Medicine and Health Sciences Commons^™

Isolated Cerebral Mucormycosis And Aspergillosis Coinfection In An Immunocompromised Adult, George Sun, Allison Weiss, Joy Zhao, Mitchell Silver, Michael Demaio, Sara Dehbashi

Department of Neurology Faculty Papers

Opportunistic fungal infections are a major cause of mortality in immunosuppressed patients, with mucormycosis and aspergillosis as two of the most commonly identified fungal organisms. Coinfection with mucormycosis and aspergillosis is rare, but cases have been reported in literature, most commonly presenting as disseminated invasive fungal infection with cerebrorhino-orbital involvement in an immunocompromised patient. Infections are most commonly caused by direct implantation of spores with localised angioinvasion. Haematogenous spread is rare, with most cases secondary to haematological malignancies or intravenous drug use. Coinfection with mucormycosis and aspergillosis portends a poor prognosis, with a high mortality rate. Thus, prompt recognition and …

Editorial: Targeting Dna Damage Response To Enhance Antitumor Innate Immunity In Radiotherapy, Victoria Valvo, Emanuele Vitale, Marco Tigano, Rachel Evans, Meredith A. Morgan, Qiang Zhang

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

No abstract provided.

Structural Insights Into Rna Bridging Between Hiv-1 Vif And Antiviral Factor Apobec3g, Takahide Kouno, Satoshi Shibata, Megumi Shigematsu, Jaekyung Hyun, Tae Gyun Kim, Hiroshi Matsuo, Matthias Wolf

Computational Medicine Center Faculty Papers

Great effort has been devoted to discovering the basis of A3G-Vif interaction, the key event of HIV's counteraction mechanism to evade antiviral innate immune response. Here we show reconstitution of the A3G-Vif complex and subsequent A3G ubiquitination in vitro and report the cryo-EM structure of the A3G-Vif complex at 2.8 Å resolution using solubility-enhanced variants of A3G and Vif. We present an atomic model of the A3G-Vif interface, which assembles via known amino acid determinants. This assembly is not achieved by protein-protein interaction alone, but also involves RNA. The cryo-EM structure and in vitro ubiquitination assays identify an adenine/guanine base …

Adjuvanted Fusion Protein Vaccine Induces Durable Immunity To Onchocerca Volvulus In Mice And Non-Human Primates, Nathan M. Ryan, Jessica A. Hess, Erica J. Robertson, Nancy Tricoche, Cheri Turner, Jenn Davis, Nikolai Petrovsky, Melissa Ferguson, William J. Rinaldi, Valerie M. Wong, Ayako Shimada, Bin Zhan, Maria Elena Bottazzi, Benjamin L. Makepece, Sean A. Gray, Darrick Carter, Sara Lustigman, David Abraham

Department of Microbiology and Immunology Faculty Papers

Onchocerciasis remains a debilitating neglected tropical disease. Due to the many challenges of current control methods, an effective vaccine against the causative agent Onchocerca volvulus is urgently needed. Mice and cynomolgus macaque non-human primates (NHPs) were immunized with a vaccine consisting of a fusion of two O. volvulus protein antigens, Ov-103 and Ov-RAL-2 (Ov-FUS-1), and three different adjuvants: Advax-CpG, alum, and AlT4. All vaccine formulations induced high antigen-specific IgG titers in both mice and NHPs. Challenging mice with O. volvulus L3 contained within subcutaneous diffusion chambers demonstrated that Ov-FUS-1/Advax-CpG-immunized animals developed protective immunity, durable for at least 11 weeks. Passive …

Il-11 Induces Nlrp3 Inflammasome Activation In Monocytes And Inflammatory Cell Migration To The Central Nervous System, Maryamsadat Seyedsadr, Yan Wang, Manal Elzoheiry, Sowmya Shree Gopal, Soohwa Jang, Gayel Duran, Inna Chervoneva, Ezgi Kasimoglu, John A. Wrobel, Daniel Hwang, James Garifallou, Xin Zhang, Tabish H. Khan, Ulrike Lorenz, Maureen Su, Jenny P. Ting, Bieke Broux, A M Rostami, Dhanashri Miskin, Silva Markovic-Plese

Department of Neurology Faculty Papers

The objective of this study is to examine IL-11-induced mechanisms of inflammatory cell migration to the central nervous system (CNS). We report that IL-11 is produced at highest frequency by myeloid cells among the peripheral blood mononuclear cell (PBMC) subsets. Patients with relapsing-remitting multiple sclerosis (RRMS) have an increased frequency of IL-11+ monocytes, IL-11+ and IL-11R+ CD4+ lymphocytes, and IL-11R+ neutrophils in comparison to matched healthy controls. IL-11+ and granulocyte-macrophage colony-stimulating factor (GM-CSF)+ monocytes, CD4+ lymphocytes, and neutrophils accumulate in the cerebrospinal fluid (CSF). The effect of IL-11 in-vitro stimulation, examined using single-cell RNA sequencing, revealed the highest number of …

Assessment Of The First Presentations Of Common Variable Immunodeficiency In A Large Cohort Of Patients, Hossein Esmaeilzadeh, Armita Jokar-Derisi, Amir Hossein Hassani, Reza Yazdani, Samaneh Delavari, Hassan Abolhassani, Negar Mortazavi, Aida Askarisarvestani

Department of Neurology Faculty Papers

BACKGROUND: Common Variable Immunodeficiency (CVID) is a primary immunodeficiency syndrome resulting in recurrent infections, autoimmunity, and granulomatous manifestations.

METHODS AND MATERIALS: This retrospective study was conducted on an Iranian national registry of immunodeficient patients from 2010 to 2021. The frequency of first presentations of CVID and its association with sex, age of onset, and family history of CVID was evaluated.

RESULTS: A total of 383 patients entered the study, 164 of whom were female, and the rest were male. The mean age of the patients was 25.3 ± 14.5 years. The most frequent first presentations of CVID were pneumonia (36.8%) …

Ido1 And Inflammatory Neovascularization: Bringing New Blood To Tumor-Promoting Inflammation, Alexander J. Muller, Arpita Mondal, Souvik Dey, George C Prendergast

Kimmel Cancer Center Faculty Papers

In parallel with the genetic and epigenetic changes that accumulate in tumor cells, chronic tumor-promoting inflammation establishes a local microenvironment that fosters the development of malignancy. While knowledge of the specific factors that distinguish tumor-promoting from non-tumor-promoting inflammation remains inchoate, nevertheless, as highlighted in this series on the 'Hallmarks of Cancer', it is clear that tumor-promoting inflammation is essential to neoplasia and metastatic progression making identification of specific factors critical. Studies of immunometabolism and inflamometabolism have revealed a role for the tryptophan catabolizing enzyme IDO1 as a core element in tumor-promoting inflammation. At one level, IDO1 expression promotes immune tolerance …

Antibodies For Β2-Microglobulin And The Heavy Chains Of Hla-E, Hla-F, And Hla-G Reflect The Hla-Variants On Activated Immune Cells And Phases Of Disease Progression In Rheumatoid Arthritis Patients Under Treatment, Mepur H. Ravindranath, Narendranath M. Ravindranath, Carly J. Amato-Menker, Fatiha El Hilali, Senthamil R. Selvan, Edward J Filippone, Luis Eduardo Morales-Buenrostro

Department of Medicine Faculty Papers

Rheumatoid arthritis (RA) is a progressive, inflammatory, autoimmune, symmetrical polyarticular arthritis. It is characterized by synovial infiltration and activation of several types of immune cells, culminating in their apoptosis and antibody generation against "altered" autoantigens. β2-microglobulin (β2m)-associated heavy chains (HCs) of HLA antigens, also known as closed conformers (Face-1), undergo "alteration" during activation of immune cells, resulting in β2m-free structural variants, including monomeric open conformers (Face-2) that are capable of dimerizing as either homodimers (Face-3) or as heterodimers (Face-4). β2m-free HCs uncover the cryptic epitopes that can elicit antibodies (Abs). We report here the levels of IgM and IgG Abs …

Design And Preclinical Evaluation Of A Universal Sars-Cov-2 Mrna Vaccine, Jane Qin, Ju Hyeong Jeon, Jiangsheng Xu, Laura Katherine Langston, Ramesh Marasini, Stephanie Mou, Brian Montoya, Carolina R Melo-Silva, Hyo Jin Jeon, Tianyi Zhu, Luis J. Sigal, Renhuan Xu, Huabin Zhu

Department of Microbiology and Immunology Faculty Papers

Because of the rapid mutations of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), an effective vaccine against SARS-CoV-2 variants is needed to prevent coronavirus disease 2019 (COVID-19). T cells, in addition to neutralizing antibodies, are an important component of naturally acquired protective immunity, and a number of studies have shown that T cells induced by natural infection or vaccination contribute significantly to protection against several viral infections including SARS-CoV-2. However, it has never been tested whether a T cell-inducing vaccine can provide significant protection against SARS-CoV-2 infection in the absence of preexisting antibodies. In this study, we designed and evaluated …

Sleep Duration, Hypnotic Drug Use, And Risk Factors: Cross- Sectional Study, Nazanin Jalali, Parvin Khalili, Zahra Jamali, Zahra Jalali, Amir Moghadam-Ahmadi, Alireza Vakilian, Fatemeh Ayoobi

Department of Neurology Faculty Papers

Both short sleep duration (SSD) and long sleep duration (LSD) are associated with an increased risk of morbidity and mortality. Here, we aimed to assess the prevalence of sleep duration disturbances among adults in association with demographic, medication use, personal habits, and chronic diseases, while also considering the impact of hypnotic drug use. We performed a cross-sectional study of 9991 adult participants of the Rafsanjan Cohort Study (RCS), as part of the Prospective epidemiological research studies in Iran (PERSIAN). Multivariate logistic regression analyses were conducted to assess the association between short (< 6 h) and long (> 9 h) sleep duration with demographic and lifestyle …

Effects Of Adjuvants In A Rabies-Vectored Ebola Virus Vaccine On Protection From Surrogate Challenge, Catherine Yankowski, Drishya Kurup, Christoph Wirblich, Matthias J. Schnell

Department of Microbiology and Immunology Faculty Papers

Ebola virus is the primary contributor to the global threat of filovirus severe hemorrhagic fever, and Ebola virus disease has a case fatality rate of 50-90%. An inactivated, bivalent filovirus/rabies virus vaccine, FILORAB1, consists of recombinant rabies virus virions expressing the Ebola virus glycoprotein. FILORAB1 is immunogenic and protective from Ebola virus challenge in mice and non-human primates, and protection is enhanced when formulated with toll-like receptor 4 agonist Glucopyranosyl lipid adjuvant (GLA) in a squalene oil-in-water emulsion (SE). Through an adjuvant comparison in mice, we demonstrate that GLA-SE improves FILORAB1 efficacy by activating the innate immune system and shaping …

Safety Of Adenosine For The Treatment Of Supraventricular Tachycardia In Hospitalized Patients With Covid-19 Pneumonia, T. Zivan, Ramon L Ruiz, Alexandre Martinez, Behzad B. Pavri

Department of Medicine Faculty Papers

Coronavirus disease 2019 (COVID-19) is associated with pulmonary involvement and cardiac arrhythmias, including supraventricular tachycardia (SVT). Adenosine is commonly used to treat SVT and is generally safe, but is rarely associated with bronchospasm. There are no data regarding the safety of adenosine use in patients with COVID-19 pneumonia and physicians may hesitate to use it in such patients. We surveyed resident physicians and cardiology attendings regarding their level of comfort in administering adenosine to hospitalized COVID-19 patients. We compared a study group of 42 COVID-19 hospitalized patients who received adenosine for SVT to a matched (for age, sex, and co-morbidities) …

Identification Of Collaborative Cross Mouse Strains Permissive To Salmonella Enterica Serovar Typhi Infection, Kishore Alugupalli, Sudeep Kothari, Matthew P Cravens, Justin A Walker, Darren T Dougharty, Gregory S. Dickinson, Louis A Gatto, Andreas J Bäumler, Tamding Wangdi, Darla R Miller, Fernando Pardo-Manuel De Villena, Linda D Siracusa

Department of Microbiology and Immunology Faculty Papers

Salmonella enterica serovar Typhi is the causative agent of typhoid fever restricted to humans and does not replicate in commonly used inbred mice. Genetic variation in humans is far greater and more complex than that in a single inbred strain of mice. The Collaborative Cross (CC) is a large panel of recombinant inbred strains which has a wider range of genetic diversity than laboratory inbred mouse strains. We found that the CC003/Unc and CC053/Unc strains are permissive to intraperitoneal but not oral route of S. Typhi infection and show histopathological changes characteristic of human typhoid. These CC strains are immunocompetent, …

Small Extracellular Vesicle-Mediated Itgb6 Sirna Delivery Downregulates The Αvβ6 Integrin And Inhibits Adhesion And Migration Of Recipient Prostate Cancer Cells, Shiv Ram Krishn, Vaughn Garcia, Nicole M Naranjo, Fabio Quaglia, Christopher D Shields, Maisha A Harris, Andrew V Kossenkov, Qin Liu, Eva Corey, Dario C Altieri, Lucia R Languino

Department of Cancer Biology Faculty Papers

The αVβ6 integrin, an epithelial-specific cell surface receptor absent in normal prostate and expressed during prostate cancer (PrCa) progression, is a therapeutic target in many cancers. Here, we report that transcript levels of ITGB6 (encoding the β6 integrin subunit) are significantly increased in metastatic castrate-resistant androgen receptor-negative prostate tumors compared to androgen receptor-positive prostate tumors. In addition, the αVβ6 integrin protein levels are significantly elevated in androgen receptor-negative PrCa patient derived xenografts (PDXs) compared to androgen receptor-positive PDXs. In vitro, the androgen receptor-negative PrCa cells express high levels of the αVβ6 integrin compared to androgen receptor-positive PrCa cells. Additionally, …

The Lack Of Natural Igm Increases Susceptibility And Impairs Anti-Vi Polysaccharide Igg Responses In A Mouse Model Of Typhoid, Akhil S. Alugupalli, Matthew P. Cravens, Justin A. Walker, Dania Gulandijany, Gregory S. Dickinson, Genevieve Lewis, Gudrun F. Debes, Dieter M. Schifferli, Andreas J. Bäumler, Kishore R. Alugupalli

Department of Microbiology and Immunology Faculty Papers

Circulating IgM present in the body prior to any apparent Ag exposure is referred to as natural IgM. Natural IgM provides protective immunity against a variety of pathogens. Salmonella enterica serovar Typhi (S. Typhi) is the causative agent of typhoid fever in humans. Because mice are not permissive to S. Typhi infection, we employed a murine model of typhoid using S. enterica serovar Typhimurium expressing the Vi polysaccharide (ViPS) of S. Typhi (S. Typhimurium strain RC60) to evaluate the role of natural IgM in pathogenesis. We found that natural mouse IgM binds to S. Typhi and S. Typhimurium. The severity …

Interferon Partly Dictates A Divergent Transcriptional Response In Poxvirus-Infected And Bystander Inflammatory Monocytes, Carolina R Melo-Silva, Marisa I Roman, Cory J Knudson, Lingjuan Tang, Ren-Huan Xu, Michel Tassetto, Patrick Dolan, Raul Andino, Luis J. Sigal

Department of Microbiology and Immunology Faculty Papers

Inflammatory monocytes (iMOs) and B cells are the main targets of the poxvirus ectromelia virus (ECTV) in the lymph nodes of mice and play distinct roles in surviving the infection. Infected and bystander iMOs control ECTV's systemic spread, preventing early death, while B cells make antibodies that eliminate ECTV. Our work demonstrates that within an infected animal that survives ECTV infection, intrinsic and bystander infection of iMOs and B cells differentially control the transcription of genes important for immune cell function and, perhaps, cell identity. Bystander cells upregulate metabolism, antigen presentation, and interferon-stimulated genes. Infected cells downregulate many cell-type-specific genes …

Human Dectin-1 Deficiency Impairs Macrophage-Mediated Defense Against Phaeohyphomycosis, Rebecca A. Drummond, Jigar V. Desai, Amy P. Hsu, Vasileios Oikonomou, Donald C. Vinh, Joshua A. Acklin, Michael S. Abers, Magdalena A. Walkiewicz, Sarah L. Anzick, Muthulekha Swamydas, Simon Vautier, Mukil Natarajan, Andrew J. Oler, Daisuke Yamanaka, Katrin D. Mayer-Barber, Yoichiro Iwakura, David Bianchi, Brian Driscoll, Ken Hauck, Ahnika Kline, Nicholas S.P. Viall, Christa S. Zerbe, Elise M.N. Ferré, Monica M. Schmitt, Tom Dimaggio, Stefania Pittaluga, John A. Butman, Adrian M. Zelazny, Yvonne R. Shea, Cesar A. Arias, Cameron Ashbaugh, Maryam Mahmood, Zelalem Temesgen, Alexander G. Theofiles, Masayuki Nigo, Varsha Moudgal, Karen C. Bloch, Sean G. Kelly, M. Suzanne Whitworth, Ganesh Rao, Cindy J. Whitener, Neema Mafi, Juan Gea-Banacloche, Lawrence C. Kenyon, William R. Miller, Katia Boggian, Andrea Gilbert, Matthew Sincock, Alexandra F. Freeman, John E. Bennett, Rodrigo Hasbun, Constantinos M. Mikelis, Kyung J. Kwon-Chung, Yasmine Belkaid, Gordon D. Brown, Jean K. Lim, Douglas B. Kuhns, Steven M. Holland, Michail S. Lionakis

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Subcutaneous phaeohyphomycosis typically affects immunocompetent individuals following traumatic inoculation. Severe or disseminated infection can occur in CARD9 deficiency or after transplantation, but the mechanisms protecting against phaeohyphomycosis remain unclear. We evaluated a patient with progressive, refractory Corynespora cassiicola phaeohyphomycosis and found that he carried biallelic deleterious mutations in CLEC7A encoding the CARD9-coupled, β-glucan-binding receptor, Dectin-1. The patient's PBMCs failed to produce TNF-α and IL-1β in response to β-glucan and/or C. cassiicola. To confirm the cellular and molecular requirements for immunity against C. cassiicola, we developed a mouse model of this infection. Mouse macrophages required Dectin-1 and CARD9 for IL-1β and …

Caspase-8 Inactivation Drives Autophagy-Dependent Inflammasome Activation In Myeloid Cells., Yung-Hsuan Wu, Shu-Ting Mo, I-Ting Chen, Fu-Yi Hsieh, Shie-Liang Hsieh, Jianke Zhang, Ming-Zong Lai

Department of Microbiology and Immunology Faculty Papers

Caspase-8 activity controls the switch from cell death to pyroptosis when apoptosis and necroptosis are blocked, yet how caspase-8 inactivation induces inflammasome assembly remains unclear. We show that caspase-8 inhibition via IETD treatment in Toll-like receptor (TLR)-primed Fadd-/-Ripk3-/- myeloid cells promoted interleukin-1β (IL-1β) and IL-18 production through inflammasome activation. Caspase-8, caspase-1/11, and functional GSDMD, but not NLRP3 or RIPK1 activity, proved essential for IETD-triggered inflammasome activation. Autophagy became prominent in IETD-treated Fadd-/-Ripk3-/- macrophages, and inhibiting it attenuated IETD-induced cell death and IL-1β/IL-18 production. In contrast, inhibiting GSDMD or autophagy did not prevent IETD-induced septic …

Intracellular Monitoring By Dendritic Cells - A New Way To Stay Informed - From A Simple Scavenger To An Active Gatherer, Christopher Herbst, Larry A Harshyne, Botond Z Igyártó

Department of Microbiology and Immunology Faculty Papers

Dendritic cells (DCs) are required for the initiation of the adaptive immune response. Their ability to acquire antigens in the periphery is a critical step in this process. DCs express a wide variety of adhesion molecules and possess an extremely fluid plasma membrane that facilitates scavenging the extracellular environment and capturing material like exosomes, apoptotic bodies, and pathogens. Besides these standard routes, the acquisition of antigens by DCs can be further facilitated by tunneling nanotubes, trogocytosis, and gap junctions. However, in this article, we will argue that this is an incomplete picture, as certain observations in the literature cannot be …

Attenuation Of Relapsing Fever Neuroborreliosis In Mice By Il-17a Blockade, Meihui Cheng, Jingwen Xu, Kaiyun Ding, Jing Zhang, Wei Lu, Jiansheng Liu, Jiahong Gao, Kishore R Alugupalli, Hongqi Liu

Department of Microbiology and Immunology Faculty Papers

Relapsing fever due to Borrelia hermsiiis characterized by recurrent bacteremia episodes. However, infection of B. hermsii, if not treated early, can spread to various organs including the central nervous system (CNS). CNS disease manifestations are commonly referred to as relapsing fever neuroborreliosis (RFNB). In the mouse model of B. hermsiiinfection, we have previously shown that the development of RFNB requires innate immune cells as well as T cells. Here, we found that prior to the onset of RFNB, an increase in the systemic proinflammatory cytokine response followed by sustained levels of IP-10 concurrent with the CNS disease phase. RNA sequencing …

Pre-Exposure To Mrna-Lnp Inhibits Adaptive Immune Responses And Alters Innate Immune Fitness In An Inheritable Fashion, Zhen Qin, Aurélie Bouteau, Christopher Herbst, Botond Z. Igyártó

Department of Microbiology and Immunology Faculty Papers

Hundreds of millions of SARS-CoV-2 mRNA-LNP vaccine doses have already been administered to humans. However, we lack a comprehensive understanding of the immune effects of this platform. The mRNA-LNP-based SARS-CoV-2 vaccine is highly inflammatory, and its synthetic ionizable lipid component responsible for the induction of inflammation has a long in vivo half-life. Since chronic inflammation can lead to immune exhaustion and non-responsiveness, we sought to determine the effects of pre-exposure to the mRNA-LNP on adaptive immune responses and innate immune fitness. We found that pre-exposure to mRNA-LNPs or LNP alone led to long-term inhibition of the adaptive immune response, which …

Is Strongyloides Stercoralis Hyperinfection Induced By Gglucocorticoids A Result Of Both Suppressed Host Immunity And Altered Parasite Genetics?, De'broski R Herbert, Jonathan D C Stoltzfus, Heather L Rossi, David Abraham

Department of Microbiology and Immunology Faculty Papers

The gastrointestinal (GI) nematode Strongyloides stercoralis (S.s.) causes human strongyloidiasis, a potentially life-threatening disease that currently affects over 600 million people globally. The uniquely pernicious aspect of S.s. infection, as compared to all other GI nematodes, is its autoinfective larval stage (L3a) that maintains a low-grade chronic infection, allowing undetectable persistence for decades. Infected individuals who are administered glucocorticoid therapy can develop a rapid and often lethal hyperinfection syndrome within days. Hyperinfection patients often present with dramatic increases in first- and second-stage larvae and L3a in their GI tract, with L3a widely disseminating throughout host organs leading to sepsis. How …

"Don't Look Up" Your Science-Herd Immunity Or Herd Mentality?, Botond Z Igyártó

Department of Microbiology and Immunology Faculty Papers

This analysis piece will attempt to examine some of the critical pandemic-related measures implemented in the United States from an immunological perspective and pinpoint caveats that should have been considered before their implementation. I also discuss alternative measures grounded in scientific data that were not thoroughly explored and likely could have helped fight the pandemic.

B- And T-Cell Subset Abnormalities In Monogenic Common Variable Immunodeficiency, Saba Fekrvand, Shaghayegh Khanmohammadi, Hassan Abolhassani, Reza Yazdani

Department of Neurology Faculty Papers

Common variable immunodeficiency (CVID) is a heterogeneous group of inborn errors of immunity characterized by reduced serum concentrations of different immunoglobulin isotypes. CVID is the most prevalent symptomatic antibody deficiency with a broad range of infectious and non-infectious clinical manifestations. Various genetic and immunological defects are known to be involved in the pathogenesis of CVID. Monogenic defects account for the pathogenesis of about 20-50% of CVID patients, while a variety of cases do not have a defined genetic background. Deficiencies in molecules of B cell receptor signaling or other pathways involving B-cell development, activation, and proliferation could be associated with …

Genomic Features Underlie The Co-Option Of Sva Transposons As Cis-Regulatory Elements In Human Pluripotent Stem Cells, Samantha M Barnada, Andrew Isopi, Daniela Tejada-Martinez, Clément Goubert, Sruti Patoori, Luca Pagliaroli, Mason Tracewell, Marco Trizzino

Department of Biochemistry and Molecular Biology Faculty Papers

Domestication of transposable elements (TEs) into functional cis-regulatory elements is a widespread phenomenon. However, the mechanisms behind why some TEs are co-opted as functional enhancers while others are not are underappreciated. SINE-VNTR-Alus (SVAs) are the youngest group of transposons in the human genome, where ~3,700 copies are annotated, nearly half of which are human-specific. Many studies indicate that SVAs are among the most frequently co-opted TEs in human gene regulation, but the mechanisms underlying such processes have not yet been thoroughly investigated. Here, we leveraged CRISPR-interference (CRISPRi), computational and functional genomics to elucidate the genomic features that underlie SVA domestication …

A Single Dose Of The Deactivated Rabies-Virus Vectored Covid-19 Vaccine, Coravax, Is Highly Efficacious And Alleviates Lung Inflammation In The Hamster Model, Drishya Kurup, Christoph Wirblich, Leila Zabihi Diba, Rachael Lambert, Megan Watson, Noor Shaikh, Holly Ramage, Charalambos Solomides, Matthias J Schnell

Department of Microbiology and Immunology Faculty Papers

Without sufficient herd immunity through either vaccination or natural infection, the coronavirus disease 2019 pandemic is unlikely to be controlled. Waning immunity with the currently approved vaccines suggests the need to evaluate vaccines causing the induction of long-term responses. Here, we report the immunogenicity and efficacy of our adjuvanted single-dose Rabies-vectored SARS-CoV-2 S1 vaccine, CORAVAX, in hamsters. CORAVAX induces high SARS-CoV-2 S1-specific and virus-neutralizing antibodies (VNAs) that prevent weight loss, viral loads, disease, lung inflammation, and the cytokine storm in hamsters. We also observed high Rabies VNA titers. In summary, CORAVAX is a promising dual-antigen vaccine candidate for clinical evaluation …

Medical Factors Associated With Caregiver Intention To Vaccinate Their Children Against Covid-19, Thao-Ly Phan, Paul T Enlow, Michael King, Amanda M Lewis, Anne E Kazak, Jonathan M Miller

Department of Medicine Faculty Papers

Objective: To describe medical factors that are associated with caregiver intention to vaccinate their children against COVID-19.

Methods: We conducted a cross-sectional study of families receiving primary care in a mid-Atlantic pediatric healthcare system, linking caregiver-reported data from a survey completed March 19 to April 16, 2021 to comprehensive data from the child's EHR.

Results: 513 families were included (28% Black, 16% Hispanic, 44% public insurance, 21% rural, child age range 0-21 years). 44% of caregivers intended to vaccinate their children against COVID-19, while 41% were not sure and 15% would not. After adjusting for socio-demographics, the only medical factors …

Arsenic Toxicity On Metabolism And Autophagy In Adipose And Muscle Tissues, Seung-Hyun Ro, Jiyoung Bae, Yura Jang, Jacob Myers, Soonkyu Chung, Jiujiu Yu, Sathish Kumar Natarajan, Rodrigo Franco, Hyun-Seob Song

Department of Microbiology and Immunology Faculty Papers

Arsenic, a naturally occurring metalloid derived from the environment, has been studied worldwide for its causative effects in various cancers. However, the effects of arsenic toxicity on the development and progression of metabolic syndrome, including obesity and diabetes, has received less attention. Many studies suggest that metabolic dysfunction and autophagy dysregulation of adipose and muscle tissues are closely related to the development of metabolic disease. In the USA, arsenic contamination has been reported in some ground water, soil and grain samples in major agricultural regions, but the effects on adipose and muscle tissue metabolism and autophagy have not been investigated …

T-Cell Responses To Immunodominant Listeria Epitopes Limit Vaccine-Directed Responses To The Colorectal Cancer Antigen, Guanylyl Cyclase C, John C. Flickinger, Jagmohan Singh, Yanki Yarman, Robert D Carlson, Joshua Barton, Scott A Waldman, Adam E. Snook

Department of Pharmacology and Experimental Therapeutics Faculty Papers

The Gram-positive bacterium Listeria monocytogenes (Lm) is an emerging platform for cancer immunotherapy. To date, over 30 clinical trials have been initiated testing Lm cancer vaccines across a wide variety of cancers, including lung, cervical, colorectal, and pancreatic. Here, we assessed the immunogenicity of an Lm vaccine against the colorectal tumor antigen GUCY2C (Lm-GUCY2C). Surprisingly, Lm-GUCY2C vaccination did not prime naïve GUCY2C-specific CD8+ T-cell responses towards the dominant H-2Kd-restricted epitope, GUCY2C254-262. However, Lm-GUCY2C produced robust CD8+ T-cell responses towards Lm-derived peptides suggesting that GUCY2C254-262 peptide may be subdominant to Lm-derived peptides. Indeed, incorporating immunogenic Lm peptides into an adenovirus-based GUCY2C …

Comparison Of Automated Ribotyping, Spa Typing, And Mlst In 108 Clinical Isolates Of Staphylococcus Aureus From Orthopedic Infections, Stefano Ravaioli, Davide Campoccia, Werner Ruppitsch, Franz Allerberger, Alessandro Poggi, Emanuele Chisari, Lucio Montanaro, Carla Renata Arciola

Rothman Institute Faculty Papers

108 isolates of Staphylococcus aureus, belonging to six large ribogroups according to the automated Ribo-Printer® system, were studied with two highly used molecular methods for epidemiological studies, namely multi-locus sequence typing (MLST) and spa typing, followed by BURP and eBURST v3 analysis for clustering spa types and sequence (ST) types. The aim was to evaluate whether automated ribotyping could be considered a useful screening tool for identifying S. aureus genetic lineages with respect to spa typing and MLST. Clarifying the relationship of riboprinting with these typing methods and establishing whether ribogroups fit single clonal complexes were two main objectives. …