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Common Nodes Of Virus-Host Interaction Revealed Through An Integrated Network Analysis, Korbinian Bosl, Richard K. Kandasamy Oct 2019

Common Nodes Of Virus-Host Interaction Revealed Through An Integrated Network Analysis, Korbinian Bosl, Richard K. Kandasamy

Open Access Articles

Viruses are one of the major causes of acute and chronic infectious diseases and thus a major contributor to the global burden of disease. Several studies have shown how viruses have evolved to hijack basic cellular pathways and evade innate immune response by modulating key host factors and signaling pathways. A collective view of these multiple studies could advance our understanding of virus-host interactions and provide new therapeutic perspectives for the treatment of viral diseases. Here, we performed an integrative meta-analysis to elucidate the 17 different host-virus interactomes. Network and bioinformatics analyses showed how viruses with small genomes efficiently achieve ...


Evaluation Of Il-1 Blockade As A Host-Directed Therapy For Tuberculosis In Mice And Macaques, Caylin G. Winchell, Bibhuti B. Mishra, University Of Massachusetts Medical School, Samantha J. Nelson, Christopher M. Sassetti, Joanne L. Flynn Oct 2019

Evaluation Of Il-1 Blockade As A Host-Directed Therapy For Tuberculosis In Mice And Macaques, Caylin G. Winchell, Bibhuti B. Mishra, University Of Massachusetts Medical School, Samantha J. Nelson, Christopher M. Sassetti, Joanne L. Flynn

University of Massachusetts Medical School Faculty Publications

In 2017, there were over 550,000 estimated new cases of multi-drug/rifampicin resistant tuberculosis (MDR/RR-TB), emphasizing a need for new treatment strategies. Linezolid (LZD) is a potent antibiotic for antibiotic-resistant Gram-positive infections and is an effective treatment for TB. However, extended LZD use can lead to LZD-associated host toxicities, most commonly bone marrow suppression. LZD toxicities may be mediated by IL-1, a pathway important for early immunity during M. tuberculosis infection that later contributes to pathology. We hypothesized LZD efficacy could be enhanced by modulation of IL-1 pathway to reduce BM toxicity and TB associated-inflammation. We used two ...


Plasma Eicosanoid Levels In Tuberculosis And Tuberculosis-Diabetes Co-Morbidity Are Associated With Lung Pathology And Bacterial Burden, Nathella Pavan Kumar, Kadar Moideen, Arul Nancy, Vijay Viswanathan, Basavaradhya S. Shruthi, Sivakumar Shanmugam, Syed Hissar, Hardy Kornfeld, Subash Babu Oct 2019

Plasma Eicosanoid Levels In Tuberculosis And Tuberculosis-Diabetes Co-Morbidity Are Associated With Lung Pathology And Bacterial Burden, Nathella Pavan Kumar, Kadar Moideen, Arul Nancy, Vijay Viswanathan, Basavaradhya S. Shruthi, Sivakumar Shanmugam, Syed Hissar, Hardy Kornfeld, Subash Babu

Open Access Articles

Host eicosanoids are lipid mediators of inflammation that are commonly accepted as important modulators of the host immune response in Mycobacterium tuberculosis infection. During active tuberculosis (TB), eicosanoids may play an important role in the regulation of inflammatory responses. However, a detailed investigation of the relationship of eicosanoids in TB and TB-diabetes comorbidity (TB-DM) and association to disease pathology or bacterial burdens has not been studied. To study this, we examined the plasma levels of Lipoxin A4 (LXA4), 15-epi-LXA4, Leukotriene B4 (LTB4), and Prostaglandin E2 (PGE2) in individuals with either TB-DM, TB, diabetes mellitus (DM) or healthy controls (HC). Plasma ...


Chitosan Biosynthesis And Virulence In The Human Fungal Pathogen Cryptococcus Gattii, Woei C. Lam, Rajendra Upadhya, Charles A. Specht, Abigail E. Ragsdale, Camaron R. Hole, Stuart M. Levitz, Jennifer K. Lodge Sep 2019

Chitosan Biosynthesis And Virulence In The Human Fungal Pathogen Cryptococcus Gattii, Woei C. Lam, Rajendra Upadhya, Charles A. Specht, Abigail E. Ragsdale, Camaron R. Hole, Stuart M. Levitz, Jennifer K. Lodge

University of Massachusetts Medical School Faculty Publications

Cryptococcus gattii R265 is a hyper-virulent fungal strain responsible for the major outbreak of cryptococcosis in Vancouver Island of British Columbia in 1999. It differs significantly from C. neoformans in its natural environment, its preferred site in the mammalian host, and in the nature and mode of pathogenesis. Our previous studies in C. neoformans have shown that the presence of chitosan, the deacetylated form of chitin, in the cell wall attenuates inflammatory responses in the host, while its absence induces robust immune responses, which in turn facilitate clearance of the fungus and induces a protective response. The results of the ...


Postnatal Zika Virus Infection Of Nonhuman Primate Infants Born To Mothers Infected With Homologous Brazilian Zika Virus, Nicholas J. Maness, Diogo Magnani Sep 2019

Postnatal Zika Virus Infection Of Nonhuman Primate Infants Born To Mothers Infected With Homologous Brazilian Zika Virus, Nicholas J. Maness, Diogo Magnani

Open Access Articles

Recent data in a nonhuman primate model showed that infants postnatally infected with Zika virus (ZIKV) were acutely susceptible to high viremia and neurological damage, suggesting the window of vulnerability extends beyond gestation. In this pilot study, we addressed the susceptibility of two infant rhesus macaques born healthy to dams infected with Zika virus during pregnancy. Passively acquired neutralizing antibody titers dropped below detection limits between 2 and 3 months of age, while binding antibodies remained detectable until viral infection at 5 months. Acute serum viremia was comparatively lower than adults infected with the same Brazilian isolate of ZIKV (n ...


Systemic Inflammation Impairs Microglial Abeta Clearance Through Nlrp3 Inflammasome, Dario Tejera, Dilek Mercan, Juan M. Sanchez-Caro, Mor Hanan, David Greenberg, Hermona Soreq, Eicke Latz, Douglas T. Golenbock, Michael T. Heneka Sep 2019

Systemic Inflammation Impairs Microglial Abeta Clearance Through Nlrp3 Inflammasome, Dario Tejera, Dilek Mercan, Juan M. Sanchez-Caro, Mor Hanan, David Greenberg, Hermona Soreq, Eicke Latz, Douglas T. Golenbock, Michael T. Heneka

Open Access Articles

Alzheimer's disease is the most prevalent type of dementia and is caused by the deposition of extracellular amyloid-beta and abnormal tau phosphorylation. Neuroinflammation has emerged as an additional pathological component. Microglia, representing the brain's major innate immune cells, play an important role during Alzheimer's. Once activated, microglia show changes in their morphology, characterized by a retraction of cell processes. Systemic inflammation is known to increase the risk for cognitive decline in human neurogenerative diseases including Alzheimer's. Here, we assess for the first time microglial changes upon a peripheral immune challenge in the context of aging and ...


Ak002, A Humanized Sialic Acid-Binding Immunoglobulin-Like Lectin-8 Antibody That Induces Antibody-Dependent Cell-Mediated Cytotoxicity Against Human Eosinophils And Inhibits Mast Cell-Mediated Anaphylaxis In Mice, Bradford A. Youngblood, Emily C. Brock, John Leung, Rustom Falahati, Paul J. Bryce, Jessica Bright, Jason Williams, Leonard D. Shultz, Dale L. Greiner, Michael A. Brehm, Christopher Bebbington, Nenad Tomasevic Aug 2019

Ak002, A Humanized Sialic Acid-Binding Immunoglobulin-Like Lectin-8 Antibody That Induces Antibody-Dependent Cell-Mediated Cytotoxicity Against Human Eosinophils And Inhibits Mast Cell-Mediated Anaphylaxis In Mice, Bradford A. Youngblood, Emily C. Brock, John Leung, Rustom Falahati, Paul J. Bryce, Jessica Bright, Jason Williams, Leonard D. Shultz, Dale L. Greiner, Michael A. Brehm, Christopher Bebbington, Nenad Tomasevic

Open Access Articles

INTRODUCTION: Pathologic accumulation and activation of mast cells and eosinophils are implicated in allergic and inflammatory diseases. Sialic acid-binding immunoglobulin-like lectin (Siglec)-8 is an inhibitory receptor selectively expressed on mast cells, eosinophils and, at a lower extent, basophils. When engaged with an antibody, Siglec-8 can induce apoptosis of activated eosinophils and inhibit mast cell activation. AK002 is a humanized, non-fucosylated IgG1 anti-Siglec-8 antibody undergoing clinical investigation for treatment of allergic, inflammatory, and proliferative diseases. Here we examine the human tissue selectivity of AK002 and evaluate the in vitro, ex vivo, and in vivo activity of AK002 on eosinophils and ...


Cxcr3 Chemokine Receptor Guides Trypanosoma Cruzi-Specific T-Cells Triggered By Dna/Adenovirus Asp2 Vaccine To Heart Tissue After Challenge, Camila Pontes Ferreira, Leonardo Moro Cariste, Barbara Ferri Moraschi, Bianca Ferrarini Zanetti, Sang Won Han, Daniel Araki Ribeiro, Alexandre Vieira Machado, Joseli Lannes-Vieira, Ricardo T. Gazzinelli, Jose Ronnie Vasconcelos Carvalho Jul 2019

Cxcr3 Chemokine Receptor Guides Trypanosoma Cruzi-Specific T-Cells Triggered By Dna/Adenovirus Asp2 Vaccine To Heart Tissue After Challenge, Camila Pontes Ferreira, Leonardo Moro Cariste, Barbara Ferri Moraschi, Bianca Ferrarini Zanetti, Sang Won Han, Daniel Araki Ribeiro, Alexandre Vieira Machado, Joseli Lannes-Vieira, Ricardo T. Gazzinelli, Jose Ronnie Vasconcelos Carvalho

Open Access Articles

CD8+ T lymphocytes play an important role in controlling infections by intracellular pathogens. Chemokines and their receptors are crucial for the migration of CD8+ T-lymphocytes, which are the main IFNgamma producers and cytotoxic effectors cells. Although the participation of chemokine ligands and receptors has been largely explored in viral infection, much less is known in infection by Trypanosoma cruzi, the causative agent of Chagas disease. After T. cruzi infection, CXCR3 chemokine receptor is highly expressed on the surface of CD8+ T-lymphocytes. Here, we hypothesized that CXCR3 is a key molecule for migration of parasite-specific CD8+ T-cells towards infected tissues, where ...


Alternative Splicing Regulates Stochastic Nlrp3 Activity, Florian Hoss, James L. Mueller, Francisca Rojas Ringeling, Juan F. Rodriguez-Alcazar, Rebecca Brinkschulte, Gerald Seifert, Rainer Stahl, Lori Broderick, Chris D. Putnam, Richard D. Kolodner, Stefan Canzar, Matthias Geyer, Hal M. Hoffman, Eicke Latz Jul 2019

Alternative Splicing Regulates Stochastic Nlrp3 Activity, Florian Hoss, James L. Mueller, Francisca Rojas Ringeling, Juan F. Rodriguez-Alcazar, Rebecca Brinkschulte, Gerald Seifert, Rainer Stahl, Lori Broderick, Chris D. Putnam, Richard D. Kolodner, Stefan Canzar, Matthias Geyer, Hal M. Hoffman, Eicke Latz

Open Access Articles

Leucine-rich repeat (LRR) domains are evolutionarily conserved in proteins that function in development and immunity. Here we report strict exonic modularity of LRR domains of several human gene families, which is a precondition for alternative splicing (AS). We provide evidence for AS of LRR domain within several Nod-like receptors, most prominently the inflammasome sensor NLRP3. Human NLRP3, but not mouse NLRP3, is expressed as two major isoforms, the full-length variant and a variant lacking exon 5. Moreover, NLRP3 AS is stochastically regulated, with NLRP3 exon 5 lacking the interaction surface for NEK7 and hence loss of activity. Our data thus ...


A Permethrin Metabolite Is Associated With Adaptive Immune Responses In Gulf War Illness, Utsav Joshi, Lawrence J. Stern, Laila Abdullah Jul 2019

A Permethrin Metabolite Is Associated With Adaptive Immune Responses In Gulf War Illness, Utsav Joshi, Lawrence J. Stern, Laila Abdullah

Open Access Articles

Gulf War Illness (GWI), affecting 30% of veterans from the 1991 Gulf War (GW), is a multi-symptom illness with features similar to those of patients with autoimmune diseases. The objective of the current work is to determine if exposure to GW-related pesticides, such as permethrin (PER), activates peripheral and central nervous system (CNS) adaptive immune responses. In the current study, we focused on a PER metabolite, 3-phenoxybenzoic acid (3-PBA), as this is a common metabolite previously shown to form adducts with endogenous proteins. We observed the presence of 3-PBA and 3-PBA modified lysine of protein peptides in the brain, blood ...


Mtorc2/Akt Activation In Adipocytes Is Required For Adipose Tissue Inflammation In Tuberculosis, Nuria Martinez, Catherine Y. Cheng, Natkunam Ketheesan, Aidan Cullen, Yuefeng Tang, Josephine Lum, Kim West, Michael Poidinger, David A. Guertin, Amit Singhal, Hardy Kornfeld Jul 2019

Mtorc2/Akt Activation In Adipocytes Is Required For Adipose Tissue Inflammation In Tuberculosis, Nuria Martinez, Catherine Y. Cheng, Natkunam Ketheesan, Aidan Cullen, Yuefeng Tang, Josephine Lum, Kim West, Michael Poidinger, David A. Guertin, Amit Singhal, Hardy Kornfeld

Open Access Articles

BACKGROUND: Mycobacterium tuberculosis has co-evolved with the human host, adapting to exploit the immune system for persistence and transmission. While immunity to tuberculosis (TB) has been intensively studied in the lung and lymphoid system, little is known about the participation of adipose tissues and non-immune cells in the host-pathogen interaction during this systemic disease.

METHODS: C57BL/6J mice were aerosol infected with M. tuberculosis Erdman and presence of the bacteria and the fitness of the white and brown adipose tissues, liver and skeletal muscle were studied compared to uninfected mice.

FINDINGS: M. tuberculosis infection in mice stimulated immune cell infiltration ...


Tethering Of Vesicles To The Golgi By Gmap210 Controls Lat Delivery To The Immune Synapse, Andres Ernesto Zucchetti, Laurence Bataille, Jean-Marie Carpier, Stephanie Dogniaux, Mabel San Roman-Jouve, Mathieu Maurin, Michael W. Stuck, Rosa M. Rios, Cosima T. Baldari, Gregory J. Pazour, Claire Hivroz Jun 2019

Tethering Of Vesicles To The Golgi By Gmap210 Controls Lat Delivery To The Immune Synapse, Andres Ernesto Zucchetti, Laurence Bataille, Jean-Marie Carpier, Stephanie Dogniaux, Mabel San Roman-Jouve, Mathieu Maurin, Michael W. Stuck, Rosa M. Rios, Cosima T. Baldari, Gregory J. Pazour, Claire Hivroz

Open Access Articles

The T cell immune synapse is a site of intense vesicular trafficking. Here we show that the golgin GMAP210, known to capture vesicles and organize membrane traffic at the Golgi, is involved in the vesicular transport of LAT to the immune synapse. Upon activation, more GMAP210 interact with LAT-containing vesicles and go together with LAT to the immune synapse. Regulating LAT recruitment and LAT-dependent signaling, GMAP210 controls T cell activation. Using a rerouting and capture assay, we show that GMAP210 captures VAMP7-decorated vesicles. Overexpressing different domains of GMAP210, we also show that GMAP210 allows their specific delivery to the immune ...


A Novel Phox/Cd38/Mcoln1/Tfeb Axis Important For Macrophage Activation During Bacterial Phagocytosis, Mehran Najibi, Joseph A. Moreau, Havisha H. Honwad, Javier E. Irazoqui Jun 2019

A Novel Phox/Cd38/Mcoln1/Tfeb Axis Important For Macrophage Activation During Bacterial Phagocytosis, Mehran Najibi, Joseph A. Moreau, Havisha H. Honwad, Javier E. Irazoqui

University of Massachusetts Medical School Faculty Publications

Macrophages are a key and heterogenous class of phagocytic cells of the innate immune system, which act as sentinels in peripheral tissues and are mobilized during infection. Macrophage activation in the presence of bacterial cells and molecules entails specific and complex programs of gene expression. How such triggers elicit the gene expression programs is incompletely understood. We previously discovered that transcription factor TFEB is a key contributor to macrophage activation during bacterial phagocytosis. However, the mechanism linking phagocytosis of bacterial cells to TFEB activation remained unknown. In this article, we describe a previously unknown pathway that links phagocytosis with the ...


Trav1-2(+) Cd8(+) T-Cells Including Oligoconal Expansions Of Mait Cells Are Enriched In The Airways In Human Tuberculosis, Emily B. Wong, Samuel M. Behar, David M. Lewinsohn Jun 2019

Trav1-2(+) Cd8(+) T-Cells Including Oligoconal Expansions Of Mait Cells Are Enriched In The Airways In Human Tuberculosis, Emily B. Wong, Samuel M. Behar, David M. Lewinsohn

Open Access Articles

Mucosal-associated invariant T (MAIT) cells typically express a TRAV1-2(+) semi-invariant TCRalpha that enables recognition of bacterial, mycobacterial, and fungal riboflavin metabolites presented by MR1. MAIT cells are associated with immune control of bacterial and mycobacterial infections in murine models. Here, we report that a population of pro-inflammatory TRAV1-2(+) CD8(+) T cells are present in the airways and lungs of healthy individuals and are enriched in bronchoalveolar fluid of patients with active pulmonary tuberculosis (TB). High-throughput T cell receptor analysis reveals oligoclonal expansions of canonical and donor-unique TRAV1-2(+) MAIT-consistent TCRalpha sequences within this population. Some of these cells demonstrate MR1-restricted mycobacterial ...


Control Of Antiviral Innate Immune Response By Protein Geranylgeranylation, Shigao Yang, Zhaozhao Jiang, Katherine A. Fitzgerald, Donghai Wang May 2019

Control Of Antiviral Innate Immune Response By Protein Geranylgeranylation, Shigao Yang, Zhaozhao Jiang, Katherine A. Fitzgerald, Donghai Wang

Open Access Articles

The mitochondrial antiviral signaling protein (MAVS) orchestrates host antiviral innate immune response to RNA virus infection. However, how MAVS signaling is controlled to eradicate virus while preventing self-destructive inflammation remains obscure. Here, we show that protein geranylgeranylation, a posttranslational lipid modification of proteins, limits MAVS-mediated immune signaling by targeting Rho family small guanosine triphosphatase Rac1 into the mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) at the mitochondria-ER junction. Protein geranylgeranylation and subsequent palmitoylation promote Rac1 translocation into MAMs upon viral infection. MAM-localized Rac1 limits MAVS' interaction with E3 ligase Trim31 and hence inhibits MAVS ubiquitination, aggregation, and activation. Rac1 also facilitates ...


Exploiting Unique Biological Features Of Leukemia Stem Cells For Therapeutic Benefit, Haojian Zhang, Shaoguang Li Apr 2019

Exploiting Unique Biological Features Of Leukemia Stem Cells For Therapeutic Benefit, Haojian Zhang, Shaoguang Li

Open Access Articles

Cancer stem cells play a critical role in disease initiation and insensitivity to chemotherapy in numerous hematologic malignancies and some solid tumors, and these stem cells need to be eradicated to achieve a cure. Key to successful targeting of cancer stem cells is to identify and functionally test critical target genes and to fully understand their associated molecular network in these stem cells. Human chronic myeloid leukemia (CML) is well accepted as one of the typical types of hematopoietic malignancies that are derived from leukemia stem cells (LSCs), serving as an excellent model disease for understanding the biology of LSCs ...


The Role Of Platelets In Mediating A Response To Human Influenza Infection, Milka Koupenova-Zamor, Heather A. Corkrey, Olga Vitseva, Giorgia Manni, Catherine J. Pang, Lauren Clancy, Chen Yao, Jeffrey J. Rade, Daniel Levy, Jennifer P. Wang, Robert W. Finberg, Evelyn A. Kurt-Jones, Jane E. Freedman Apr 2019

The Role Of Platelets In Mediating A Response To Human Influenza Infection, Milka Koupenova-Zamor, Heather A. Corkrey, Olga Vitseva, Giorgia Manni, Catherine J. Pang, Lauren Clancy, Chen Yao, Jeffrey J. Rade, Daniel Levy, Jennifer P. Wang, Robert W. Finberg, Evelyn A. Kurt-Jones, Jane E. Freedman

Open Access Articles

Influenza infection increases the incidence of myocardial infarction but the reason is unknown. Platelets mediate vascular occlusion through thrombotic functions but are also recognized to have immunomodulatory activity. To determine if platelet processes are activated during influenza infection, we collected blood from 18 patients with acute influenza infection. Microscopy reveals activated platelets, many containing viral particles and extracellular-DNA associated with platelets. To understand the mechanism, we isolate human platelets and treat them with influenza A virus. Viral-engulfment leads to C3 release from platelets as a function of TLR7 and C3 leads to neutrophil-DNA release and aggregation. TLR7 specificity is confirmed ...


Streptolysin O Induces The Ubiquitination And Degradation Of Pro-Il-1beta, Dora Hancz, Elsa Westerlund, Christine Valfridsson, Getachew Melkamu Aemero, Benedicte Bastiat-Sempe, M. Pontus A. Orning, Egil Lien, Michael R. Wessels, Jenny J. Persson Mar 2019

Streptolysin O Induces The Ubiquitination And Degradation Of Pro-Il-1beta, Dora Hancz, Elsa Westerlund, Christine Valfridsson, Getachew Melkamu Aemero, Benedicte Bastiat-Sempe, M. Pontus A. Orning, Egil Lien, Michael R. Wessels, Jenny J. Persson

Open Access Articles

Group A Streptococcus (GAS) is a common and versatile human pathogen causing a variety of diseases. One of the many virulence factors of GAS is the secreted pore-forming cytotoxin streptolysin O (SLO), which has been ascribed multiple properties, including inflammasome activation leading to release of the potent inflammatory cytokine IL-1beta from infected macrophages. IL-1beta is synthesized as an inactive pro-form, which is activated intracellularly through proteolytic cleavage. Here, we use a macrophage infection model to show that SLO specifically induces ubiquitination and degradation of pro-IL-1beta. Ubiquitination was dependent on SLO being released from the infecting bacterium, and pore formation by ...


The Tlr4 Adaptor Tram Controls The Phagocytosis Of Gram-Negative Bacteria By Interacting With The Rab11-Family Interacting Protein 2, Astrid Skjesol, Douglas T. Golenbock, Harald Husebye Mar 2019

The Tlr4 Adaptor Tram Controls The Phagocytosis Of Gram-Negative Bacteria By Interacting With The Rab11-Family Interacting Protein 2, Astrid Skjesol, Douglas T. Golenbock, Harald Husebye

Open Access Articles

Phagocytosis is a complex process that eliminates microbes and is performed by specialised cells such as macrophages. Toll-like receptor 4 (TLR4) is expressed on the surface of macrophages and recognizes Gram-negative bacteria. Moreover, TLR4 has been suggested to play a role in the phagocytosis of Gram-negative bacteria, but the mechanisms remain unclear. Here we have used primary human macrophages and engineered THP-1 monocytes to show that the TLR4 sorting adapter, TRAM, is instrumental for phagocytosis of Escherichia coli as well as Staphylococcus aureus. We find that TRAM forms a complex with Rab11 family interacting protein 2 (FIP2) that is recruited ...


The Immune Checkpoint Molecules Pd-1, Pd-L1, Tim-3 And Lag-3 In Diffuse Large B-Cell Lymphoma, Benjamin J. Chen, Ravi Dashnamoorthy, Pallavi Galera, Vladislav Makarenko, Hong Chang, Srimoyee Ghosh, Andrew M. Evens Mar 2019

The Immune Checkpoint Molecules Pd-1, Pd-L1, Tim-3 And Lag-3 In Diffuse Large B-Cell Lymphoma, Benjamin J. Chen, Ravi Dashnamoorthy, Pallavi Galera, Vladislav Makarenko, Hong Chang, Srimoyee Ghosh, Andrew M. Evens

Open Access Articles

Signaling through immune checkpoint receptors may lead to T-cell exhaustion and function as immune escape mechanisms in cancer. For diffuse large B-cell lymphoma (DLBCL), the mechanistic and prognostic importance of these markers on tumor cells and the tumor microenvironment remains unclear. We determined the immunohistochemical expression of PD-1, PD-L1, TIM-3, and LAG-3 on tumor cells and on tumor infiltrating lymphocytes (TILs) among 123 DLBCL patients. TIM-3 showed positive staining on tumor cells in 39% of DLBCL cases and PD-L1 expression was noted in 15% of cases. Both PD-1 and LAG-3 were positive on tumor cells in a minority of DLBCL ...


Targeting Lipooligosaccharide (Los) For A Gonococcal Vaccine, Sunita Gulati, Jutamas Shaughnessy, Sanjay Ram, Peter A. Rice Feb 2019

Targeting Lipooligosaccharide (Los) For A Gonococcal Vaccine, Sunita Gulati, Jutamas Shaughnessy, Sanjay Ram, Peter A. Rice

Open Access Articles

The increasing incidence of gonorrhea worldwide and the global spread of multidrug-resistant strains of Neisseria gonorrhoeae, constitute a public health emergency. With dwindling antibiotic treatment options, there is an urgent need to develop safe and effective vaccines. Gonococcal lipooligosaccharides (LOSs) are potential vaccine candidates because they are densely represented on the bacterial surface and are readily accessible as targets of adaptive immunity. Less well-understood is whether LOSs evoke protective immune responses. Although gonococcal LOS-derived oligosaccharides (OSs) are major immune targets, often they undergo phase variation, a feature that seemingly makes LOS less desirable as a vaccine candidate. However, the identification ...


The Tec Kinase Itk Is Essential For Ilc2 Survival And Epithelial Integrity In The Intestine, Hyoung-Soo Cho, Andrea Reboldi, Jason A. Hall, Leslie J. Berg Feb 2019

The Tec Kinase Itk Is Essential For Ilc2 Survival And Epithelial Integrity In The Intestine, Hyoung-Soo Cho, Andrea Reboldi, Jason A. Hall, Leslie J. Berg

Open Access Articles

Innate lymphoid cells (ILC) are lymphocytes that lack an antigen-specific receptor and are preferentially localized in non-lymphoid tissues, such as mucosal barriers. In these locations ILC respond to tissue perturbations by producing factors that promote tissue repair and improve barrier integrity. We show that mice lacking the Tec kinase ITK have impaired intestinal tissue integrity, and a reduced ability to restore homeostasis after tissue damage. This defect is associated with a substantial loss of Type 2 ILC (ILC2) in the intestinal lamina propria. Adoptive transfer of bone marrow ILC2 precursors confirms a cell-intrinsic role for ITK. Intestinal ILC2 numbers in ...


Comparison Of Immune Responses To Different Versions Of Vlp Associated Stabilized Rsv Pre-Fusion F Protein, Lori M. Cullen, Madelyn R. Schmidt, Gretel M. Torres, Adam A. Capoferri, Trudy G. Morrison Feb 2019

Comparison Of Immune Responses To Different Versions Of Vlp Associated Stabilized Rsv Pre-Fusion F Protein, Lori M. Cullen, Madelyn R. Schmidt, Gretel M. Torres, Adam A. Capoferri, Trudy G. Morrison

Open Access Articles

Efforts to develop a vaccine for respiratory syncytial virus (RSV) have primarily focused on the RSV fusion protein. The pre-fusion conformation of this protein induces the most potent neutralizing antibodies and is the focus of recent efforts in vaccine development. Following the first identification of mutations in the RSV F protein (DS-Cav1 mutant protein) that stabilized the pre-fusion conformation, other mutant stabilized pre-fusion F proteins have been described. To determine if there are differences in alternate versions of stabilized pre-fusion F proteins, we explored the use, as vaccine candidates, of virus-like particles (VLPs) containing five different pre-fusion F proteins, including ...


The Neutrophil-To-Lymphocyte And Monocyte-To-Lymphocyte Ratios Are Independently Associated With Neurological Disability And Brain Atrophy In Multiple Sclerosis, Christopher C. Hemond, Bonnie I. Glanz, Rohit Bakshi, Tanuja Chitnis, Brian C. Healy Feb 2019

The Neutrophil-To-Lymphocyte And Monocyte-To-Lymphocyte Ratios Are Independently Associated With Neurological Disability And Brain Atrophy In Multiple Sclerosis, Christopher C. Hemond, Bonnie I. Glanz, Rohit Bakshi, Tanuja Chitnis, Brian C. Healy

Open Access Articles

BACKGROUND: Serum hematological indices such as the neutrophil-lymphocyte ratio (NLR) or monocyte-lymphocyte ratio (MLR) have been used as biomarkers of pathogenic inflammation and prognostication in multiple areas of medicine; recent evidence shows correlation with psychological parameters as well.

OBJECTIVES/AIMS: To characterize clinical, neuroimaging, and psycho-neuro-immunological associations with NLR and MLR in persons with multiple sclerosis (MS).

METHODS: We identified a large cohort of clinically well-defined patients from our longitudinal database that included MS-related outcomes, disease-modifying therapy, patient-reported outcome (PRO) measures, and quantified cerebral MRI at 1.5 T. We queried hospital records for complete blood counts within 2 months ...


Compartmentalization Of Immune Response And Microbial Translocation In Decompensated Cirrhosis, Camila Alvarez-Silva, Robert Schierwagen, Alessandra Pohlmann, Fernando Magdaleno, Frank E. Uschner, Patrick Ryan, Maria J.G.T. Vehreschild, Joan Claria, Eicke Latz, Benjamin Lelouvier, Manimozhiyan Arumugam, Jonel Trebicka Feb 2019

Compartmentalization Of Immune Response And Microbial Translocation In Decompensated Cirrhosis, Camila Alvarez-Silva, Robert Schierwagen, Alessandra Pohlmann, Fernando Magdaleno, Frank E. Uschner, Patrick Ryan, Maria J.G.T. Vehreschild, Joan Claria, Eicke Latz, Benjamin Lelouvier, Manimozhiyan Arumugam, Jonel Trebicka

Open Access Articles

Background: Acquired dysfunctional immunity in cirrhosis predisposes patients to frequent bacterial infections, especially spontaneous bacterial peritonitis (SBP), leading to systemic inflammation that is associated with poor outcome. But systemic inflammation can also be found in the absence of a confirmed infection. Detection of bacterial DNA has been investigated as a marker of SBP and as a predictor of prognosis. Data is, however, contradictory. Here we investigated whether levels of IL-6 and IL-8 putatively produced by myeloid cells in ascites are associated with systemic inflammation and whether inflammation depends on the presence of specific bacterial DNA.

Methods and Materials: We enrolled ...


No Detection Of Cd4-Independent Human Immunodeficiency Virus 1 Envelope Glycoproteins In Brain Tissue Of Patients With Or Without Neurological Complications, Briana Quitadamo, Paul J. Peters, Matthew Koch, Katherine Luzuriaga, Cecilia Cheng-Mayer, Paul R. Clapham, Maria Paz Gonzalez-Perez Feb 2019

No Detection Of Cd4-Independent Human Immunodeficiency Virus 1 Envelope Glycoproteins In Brain Tissue Of Patients With Or Without Neurological Complications, Briana Quitadamo, Paul J. Peters, Matthew Koch, Katherine Luzuriaga, Cecilia Cheng-Mayer, Paul R. Clapham, Maria Paz Gonzalez-Perez

Open Access Articles

Macrophage (mac)-tropic human immnunodeficiency virus type 1 (HIV-1) and simian immnunodeficiency virus (SIV) in brain are associated with neurological disease. Mac-tropic HIV-1 evolves enhanced CD4 interactions that enable macrophage infection via CD4, which is in low abundance. In contrast, mac-tropic SIV is associated with CD4-independent infection via direct CCR5 binding. Recently, mac-tropic simian-human immunodeficiency virus (SHIV) from macaque brain was also reported to infect cells via CCR5 without CD4. Since SHIV envelope proteins (Envs) are derived from HIV-1, we tested more than 100 HIV-1 clade B Envs for infection of CD4-negative, CCR5(+) Cf2Th/CCR5 cells. However, no infection was ...


Candida Albicans Factor H Binding Molecule Hgt1p - A Low Glucose-Induced Transmembrane Protein Is Trafficked To The Cell Wall And Impairs Phagocytosis And Killing By Human Neutrophils, Samyr Kenno, Cornelia Speth, Gunter Rambach, Ulrike Binder, Sneha Chatterjee, Rita Caramalho, Hubertus Haas, Cornelia Lass-Florl, Jutamas Shaughnessy, Sanjay Ram, Neil A.R. Gow, Dorothea Orth-Holler, Reinhard Wurzner Jan 2019

Candida Albicans Factor H Binding Molecule Hgt1p - A Low Glucose-Induced Transmembrane Protein Is Trafficked To The Cell Wall And Impairs Phagocytosis And Killing By Human Neutrophils, Samyr Kenno, Cornelia Speth, Gunter Rambach, Ulrike Binder, Sneha Chatterjee, Rita Caramalho, Hubertus Haas, Cornelia Lass-Florl, Jutamas Shaughnessy, Sanjay Ram, Neil A.R. Gow, Dorothea Orth-Holler, Reinhard Wurzner

Open Access Articles

Complement is a tightly controlled arm of the innate immune system, facilitating phagocytosis and killing of invading pathogens. Factor H (FH) is the main fluid-phase inhibitor of the alternative pathway. Many pathogens can hijack FH from the host and protect themselves from complement-dependent killing. Candida albicans is a clinically important opportunistic yeast, expressing different FH binding molecules on its cell surface, which allow complement evasion. One such FH binding molecule is the transmembrane protein "High affinity glucose transporter 1" (Hgt1p), involved in glucose metabolism. This study demonstrated that Hgt1p transcription and expression is induced and highest at the low, but ...


Evolution Of The Exclusively Human Pathogen Neisseria Gonorrhoeae: Human-Specific Engagement Of Immunoregulatory Siglecs, Corinna S. Landig, Ashley Hazel, Benjamin P. Kellman, Jerry J. Fong, Flavio Schwarz, Sarika Agarwal, Nissi Varki, Paola Massari, Nathan E. Lewis, Sanjay Ram, Ajit Varki Jan 2019

Evolution Of The Exclusively Human Pathogen Neisseria Gonorrhoeae: Human-Specific Engagement Of Immunoregulatory Siglecs, Corinna S. Landig, Ashley Hazel, Benjamin P. Kellman, Jerry J. Fong, Flavio Schwarz, Sarika Agarwal, Nissi Varki, Paola Massari, Nathan E. Lewis, Sanjay Ram, Ajit Varki

Open Access Articles

Neisseria gonorrhoeae causes the sexually transmitted disease gonorrhea exclusively in humans and uses multiple strategies to infect, including acquisition of host sialic acids that cap and mask lipooligosaccharide termini, while restricting complement activation. We hypothesized that gonococci selectively target human anti-inflammatory sialic acid-recognizing Siglec receptors on innate immune cells to blunt host responses and that pro-inflammatory Siglecs and SIGLEC pseudogene polymorphisms represent host evolutionary adaptations to counteract this interaction. N. gonorrhoeae can indeed engage multiple human but not chimpanzee CD33rSiglecs expressed on innate immune cells and in the genitourinary tract--including Siglec-11 (inhibitory) and Siglec-16 (activating), which we detected for the ...


Necroptosis In Anti-Viral Inflammation, Himani Nailwal, Francis Ka-Ming Chan Jan 2019

Necroptosis In Anti-Viral Inflammation, Himani Nailwal, Francis Ka-Ming Chan

Open Access Articles

The primary function of the immune system is to protect the host from invading pathogens. In response, microbial pathogens have developed various strategies to evade detection and destruction by the immune system. This tug-of-war between the host and the pathogen is a powerful force that shapes organismal evolution. Regulated cell death (RCD) is a host response that limits the reservoir for intracellular pathogens such as viruses. Since pathogen-specific T cell and B cell responses typically take several days and is therefore slow-developing, RCD of infected cells during the first few days of the infection is critical for organismal survival. This ...


Constitutive Interferon Signaling Maintains Critical Threshold Of Mlkl Expression To License Necroptosis, Joseph Sarhan, Beiyun C. Liu, Hayley I. Muendlein, Chi G. Weindel, Irina Smirnova, Amy Y. Tang, Vladimir Ilyukha, Maxim Sorokin, Anton Buzdin, Katherine A. Fitzgerald, Alexander Poltorak Jan 2019

Constitutive Interferon Signaling Maintains Critical Threshold Of Mlkl Expression To License Necroptosis, Joseph Sarhan, Beiyun C. Liu, Hayley I. Muendlein, Chi G. Weindel, Irina Smirnova, Amy Y. Tang, Vladimir Ilyukha, Maxim Sorokin, Anton Buzdin, Katherine A. Fitzgerald, Alexander Poltorak

Open Access Articles

Interferons (IFNs) are critical determinants in immune-competence and autoimmunity, and are endogenously regulated by a low-level constitutive feedback loop. However, little is known about the functions and origins of constitutive IFN. Recently, lipopolysaccharide (LPS)-induced IFN was implicated as a driver of necroptosis, a necrotic form of cell death downstream of receptor-interacting protein (RIP) kinase activation and executed by mixed lineage kinase like-domain (MLKL) protein. We found that the pre-established IFN status of the cell, instead of LPS-induced IFN, is critical for the early initiation of necroptosis in macrophages. This pre-established IFN signature stems from cytosolic DNA sensing via cGAS ...