSK9, an important regulator of cholesterol homeostasis. Collectively, our results show that the choice of biofluid may impact study outcome when screening for obesity-related biomarkers and we identify several markers where this will be the case.

1 - 4 of 4
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