Immunology and Infectious Disease Commons^™

Locoregional Therapies In Immunologically "Cold" Tumors: Opportunities And Clinical Trial Design Considerations, Pavlos Msaouel, Rahul A Sheth

Faculty, Staff and Student Publications

Immunotherapy has revolutionized cancer management, but many tumors, particularly immunologically "cold" tumors, remain resistant to the therapy. The combination of conventional systemic immunotherapies and locoregional interventional radiology approaches is being explored to transform these cold tumors into immunologically active "hot" ones. The present article uses the example of chromophobe renal cell carcinoma (ChRCC), a renal cell carcinoma subtype resistant to current systemic immunotherapies, to address practical and conceptual challenges that have prevented the activation of clinical trials specifically designed for this malignancy to date. The practical framework discussed herein can help overcome logistic and funding limitations and facilitate the development …

Autophagy And Cell Wall Integrity Pathways Coordinately Regulate The Development And Pathogenicity Through Moatg4 Phosphorylation In Magnaporthe Oryzae, Pusheng Guo, Yurong Wang, Jiayun Xu, Zhixiang Yang, Ziqi Zhang, Jinyi Qian, Jiexiong Hu, Ziyi Yin, Leiyun Yang, Muxing Liu, Xinyu Liu, Gang Li, Haifeng Zhang, Ryan Rumsey, Ping Wang, Zhengguang Zhang

School of Medicine Faculty Publications

Autophagy and Cell wall integrity (CWI) signaling are critical stress-responsive processes during fungal infection of host plants. In the rice blast fungus Magnaporthe oryzae, autophagy-related (ATG) proteins phosphorylate CWI kinases to regulate virulence; however, how autophagy interplays with CWI signaling to coordinate such regulation remains unknown. Here, we have identified the phosphorylation of ATG protein MoAtg4 as an important process in the coordination between autophagy and CWI in M. oryzae. The ATG kinase MoAtg1 phosphorylates MoAtg4 to inhibit the deconjugation and recycling of the key ATG protein MoAtg8. At the same time, MoMkk1, a core kinase of CWI, also phosphorylates …

Targeted Repression Of Topa By Crispri Reveals A Critical Function For Balanced Dna Topoisomerase I Activity In The Chlamydia Trachomatis Developmental Cycle, Li Shen, Leiqiong Gao, Abigail R. Swoboda, Scot P. Ouellette

School of Medicine Faculty Publications

Chlamydia trachomatis is an obligate intracellular bacterium that is responsible for the most prevalent bacterial sexually transmitted infection. Changes in DNA topology in this pathogen have been linked to its pathogenicity-associated developmental cycle. Here, evidence is provided that the balanced activity of DNA topoisomerases contributes to controlling Chlamydia developmental processes. Utilizing catalytically inactivated Cas12 (dCas12)-based clustered regularly interspaced short palindromic repeats interference (CRISPRi) technology, we demonstrate targeted knockdown of chromosomal topA transcription in C. trachomatis without detected toxicity of dCas12. Repression of topA impaired the developmental cycle of C. trachomatis mostly through disruption of its differentiation from a replicative form …

Interplay Between Acetylation And Ubiquitination Of Imitation Switch Chromatin Remodeler Isw1 Confers Multidrug Resistance In Cryptococcus Neoformans, Yang Meng, Yue Ni, Zhuoran Li, Tianhang Jiang, Tianshu Sun, Yanjian Li, Xindi Gao, Hailong Li, Chenhao Suo, Chao Li, Sheng Yang, Tian Lan, Guojian Liao, Tongbao Liu, Ping Wang, Chen Ding

School of Medicine Faculty Publications

Cryptococcus neoformans poses a threat to human health, but anticryptococcal therapy is hampered by the emergence of drug resistance, whose underlying mechanisms remain poorly understood. Herein, we discovered that Isw1, an imitation switch chromatin remodeling ATPase, functions as a master modulator of genes responsible for in vivo and in vitro multidrug resistance in C. neoformans. Cells with the disrupted ISW1 gene exhibited profound resistance to multiple antifungal drugs. Mass spectrometry analysis revealed that Isw1 is both acetylated and ubiquitinated, suggesting that an interplay between these two modification events exists to govern Isw1 function. Mutagenesis studies of acetylation and ubiquitination sites …

Gene Editing Of Pigs To Control Influenza A Virus Infections, Taeyong Kwon, Bianca L. Artiaga, Chester D. Mcdowell, Kristin M. Whitworth, Kevin D. Wells, Randall S. Prather, Gustavo Delhon, Mark Cigan, Stephen N. White, Jamie Retallick, Natasha N. Gaudreault, Igor Morozov, Juergen A. Richt

School of Veterinary and Biomedical Sciences: Faculty Publications

Proteolytic activation of the hemagglutinin (HA) glycoprotein by host cellular proteases is pivotal for influenza A virus (IAV) infectivity. Highly pathogenic avian influenza viruses possess the multibasic cleavage site of the HA which is cleaved by ubiquitous proteases, such as furin; in contrast, the monobasic HA motif is recognized and activated by trypsin-like proteases, such as the transmembrane serine protease 2 (TMPRSS2). Here, we aimed to determine the effects of TMPRSS2 on the replication of pandemic H1N1 and H3N2 subtype IAVs in the natural host, the pig. The use of the CRISPR/Cas 9 system led to the establishment of homozygous …

The Development Of A Rabies Virus-Vectored Vaccine Against Borrelia Burgdorferi, Targeting Bbi39, Shantel Rios, Bibek Bhattachan, Kruthi Vavilikolanu, Chrysoula Kitsou, Utpal Pal, Matthias J. Schnell

Department of Microbiology and Immunology Faculty Papers

Lyme disease (LD) is the most common tick-borne illness in the United States (U.S.), Europe, and Asia. Borrelia burgdorferi, a spirochete bacterium transmitted by the tick vector Ixodes scapularis, causes LD in the U.S. If untreated, Lyme arthritis, heart block, and meningitis can occur. Given the absence of a human Lyme disease vaccine, we developed a vaccine using the rabies virus (RABV) vaccine vector BNSP333 and an outer surface borrelial protein, BBI39. BBI39 was previously utilized as a recombinant protein vaccine and was protective in challenge experiments; therefore, we decided to utilize this protective antigen in a rabies virus-vectored vaccine …

Naturally Derived Phenethyl Isothiocyanate Modulates Induction Of Oxidative Stress Via Its N-Acetylated Cysteine Conjugated Form In Malignant Melanoma, Sotiris Kyriakou, Nikoletta Demosthenous, Tom Amery, Kyle J. Stewart, Paul G. Winyard, Rodrigo Franco, Aglaia Pappa, Mihalis I. Panayiotidis

School of Veterinary and Biomedical Sciences: Faculty Publications

Phenethyl isothiocyanate (PEITC) is a secondary metabolic product yielded upon the hydrolysis of gluconasturtiin and it is highly accumulated in the flowers of watercress. The aim of the current study was to assess the role of a naturally derived PEITC-enriched extract in the induction of oxidative stress and to evaluate its anti-melanoma potency through the regulation of its metabolism with the concurrent production of the N-acetyl cysteine conjugated by-product. For this purpose, an in vitro melanoma model was utilized consisting of human primary (A375) cells as well as metastatic (COLO-679) malignant melanoma cells together with non-tumorigenic immortalized keratinocytes (HaCaT). …

Computational Analysis Of Cas Proteins Unlocks New Potential In Hiv-1 Targeted Gene Therapy, Will Dampier, Rachel Berman, Michael Nonnemacher, Brian Wigdahl

Kimmel Cancer Center Faculty Papers

Introduction: The human immunodeficiency virus type 1 (HIV-1) pandemic has been slowed with the advent of anti-retroviral therapy (ART). However, ART is not a cure and as such has pushed the disease into a chronic infection. One potential cure strategy that has shown promise is the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas gene editing system. It has recently been shown to successfully edit and/or excise the integrated provirus from infected cells and inhibit HIV-1 in vitro, ex vivo, and in vivo. These studies have primarily been conducted with SpCas9 or SaCas9. However, additional Cas proteins are …

A Diagnostic Challenge – Tinu Syndrome, Sophia Lee, Md, Claire Kassakian, Md

Poster Presentations

No abstract provided.

Artificial Intelligence, Big Data, And Regulation Of Immunity: Challenges And Opportunities, Bhagirath Singh, Anthony M Jevnikar, Eric Desjardins

Microbiology & Immunology Publications

The immune system is regulated by a complex set of genetic, molecular, and cellular interactions. Rapid advances in the study of immunity and its network of interactions have been boosted by a spectrum of "omics" technologies that have generated huge amounts of data that have reached the status of big data (BD). With recent developments in artificial intelligence (AI), theoretical and clinical breakthroughs could emerge. Analyses of large data sets with AI tools will allow the formulation of new testable hypotheses open new research avenues and provide innovative strategies for regulating immunity and treating immunological diseases. This includes diagnosis and …

Concepts In Animal Parasitology, Chapter 61: Transversotrematidae Witenberg, 1944 (Family): Ectoparasitic Trematodes [Platyhelminthes], Scott C. Cutmore, Thomas H. Cribb

Concepts in Animal Parasitology

An overview of the family Transversotrematidae Witemberg, 1944, a small but biologically significant group of plagiorchiid digenean trematodes (flukes), including discussion of identification, general morphology, life cycles, host range, and the significance of their evolutionary position and biology.

Chapter 61 in Concepts in Animal Parasitology, by Scott C. Cutmore and Thomas H. Cribb. 2024. S. L. Gardner and S. A. Gardner, editors. Zea Books, Lincoln, Nebraska, United States. doi: 10.32873/unl.dc.ciap061

Concepts In Animal Parasitology, Chapter 62: Hirudinea (Subclass): Parasitic Leeches, Alejandro Oceguera-Figueroa, Sebastian Kvist

Concepts in Animal Parasitology

An overview of the parasitic leeches, subclass Hirudinea, including discussion of leeches as parasites, vectors, and hosts, their general morphology, reproduction, zoogeography, classification, phylogeny, medical uses, and preparation of specimens.

Chapter 62 in Concepts in Animal Parasitology, by Alejandro Oceguera-Figueroa and Sebastian Kvist. 2024. S. L. Gardner and S. A. Gardner, editors. Zea Books, Lincoln, Nebraska, United States. doi: 10.32873/unl.dc.ciap062

Immunomodulation In Osteosarcoma: From Therapy To Diagnostics, Ryan Austin Lacinski

Graduate Theses, Dissertations, and Problem Reports (ETD)

Osteosarcoma (OS) is a rare pediatric bone malignancy. Those who develop advanced disease, often in the form of metastasis to the lung, experience poor five-year survival rates near approximately 25%. Considering minimal-to-no therapeutic breakthroughs have occurred for treatment of this disease since the 1980s, efforts to develop new therapeutics are underway. The goal of this dissertation was to initiate the preclinical efforts necessary to reinvigorate the use of immunostimulatory cytokine therapy for the treatment of OS and other solid tumors. This effort would not only include the development of the immunotherapeutic known as IL12ns, but also the clinical diagnostic tools …

Vascular And Metabolic Consequences Of T Cell Aging, David J. Buckley

Kinesiology Dissertations - Archive

Aging is the major non-modifiable risk factor for cardiovascular disease (CVD), which is the leading cause of death in the United States. Many common CVD are diseases of the arteries. Two major hallmarks of arterial aging are 1) increased large artery stiffness and 2) endothelial dysfunction which is characterized by impaired endothelium dependent vasodilation and blunted nitric oxide (NO) bioavailability. Importantly, these adverse alterations in the arteries occur prior to, and are predictors of the onset of overt CVD. Advancing age is also a non-modifiable risk factor for impaired glucose homeostasis and is directly or indirectly associated with almost every …

The Critical Role Of Nac1 In Triple-Negative Breast Cancer Stemness And Immunosuppression, Chrispus Ngule

Theses and Dissertations--Toxicology and Cancer Biology

Triple-negative breast cancer (TNBC) is a highly heterogeneous and the most lethal breast cancer (BC) subtype. We report here a new role of nucleus accumbens associated protein 1 (NAC1) in maintaining stemness signature and features of TNBC and controlling the status of myeloid-derived suppressor cells, which accounts for its role in tumor progression and metastasis. This report demonstrates increased NAC1 amplification in TNBC metastatic samples compared to nonmetastatic tissues. In vitro, NAC1 depletion in TNBC cells suppressed their proliferation, colony formation, migration, and invasion. In vivo, NAC1 knockdown in TNBC cells reduced tumorigenic ability, diminished tumor growth rate, and abolished …

The Influence Of Intracellular Photosymbiosis On The Evolution And Function Of Cnidarian Immunity, Madison A. Emery

Biology Dissertations - Archive

Intracellular photosymbiosis with Symbiodiniaceae is facilitated by cnidarian immunity as it is required for symbiont recognition and is subsequently suppressed to maintain stable intracellular symbiosis. To date, it is unclear how the cnidarian-Symbiodiniaceae symbiosis influences immune gene repertoires, immune gene expression, and disease pathology across its independent evolutions. To address these knowledge gaps, my dissertation approaches studying the cnidarian-Symbiodiniaceae symbiosis through a comparative lens to determine how it shapes immune gene evolution and immune responses in divergent symbiotic cnidarian species. In chapter two I survey eight non-symbiotic and seven symbiotic cnidarians proteomes for four families of pattern recognition receptors (PRRs) …

Malate Dehydrogenase In Parasitic Protozoans: Roles In Metabolism And Potential Therapeutic Applications, Amy L. Springer, Swati Agrawal, Eric P. Chang

Biological Sciences Research

The role of malate dehydrogenase (MDH) in the metabolism of various medically significant protozoan parasites is reviewed. MDH is an NADH-dependent oxidoreductase that catalyzes interconversion between oxaloacetate and malate, provides metabolic intermediates for both catabolic and anabolic pathways, and can contribute to NAD+/NADH balance in multiple cellular compartments. MDH is present in nearly all organisms; isoforms of MDH from apicomplexans (Plasmodium falciparum, Toxoplasma gondii, Cryptosporidium spp.), trypanosomatids (Trypanosoma brucei, T. cruzi) and anaerobic protozoans (Trichomonas vaginalis, Giardia duodenalis) are presented here. Many parasitic species have complex life cycles and depend on the environment …

Revolutionizing Our Understanding Of Specific Platelet-Pathogen Interactions, Hammodah Rawhi Hammodah Alfar

Theses and Dissertations--Molecular and Cellular Biochemistry

Aside from their classical role in maintaining hemostasis, platelets are considered first-line vascular guardians that influence both the innate and adaptive immune systems. This is mediated by either direct interactions with immune cells or through the release of pre-stored cytokines and chemokines upon interacting with pathogens such as viruses. While this establishes platelets as potential players in the response to pathogens, it remains unclear what platelets can do with pathogens and how important that is to immune responses, especially against viruses. Most systemic viremias, such as HIV-1, present with mild thrombocytopenia, which is mediated through several mechanisms such as a …

Investigating The Mechanisms For Priming And Maintaining Tumor Ag Specific Cd8+ T Cell Responses In The Context Of Cd4-Depletion, Delaney E. Ramirez

Dartmouth College Ph.D Dissertations

Achieving durable, systemic CD8+ T cell responses against tumors is an imperative goal in treating cancer. However, suppressive cells, including Foxp3+CD4+ regulatory T cells (Tregs) are widely recognized to inhibit CD8+ T cell activity. For nearly two decades, anti-CD4 treatment has been used to eliminate Tregs and induces durable tumor antigen (Ag) specific CD8+ T cells, despite also depleting Foxp3-negative conventional CD4+ T (Tconv) cells. However, the underlying mechanism of anti-CD4 efficacy is not understood. In Chapter Three, we look beyond Treg depletion and investigate the potential contributions of other factors including homeostatic space, depletion of CD4+ APCs, and presence …

Transcriptional Induction Of Immune Pathway Genes And Subsequent Antibacterial Activity In The Digestive Tract Of The Cat Flea (Ctenocephalides Felis)., Katie A. Weber

College of Graduate Studies: Theses & Dissertations

Fleas (Order Siphonaptera) are ectoparasites that serve as vectors of several human diseases (cat scratch disease, flea-borne spotted fever, murine typhus, and plague). Typically, these pathogens are acquired through the ingestion of a host-derived bloodmeal; thus, the lumen of the gut is the first barrier encountered by imbibed pathogens. During the early stages of infection, microbes come into contact with surrounding midgut epithelial cells which trigger a series of host responses to combat local infection. Specifically, pathogen recognition leads to intracellular signaling and an increase in the production of antimicrobial peptides (AMPs) via the IMD and Toll immune pathways. While …

Coral Scar Investigation: An Application Of Machine Learning And Computational Biology Methods To Understand Coral Holobiont Response To Various Tissue Loss Diseases, Emily W. Van Buren

Biology Dissertations - Archive

Coral disease is one of the biggest challenges facing coral reefs that actively changes biodiversity resulting in coral decline. With the rising threat of diseases, corals require biomarkers that reflect the immune systems and differences between common coral tissue loss diseases to best assist in coral restoration efforts. To obtain these biomarkers, my dissertation leverages two previously published datasets from two tissue loss disease exposure studies to investigate genes that are relevant for coral immune pathways, disease susceptibility, and classification between the diseases. In Chapter 2, I use comparative computational biology tools and protein assays to identify the melanin cascade …

Corals In Crisis: A Transcriptomic Investigation Of Stony Coral Tissue Loss Disease, Kelsey M. Beavers

Biology Dissertations - Archive

Coral reefs face existential threats due to climate change and human activities. The combined effects of ocean warming, overfishing, pollution, and habitat destruction have fundamentally altered the functionality of coral reefs and are driving a drastic increase in the prevalence and severity of coral disease outbreaks. Stony coral tissue loss disease (SCTLD) has emerged one of the most devastating disturbances to Caribbean reef ecosystems on record. Despite notable progress, the cellular mechanisms driving SCTLD pathogenesis remain poorly understood. To address this issue, my dissertation investigates the gene expression, histopathology, immune protein activity, and symbiont community dynamics involved in SCTLD progression …

Characterization Of The Interaction Of Three Domains Of Nlrp2 (Pyd, Lrr, And Nacht) With Ebp1 Protein, Rakshya Bhatta

Graduate Theses/Dissertations

NOD-like receptors (NLRs) are cytoplasmic proteins essential for various immune responses such as reactions to infectious diseases, metabolic and cellular damage, fetal development, and cancer. Among the 22 identified NLR proteins, research has highlighted the significant roles of NLRP2 in fetal development. NLRP2 is also classified as a maternal effect gene and the mutation to this gene can lead to DNA methylation imprinting defects, altered gene expression, and conditions such as recurrent miscarriages (RMs). The protein EBP1, which has been found to have roles in embryonic development has been implicated in the regulation of DNA methylation. Recent studies have also …

How Individuals’ Opinions Influence Society’S Resistance To Epidemics: An Agent-Based Model Approach, Geonsik Yu, Michael J. Garee, Mario Ventresca, Yuehwern Yih

Faculty Publications

Background: Protecting public health from infectious diseases often relies on the cooperation of citizens, especially when self-care interventions are the only viable tools for disease mitigation. Accordingly, social aspects related to public opinion have been studied in the context of the recent COVID-19 pandemic. However, a comprehensive understanding of the effects of opinion-related factors on disease spread still requires further exploration. Methods: We propose an agent-based simulation framework incorporating opinion dynamics within an epidemic model based on the assumption that mass media channels play a leading role in opinion dynamics. The model simulates how opinions about preventive interventions change over …

High Prevalence Of Trypanosoma Cruzi Infection In Raccoons (Procyon Lotor) And Associated Risk To Humans In Central Illinois, Esther Onuselogu

Masters Theses

Chagas disease, caused by the protozoan parasite Trypanosoma cruzi, remains a neglected tropical disease and a growing health threat in the United States. Raccoons (Procyon lotor) often coexist with humans in urban and suburban areas and serve as reservoir hosts for T. cruzi. While T. cruzi is rare in humans and domestic animals in the U.S., it is common in wildlife species, particularly raccoons and Virginia opossums (Didelphis virginiana). This study aimed to assess the prevalence of T. cruzi infection in the raccoon population of Central Illinois and evaluate the risk of transmission to humans. …

Delineating Contributions Of Genotype And Lineage To Lung Cancer Therapy Response, Kassandra Jo Naughton

Theses and Dissertations--Toxicology and Cancer Biology

Non-small cell lung cancer (NSCLC) heterogeneity is a major challenge for determining effective treatment strategies. Adenocarcinomas (ADCs) and squamous cell carcinomas (SCCs) are histologically and epigenetically distinct subtypes of NSCLC. Patients with ADC tumors harboring mutations in both KRAS and LKB1 (aka STK11) have lower survival rates than those with KRAS-only tumors. KRAS/LKB1 tumors are not only aggressive, but also respond poorly to immunotherapy. However, these data are limited to ADCs, and it is unclear if SCCs with this genotype are also resistant to immunotherapy. We developed a mouse model of Kras^mut/Lkb1^mut capable of producing …

Concepts In Animal Parasitology, Chapter 39: Haplosplanchnata Olson Et Al., 2003 (Suborder): Two Hosts With Half The Guts [Platyhelminthes, Trematoda, Digenea, Plagiorchiida], Daniel C. Huston

Concepts in Animal Parasitology

An overview of the suborder Haplosplanchnata Olson et al., 2003, a small, but distinct lineage within the Plagiorchiida. Includes a discussion of the methods of identification, general morphological characteristics, taxonomy, and life cycles.

Chapter 39 in Concepts in Animal Parasitology, by Daniel C. Huston. 2024. S. L. Gardner and S. A. Gardner, editors. Zea Books, Lincoln, Nebraska, United States. doi: 10.32873/unl.dc.ciap039

Concepts In Animal Parasitology, Chapter 47: Summary Of The Digenea (Subclass): Insights And Lessons From A Prominent Parasitologist [Platyhelminthes, Trematoda, Digenea], Robin M. Overstreet

Concepts in Animal Parasitology

An overview of the digenean trematodes (subclass Digenea) including insights and lessons from a prominent parasitologist, Robin M. Overstreet. Includes discussion of general morphology, biology, preparation methods, phylogeny, classification, life cycles, host-digenean relationships, effects on host behavior, hyperparasitism, ecology, digeneans as indicators, and literature on the digeneans.

Chapter 47 in Concepts in Animal Parasitology, by Robin M. Overstreet. 2024. S. L. Gardner and S. A. Gardner, editors. Zea Books, Lincoln, Nebraska, United States. doi: 10.32873/unl.dc.ciap047

Concepts In Animal Parasitology, Chapter 60: Monogenea Van Beneden, 1858 (Class) [Platyhelminthes], Griselda Pulido-Flores

Concepts in Animal Parasitology

An overview of the class Monogenea van Beneden, 1858, mainly ectoparasites of the skin, fins, gills, and urinary bladder of fishes, amphibians, and some reptiles. Includes discussion of their classification (both historical and current), general morphology, life cycles, and taxonomy.

Chapter 60 in Concepts in Animal Parasitology, by Griselda Pulido-Flores. 2024. S. L. Gardner and S. A. Gardner, editors. Zea Books, Lincoln, Nebraska, United States. doi: 10.32873/unl.dc.ciap060

Concepts In Animal Parasitology, Chapter 64: Phthiraptera (Order): Lice [Arthropoda], Lajos Rózsa, Haylee J. Weaver

Concepts in Animal Parasitology

An overview of lice, order Phthiraptera, including discussion of their general morphology, feeding, host range, host distribution, life cycle, macroecology, transmission, effects on hosts and role as vectors, host defenses, conservation, evolutionary origins, phylogeny, lice nuclear genome, taxonomy, and medical implications including their control.

Chapter 64 in Concepts in Animal Parasitology, by Lajos Rózsa and Haylee J. Weaver. 2024. S. L. Gardner and S. A. Gardner, editors. Zea Books, Lincoln, Nebraska, United States. doi: 10.32873/unl.dc.ciap064