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M. Tuberculosis Reprograms Hematopoietic Stem Cells To Limit Myelopoiesis And Impair Trained Immunity, Nargis Khan, Christopher M. Sassetti, Maziar Divangahi 2020 McGill University

M. Tuberculosis Reprograms Hematopoietic Stem Cells To Limit Myelopoiesis And Impair Trained Immunity, Nargis Khan, Christopher M. Sassetti, Maziar Divangahi

Open Access Publications by UMMS Authors

A greater understanding of hematopoietic stem cell (HSC) regulation is required for dissecting protective versus detrimental immunity to pathogens that cause chronic infections such as Mycobacterium tuberculosis (Mtb). We have shown that systemic administration of Bacille Calmette-Guerin (BCG) or beta-glucan reprograms HSCs in the bone marrow (BM) via a type II interferon (IFN-II) or interleukin-1 (IL1) response, respectively, which confers protective trained immunity against Mtb. Here, we demonstrate that, unlike BCG or beta-glucan, Mtb reprograms HSCs via an IFN-I response that suppresses myelopoiesis and impairs development of protective trained immunity to Mtb. Mechanistically, IFN-I signaling dysregulates iron metabolism, depolarizes mitochondrial ...


Development Of Complement Factor H-Based Immunotherapeutic Molecules In Tobacco Plants Against Multidrug-Resistant Neisseria Gonorrhoeae, Jutamas Shaughnessy, Y. Tran, Bo Zheng, Rosane B. DeOliveira, Sunita Gulati, Wen-Chao Song, James M. Maclean, Keith L. Wycoff, Sanjay Ram 2020 University of Massachusetts Medical School

Development Of Complement Factor H-Based Immunotherapeutic Molecules In Tobacco Plants Against Multidrug-Resistant Neisseria Gonorrhoeae, Jutamas Shaughnessy, Y. Tran, Bo Zheng, Rosane B. Deoliveira, Sunita Gulati, Wen-Chao Song, James M. Maclean, Keith L. Wycoff, Sanjay Ram

Open Access Publications by UMMS Authors

Novel therapeutics against the global threat of multidrug-resistant Neisseria gonorrhoeae are urgently needed. Gonococci possess several mechanisms to evade killing by human complement, including binding of factor H (FH), a key inhibitor of the alternative pathway. FH comprises 20 short consensus repeat (SCR) domains organized in a head-to-tail manner as a single chain. N. gonorrhoeae binds two regions in FH; domains 6 and 7 and domains 18 through 20. We designed a novel anti-infective immunotherapeutic molecule that fuses domains 18-20 of FH containing a D-to-G mutation in domain 19 at position 1119 (called FH*) with human IgG1 Fc. FH*/Fc ...


Coxsackievirus B Type 4 Infection In Beta Cells Downregulates The Chaperone Prefoldin Uri To Induce A Mody4-Like Diabetes Via Pdx1 Silencing, Hugo Bernard, Ana Teijeiro, Almudena Chaves-Perez, Cristian Perna, Basanthi Satish, Anna Novials, Jennifer P. Wang, Nabil Djouder 2020 National Cancer Research Center

Coxsackievirus B Type 4 Infection In Beta Cells Downregulates The Chaperone Prefoldin Uri To Induce A Mody4-Like Diabetes Via Pdx1 Silencing, Hugo Bernard, Ana Teijeiro, Almudena Chaves-Perez, Cristian Perna, Basanthi Satish, Anna Novials, Jennifer P. Wang, Nabil Djouder

University of Massachusetts Medical School Faculty Publications

Enteroviruses are suspected to contribute to insulin-producing beta cell loss and hyperglycemia-induced diabetes. However, mechanisms are not fully defined. Here, we show that coxsackievirus B type 4 (CVB4) infection in human islet-engrafted mice and in rat insulinoma cells displays loss of unconventional prefoldin RPB5 interactor (URI) and PDX1, affecting beta cell function and identity. Genetic URI ablation in the mouse pancreas causes PDX1 depletion in beta cells. Importantly, diabetic PDX1 heterozygous mice overexpressing URI in beta cells are more glucose tolerant. Mechanistically, URI loss triggers estrogen receptor nuclear translocation leading to DNA methyltransferase 1 (DNMT1) expression, which induces Pdx1 promoter ...


A Natural Polymorphism Of Mycobacterium Tuberculosis In The Esxh Gene Disrupts Immunodomination By The Tb10.4-Specific Cd8 T Cell Response, Rujapak Sutiwisesak, Nathan D. Hicks, Shayla Boyce, Kenan C. Murphy, Kadamba Papavinasasundaram, Stephen M. Carpenter, Julie Boucau, Neelambari Joshi, Sylvie Le Gall, Sarah M. Fortune, Christopher M. Sassetti, Samuel M. Behar 2020 University of Massachusetts Medical School

A Natural Polymorphism Of Mycobacterium Tuberculosis In The Esxh Gene Disrupts Immunodomination By The Tb10.4-Specific Cd8 T Cell Response, Rujapak Sutiwisesak, Nathan D. Hicks, Shayla Boyce, Kenan C. Murphy, Kadamba Papavinasasundaram, Stephen M. Carpenter, Julie Boucau, Neelambari Joshi, Sylvie Le Gall, Sarah M. Fortune, Christopher M. Sassetti, Samuel M. Behar

Open Access Publications by UMMS Authors

CD8 T cells provide limited protection against Mycobacterium tuberculosis (Mtb) infection in the mouse model. As Mtb causes chronic infection in mice and humans, we hypothesize that Mtb impairs T cell responses as an immune evasion strategy. TB10.4 is an immunodominant antigen in people, nonhuman primates, and mice, which is encoded by the esxH gene. In C57BL/6 mice, 30-50% of pulmonary CD8 T cells recognize the TB10.44-11 epitope. However, TB10.4-specific CD8 T cells fail to recognize Mtb-infected macrophages. We speculate that Mtb elicits immunodominant CD8 T cell responses to antigens that are inefficiently presented by infected ...


Two-Plasmid Packaging System For Recombinant Adeno-Associated Virus, Qiushi Tang, Allison M. Keeler, Songbo Zhang, Qin Su, Zhuoyao Lyu, Yangfan Cheng, Guangping Gao, Terence R. Flotte 2020 University of Massachusetts Medical School

Two-Plasmid Packaging System For Recombinant Adeno-Associated Virus, Qiushi Tang, Allison M. Keeler, Songbo Zhang, Qin Su, Zhuoyao Lyu, Yangfan Cheng, Guangping Gao, Terence R. Flotte

Open Access Publications by UMMS Authors

A number of packaging systems are available for production of recombinant adeno-associated virus vectors (rAAVs). Among these, the use of a two-plasmid cotransfection system, in which Rep and Cap genes and Ad helper genes are on the same plasmid, has not been frequently employed for good manufacturing practices (GMP) production, even though it presents some practical advantages over the common three-plasmid (triple) transfection method. To confirm and expand the utility of the two-plasmid system, we generated GMP-compatible versions of this system and used those package reporter genes in multiple capsid variants in direct comparison with triple transfection. Vector yields, purity ...


Response Of Extensively Drug Resistant Salmonella Typhi To Treatment With Meropenem And Azithromycin, In Pakistan, Sonia Qureshi, Abdullah B. Naveed, Mohammad Tahir Yousafzai, Khalil Ahmad, Sarwat Ansari, Heeramani Lohana, Aiman Mukhtar, Farah Naz Qamar 2020 Aga Khan University

Response Of Extensively Drug Resistant Salmonella Typhi To Treatment With Meropenem And Azithromycin, In Pakistan, Sonia Qureshi, Abdullah B. Naveed, Mohammad Tahir Yousafzai, Khalil Ahmad, Sarwat Ansari, Heeramani Lohana, Aiman Mukhtar, Farah Naz Qamar

Department of Paediatrics and Child Health

Introduction: Salmonella Typhi is one of the leading health problems in Pakistan. With the emergence of extensively drug resistant (XDR) Salmonella Typhi, treatment options are limited. Here we report the clinical manifestations and the response to treatment of patients with XDR Typhoid fever. The patients were treated with either Meropenem or Azithromycin or a combination of both.
Methods: We reviewed the records of culture confirmed XDR typhoid who visited Aga Khan University Hospital (AKUH), Karachi and Aga Khan Secondary Care Hospital, Hyderabad from April 2017 to June 2018. Symptoms developed during disease, unplanned treatment extension and complications developed while on ...


Precision Cas9 Genome Editing In Vivo With All-In-One, Self-Targeting Aav Vectors [Preprint], Raed Ibraheim, Phillip W. L. Tai, Aamir Mir, Nida Javeed, Jiaming Wang, Tomas Rodriguez, Samantha J. Nelson, Eraj Khokhar, Esther Mintzer, Stacy Maitland​, Yueying Cao, Guangping Gao, Erik J. Sontheimer 2020 University of Massachusetts Medical School

Precision Cas9 Genome Editing In Vivo With All-In-One, Self-Targeting Aav Vectors [Preprint], Raed Ibraheim, Phillip W. L. Tai, Aamir Mir, Nida Javeed, Jiaming Wang, Tomas Rodriguez, Samantha J. Nelson, Eraj Khokhar, Esther Mintzer, Stacy Maitland​, Yueying Cao, Guangping Gao, Erik J. Sontheimer

University of Massachusetts Medical School Faculty Publications

Adeno-associated virus (AAV) vectors are important delivery platforms for therapeutic genome editing but are severely constrained by cargo limits, especially for large effectors like Cas9s. Simultaneous delivery of multiple vectors can limit dose and efficacy and increase safety risks. The use of compact effectors has enabled single-AAV delivery of Cas9s with 1-3 guides for edits that use end-joining repair pathways, but many precise edits that correct disease-causing mutations in vivo require homology-directed repair (HDR) templates. Here, we describe single-vector, ~4.8-kb AAV platforms that express Nme2Cas9 and either two sgRNAs to produce segmental deletions, or a single sgRNA with an ...


Vitamin D In Covid-19 Pneumonia: High Yield With Low Risk, Shahan Waheed, Emaduddin Siddiqui 2020 Aga Khan University

Vitamin D In Covid-19 Pneumonia: High Yield With Low Risk, Shahan Waheed, Emaduddin Siddiqui

Department of Emergency Medicine

No abstract provided.


An Approach For The In-Vivo Characterization Of Brain And Heart Inflammation In Duchenne Muscular Dystrophy, Joanne Tang 2020 The University of Western Ontario

An Approach For The In-Vivo Characterization Of Brain And Heart Inflammation In Duchenne Muscular Dystrophy, Joanne Tang

Electronic Thesis and Dissertation Repository

Duchenne muscular dystrophy (DMD) is a neuromuscular disorder caused by dystrophin loss—notably within muscles and CNS neurons. DMD presents as cognitive weakness, progressive skeletal and cardiac muscle degeneration until pre-mature death from cardiac or respiratory failure. Innovative therapies improved life expectancy, but this is accompanied by increased late-onset heart failure and emergent cognitive degeneration. Thus, there is an increasing need to both better understand and track disease pathophysiology in the dystrophic heart and brain prior to onset of severe degenerative symptoms. Chronic inflammation is strongly associated with skeletal and cardiac muscle degeneration, however chronic neuroinflammation’s role is largely ...


Astrocyte- And Neuron-Derived Cxcl1 Drives Neutrophil Transmigration And Blood-Brain Barrier Permeability In Viral Encephalitis, Benedict D. Michael, Laura Bricio-Moreno, Elizabeth W. Sorensen, Yoshishige Miyabe, Jeffrey Lian, Tom Solomon, Evelyn A. Kurt-Jones, Andrew D. Luster 2020 Harvard Medical School

Astrocyte- And Neuron-Derived Cxcl1 Drives Neutrophil Transmigration And Blood-Brain Barrier Permeability In Viral Encephalitis, Benedict D. Michael, Laura Bricio-Moreno, Elizabeth W. Sorensen, Yoshishige Miyabe, Jeffrey Lian, Tom Solomon, Evelyn A. Kurt-Jones, Andrew D. Luster

Open Access Publications by UMMS Authors

Herpes simplex virus (HSV)-1 encephalitis has significant morbidity partly because of an over-exuberant immune response characterized by leukocyte infiltration into the brain and increased blood-brain barrier (BBB) permeability. Determining the role of specific leukocyte subsets and the factors that mediate their recruitment into the brain is critical to developing targeted immune therapies. In a murine model, we find that the chemokines CXCL1 and CCL2 are induced in the brain following HSV-1 infection. Ccr2 (CCL2 receptor)-deficient mice have reduced monocyte recruitment, uncontrolled viral replication, and increased morbidity. Contrastingly, Cxcr2 (CXCL1 receptor)-deficient mice exhibit markedly reduced neutrophil recruitment, BBB ...


Flexible Usage And Interconnectivity Of Diverse Cell Death Pathways Protect Against Intracellular Infection, Marcel Doerflinger, Milton Pereira, Andreas Strasser, Sammy Bedoui, Marco J. Herold 2020 University of Melbourne

Flexible Usage And Interconnectivity Of Diverse Cell Death Pathways Protect Against Intracellular Infection, Marcel Doerflinger, Milton Pereira, Andreas Strasser, Sammy Bedoui, Marco J. Herold

Open Access Publications by UMMS Authors

Programmed cell death contributes to host defense against pathogens. To investigate the relative importance of pyroptosis, necroptosis, and apoptosis during Salmonella infection, we infected mice and macrophages deficient for diverse combinations of caspases-1, -11, -12, and -8 and receptor interacting serine/threonine kinase 3 (RIPK3). Loss of pyroptosis, caspase-8-driven apoptosis, or necroptosis had minor impact on Salmonella control. However, combined deficiency of these cell death pathways caused loss of bacterial control in mice and their macrophages, demonstrating that host defense can employ varying components of several cell death pathways to limit intracellular infections. This flexible use of distinct cell death ...


The Development Of Bacterial Magnetic Resonance Imaging For Microbiota Analyses, Sarah C. Donnelly 2020 The University of Western Ontario

The Development Of Bacterial Magnetic Resonance Imaging For Microbiota Analyses, Sarah C. Donnelly

Electronic Thesis and Dissertation Repository

Current microbial analyses to assess either the commensal microbiota or microorganism infection and disease typically require ex vivo techniques that risk contamination and are not undertaken in real time. The possibilities for employing imaging techniques in the microbiology field is becoming more prominent as studies expand on the use of positron emission tomography, ultrasound and numerous microscopy techniques. However, magnetic resonance imaging (MRI), a non-invasive in vivo modality that can produce real-time results is falling behind. Here, we examined the feasibility of detecting bacteria using clinical field strength MRI. Commensal, probiotic and uropathogenic Escherichia coli were scanned by 3 Tesla ...


Antibacterial Fusion Proteins Enhance Moraxella Catarrhalis Killing, Maisem Laabei, Lucie Colineau, Serena Bettoni, Karolina Maziarz, David Ermert, Kristian Riesbeck, Sanjay Ram, Anna M. Blom 2020 Lund University

Antibacterial Fusion Proteins Enhance Moraxella Catarrhalis Killing, Maisem Laabei, Lucie Colineau, Serena Bettoni, Karolina Maziarz, David Ermert, Kristian Riesbeck, Sanjay Ram, Anna M. Blom

Open Access Publications by UMMS Authors

Moraxella catarrhalis is a human-specific commensal of the respiratory tract and an opportunistic pathogen. It is one of the leading cause of otitis media in children and of acute exacerbations in patients with chronic obstructive pulmonary disease, resulting in significant morbidity and economic burden. Vaccines and new immunotherapeutic strategies to treat this emerging pathogen are needed. Complement is a key component of innate immunity that mediates the detection, response, and subsequent elimination of invading pathogens. Many pathogens including M. catarrhalis have evolved complement evasion mechanisms, which include the binding of human complement inhibitors such as C4b-binding protein (C4BP) and Factor ...


Host Immunity Increases Mycobacterium Tuberculosis Reliance On Cytochrome Bd Oxidase [Preprint], Yi Cai, Eleni Jaecklein, Jared Mackenzie, Kadamba Papavinasasundaram, Michigan State University, Xinchun Chen, Africa Health Research Institute, Christopher M. Sassetti 2020 Shenzhen University

Host Immunity Increases Mycobacterium Tuberculosis Reliance On Cytochrome Bd Oxidase [Preprint], Yi Cai, Eleni Jaecklein, Jared Mackenzie, Kadamba Papavinasasundaram, Michigan State University, Xinchun Chen, Africa Health Research Institute, Christopher M. Sassetti

University of Massachusetts Medical School Faculty Publications

In order to sustain a persistent infection, Mycobacterium tuberculosis (Mtb) must adapt to a changing environment that is shaped by the developing immune response. This necessity to adapt is evident in the flexibility of many aspects of Mtb metabolism, including a respiratory chain that consists of two distinct terminal cytochrome oxidase complexes. Under the conditions tested thus far, the bc1/aa3 complex appears to play a dominant role, while the alternative bd oxidase is largely redundant. However, presence of two terminal oxidases in this obligate pathogen implies that respiratory requirements might change during infection. We report that the ...


Extracellular Vesicles From Pseudomonas Aeruginosa Suppress Mhc-Related Molecules In Human Lung Macrophages, David A. Armstrong, Min Kyung. Lee, Haley F. Hazlett, John A. Dessaint, Diane L. Mellinger, Daniel S. Aridgides, Gregory M. Hendricks, Moemen A. K. Abdalla, Brock C. Christensen, Alix Ashare 2020 Dartmouth-Hitchcock Medical Center

Extracellular Vesicles From Pseudomonas Aeruginosa Suppress Mhc-Related Molecules In Human Lung Macrophages, David A. Armstrong, Min Kyung. Lee, Haley F. Hazlett, John A. Dessaint, Diane L. Mellinger, Daniel S. Aridgides, Gregory M. Hendricks, Moemen A. K. Abdalla, Brock C. Christensen, Alix Ashare

Radiology Publications

Pseudomonas aeruginosa, a Gram-negative bacterium, is one of the most common pathogens colonizing the lungs of cystic fibrosis patients. P. aeruginosa secrete extracellular vesicles (EVs) that contain LPS and other virulence factors that modulate the host's innate immune response, leading to an increased local proinflammatory response and reduced pathogen clearance, resulting in chronic infection and ultimately poor patient outcomes. Lung macrophages are the first line of defense in the airway innate immune response to pathogens. Proper host response to bacterial infection requires communication between APC and T cells, ultimately leading to pathogen clearance. In this study, we investigate whether ...


Epstein-Barr Virus Genomes Reveal Population Structure And Type 1 Association With Endemic Burkitt Lymphoma, Yasin Kaymaz, Cliff I. Oduor, Ozkan Aydemir, Micah A. Luftig, Juliana A. Otieno, John Michael. Ong'echa, Jeffrey A. Bailey, Ann M. Moormann 2020 University of Massachusetts Medical School

Epstein-Barr Virus Genomes Reveal Population Structure And Type 1 Association With Endemic Burkitt Lymphoma, Yasin Kaymaz, Cliff I. Oduor, Ozkan Aydemir, Micah A. Luftig, Juliana A. Otieno, John Michael. Ong'echa, Jeffrey A. Bailey, Ann M. Moormann

UMass Center for Clinical and Translational Science Supported Publications

Endemic Burkitt lymphoma (eBL), the most prevalent pediatric cancer in sub-Saharan Africa, is distinguished by its inclusion of Epstein-Barr virus (EBV). In order to better understand the impact of EBV variation in eBL tumorigenesis, we improved viral DNA enrichment methods and generated a total of 98 new EBV genomes from both eBL cases (n = 58) and healthy controls (n = 40) residing in the same geographic region in Kenya. Using our unbiased methods, we found that EBV type 1 was significantly more prevalent in eBL patients (74.5%) than in healthy children (47.5%) (odds ratio = 3.24, 95% confidence interval ...


Investigating Virological, Immunological, And Pathological Avenues To Identify Potential Targets For Developing Covid-19 Treatment And Prevention Strategies, Zafar Mahmood, Hani Alrefai Alrefai, Helal F. Hetta, Hidaya A. Kader 2020 United Arab Emirates University

Investigating Virological, Immunological, And Pathological Avenues To Identify Potential Targets For Developing Covid-19 Treatment And Prevention Strategies, Zafar Mahmood, Hani Alrefai Alrefai, Helal F. Hetta, Hidaya A. Kader

Books and Book Chapters

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an emerging coronavirus causing respiratory disease commonly known as COVID-19. This novel coronavirus transmits from human to human and has caused profound morbidity and mortality worldwide leading to the ongoing pandemic. Moreover, disease severity differs considerably from individual to individual. Investigating the virology of COVID-19 and immunological pathways underlying its clinical manifestations will enable the identification and design of effective vaccines and potential therapies. In this review, we explore COVID-19 virology, the contribution of the immune system (innate and adaptive) during infection and control of the virus. Finally, we highlight vaccine development ...


Distinct Bacterial Pathways Influence The Efficacy Of Antibiotics Against Mycobacterium Tuberculosis, Michelle Bellerose, Megan K. Proulx, Clare M. Smith, Richard E. Baker, Thomas R. Ioerger, Christopher M. Sassetti 2020 University of Massachusetts Medical School

Distinct Bacterial Pathways Influence The Efficacy Of Antibiotics Against Mycobacterium Tuberculosis, Michelle Bellerose, Megan K. Proulx, Clare M. Smith, Richard E. Baker, Thomas R. Ioerger, Christopher M. Sassetti

Open Access Publications by UMMS Authors

Effective tuberculosis treatment requires at least 6 months of combination therapy. Alterations in the physiological state of the bacterium during infection are thought to reduce drug efficacy and prolong the necessary treatment period, but the nature of these adaptations remain incompletely defined. To identify specific bacterial functions that limit drug effects during infection, we employed a comprehensive genetic screening approach to identify mutants with altered susceptibility to the first-line antibiotics in the mouse model. We identified many mutations that increase the rate of bacterial clearance, suggesting new strategies for accelerating therapy. In addition, the drug-specific effects of these mutations suggested ...


The Inhibitory Effects Of An Antimicrobial Gel On The Staphylococcus Species, Mara Trinkle 2020 East Tennessee State University

The Inhibitory Effects Of An Antimicrobial Gel On The Staphylococcus Species, Mara Trinkle

Undergraduate Honors Theses

The prevalence of antibiotic resistant bacteria has made the choices for topical treatments for patients who experience burns wounds extremely limited. The Staphylococcus genus is naturally occurring in and on the human body but can become harmful once it enters the bloodstream. A novel antimicrobial gel has been shown by our laboratory to inhibit both the planktonic growth and biofilm formation of Staphylococcus aureus in previous studies. The antimicrobial gel is made of seven natural compounds including antioxidants (vitamin C and E). We wanted to examine the effects of the antimicrobial gel on numerous other Staphylococcal species because it is ...


The Use Of Animal-Assisted Therapeutic Interventions In The Hospital Setting During The Covid-19 Pandemic, Alicia Cesare 2020 Missouri State University

The Use Of Animal-Assisted Therapeutic Interventions In The Hospital Setting During The Covid-19 Pandemic, Alicia Cesare

MSU Graduate Theses

Handlers of therapy and/or facility dogs working within hospital settings have experienced various barriers and challenges within their practice during the COVID-19 pandemic. Animal-assisted interventions, specifically therapeutic working dogs, are a valued source of support to individuals, communities, hospital settings, and disaster sites during times of community distress. The purpose of this study was to identify barriers and solutions to the continued use of animal-assisted therapeutic interventions in support of patients and families within the hospital setting during the COVID-19 pandemic. This researcher’s position within the research is the knowledge and experience of being a facility dog handler ...


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