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The Aminoalkylindole Bml-190 Negatively Regulates Chitosan Synthesis Via The Cyclic Amp/Protein Kinase A1 Pathway In Cryptococcus Neoformans, Brian T. Maybruck, Woei C. Lam, Charles A. Specht, Xenia G. Ilagan, Maureen J. Donlin, Jennifer K. Lodge 2019 Washington University in St. Louis

The Aminoalkylindole Bml-190 Negatively Regulates Chitosan Synthesis Via The Cyclic Amp/Protein Kinase A1 Pathway In Cryptococcus Neoformans, Brian T. Maybruck, Woei C. Lam, Charles A. Specht, Xenia G. Ilagan, Maureen J. Donlin, Jennifer K. Lodge

Open Access Articles

Cryptococcus neoformans can cause fatal meningoencephalitis in patients with AIDS or other immunocompromising conditions. Current antifungals are suboptimal to treat this disease; therefore, novel targets and new therapies are needed. Previously, we have shown that chitosan is a critical component of the cryptococcal cell wall and is required for survival in the mammalian host and that chitosan deficiency results in rapid clearance from the mammalian host. We had also identified several specific proteins that were required for chitosan biosynthesis, and we hypothesize that screening for compounds that inhibit chitosan biosynthesis would identify additional genes/proteins that influence chitosan biosynthesis. To ...


Impact Of Th1 Cd4 Tfh Skewing On Antibody Responses To An Hiv-1 Vaccine In Rhesus Macaques, Anil Verma, Keith A. Reimann, David H. Foehl, Smita S. Iyer 2019 University of California, Davis

Impact Of Th1 Cd4 Tfh Skewing On Antibody Responses To An Hiv-1 Vaccine In Rhesus Macaques, Anil Verma, Keith A. Reimann, David H. Foehl, Smita S. Iyer

Open Access Articles

Generating durable humoral immunity through vaccination depends upon effective interaction of follicular helper T cells (Tfh) with germinal center (GC) B cells. Th1 polarization of Tfh cells is an important process shaping the success of Tfh-GC B cell interactions by influencing co-stimulatory and cytokine-dependent Tfh help to B cells. However, the question remains whether adjuvant-dependent modulation of Tfh cells enhances HIV-1 vaccine-induced anti-Envelope (Env) antibody responses. We investigated whether an HIV-1 vaccine platform designed to increase the number of Th1-polarized Tfh cells enhances the magnitude and quality of anti-Env antibodies. Utilizing a novel interferon-induced protein (IP)-10-adjuvanted HIV-1 DNA prime ...


Differential Skewing Of Donor-Unrestricted And Gammadelta T Cell Repertoires In Tuberculosis-Infected Human Lungs, Paul Ogongo, Adrie Jc. Steyn, Farina Karim, Kaylesh J. Dullabh, Ismael Awala, Rajhmun Madansein, Alasdair Leslie, Samuel M. Behar 2019 University of KwaZulu-Natal

Differential Skewing Of Donor-Unrestricted And Gammadelta T Cell Repertoires In Tuberculosis-Infected Human Lungs, Paul Ogongo, Adrie Jc. Steyn, Farina Karim, Kaylesh J. Dullabh, Ismael Awala, Rajhmun Madansein, Alasdair Leslie, Samuel M. Behar

Open Access Articles

Unconventional T cells that recognize mycobacterial antigens are of great interest as potential vaccine targets against tuberculosis (TB). This includes donor-unrestricted T cells (DURTs), such as mucosa-associated invariant T cells (MAITs), CD1-restricted T cells, and gammadelta T cells. We exploited the distinctive nature of DURTs and gammadelta T cell receptors (TCRs) to investigate the involvement of these T cells during TB in the human lung by global TCR sequencing. Making use of surgical lung resections, we investigated the distribution, frequency, and characteristics of TCRs in lung tissue and matched blood from individuals infected with TB. Despite depletion of MAITs and ...


Cdr3alpha Drives Selection Of The Immunodominant Epstein Barr Virus (Ebv) Brlf1-Specific Cd8 T Cell Receptor Repertoire In Primary Infection, Larisa Kamga, Anna Gil, InYoung Song, Robin M. Brody, Dario Ghersi, Nuray Aslan, Lawrence J. Stern, Liisa K. Selin, Katherine Luzuriaga 2019 University of Massachusetts Medical School

Cdr3alpha Drives Selection Of The Immunodominant Epstein Barr Virus (Ebv) Brlf1-Specific Cd8 T Cell Receptor Repertoire In Primary Infection, Larisa Kamga, Anna Gil, Inyoung Song, Robin M. Brody, Dario Ghersi, Nuray Aslan, Lawrence J. Stern, Liisa K. Selin, Katherine Luzuriaga

Open Access Articles

The T cell receptor (TCR) repertoire is an essential component of the CD8 T-cell immune response. Here, we seek to investigate factors that drive selection of TCR repertoires specific to the HLA-A2-restricted immunodominant epitope BRLF1109-117 (YVLDHLIVV) over the course of primary Epstein Barr virus (EBV) infection. Using single-cell paired TCRalphabeta sequencing of tetramer sorted CD8 T cells ex vivo, we show at the clonal level that recognition of the HLA-A2-restricted BRLF1 (YVL-BR, BRLF-1109) epitope is mainly driven by the TCRalpha chain. For the first time, we identify a CDR3alpha (complementarity determining region 3 alpha) motif, KDTDKL, resulting from an obligate ...


Preclinical Efficacy Of A Lipooligosaccharide Peptide Mimic Candidate Gonococcal Vaccine, Sunita Gulati, Michael W. Pennington, Andrzej Czerwinski, Darrick Carter, Bo Zheng, Nancy Nowak, Rosane B. DeOliveira, Jutamas Shaughnessy, George W. Reed, Sanjay Ram, Peter A. Rice 2019 University of Massachusetts Medical School

Preclinical Efficacy Of A Lipooligosaccharide Peptide Mimic Candidate Gonococcal Vaccine, Sunita Gulati, Michael W. Pennington, Andrzej Czerwinski, Darrick Carter, Bo Zheng, Nancy Nowak, Rosane B. Deoliveira, Jutamas Shaughnessy, George W. Reed, Sanjay Ram, Peter A. Rice

Open Access Articles

The global spread of multidrug-resistant strains of Neisseria gonorrhoeae constitutes a public health emergency. With limited antibiotic treatment options, there is an urgent need for development of a safe and effective vaccine against gonorrhea. Previously, we constructed a prototype vaccine candidate comprising a peptide mimic (mimitope) of a glycan epitope on gonococcal lipooligosaccharide (LOS), recognized by monoclonal antibody 2C7. The 2C7 epitope is (i) broadly expressed as a gonococcal antigenic target in human infection, (ii) a critical requirement for gonococcal colonization in the experimental setting, and (iii) a virulence determinant that is maintained and expressed by gonococci. Here, we have ...


#20 - A Role For Circadian Rhythms In Chlamydial Pathogenesis, Vincentiu S. Olteanu 2019 Georgia Gwinnett College

#20 - A Role For Circadian Rhythms In Chlamydial Pathogenesis, Vincentiu S. Olteanu

Georgia Undergraduate Research Conference (GURC)

Genital chlamydia infection causes complications such as pelvic inflammatory disease and tubal factor infertility, with some women being more susceptible to these conditions than others. However, the effect of circadian rhythms on chlamydia pathogenesis is not known. Using a genital chlamydia mouse model, we had previously shown that the time of day of chlamydia infection was important in determining the extent of chlamydial infectivity and pathogenesis. There is a need to verify if these differences in disease outcome is under circadian or diurnal control. To that end, we placed mice under constant dark conditions (24 hours dark), which is normally ...


A Novel Vaccine Platform Using Glucan Particles For Induction Of Protective Responses Against Francisella Tularensis And Other Pathogens, Ambily Abraham, Gary R. Ostroff, Stuart M. Levitz, P. C. F. Oyston 2019 University of Massachusetts Medical School

A Novel Vaccine Platform Using Glucan Particles For Induction Of Protective Responses Against Francisella Tularensis And Other Pathogens, Ambily Abraham, Gary R. Ostroff, Stuart M. Levitz, P. C. F. Oyston

Open Access Articles

Vaccines are considered the bedrock of preventive medicine. However, for many pathogens, it has been challenging to develop vaccines that stimulate protective, long-lasting immunity. We have developed a novel approach using beta-1,3-D-glucans (BGs), natural polysaccharides abundantly present in fungal cell walls, as a biomaterial platform for vaccine delivery. BGs simultaneously provide for receptor-targeted antigen delivery to specialized antigen-presenting cells together with adjuvant properties to stimulate antigen-specific and trained non-specific immune responses. This review focuses on various approaches of using BG particles (GPs) to develop bacterial and fungal vaccine candidates. A special case history for the development of an effective ...


Common Nodes Of Virus-Host Interaction Revealed Through An Integrated Network Analysis, Korbinian Bosl, Richard K. Kandasamy 2019 Norwegian University of Science and Technology

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 ...


Intravital Imaging In A Zebrafish Model Elucidates Interactions Between Mucosal Immunity And Pathogenic Fungi, Linda S. Archambault 2019 University of Maine

Intravital Imaging In A Zebrafish Model Elucidates Interactions Between Mucosal Immunity And Pathogenic Fungi, Linda S. Archambault

Electronic Theses and Dissertations

Candida yeasts are common commensals that can cause mucosal disease and life-threatening systemic infections. While many of the components required for defense against Candida albicans infection are well established, questions remain about how various host cells at mucosal sites assess threats and coordinate defenses to prevent normally commensal organisms from becoming pathogenic. Using two Candida species, C. albicans and C. parapsilosis, which differ in their abilities to damage epithelial tissues, we used traditional methods (pathogen CFU, host survival, and host cytokine expression) combined with high-resolution intravital imaging of transparent zebrafish larvae to illuminate host-pathogen interactions at the cellular level in ...


Memory Cd4 T Cell-Derived Il-2 Synergizes With Viral Infection To Exacerbate Lung Inflammation, K. Kai McKinstry, Fahmida Alam, Valeria Flores-Malavet, Mate Z. Nagy, Stewart Sell, Andrea M. Cooper, Susan L. Swain, Tara M. Strutt 2019 University of Central Florida

Memory Cd4 T Cell-Derived Il-2 Synergizes With Viral Infection To Exacerbate Lung Inflammation, K. Kai Mckinstry, Fahmida Alam, Valeria Flores-Malavet, Mate Z. Nagy, Stewart Sell, Andrea M. Cooper, Susan L. Swain, Tara M. Strutt

Open Access Articles

Defining the most penetrating correlates of protective memory T cells is key for designing improved vaccines and T cell therapies. Here, we evaluate how interleukin (IL-2) production by memory CD4 T cells, a widely held indicator of their protective potential, impacts immune responses against murine influenza A virus (IAV). Unexpectedly, we show that IL-2-deficient memory CD4 T cells are more effective on a per cell basis at combating IAV than wild-type memory cells that produce IL-2. Improved outcomes orchestrated by IL-2-deficient cells include reduced weight loss and improved respiratory function that correlate with reduced levels of a broad array of ...


White-Nose Syndrome And Immune Responses In A Resistant Bat Species (Eptesicus Fuscus), Keslie Skye Naffa 2019 Missouri State University

White-Nose Syndrome And Immune Responses In A Resistant Bat Species (Eptesicus Fuscus), Keslie Skye Naffa

MSU Graduate Theses

White-nose syndrome (WNS) has had a large negative impact on bat populations across eastern North America since its arrival in 2006. Bats affected by WNS appear to die of starvation, possibly due to the increased arousals during hibernation when there is no food present to replace the energy used to arouse. During hibernation, the bat’s immune system should be suppressed. However, once a bat of a susceptible species is exposed to the fungus that causes WNS, Psuedogymnoascus destructans (Pd), the immune system seems to respond, potentially causing an elevation in metabolic rate, which may cause the bat to arouse ...


Sustained Antigen Release Polyanhydride-Based Vaccine Platform For Immunization Against Bovine Brucellosis, Paola M. Boggiatto, Robert G. Schaut, Carly Kanipe, Sean M. Kelly, Balaji Narasimhan, Douglas E. Jones, Steven C. Olsen 2019 United States Department of Agriculture

Sustained Antigen Release Polyanhydride-Based Vaccine Platform For Immunization Against Bovine Brucellosis, Paola M. Boggiatto, Robert G. Schaut, Carly Kanipe, Sean M. Kelly, Balaji Narasimhan, Douglas E. Jones, Steven C. Olsen

Chemical and Biological Engineering Publications

Brucellosis is a bacterial zoonosis and a significant source of economic loss and a major public health concern, worldwide. Bovine brucellosis, as caused primarily by Brucella abortus, is an important cause of reproductive loss in cattle. Vaccination has been the most effective way to reduce disease prevalence contributing to the success of control and eradication programs. Currently, there are no human vaccines available, and despite the success of commercial vaccines for livestock, such as B. abortus strain RB51 (RB51), there is need for development of novel and safer vaccines against brucellosis. In the current study, we report the fabrication of ...


Polymicrobial Sepsis Influences Cd8 T Cell Responses And Alters Host Susceptibility To Infection And Cancer, Derek Brett Danahy 2019 University of Iowa

Polymicrobial Sepsis Influences Cd8 T Cell Responses And Alters Host Susceptibility To Infection And Cancer, Derek Brett Danahy

Theses and Dissertations

Sepsis occurs when infection enters the circulation resulting in harmful or lethal levels of pro- and anti-inflammatory cytokines that affects nearly 2 million people in the U.S. annually. Improved identification and treatment options have increased survival of patients shortly after sepsis. However, this management of sepsis subsequently revealed survivors have increased long-term mortality rates due to altered immune responses that increase susceptibility to secondary complications. My thesis further revealed how sepsis impacts CD8 T cell-mediated immunity that protects the host against sepsis unrelated complications that will be useful for improving the outcome of sepsis survivors.

Using vaccinia virus (VacV ...


Combating Tuberculosis: Using Time-Dependent Sensitivity Analysis To Develop Strategies For Treatment And Prevention, Kendall B. Clark, Mayleen Cortez, Cristian Hernandez, Beth E. Thomas, Allison L. Lewis 2019 Northwestern University

Combating Tuberculosis: Using Time-Dependent Sensitivity Analysis To Develop Strategies For Treatment And Prevention, Kendall B. Clark, Mayleen Cortez, Cristian Hernandez, Beth E. Thomas, Allison L. Lewis

Spora: A Journal of Biomathematics

Although many organizations throughout the world have worked tirelessly to control tuberculosis (TB) epidemics, no country has yet been able to eradicate the disease completely. We present two compartmental models representing the spread of a TB epidemic through a population. The first is a general TB model; the second is an adaptation for regions in which HIV is prevalent, accounting for the effects of TB/HIV co-infection. Using active subspaces, we conduct time-dependent sensitivity analysis on both models to explore the significance of certain parameters with respect to the spread of TB. We use the results of this sensitivity analysis ...


Iiv-6 Inhibits Nf-Kappab Responses In Drosophila, Cara C. West, Florentina Rus, Ying Chen, Anni Kleino, Monique Gangloff, Don B. Gammon, Neal S. Silverman 2019 University of Massachusetts Medical School

Iiv-6 Inhibits Nf-Kappab Responses In Drosophila, Cara C. West, Florentina Rus, Ying Chen, Anni Kleino, Monique Gangloff, Don B. Gammon, Neal S. Silverman

Neal Silverman

The host immune response and virus-encoded immune evasion proteins pose constant, mutual selective pressure on each other. Virally encoded immune evasion proteins also indicate which host pathways must be inhibited to allow for viral replication. Here, we show that IIV-6 is capable of inhibiting the two Drosophila NF-kappaB signaling pathways, Imd and Toll. Antimicrobial peptide (AMP) gene induction downstream of either pathway is suppressed when cells infected with IIV-6 are also stimulated with Toll or Imd ligands. We find that cleavage of both Imd and Relish, as well as Relish nuclear translocation, three key points in Imd signal transduction, occur ...


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

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

Katherine A. Fitzgerald

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 ...


Persistent Inflammation During Anti-Tuberculosis Treatment With Diabetes Comorbidity, Nathella Pavan Kumar, Kiyoshi F. Fukutani, Basavaradhya S. Shruthi, Thabata Alves, Paulo S. Silveira-Mattos, Michael S. Rocha, Kim West, Mohan Natarajan, Vijay Viswanathan, Subash Babu, Bruno B. Andrade, Hardy Kornfeld 2019 National Institutes of Health

Persistent Inflammation During Anti-Tuberculosis Treatment With Diabetes Comorbidity, Nathella Pavan Kumar, Kiyoshi F. Fukutani, Basavaradhya S. Shruthi, Thabata Alves, Paulo S. Silveira-Mattos, Michael S. Rocha, Kim West, Mohan Natarajan, Vijay Viswanathan, Subash Babu, Bruno B. Andrade, Hardy Kornfeld

Open Access Articles

Diabetes mellitus (DM) increases risk for pulmonary tuberculosis (TB) and adverse treatment outcomes. Systemic hyper-inflammation is characteristic in people with TB and concurrent DM (TBDM) at baseline, but the impact of TB treatment on this pattern has not been determined. We measured 17 plasma cytokines and growth factors in longitudinal cohorts of Indian and Brazilian pulmonary TB patients with or without DM. Principal component analysis revealed virtually complete separation of TBDM from TB individuals in both cohorts at baseline, with hyper-inflammation in TBDM that continued through treatment completion at six months. By one year after treatment completion, there was substantial ...


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 2019 University of Massachusetts Medical School

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 ...


The Wet Bridge Transfer System: An Novel In Vitro Tool For Assessing Exogenous Surfactant As A Pulmonary Drug Delivery Vehicle, Brandon J. Baer 2019 University of Western Ontario

The Wet Bridge Transfer System: An Novel In Vitro Tool For Assessing Exogenous Surfactant As A Pulmonary Drug Delivery Vehicle, Brandon J. Baer

Western Research Forum

Background:

Due to its complex branching structure, direct drug delivery to the remote areas of the lung is a major challenge. Consequently, most therapies, such as those treating pulmonary infection and inflammation, must utilize large systemic dosing, with the potential for adverse side effects. A novel alternative strategy is to use exogenous surfactant, a material capable of distributing throughout the lung, as a pulmonary drug delivery vehicle.

Objective:

Utilize an in vitro transferring system to assess exogenous surfactant (BLES) as a pulmonary delivery vehicle for different therapeutics.

Methods:

An in vitro technique was developed to simultaneously study surfactant delivery and ...


Complement Alone Drives Efficacy Of A Chimeric Antigonococcal Monoclonal Antibody, Sunita Gulati, Frank J. Beurskens, Bo Zheng, Rosane B. DeOliveira, Jutamas Shaughnessy, Nancy Nowak, Peter A. Rice, Sanjay Ram 2019 University of Massachusetts Medical School

Complement Alone Drives Efficacy Of A Chimeric Antigonococcal Monoclonal Antibody, Sunita Gulati, Frank J. Beurskens, Bo Zheng, Rosane B. Deoliveira, Jutamas Shaughnessy, Nancy Nowak, Peter A. Rice, Sanjay Ram

Open Access Articles

Multidrug-resistant Neisseria gonorrhoeae is a global health problem. Monoclonal antibody (mAb) 2C7 recognizes a gonococcal lipooligosaccharide epitope that is expressed by > 95% of clinical isolates and hastens gonococcal vaginal clearance in mice. Chimeric mAb 2C7 (human immunoglobulin G1 [IgG1]) with an E430G Fc modification that enhances Fc:Fc interactions and hexamerization following surface-target binding and increases complement activation (HexaBody technology) showed significantly greater C1q engagement and C4 and C3 deposition compared to mAb 2C7 with wild-type Fc. Greater complement activation by 2C7-E430G Fc translated to increased bactericidal activity in vitro and, consequently, enhanced efficacy in mice, compared with "Fc-unmodified" chimeric ...


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