Medical Immunology Commons^™

Integrated Mrna Sequence Optimization Using Deep Learning, Haoran Gong, Jianguo Wen, Ruihan Luo, Yuzhou Feng, Jingjing Guo, Hongguang Fu, Xiaobo Zhou

Faculty, Staff and Student Publications

The coronavirus disease of 2019 pandemic has catalyzed the rapid development of mRNA vaccines, whereas, how to optimize the mRNA sequence of exogenous gene such as severe acute respiratory syndrome coronavirus 2 spike to fit human cells remains a critical challenge. A new algorithm, iDRO (integrated deep-learning-based mRNA optimization), is developed to optimize multiple components of mRNA sequences based on given amino acid sequences of target protein. Considering the biological constraints, we divided iDRO into two steps: open reading frame (ORF) optimization and 5' untranslated region (UTR) and 3'UTR generation. In ORF optimization, BiLSTM-CRF (bidirectional long-short-term memory with conditional random …

Antibody-Dependent Enhancement Activity Of A Plant-Made Vaccine Against West Nile Virus, Amber M. Paul, Haiyan Sun, Dhiraj Acharya, Huafang Lai, Junyun He, Fengwei Bai, Qiang Chen

Publications

West Nile virus (WNV) causes annual outbreaks globally and is the leading cause of mosquito-borne disease in Unite States. In the absence of licensed therapeutics, there is an urgent need to develop effective and safe human vaccines against WNV. One of the major safety concerns for WNV vaccine development is the risk of increasing infection by related flaviviruses in vaccinated subjects via antibody-dependent enhancement of infection (ADE). Herein, we report the development of a plant-based vaccine candidate that provides protective immunity against a lethal WNV challenge mice, while minimizes the risk of ADE for infection by Zika (ZIKV) and dengue …

Tlr5 Agonists Enhance Anti-Tumor Immunity And Overcome Resistance To Immune Checkpoint Therapy, Caleb Gonzalez, Sarah Williamson, Seth T Gammon, Sarah Glazer, Joon Haeng Rhee, David Piwnica-Worms

Faculty, Staff and Student Publications

Primary and adaptive resistance to immune checkpoint therapies (ICT) represent a considerable obstacle to achieving enhanced overall survival. Innate immune activators have been actively pursued for their antitumor potential. Herein we report that a syngeneic 4T1 mammary carcinoma murine model for established highly-refractory triple negative breast cancer showed enhanced survival when treated intra-tumorally with either the TLR5 agonist flagellin or CBLB502, a flagellin derivative, in combination with antibodies targeting CTLA-4 and PD-1. Long-term survivor mice showed immunologic memory upon tumor re-challenge and a distinctive immune activating cytokine profile that engaged both innate and adaptive immunity. Low serum levels of G-CSF …

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, …

The Lysosomal Ragulator Complex Activates Nlrp3 Inflammasome In Vivo Via Hdac6, Kohei Tsujimoto, Tatsunori Jo, Daiki Nagira, Hachiro Konaka, Jeong Hoon Park, Shin-Ichiro Yoshimura, Akinori Ninomiya, Fuminori Sugihara, Takehiro Hirayama, Eri Itotagawa, Yusei Matsuzaki, Yuki Takaichi, Wataru Aoki, Shotaro Saita, Shuhei Nakamura, Andrea Ballabio, Shigeyuki Nada, Masato Okada, Hyota Takamatsu, Atsushi Kumanogoh

Duncan NRI Faculty and Staff Publications

The cellular activation of the NLRP3 inflammasome is spatiotemporally orchestrated by various organelles, but whether lysosomes contribute to this process remains unclear. Here, we show the vital role of the lysosomal membrane-tethered Ragulator complex in NLRP3 inflammasome activation. Deficiency of Lamtor1, an essential component of the Ragulator complex, abrogated NLRP3 inflammasome activation in murine macrophages and human monocytic cells. Myeloid-specific Lamtor1-deficient mice showed marked attenuation of NLRP3-associated inflammatory disease severity, including LPS-induced sepsis, alum-induced peritonitis, and monosodium urate (MSU)-induced arthritis. Mechanistically, Lamtor1 interacted with both NLRP3 and histone deacetylase 6 (HDAC6). HDAC6 enhances the interaction between Lamtor1 and NLRP3, resulting …

Infiltrating Cd8+ T Cells Exacerbate Alzheimer’S Disease Pathology In A 3d Human Neuroimmune Axis Model, Jefin Jose, Devam Purohit

VCU's Medical Journal Club: The Work of Future Health Professionals

In this study, Jorfi et al. employed a neuroimmune axis model containing neurons, astrocytes, and microglia to examine the role of immune cells in Alzheimer's disease. Jorfi et al. found that T cells selectively infiltrated the BRAIN compartment of the neuroimmune axis model as compared to B cells and monocytes. Jorfi et al. further found that CD8+ T cells demonstrated heightened cytotoxicity in the Alzheimer's disease brain, illuminating the role of immune cells in neurodegeneration. Upon further examination, the CXCR3-CXCL10 signaling pathway was found to have an important role in inflammation.

A Genome-Wide In Vivo Crispr Screen Identifies Essential Regulators Of T Cell Migration To The Cns In A Multiple Sclerosis Model, Jefin Jose

VCU's Medical Journal Club: The Work of Future Health Professionals

Kendirli et al. (2023) used a CRISPR screen to determine the proteins involved in T cell migration into the CNS in multiple sclerosis. Overall, eighteen facilitators and five brakes to T cell infiltration into the CNS were identified. Kendirli et al. specifically identified ITGA4, FERMT3, and HSP90B1 to make up the adhesion module, CXCR3, GNAI2, and TBX21 to make up the chemotaxis module, and GRK2 and S1PR2 to make up the egress module. This study demonstrated the ability of a CRISPR screen to identify elements in a disease process and thus identify targets for future multiple sclerosis therapies.

Elucidating The Impact Of Western Diet On Bone Marrow Cytokine Signatures: Understanding Poor Outcomes In Susceptibility To Infection And Progression Of Cancer, Lahari Kondeti

Theses, Dissertations and Capstones

Among other disease outcomes, obesity is associated with 1) reduction in long-lasting immune protection and 2) acquisition of cancer. Given our interest in hematopoietic stem and progenitor cell (HSPC) dynamics, we questioned if similar mechanisms in the bone marrow microenvironment contribute to obesity-induced HSPC alterations responsible for 1) decreased immune protection and 2) transformation of HSPCs in the pathogenesis of hematologic malignancies. The negative effects of obesity on immune protection are most notably established in influenza models. Influenza infection susceptibility is increased and influenza vaccine-induced immunity wains in obese individuals. Ongoing studies aim to define mechanisms for waning immunity at …

Isoprenylation Inhibition Suppresses Fcεri-Mediated Mast Cell Function And Allergic Inflammation, Aditya Kotha, Jordan M. Dailey, Aslamuzzaman Kazi, Said Sebti, John J. Ryan

UROP Posters

Allergic disease is driven by cell signaling cascades that activate immune cells. One key player is mast cells, which is activated by IgE antibodies signaling through the high affinity IgE receptor, FceRI. Therefore, targeting FceRI-mediated cascades can offer for novel treatments for allergic disease. Statins have been demonstrated to reduce the severity of asthma, a common allergic airway disease. Statins are an FDA approved class of drugs with the intended purpose of lowering blood cholesterol. We previously found that while statins inhibit mast cell function in allergic disease, these anti-inflammatory effects vary widely amongst differing mouse strains and human donors, …

Covid-19 Vaccine Hesitancy In Asean: Insights From A Multi-Wave Survey Database From July 2020 To March 2021, Kenneth Y. Hartigan-Go, Ronald U. Mendoza, Madeline Mae A. Ong, Jurel K. Yap

Ateneo School of Medicine and Public Health Publications

Objectives

Early studies on COVID-19 vaccine hesitancy showed varied intensity across countries, which was linked to various factors such as socio-economic conditions, information sources, and issues of trust in government, scientific experts, and the health sector. This study aims to evaluate the determinants of vaccine hesitancy to offer insights into the strategies that may be successful in designing communications campaigns for enhanced vaccination uptake.

Methods

Through logistic regression, this study examines correlates of survey data from five Southeast Asian countries, namely Indonesia (ID), Malaysia (MY), Philippines (PH), Thailand (TH), Vietnam (VN) collected by the Massachusetts Institute of Technology Initiative on …

Hmgb2 Regulates The Differentiation And Stemness Of Exhausted Cd8+ T Cells During Chronic Viral Infection And Cancer, Emily N. Neubert, Julia M. Derogatis, Sloan A. Lewis, Karla M. Viramontes, Pedro Ortega, Monique L. Henriquez, Rémi Buisson, Ilhem Messaoudi, Roberto Tinoco

Microbiology, Immunology, and Molecular Genetics Faculty Publications

Chronic infections and cancers evade the host immune system through mechanisms that induce T cell exhaustion. The heterogeneity within the exhausted CD8⁺ T cell pool has revealed the importance of stem-like progenitor (Tpex) and terminal (Tex) exhausted T cells, although the mechanisms underlying their development are not fully known. Here we report High Mobility Group Box 2 (HMGB2) protein expression is upregulated and sustained in exhausted CD8⁺ T cells, and HMGB2 expression is critical for their differentiation. Through epigenetic and transcriptional programming, we identify HMGB2 as a cell-intrinsic regulator of the differentiation and maintenance of Tpex cells during …

Campylobacter Vaccination Reduces Diarrheal Disease And Infant Growth Stunting Among Rhesus Macaques, Sara M. Hendrickson, Archana Thomas, Hans-Peter Raué, Kamm Prongay, Andrew J. Haertel, Nicholas S. Rhoades, Jacob F. Slifka, Lina Gao, Benjamin K. Quintel, Ian J. Amanna, Ilhem Messaoudi, Mark K. Slifka

Microbiology, Immunology, and Molecular Genetics Faculty Publications

Campylobacter-associated enteric disease is estimated to be responsible for more than 160 million cases of gastroenteritis each year and is linked to growth stunting of infants living under conditions of poor sanitation and hygiene. Here, we examine naturally occurring Campylobacter-associated diarrhea among rhesus macaques as a model to determine if vaccination could reduce severe diarrheal disease and infant growth stunting. Compared to unvaccinated controls, there are no Campylobacter diarrhea-associated deaths observed among vaccinated infant macaques and all-cause diarrhea-associated infant mortality is decreased by 76% (P = 0.03). By 9 months of age, there is a 1.3 cm increase in dorsal …

Chronic Alcohol Consumption Dysregulates Innate Immune Response To Sars-Cov-2 In The Lung, Sloan A. Lewis, Isaac R. Cinco, Brianna M. Doratt, Madison B. Blanton, Cherise Hoagland, Natali Newman, Michael Davies, Kathleen A. Grant, Ilhem Messaoudi

Microbiology, Immunology, and Molecular Genetics Faculty Publications

Background Alcohol consumption is widespread with over half of the individuals over 18 years of age in the U.S. reporting alcohol use in the last 30 days. Moreover, 9 million Americans engaged in binge or chronic heavy drinking (CHD) in 2019. CHD negatively impacts pathogen clearance and tissue repair, including in the respiratory tract, thereby increasing susceptibility to infection. Although, it has been hypothesized that chronic alcohol consumption negatively impacts COVID-19 outcomes; the interplay between chronic alcohol use and SARS-CoV-2 infection outcomes has yet to be elucidated.

Methods In this study we employed luminex, scRNA sequencing, and flow cytometry to …

Monoclonal Antibody Therapy Of Breastfeeding Patient Infected With Sars-Cov-2: A Case Report, Nicole E. Marshall, Madison B. Blanton, Brianna M. Doratt, Delphine C. Malherbe, Monica Rincon, Ilhem Messaoudi

Microbiology, Immunology, and Molecular Genetics Faculty Publications

Introduction: Although safety data demonstrated the efficacy and effectiveness of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination for all individuals over 6 months of age, including pregnant and breastfeeding individuals, optimal treatment courses for symptomatic pregnant and lactating individuals infected with SARS-CoV-2 remain to be defined. Case Description: A coronavirus disease 2019 (COVID-19)-vaccinated breastfeeding woman received anti-SARS-CoV-2 monoclonal antibody treatment casirivimab–imdevimab 5 days after diagnosis of a symptomatic breakthrough SARS-CoV-2 infection. Results and Conclusions: The patient did not present with obvious defects in innate or adaptive cellular subsets, but compared with controls had minimal maternal antibody response to recommended …

Mild/Asymptomatic Covid-19 In Unvaccinated Pregnant Mothers Impairs Neonatal Immune Responses, Brianna M. Doratt, Suhas Sureshchandra, Heather E. True, Monica Rincon, Nicole E. Marshall, Ilhem Messaoudi

Microbiology, Immunology, and Molecular Genetics Faculty Publications

Maternal SARS-CoV-2 infection triggers placental inflammation and alters cord blood immune cell composition. However, most studies focus on outcomes of severe maternal infection. Therefore, we analyzed cord blood and chorionic villi from newborns of unvaccinated mothers who experienced mild/asymptomatic SARS-CoV-2 infection during pregnancy. We investigated immune cell rewiring using flow cytometry, single-cell RNA sequencing, and functional readouts using ex vivo stimulation with TLR agonists and pathogens. Maternal infection was associated with increased frequency of memory T and B cells and nonclassical monocytes in cord blood. Ex vivo T and B cell responses to stimulation were attenuated, suggesting a tolerogenic state. …

Integrated Single Cell Analysis Shows Chronic Alcohol Drinking Disrupts Monocyte Differentiation In The Bone Marrow, Sloan A. Lewis, Brianna M. Doratt, Qi Qiao, Madison B. Blanton, Kathleen A. Grant, Ilhem Messaoudi

Microbiology, Immunology, and Molecular Genetics Faculty Publications

Chronic heavy alcohol drinking (CHD) rewires monocytes and macrophages toward heightened inflammatory states with compromised antimicrobial defenses that persist after 1-month abstinence. To determine whether these changes are mediated through alterations in the bone marrow niche, we profiled monocytes and hematopoietic stem cell progenitors (HSCPs) from CHD rhesus macaques using a combination of functional assays and single cell genomics. CHD resulted in transcriptional profiles consistent with increased activation and inflammation within bone marrow resident monocytes and macrophages. Furthermore, CHD resulted in transcriptional signatures associated with increased oxidative and cellular stress in HSCP. Differentiation of HSCP in vitro revealed skewing toward …

Multimodal Profiling Of Term Human Decidua Demonstrates Immune Adaptations With Pregravid Obesity, Suhas Sureshchandra, Brianna M. Doratt, Heather E. True, Norma Mendoza, Monica Rincon, Nicole E. Marshall, Ilhem Messaoudi

Microbiology, Immunology, and Molecular Genetics Faculty Publications

Leukocyte diversity of the first-trimester maternal-fetal interface has been extensively described; however, the immunological landscape of the term decidua remains poorly understood. We therefore profiled human leukocytes from term decidua collected via scheduled cesarean delivery. Relative to the first trimester, our analyses show a shift from NK cells and macrophages to T cells and enhanced immune activation. Although circulating and decidual T cells are phenotypically distinct, they demonstrate significant clonotype sharing. We also report significant diversity within decidual macrophages, the frequency of which positively correlates with pregravid maternal body mass index. Interestingly, the ability of decidual macrophages to respond to …

Therapeutic Neutralizing Monoclonal Antibody Administration Protects Against Lethal Yellow Fever Virus Infection, Michael J. Ricciardi, Lauren N. Rust, Nuria Pedreño-Lopez, Sofiya Yusova, Sreya Biswas, Gabriela M. Webb, Lucas Gonzalez-Nieto, Thomas B. Voigt, Johan J. Louw, Fernanda D. Laurino, John R. Dibello, Hans-Peter Raué, Aaron M. Barber-Axthelm, Kimberly Chun, Samantha Uttke, Lidiane M. S. Raphael, Aaron Yrizarry-Medina, Brandon C. Rosen, Rebecca Agnor, Lina Gao, Caralyn Labriola, Michael Axthelm, Jeremy Smedley, Justin G. Julander, Myrna C. Bonaldo, Laura M. Walker, Ilhem Messaoudi, Mark K. Slifka, Dennis R. Burton, Esper G. Kallas, Jonah B. Sacha, David I. Watkins, Benjamin J. Burwitz

Microbiology, Immunology, and Molecular Genetics Faculty Publications

Yellow fever virus (YFV) is a reemerging global health threat, driven by several factors, including increased spread of the mosquito vector and rapid urbanization. Although a prophylactic vaccine exists, vaccine hesitancy, supply deficits, and distribution difficulties leave specific populations at risk of severe YFV disease, as evidenced by recent outbreaks in South America. To establish a treatment for patients with severe YFV infection, we tested 37 YFV-specific monoclonal antibodies isolated from vaccinated humans and identified two capable of potently neutralizing multiple pathogenic primary YFV isolates. Using both hamster and nonhuman primate models of lethal YFV infection, we demonstrate that a …

Vitamin D Enhanced Vitamin D Receptor (Vdr) Inhibition Of Nlrp3 Inflammasome Activation Can Attenuate The Development Of Autoimmune Thyroiditis, Alexzon Mandac

Capstone Showcase

Autoimmune Thyroiditis (AIT) is a prevalent autoimmune disease affecting approximately 2% of the population. Characterized by the gradual loss of thyroid function through an autoimmune attack on the thyroid gland, the disease manifests symptoms that negatively affect one’s quality of life. The mechanisms behind the disease’s pathophysiology are not fully understood; however, researchers are examining the involvement of the NLRP3 inflammasome in the disease. This thesis will address the question of whether Vitamin D can act as an inhibitor of the NLRP3 inflammasome and attenuate the progression of AIT in mouse model. Current investigations explore the effects of NLRP3 inhibition …

Can Testing The Environment For Severe Acute Respiratory Coronavirus Virus 2 (Sars-Cov-2) Be A Signal For Coronavirus Disease 2019 (Covid-19) Cases Among Nursing Home Staff?, Gabrielle M. Gussin, Raveena D. Singh, Izabela Coimbra Ibraim, Raheeb Saavedra, Thomas T. Tjoa, Micaila Curtis, Kristine P. Nguyen, Ilhem Messaoudi, Susan S. Huang

Microbiology, Immunology, and Molecular Genetics Faculty Publications

Prior to widespread COVID-19 vaccination, nursing homes were required to perform comprehensive weekly testing of staff. After the vaccine became available, testing became symptom-based for vaccinated staff despite continued waves of different severe acute respiratory coronavirus virus 2 (SARS-CoV-2) variants. Nursing homes need pragmatic, affordable strategies to identify SARS-CoV-2–positive staff because financial and job-related pressures drive reluctance to disclose mild symptoms. We sought to determine whether positive environmental samples for SARS-CoV-2 could serve as trigger for comprehensive staff testing in lieu of weekly testing of all staff.