Medical Microbiology Commons^™

Engineered Bifidobacterium Strains Colonization At Tumor Sites: A Novel Approach To The Delivery Of Cancer Treatments, Rhea Amonkar, Ashley Ann Uy, Pablo Ramirez, Harina Patel, Jae Jin Jeong, Nicole Oyinade Shoyele, Vidhi Vaghela, Ashakumary Lakshmikuttyamma

Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers

Bacteria-mediated cancer therapy represents a novel and promising strategy for targeted drug delivery to solid tumors. Multiple studies have demonstrated that various Bifidobacterium species can selectively colonize the hypoxic microenvironments characteristic of solid tumors. Leveraging this property, Bifidobacterium has been explored as a delivery vector for a range of anti-cancer approaches such as immunotherapy, nanoformulated chemotherapeutics, and gene therapy. Notably, anti-angiogenic genes such as endostatin and tumstatin have been successfully delivered to colorectal tumors using Bifidobacterium infantis and Bifidobacterium longum, respectively. Additionally, Bifidobacterium bifidum has been employed to transport doxorubicin and paclitaxel nanoparticles to breast and lung tumor sites. …

Immune Responses Drive Chorioretinitis And Retinal Pathology After Neonatal Cmv Infection, Jessica L. Mccord, John Y.S. Han, Ross E. Staudt, Nancy J. Philp Phd, Christopher M. Snyder

Department of Microbiology and Immunology Faculty Papers

Human cytomegalovirus (CMV) causes a common congenital infection leading to long-term neurological impairments including brain, cochlear, and ocular pathology. Infection of newborn mice with murine (M)CMV is an established model of neuropathology caused by congenital CMV infection, with recent work suggesting that brain pathology may be driven by immune responses. In the eye, however, CMV retinitis is thought to result from virus-driven necrosis in the absence of T cell responses. We found that MCMV infection of newborn mice recapitulates human eye disease after congenital CMV infection, including focal chorioretinitis, inflamed vasculature, and disrupted blood-retinal barriers. Moreover, infection drove extensive T …

Characterization Of Turbo, A Tlr Ligand-Based Adjuvant For Glycoconjugate Vaccines, Kishore R. Alugupalli

Department of Microbiology and Immunology Faculty Papers

Many bacterial polysaccharide vaccines, including the typhoid Vi polysaccharide (ViPS) and tetravalent meningococcal polysaccharide conjugate (MCV4) vaccines, do not incorporate adjuvants and are not highly immunogenic, particularly in infants. I found that endotoxin, a TLR4 ligand in ViPS, contributes to the immunogenicity of typhoid vaccines. Because endotoxin is pyrogenic, and its levels are highly variable in vaccines, I developed monophosphoryl lipid A, a nontoxic TLR4 ligand-based adjuvant named Turbo. Admixing Turbo with ViPS and MCV4 vaccines improved their immunogenicity across all ages and eliminated booster requirement. To understand the characteristics of this adjuvanticity, I compared Turbo with alum. Unlike alum, …

Refining The Optimal Caf Cluster Marker For Predicting Tme-Dependent Survival Expectancy And Treatment Benefits In Nsclc Patients, Kai Li, Rui Wang, Guo-Wei Liu, Zi-Yang Peng, Ji-Chang Wang, Guo-Dong Xiao, Shou-Ching Tang, Ning Du, Jia Zhang, Jing Zhang, Hong Ren, Xin Sun, Yi-Ping Yang, Da-Peng Liu

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

The tumor microenvironment (TME) plays a pivotal role in the onset, progression, and treatment response of cancer. Among the various components of the TME, cancer-associated fibroblasts (CAFs) are key regulators of both immune and non-immune cellular functions. Leveraging single-cell RNA sequencing (scRNA) data, we have uncovered previously hidden and promising roles within this specific CAF subgroup, paving the way for its clinical application. However, several critical questions persist, primarily stemming from the heterogeneous nature of CAFs and the use of different fibroblast markers in various sample analyses, causing confusion and hindrance in their clinical implementation. In this groundbreaking study, we …

Molecular Characterization Of Streptococcus Pneumoniae Causing Disease Among Children In Nigeria During The Introduction Of Pcv10 (Gsk), Stephanie W. Lo, Paulina A. Hawkins, Binta Jibir, Fatimah Hassan-Hanga, Mahmoud Gambo, Rasaq Olaosebikan, Grace Olanipekun, Huda Munir, Nicholas Kocmich, Amy Rezac-Elgohary, Safiya Gambo, Danstan Bagenda, Paul Fey, Robert F. Breiman, Lesley Mcgee, Stephen D. Bentley, Stephen K. Obaro, Community Acquired Pneumonia And Invasive Bacterial Disease Capibd Consortium

Student Papers, Posters & Projects

Streptococcus pneumoniae (pneumococcus) is a leading vaccine-preventable cause of childhood invasive disease. Nigeria has the second highest pneumococcal disease burden globally, with an estimated ~49 000 child deaths caused by pneumococcal infections each year. Ten-valent pneumococcal conjugate vaccine (GSK; PCV10) was introduced in December 2014 in a phased approach. However, few studies have characterized the disease-causing pneumococci from Nigeria. This study assessed the prevalence of serotypes, antibiotic susceptibility and genomic lineages using whole genome sequencing and identified lineages that could potentially escape PCV10 (GSK). We also investigated the potential differences in pneumococcal lineage features between children with and without sickle …

Igg3 Subclass Antibodies Recognize Antigenically Drifted Influenza Viruses And Sars-Cov-2 Variants Through Efficient Bivalent Binding, Marcus J. Bolton, Jefferson J.S. Santos, Claudia P. Arevalo, Trevor Griesman, Megan Watson, Shuk Hang Li, Paul Bates, Holly Ramage, Patrick C. Wilson, Scott E. Hensley

Department of Microbiology and Immunology Faculty Papers

The constant domains of antibodies are important for effector functions, but less is known about how they can affect binding and neutralization of viruses. Here, we evaluated a panel of human influenza virus monoclonal antibodies (mAbs) expressed as IgG1, IgG2, or IgG3. We found that many influenza virus-specific mAbs have altered binding and neutralization capacity depending on the IgG subclass encoded and that these differences result from unique bivalency capacities of the subclasses. Importantly, subclass differences in antibody binding and neutralization were greatest when the affinity for the target antigen was reduced through antigenic mismatch. We found that antibodies expressed …

Species Delineation And Comparative Genomics Within The Campylobacter Ureolyticus Complex, Joel J Maki, Mondraya Howard, Sara Connelly, Matthew Pettengill, Dwight J Hardy, Andrew Cameron

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Campylobacter ureolyticus is an emerging pathogen increasingly appreciated as a common cause of gastroenteritis and extra-intestinal infections in humans. Outside the setting of gastroenteritis, little work has been done to describe the genomic content and relatedness of the species, especially regarding clinical isolates. We reviewed the epidemiology of clinical C. ureolyticus cultured by our institution over the past 10 years. Fifty-one unique C. ureolyticus isolates were identified between January 2010 and August 2022, mostly originating from abscesses and blood cultures. To clarify the taxonomic relationships between isolates and to attribute specific genes with different clinical manifestations, we sequenced 19 available …

Multiple And Consecutive Genome Editing Using I-Gonad And Breeding Enrichment Facilitates The Production Of Genetically Modified Mice, Carolina R Melo-Silva, Cory J Knudson, Lingjuan Tang, Samita Kafle, Lauren E. Springer, Jihae Choi, Christopher M. Snyder, Yajing Wang, Sangwon V. Kim, Luis J. Sigal

Department of Microbiology and Immunology Faculty Papers

Genetically modified (GM) mice are essential tools in biomedical research. Traditional methods for generating GM mice are expensive and require specialized personnel and equipment. The use of clustered regularly interspaced short palindromic repeats (CRISPR) coupled with improved-Genome editing via Oviductal Nucleic Acids Delivery (i-GONAD) has highly increased the feasibility of producing GM mice in research laboratories. However, genetic modification in inbred mouse strains of interest such as C57BL/6 (B6) is still challenging because of their low fertility and embryo fragility. We have successfully generated multiple novel GM mouse strains in the B6 background while attempting to optimize i-GONAD. We found …

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 …

Intestinal Neuropod Cell Gucy2c Regulates Visceral Pain, Joshua R. Barton, Annie K. Londregran, Tyler D. Alexander, Ariana A. Entezari, Shely Bar-Ad, Lan Cheng, Angelo C. Lepore, Adam E. Snook, Manuel Covarrubias, Scott A. Waldman

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Visceral pain (VP) is a global problem with complex etiologies and limited therapeutic options. Guanylyl cyclase C (GUCY2C), an intestinal receptor producing cyclic GMP(cGMP), which regulates luminal fluid secretion, has emerged as a therapeutic target for VP. Indeed, FDA-approved GUCY2C agonists ameliorate VP in patients with chronic constipation syndromes, although analgesic mechanisms remain obscure. Here, we revealed that intestinal GUCY2C was selectively enriched in neuropod cells, a type of enteroendocrine cell that synapses with submucosal neurons in mice and humans. GUCY2Chi neuropod cells associated with cocultured dorsal root ganglia neurons and induced hyperexcitability, reducing the rheobase and increasing the resulting …

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 …

A Rodent Model For Dirofilaria Immitis, Canine Heartworm: Parasite Growth, Development, And Drug Sensitivity In Nsg Mice, Jessica A. Hess, Mark L. Eberhard, Marcelo Segura-Lepe, Kathrin Grundner-Culemann, Barbara Kracher, Jeffrey Shryock, John Harrington, David Abraham

Department of Microbiology and Immunology Faculty Papers

Heartworm disease, caused by Dirofilaria immitis, remains a significant threat to canines and felines. The development of parasites resistant to macrocyclic lactones (ML) has created a significant challenge to the control of the infection. The goal of this study was to determine if mice lacking a functional immune response would be susceptible to D. immitis. Immunodeficient NSG mice were susceptible to the infection, sustaining parasites for at least 15 weeks, with infective third-stage larvae molting and developing into the late fourth-stage larvae. Proteomic analysis of host responses to the infection revealed a complex pattern of changes after infection, with at …

Chlamydia Trachomatis Subverts Alpha-Actinins To Stabilize Its Inclusion, A. Haines, J. Wesolowski, F. Paumet

Department of Microbiology and Immunology Faculty Papers

Chlamydia trachomatis is the leading cause of sexually transmitted bacterial disease and a global health burden. As an obligate intracellular pathogen, Chlamydia has evolved many strategies to manipulate its host and establish its intracellular niche called the inclusion. C. trachomatis reorganizes the host actin cytoskeleton to form scaffolds around the inclusion and reinforce the growing inclusion membrane. To control the kinetics and formation of actin scaffolds, Chlamydia expresses the effector InaC/CT813, which activates the host GTPase RhoA. Here, we have discovered that InaC stabilizes actin scaffolds through the host actin cross-linking proteins α-actinins 1 and 4. We demonstrate that α-actinins …

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, …

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 …

Role Of Hla-I Structural Variants And The Polyreactive Antibodies They Generate In Immune Homeostasis, Mepur H Ravindranath, Fatiha El Hilali, Carly J Amato-Menker, Hajar El Hilali, Senthamil R Selvan, Edward J Filippone

Department of Medicine Faculty Papers

Cell-surface HLA-I molecules consisting of β2-microglobulin (β2m) associated heavy chains (HCs), referred to as Face-1, primarily present peptides to CD8+ T-cells. HCs consist of three α-domains, with selected amino acid sequences shared by all alleles of all six isoforms. The cell-surface HLA undergoes changes upon activation by pathological conditions with the expression of β2m-free HCs (Face-2) resulting in exposure of β2m-masked sequences shared by almost all alleles and the generation of HLA-polyreactive antibodies (Abs) against them. Face-2 may homodimerize or heterodimerize with the same (Face-3) or different alleles (Face-4) preventing exposure of shared epitopes. Non-allo immunized males naturally carry HLA-polyreactive …

Gut Permeability May Be Associated With Periprosthetic Joint Infection After Total Hip And Knee Arthroplasty, Emanuele Chisari, Jeongeun Cho, Marjan Wouthuyzen-Bakker, Javad Parvizi

Rothman Institute Papers

A growing number of recent investigations on the human genome, gut microbiome, and proteomics suggests that the loss of mucosal barrier function, particularly in the gastrointestinal tract, may substantially affect antigen trafficking, ultimately influencing the close bidirectional interaction between the gut microbiome and the immune system. This cross-talk is highly influential in shaping the host immune system function and ultimately affecting the outcome of interventions. We hypothesized that the loss of mucosal barrier in the gut may be associatedto acute and chronic periprosthetic joint infections (PJI). Zonulin, soluble CD14 (sCD14), and lipopolysaccharide (LPS) were tested in plasma as part of …

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 …

Defining The Role Of Powassan Virus In Evading Host Antiviral Immunity (September 2022), Melissa Molho, Phd, Holly Ramage, Phd

Department of Microbiology and Immunology Posters

Background

Powassan Virus (POWV) is an emerging neurotropic flavivirus transmitted to humans through the bite of an infected tick. Currently, there is no specific antiviral treatment nor approved vaccine for POWV. During infection, many interferon-independent host proteins and pathways sense and respond to viral infection. Flaviviruses have evolved multiple mechanisms to counteract host antiviral programs, often with individual viral proteins mediating this antagonism. However, it has not been determined if these mechanisms are conserved across diverse flaviviruses.

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.

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 …

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 …

Four Faces Of Cell-Surface Hla Class-I: Their Antigenic And Immunogenic Divergence Generating Novel Targets For Vaccines, Mepur H Ravindranath, Narendranath M Ravindranath, Senthamil R Selvan, Edward J Filippone, Carly J Amato-Menker, Fatiha El Hilali

Department of Medicine Faculty Papers

Leukocyte cell-surface HLA-I molecules, involved in antigen presentation of peptides to CD8+ T-cells, consist of a heavy chain (HC) non-covalently linked to β2-microglobulin (β2m) (Face-1). The HC amino acid composition varies across all six isoforms of HLA-I, while that of β2m remains the same. Each HLA-allele differs in one or more amino acid sequences on the HC α1 and α2 helices, while several sequences among the three helices are conserved. HCs without β2m (Face-2) are also observed on human cells activated by malignancy, viral transformation, and cytokine or chemokine-mediated inflammation. In the absence of β2m, the monomeric Face-2 exposes immunogenic …

Langerhans Cells And Cdc1s Play Redundant Roles In Mrna-Lnp Induced Protective Anti-Influenza And Anti-Sars-Cov-2 Immune Responses, Sonia Ndeupen, Aurélie Bouteau, Christopher Herbst, Zhen Qin, Sonya Jacobsen, Nicholas E Powers, Zachary Hutchins, Drishya Kurup, Leila Zabihi Diba, Megan Watson, Holly Ramage, Botond Z. Igyártó

Department of Microbiology and Immunology Faculty Papers

Nucleoside modified mRNA combined with Acuitas Therapeutics' lipid nanoparticles (LNPs) has been shown to support robust humoral immune responses in many preclinical animal vaccine studies and later in humans with the SARS-CoV-2 vaccination. We recently showed that this platform is highly inflammatory due to the LNPs' ionizable lipid component. The inflammatory property is key to support the development of potent humoral immune responses. However, the mechanism by which this platform drives T follicular helper (Tfh) cells and humoral immune responses remains unknown. Here we show that lack of Langerhans cells or cDC1s neither significantly affected the induction of PR8 HA …

Anti-Cd40 Antibody Fused To Cd40 Ligand Is A Superagonist Platform For Adjuvant Intrinsic Dc-Targeting Vaccines., Valentina Ceglia, Sandra Zurawski, Monica Montes, Mitchell Kroll, Aurélie Bouteau, Zhiqing Wang, Jerome Ellis, Botond Z Igyártó, Yves Lévy, Gerard Zurawski

Department of Microbiology and Immunology Faculty Papers

CD40 is a potent activating receptor expressed on antigen-presenting cells (APCs) of the immune system. CD40 regulates many aspects of B and T cell immunity via interaction with CD40L expressed on activated T cells. Targeting antigens to CD40 via agonistic anti-CD40 antibody fusions promotes both humoral and cellular immunity, but current anti-CD40 antibody-antigen vaccine prototypes require co-adjuvant administration for significant in vivo efficacy. This may be a consequence of dulling of anti-CD40 agonist activity via antigen fusion. We previously demonstrated that direct fusion of CD40L to anti-CD40 antibodies confers superagonist properties. Here we show that anti-CD40-CD40L-antigen fusion constructs retain strong …