Medical Immunology Commons^™

Intranasal Sensitization Model Of Alopecia Areata Using Pertussis Toxin As Adjuvant, Yuying Liu, Jasmin Freeborn, Beanna Okeugo, Shabba A Armbrister, Zeina M Saleh, Ana Beatriz Fadhel Alvarez, Thomas K Hoang, Evelyn S Park, John William Lindsey, Ronald P Rapini, Steven Glazer, Keith Rubin, Jon Marc Rhoads

Faculty, Staff and Student Publications

Background: Nasopharyngeal Bordetella pertussis (BP) colonization is common, with about 5% of individuals having PCR evidence of subclinical BP infection on nasal swab, even in countries with high vaccination rates. BP secretes pertussis toxin (PTx). PTx is an adjuvant commonly used to induce autoimmunity in multiple animal models of human disease. Colocalization of PTx and myelin from myelinated nerves in the nasopharynx may lead to host sensitization to myelin with subsequent autoimmune pathology.

Methods: C57BL/6J female adult mice were given varied doses and schedules of intranasal PTx, MOG35-55 antigen, or controls to test whether intranasal administration of PTx and myelin …

Hypoxia-Adenosine Axis As Therapeutic Targets For Acute Respiratory Distress Syndrome, Katherine Figarella, Jieun Kim, Wei Ruan, Tingting Mills, Holger Klaus Eltzschig, Xiaoyi Yuan

Faculty, Staff and Student Publications

The human respiratory and circulatory systems collaborate intricately to ensure oxygen delivery to all cells, which is vital for ATP production and maintaining physiological functions and structures. During limited oxygen availability, hypoxia-inducible factors (HIFs) are stabilized and play a fundamental role in maintaining cellular processes for hypoxia adaptation. First discovered during investigations of erythropoietin production regulation, HIFs influence physiological and pathological processes, including development, inflammation, wound healing, and cancer. HIFs promote extracellular adenosine signaling by enhancing adenosine generation and receptor signaling, representing an endogenous feedback mechanism that curbs excessive inflammation, supports injury resolution, and enhances hypoxia tolerance. This is especially …

Clinical Utility Of Plasma Microbial Cell-Free Dna Sequencing In Determining Microbiologic Etiology Of Infectious Syndromes In Solid Organ Transplant Recipients, Jesal R Shah, Muhammad Rizwan Sohail, Todd Lasco, John A Goss, Mayar Al Mohajer, Sarwat Khalil

Faculty, Staff and Students Publications

BACKGROUND: Metagenomic next-generation sequencing (mNGS) is increasingly being used for microbial detection in various infectious syndromes. However, data regarding the use of mNGS in solid organ transplant recipients (SOTR) are lacking.

OBJECTIVES: To describe and analyze real-world clinical impact of mNGS using plasma microbial cell-free DNA (mcfDNA) in SOTR.Design: Retrospectively reviewed all adult SOTR who underwent mNGS testing using plasma mcfDNA at Baylor St Luke's Medical Center from March 2017 to February 2023.

METHODS: Clinical impact (positive, neutral, and negative) was assessed using standardized objective criteria. Three Infectious Diseases physicians independently performed clinical adjudication to determine the correlation of mcfDNA …

Bridging The Gap: Assessing Cmv Dnaemia In Kidney Transplant Recipients With Previous Solid Organ Transplants, Goni Katz-Greenberg, Julie M Steinbrink, Krishna Shah, Jennifer S Byrns

Faculty, Staff and Students Publications

Cytomegalovirus (CMV) infection poses a significant threat to solid organ transplant (SOT) recipients and can lead to various complications and adverse outcomes. In an effort to prevent CMV infection, it is common to utilize prophylactic strategies, including antiviral medications such as valganciclovir, especially for high-risk patients. Risk factors for CMV infection in kidney transplant recipients (KTRs) include CMV mismatch between donor and recipient (i.e., donor positive, recipient negative), and intensity of immunosuppression, such as the use of T-cell depleting agents. However, little attention has been given to KTRs with a history of prior SOTs, despite their prolonged exposure to immunosuppressive …

Clinical Evaluation Of A Fully Electronic Microfluidic White Blood Cell Analyzer, Jianye Sui, Zhongtian Lin, Shahriar Azizpour, Fei Chen, Sunanda Gaur, Kelly Keene, Farzad Soleimani, Tanaya Bhowmick, Zubaid Rafique, Mehdi Javanmard

Faculty, Staff and Students Publications

The White Blood Cell (WBC) count is one of the key parameters signaling the health of the immune system. Abnormal WBC counts often signal a systemic insult to the body such as an underlying infection or an adverse side effect to medication. Typically, the blood collected is sent to a central lab for testing, and results come back within hours, which is often inconvenient and may delay time-sensitive diagnosis or treatment. Here, we present the CytoTracker, a fully electronic, microfluidic based instant WBC analyzer with the potential to be used at point-of-care. The CytoTracker is a lightweight, portable, affordable platform …

Early Immune Factors Associated With The Development Of Post-Acute Sequelae Of Sars-Cov-2 Infection In Hospitalized And Non-Hospitalized Individuals, Jacqueline M Leung, Michelle J Wu, Pouya Kheradpour, Chen Chen, Katherine A Drake, Gary Tong, Vanessa K Ridaura, Howard C Zisser, William A Conrad, Natalia Hudson, Jared Allen, Christopher Welberry, Celine Parsy-Kowalska, Isabel Macdonald, Victor F Tapson, James N Moy, Christopher R Defilippi, Ivan O Rosas, Mujeeb Basit, Jerry A Krishnan, Sairam Parthasarathy, Bellur S Prabhakar, Mirella Salvatore, Charles C Kim

Faculty, Staff and Students Publications

BACKGROUND: Infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can lead to post-acute sequelae of SARS-CoV-2 (PASC) that can persist for weeks to years following initial viral infection. Clinical manifestations of PASC are heterogeneous and often involve multiple organs. While many hypotheses have been made on the mechanisms of PASC and its associated symptoms, the acute biological drivers of PASC are still unknown.

METHODS: We enrolled 494 patients with COVID-19 at their initial presentation to a hospital or clinic and followed them longitudinally to determine their development of PASC. From 341 patients, we conducted multi-omic profiling on peripheral blood …

Translational And Oncologic Significance Of Tertiary Lymphoid Structures In Pancreatic Adenocarcinoma, Zachary Gao, Joseph Azar, Huili Zhu, Sophia Williams-Perez, Sung Wook Kang, Celia Marginean, Mark P Rubinstein, Shalini Makawita, Hyun-Sung Lee, E Ramsay Camp

Faculty, Staff and Students Publications

Pancreatic adenocarcinoma (PDAC) is an aggressive tumor with poor survival and limited treatment options. PDAC resistance to immunotherapeutic strategies is multifactorial, but partially owed to an immunosuppressive tumor immune microenvironment (TiME). However, the PDAC TiME is heterogeneous and harbors favorable tumor-infiltrating lymphocyte (TIL) populations. Tertiary lymphoid structures (TLS) are organized aggregates of immune cells that develop within non-lymphoid tissue under chronic inflammation in multiple contexts, including cancers. Our current understanding of their role within the PDAC TiME remains limited; TLS are complex structures with multiple anatomic features such as location, density, and maturity that may impact clinical outcomes such as …

Structure And Funding Of Clinical Informatics Fellowships: A National Survey Of Program Directors, Tushar N Patel, Aaron J Chaise, John J Hanna, Kunal P Patel, Karl M Kochendorfer, Richard J Medford, Dara E Mize, Edward R Melnick, Jonathan D Hron, Kenneth Youens, Deepti Pandita, Michael G Leu, Gregory A Ator, Feliciano Yu, Nicholas Genes, Carrie K Baker, Douglas S Bell, Joshua M Pevnick, Steven A Conrad, Aarti R Chandawarkar, Kendall M Rogers, David C Kaelber, Ila R Singh, Bruce P Levy, John T Finnell, Joseph Kannry, Natalie M Pageler, Vishnu Mohan, Christoph U Lehmann

Faculty, Staff and Students Publications

BACKGROUND: In 2011, the American Board of Medical Specialties established clinical informatics (CI) as a subspecialty in medicine, jointly administered by the American Board of Pathology and the American Board of Preventive Medicine. Subsequently, many institutions created CI fellowship training programs to meet the growing need for informaticists. Although many programs share similar features, there is considerable variation in program funding and administrative structures.

OBJECTIVES: The aim of our study was to characterize CI fellowship program features, including governance structures, funding sources, and expenses.

METHODS: We created a cross-sectional online REDCap survey with 44 items requesting information on program administration, …

Faslpr Gene Dosage Tunes The Extent Of Lymphoproliferation And T Cell Differentiation In Lupus, Ritu Bohat, Xiaofang Liang, Yanping Chen, Chunyu Xu, Ningbo Zheng, Ashley Guerrero, Jiakai Hou, Roshni Jaffery, Nicholas A Egan, Yaxi Li, Yitao Tang, Esra Unsal, Adolfo Robles, Si Chen, Angela M Major, Hadil Elldakli, Sang-Hyuk Chung, Han Liang, M John Hicks, Yong Du, Jamie S Lin, Xiqun Chen, Chandra Mohan, Weiyi Peng

Faculty, Staff and Student Publications

Sle1 and Fas^lpr are two lupus susceptibility loci that lead to manifestations of systemic lupus erythematosus. To evaluate the dosage effects of Fas^lpr in determining cellular and serological phenotypes associated with lupus, we developed a new C57BL/6 (B6) congenic lupus strain, B6.Sle1/Sle1.Fas^lpr/+ (Sle1homo.lprhet) and compared it with B6.Fas^lpr/lpr (lprhomo), B6.Sle1/Sle1 (Sle1homo), and B6.Sle1/Sle1.Fas^lpr/lpr (Sle1homo.lprhomo) strains. Whereas Sle1homo.lprhomo mice exhibited profound lymphoproliferation and early mortality, Sle1homo.lprhet mice had a lifespan comparable to B6 mice, with no evidence of splenomegaly or lymphadenopathy. Compared to B6 monogenic lupus strains, Sle1homo.lprhet mice exhibited significantly …

Childhood And Adolescent Relapsed/Refractory Aggressive B-Cell Lymphomas With T(8;14) And Bcl2 Expression, Burkitt Lymphoma Versus Diffuse Large B-Cell Lymphoma: A Diagnostic Challenge, Fouad El Dana, Sofia Alexandra Garces Narvaez, Nader K El-Mallawany, Jennifer E Agrusa, Zoann E Dreyer, Andrea N Marcogliese, Mohamed Tarek Elghetany, Jyotinder N Punia, Chi Young Ok, Keyur P Patel, Dolores H Lopez-Terrada, Kevin E Fisher, Choladda V Curry

Faculty, Staff and Students Publications

We present 2 diagnostically challenging cases of pediatric/adolescent relapsed/refractory aggressive mature B-cell non-Hodgkin lymphoma (B-NHL) within the spectrum of Burkitt lymphoma and diffuse large B-cell lymphoma and illustrate the different therapeutic regimens that are employed for pediatric and adult cancer centers. Both cases displayed varying-sized lymphoma cells with occasional single prominent nucleoli and heterogeneous BCL2 expression. Cytogenetics revealed complex karyotypes with t(8:14)(q24.2;q32) and IGH::MYC rearrangement by FISH. Next generation sequencing revealed deleterious TP53 and MYC mutations. We concluded that both could be diagnosed as “DLBCL-NOS with MYC rearrangement” using the current pathologic classifications, 2022 International Consensus Classification (ICC) and World …

A Novel System To Culture Human Intestinal Organoids Under Physiological Oxygen Content To Study Microbial-Host Interaction, Tatiana Y Fofanova, Umesh C Karandikar, Jennifer M Auchtung, Reid L Wilson, Antonio J Valentin, Robert A Britton, K Jane Grande-Allen, Mary K Estes, Kristi Hoffman, Sashirekha Ramani, Christopher J Stewart, Joseph F Petrosino

Faculty, Staff and Students Publications

Mechanistic investigation of host-microbe interactions in the human gut are hindered by difficulty of co-culturing microbes with intestinal epithelial cells. On one hand the gut bacteria are a mix of facultative, aerotolerant or obligate anaerobes, while the intestinal epithelium requires oxygen for growth and function. Thus, a coculture system that can recreate these contrasting oxygen requirements is critical step towards our understanding microbial-host interactions in the human gut. Here, we demonstrate Intestinal Organoid Physoxic Coculture (IOPC) system, a simple and cost-effective method for coculturing anaerobic intestinal bacteria with human intestinal organoids (HIOs). Using commensal anaerobes with varying degrees of oxygen …

Applying Market Basket Analysis To Determine Complex Coassociations Among Food Allergens In Children With Food Protein-Induced Enterocolitis Syndrome (Fpies), Ankona Banerjee, Kenneth Nobleza, Cynthia Haddad, Joshua Eubanks, Ruchit Rana, Nicholas L Rider, Lisa Pompeii, Duc Nguyen, Sara Anvari

Faculty, Staff and Students Publications

BACKGROUND: Food protein-induced enterocolitis syndrome (FPIES) is a non-IgE-mediated food allergy, characterized by delayed onset of repetitive vomiting occurring 1 to 4 h following ingestion of a food allergen. Managing FPIES requires strict avoidance of the food trigger. The concern with FPIES is determining the risk of another FPIES food trigger reaction due to potential coassociations with other foods or food groups. An effective statistical approach for analyzing FPIES-related data is essential to identify common coallergens and their associations.

METHODS: This study employed Market Basket Analysis, a data-mining technique, to examine correlations and patterns among allergens in FPIES patients at …

Case Report: P40phox Deficiency Underlying Pediatric-Onset Systemic Lupus Erythematosus, Alejandro Nieto-Patlán, Natalia S Fernández Dávila, Yuqing Wang, Michelle Zelnick, Eyal Muscal, Martha Curry, James R Lupski, Steven M Holland, Bo Yuan, Douglas B Kuhns, Tiphanie P Vogel, Ivan K Chinn

Faculty, Staff and Students Publications

Introduction

Systemic lupus erythematosus is a multi-faceted autoimmune disorder of complex etiology. Pre-pubertal onset of pediatric systemic lupus erythematosus (pSLE) is uncommon and should raise suspicion for a genetic driver of disease. Autosomal recessive p40^phox deficiency is a rare immunologic disorder characterized by defective but not abolished NADPH oxidase activity with residual production of reactive oxygen species (ROS) by phagocytic cells.

Case presentation

We report the case of a now 18-year-old female with pSLE onset at 7 years of age. She presented with recurrent fever and malar rash. Aspects of her immune dysregulation over time have included typical pSLE …

Spatial Transcriptomics Resolve An Emphysema-Specific Lymphoid Follicle B Cell Signature In Chronic Obstructive Pulmonary Disease, Joselyn Rojas-Quintero, Scott A Ochsner, Felicia New, Prajan Divakar, Chen Xi Yang, Tianshi David Wu, Jerid Robinson, Darshan Shimoga Chandrashekar, Nicholas E Banovich, Ivan O Rosas, Maor Sauler, Farrah Kheradmand, Amit Gaggar, Camilla Margaroli, Raul San Jose Estepar, Neil J Mckenna, Francesca Polverino

Faculty, Staff and Students Publications

Rationale

Within chronic obstructive pulmonary disease (COPD), emphysema is characterized by a significant yet partially understood B cell immune component.

Objectives

To characterize the transcriptomic signatures from lymphoid follicles (LFs) in ever-smokers without COPD and patients with COPD with varying degrees of emphysema.

Methods

Lung sections from 40 patients with COPD and ever-smokers were used for LF proteomic and transcriptomic spatial profiling. Formalin- and O.C.T.-fixed lung samples obtained from biopsies or lung explants were assessed for LF presence. Emphysema measurements were obtained from clinical chest computed tomographic scans. High-confidence transcriptional target intersection analyses were conducted to resolve emphysema-induced transcriptional networks. …

Development Of A Mini Pig Model Of Peanut Allergy, Akhilesh Kumar Shakya, Brittany Backus, Lazar D Nesovic, Malini Mallick, Olivia Banister, Carla M Davis, Sara Anvari, Harvinder Singh Gill

Faculty, Staff and Students Publications

INTRODUCTION: The prevalence of peanut allergies is increasing, emphasizing the need for an animal model to enhance our understanding of peanut allergy pathogenesis and to advance diagnostic tools and therapeutic interventions. While mice are frequently used as model organisms, their allergic responses do not fully mirror those observed in humans, warranting the exploration of a higher animal model. The porcine gastrointestinal system closely resembles that of humans, and exhibits allergy symptoms akin to human responses, making pigs a promising model for peanut allergy research.

METHODS: In this study we compared two allergen sensitization protocols involving either topical allergen application after …

Detection Of Invasive Bartonella Infections With Next-Generation Sequencing Of Microbial Cell-Free Dna, Fernando H Centeno, Ahmed M Hamdi, Todd M Lasco, Mayar Al Mohajer

Faculty, Staff and Students Publications

We report 9 patients with invasive Bartonella infections, including 5 with endocarditis, who were diagnosed with microbial cell-free DNA next-generation sequencing and Bartonella serology studies. Diagnosis with plasma mcfDNA NGS enabled a faster clinical and laboratory diagnosis in 8 patients. Prompt diagnosis impacted antibiotic management in all 9 patients.

A Case Report Navigating Cvid And Sarcoidosis Overlaps In Pediatric Nephritis, Amanda Salih, Amanda Brown, Amanda Grimes, Sana Hasan, Manuel Silva-Carmona, Leyat Tal, Joud Hajjar

Faculty, Staff and Students Publications

Common variable immunodeficiency (CVID) can be complicated by granulomatous disease, often granulomatous lymphocytic interstitial lung disease (GLILD). Granulomatous interstitial nephritis represents an atypical presentation in pediatrics. Our patient is a previously healthy 13-year-old white male with a recent diagnosis of CVID. He presented with a rash and laboratory findings included pancytopenia (white blood cells 2.6 cells × 103/μl, hemoglobin 11.8 g/dl, platelets 60 × 103/μl), hypercalcemia (14.9 mg/dl), elevated Vit D 1,25 OH level (>200 pg/ml), hyperuricemia (8.8 mg/dl), and acute kidney injury (AKI) (serum creatinine 1.1 mg/dl; baseline 0.64 mg/dl). A broad infectious workup was unremarkable. The rash …

Artificial Intelligence-Powered Discovery Of Small Molecules Inhibiting Ctla-4 In Cancer, Navid Sobhani, Dana Rae Tardiel-Cyril, Dafei Chai, Daniele Generali, Jian-Rong Li, Jonathan Vazquez-Perez, Jing Ming Lim, Rachel Morris, Zaniqua N Bullock, Aram Davtyan, Chao Cheng, William K Decker, Yong Li

Faculty, Staff and Students Publications

BACKGROUND/OBJECTIVES: Checkpoint inhibitors, which generate durable responses in many cancer patients, have revolutionized cancer immunotherapy. However, their therapeutic efficacy is limited, and immune-related adverse events are severe, especially for monoclonal antibody treatment directed against cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), which plays a pivotal role in preventing autoimmunity and fostering anticancer immunity by interacting with the B7 proteins CD80 and CD86. Small molecules impairing the CTLA-4/CD80 interaction have been developed; however, they directly target CD80, not CTLA-4.

SUBJECTS/METHODS: In this study, we performed artificial intelligence (AI)-powered virtual screening of approximately ten million compounds to identify those targeting CTLA-4. We validated the …

Timigp: An R Package To Depict The Tumor Microenvironment From Bulk Transcriptomics, Chenyang Li, Jianjun Zhang, Chao Cheng

Faculty, Staff and Students Publications

Exploring the clinical relevance of diverse immune cell types within the tumor microenvironment is pivotal for unraveling cancer intricacies and developing treatments. Here, we present a protocol for using tumor immune microenvironment illustration based on gene pairs, an R package to deduce cell-cell interactions, unveiling the association between immune cell relative abundance and patient prognoses from bulk gene expression and survival data. We describe steps for harnessing cell-type markers derived from single-cell RNA sequencing data to map the tumor immune microenvironment across a spectrum of cancer types. For complete details on the use and execution of this protocol, please refer …

Formate Supplementation Enhances Antitumor Cd8+ T-Cell Fitness And Efficacy Of Pd-1 Blockade, Jared H Rowe, Ilaria Elia, Osmaan Shahid, Emily F Gaudiano, Natalia E Sifnugel, Sheila Johnson, Amy G Reynolds, Megan E Fung, Shakchhi Joshi, Martin W Lafleur, Joon Seok Park, Kristen E Pauken, Joshua D Rabinowitz, Gordon J Freeman, Marcia C Haigis, Arlene H Sharpe

Faculty, Staff and Student Publications

UNLABELLED: The tumor microenvironment (TME) restricts antitumor CD8+ T-cell function and immunotherapy responses. Cancer cells compromise the metabolic fitness of CD8+ T cells within the TME, but the mechanisms are largely unknown. Here we demonstrate that one-carbon (1C) metabolism is enhanced in T cells in an antigen-specific manner. Therapeutic supplementation of 1C metabolism using formate enhances CD8+ T-cell fitness and antitumor efficacy of PD-1 blockade in B16-OVA tumors. Formate supplementation drives transcriptional alterations in CD8+ T-cell metabolism and increases gene signatures for cellular proliferation and activation. Combined formate and anti-PD-1 therapy increases tumor-infiltrating CD8+ T cells, which are essential for …

The Dna Glycosylase Neil2 Is Protective During Sars-Cov-2 Infection, Nisha Tapryal, Anirban Chakraborty, Kaushik Saha, Azharul Islam, Lang Pan, Koa Hosoki, Ibrahim M Sayed, Jason M Duran, Joshua Alcantara, Vanessa Castillo, Courtney Tindle, Altaf H Sarker, Maki Wakamiya, Victor J Cardenas, Gulshan Sharma, Laura E Crotty Alexander, Sanjiv Sur, Debashis Sahoo, Gourisankar Ghosh, Soumita Das, Pradipta Ghosh, Istvan Boldogh, Tapas K Hazra

Faculty, Staff and Students Publications

SARS-CoV-2 infection-induced aggravation of host innate immune response not only causes tissue damage and multiorgan failure in COVID-19 patients but also induces host genome damage and activates DNA damage response pathways. To test whether the compromised DNA repair capacity of individuals modulates the severity of COVID-19 infection, we analyze DNA repair gene expression in publicly available patient datasets and observe a lower level of the DNA glycosylase NEIL2 in the lungs of severely infected COVID-19 patients. This observation of lower NEIL2 levels is further validated in infected patients, hamsters and ACE2 receptor-expressing human A549 (A549-ACE2) cells. Furthermore, delivery of recombinant …

Enhanced Cd19 Activity In B Cells Contributes To Immunodeficiency In Mice Deficient In The Icf Syndrome Gene Zbtb24, Zhengzhou Ying, Swanand Hardikar, Joshua B Plummer, Tewfik Hamidi, Bin Liu, Yueping Chen, Jianjun Shen, Yunxiang Mu, Kevin M Mcbride, Taiping Chen

Faculty, Staff and Student Publications

Immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome is a rare autosomal recessive disorder characterized by DNA hypomethylation and antibody deficiency. It is caused by mutations in DNMT3B, ZBTB24, CDCA7, or HELLS. While progress has been made in elucidating the roles of these genes in regulating DNA methylation, little is known about the pathogenesis of the life-threatening hypogammaglobulinemia phenotype. Here, we show that mice deficient in Zbtb24 in the hematopoietic lineage recapitulate the major clinical features of patients with ICF syndrome. Specifically, Vav-Cre-mediated ablation of Zbtb24 does not affect lymphocyte development but results in reduced plasma cells and low levels …

Pediatric Hiv+ Kaposi Sarcoma Exhibits Clinical, Virological, And Molecular Features Different From The Adult Disease, Carolina Caro-Vegas, Alice Peng, Angelica Juarez, Allison Silverstein, William Kamiyango, Jimmy Villiera, Casey L Mcatee, Rizine Mzikamanda, Tamiwe Tomoka, Erin C Peckham-Gregory, Razia Moorad, Carrie L Kovarik, Liane R Campbell, Parth S Mehta, Peter N Kazembe, Carl E Allen, Michael E Scheurer, Nmazuo W Ozuah, Dirk P Dittmer, Nader Kim El-Mallawany

Center for Medical Ethics and Health Policy Staff Publications

BACKGROUND

Kaposi sarcoma (KS) is among the most common childhood cancers in Eastern and Central Africa. Pediatric KS has a distinctive clinical presentation compared with adult KS, which includes a tendency for primary lymph node involvement, a considerable proportion of patients lacking cutaneous lesions, and a potential for fulminant disease. The molecular mechanisms or correlates for these disease features are unknown.

METHODS

This was a cross-sectional study. All cases were confirmed by IHC for KS-associated herpesvirus (KSHV) LANA protein. Baseline blood samples were profiled for HIV and KSHV genome copy numbers by qPCR and secreted cytokines by ELISA. Biopsies were …

Establishment Of A Consensus Protocol To Explore The Brain Pathobiome In Patients With Mild Cognitive Impairment And Alzheimer’S Disease: Research Outline And Call For Collaboration, Richard Lathe, Nikki M Schultek, Brian J Balin, Garth D Ehrlich, Lavinia Alberi Auber, George Perry, Edward B Breitschwerdt, David B Corry, Richard L Doty, Robert A Rissman, Peter L Nara, Ruth Itzhaki, William A Eimer, Rudolph E Tanzi, Intracell Research Group Consortium Collaborators

Faculty, Staff and Students Publications

Microbial infections of the brain can lead to dementia, and for many decades microbial infections have been implicated in Alzheimer's disease (AD) pathology. However, a causal role for infection in AD remains contentious, and the lack of standardized detection methodologies has led to inconsistent detection/identification of microbes in AD brains. There is a need for a consensus methodology; the Alzheimer's Pathobiome Initiative aims to perform comparative molecular analyses of microbes in post mortem brains versus cerebrospinal fluid, blood, olfactory neuroepithelium, oral/nasopharyngeal tissue, bronchoalveolar, urinary, and gut/stool samples. Diverse extraction methodologies, polymerase chain reaction and sequencing techniques, and bioinformatic tools will …

Highly Invasive Biliary Cancer Presenting As Multiple Extrabiliary Lesions Masquerading As Abscesses, Alexander Lu, Alireza Mojtahedi, Lukman Cheraghvandi, David Wynne, Neda Zarrin-Khameh, Mohammad Ghasemi Rad

Faculty, Staff and Students Publications

Carcinosarcomas of the biliary tract are an extremely rare type of malignancy and may be low on a differential when presenting as multiple metastatic masses. In this case report, we report a case of a female who presented with an aggressive late-stage disease whose initial workup did not indicate a malignant process. Further complicating her care, biopsy samples taken from extra-hepatic masses were culture-positive for Lactobacillus rhamnosu. Given the late stage of the patient’s disease, hospice care was initiated. The patient passed away four months after the initial presentation.

Invasive Community-Onset Gram-Positive Infections From July 2018 Through December 2022 At 2 Children's Hospitals, Eric E Engstrom, Alexander S Plattner, J Chase Mcneil, Kristina G Hulten, Patrick J Reich, Mary G Boyle, James J Dunn, Stephanie A Fritz, Sheldon L Kaplan

Faculty, Staff and Students Publications

BACKGROUND: Invasive infections caused by Streptococcus pyogenes (invasive group A streptococcus [iGAS]) and Streptococcus pneumoniae (invasive pneumococcal disease [IPD]) decreased substantially at the beginning of the COVID-19 pandemic. Our study sought to evaluate the extent of this decrease and the trends of these infections since reversion of societal adjustments incident to the pandemic. We also wanted to compare the frequency of these infections with invasive community-onset Staphylococcus aureus (I-CO-SA) infections and common respiratory viral infections in this period.

METHODS: Cases of iGAS, IPD, and I-CO-SA infections were identified prospectively and retrospectively at 2 large US children's hospitals by positive cultures …

Toll-Like Receptor 4 And Cd11b Expressed On Microglia Coordinate Eradication Of Candida Albicans Cerebral Mycosis, Yifan Wu, Shuqi Du, Lynn H Bimler, Kelsey E Mauk, Léa Lortal, Nessim Kichik, James S Griffiths, Radim Osicka, Lizhen Song, Katherine Polsky, Lydia Kasper, Peter Sebo, Jill Weatherhead, J Morgan Knight, Farrah Kheradmand, Hui Zheng, Jonathan P Richardson, Bernhard Hube, Julian R Naglik, David B Corry

Faculty, Staff and Students Publications

The fungal pathogen Candida albicans is linked to chronic brain diseases such as Alzheimer's disease (AD), but the molecular basis of brain anti-Candida immunity remains unknown. We show that C. albicans enters the mouse brain from the blood and induces two neuroimmune sensing mechanisms involving secreted aspartic proteinases (Saps) and candidalysin. Saps disrupt tight junction proteins of the blood-brain barrier (BBB) to permit fungal brain invasion. Saps also hydrolyze amyloid precursor protein (APP) into amyloid β (Aβ)-like peptides that bind to Toll-like receptor 4 (TLR4) and promote fungal killing in vitro while candidalysin engages the integrin CD11b (Mac-1) on microglia. …

Efficacy And Safety Of Mas825 (Anti-Il-1Β/Il-18) In Covid-19 Patients With Pneumonia And Impaired Respiratory Function, Alex D Hakim, Mustafa Awili, Hollis R O'Neal, Omar Siddiqi, Naseem Jaffrani, Richard Lee, Jeffrey S Overcash, Ann Chauffe, Terese C Hammond, Bela Patel, Michael Waters, Gerard J Criner, Alok Pachori, Guido Junge, Rafael Levitch, Jen Watts, Philip Koo, Tirtha Sengupta, Lili Yu, Michael Kiffe, Anne Pinck, Richard R Stein, Jamie Bendrick-Peart, Janet Jenkins, Marianna Rowlands, Frank Waldron-Lynch, Jesse Matthews

Faculty, Staff and Student Publications

MAS825, a bispecific IL-1β/IL-18 monoclonal antibody, could improve clinical outcomes in COVID-19 pneumonia by reducing inflammasome-mediated inflammation. Hospitalized non-ventilated patients with COVID-19 pneumonia (n = 138) were randomized (1:1) to receive MAS825 (10 mg/kg single i.v.) or placebo in addition to standard of care (SoC). The primary endpoint was the composite Acute Physiology and Chronic Health Evaluation II (APACHE II) score on Day 15 or on the day of discharge (whichever was earlier) with worst-case imputation for death. Other study endpoints included safety, C-reactive protein (CRP), SARS-CoV-2 presence, and inflammatory markers. On Day 15, the APACHE II score was 14.5 …

The Gut Microbiome As A Biomarker And Therapeutic Target In Hepatocellular Carcinoma, Betul Gok Yavuz, Saumil Datar, Shadi Chamseddine, Yehia I Mohamed, Michael Lapelusa, Sunyoung S Lee, Zishuo Ian Hu, Eugene J Koay, Hop S Tran Cao, Prasun Kumar Jalal, Carrie Daniel-Macdougall, Manal Hassan, Dan G Duda, Hesham M Amin, Ahmed O Kaseb

Faculty, Staff and Student Publications

The microbiome is pivotal in maintaining health and influencing disease by modulating essential inflammatory and immune responses. Hepatocellular carcinoma (HCC), ranking as the third most common cause of cancer-related fatalities globally, is influenced by the gut microbiome through bidirectional interactions between the gut and liver, as evidenced in both mouse models and human studies. Consequently, biomarkers based on gut microbiota represent promising non-invasive tools for the early detection of HCC. There is a growing body of evidence suggesting that the composition of the gut microbiota may play a role in the efficacy of immunotherapy in different types of cancer; thus, …

A Pilot Genome-Wide Association Study Meta-Analysis Of Gastroparesis, Leticia Camargo Tavares, Tenghao Zheng, Madeline Kwicklis, Emily Mitchell, Anita Pandit, Suraj Pullapantula, Cheryl Bernard, Maris Teder-Laving, Francine Z Marques, Tonu Esko, Braden Kuo, Robert J Shulman, Bruno P Chumpitazi, Kenneth L Koch, Irene Sarosiek, Thomas L Abell, Richard W Mccallum, Henry P Parkman, Pankaj J Pasricha, Frank A Hamilton, James Tonascia, Matthew Zawistowski, Gianrico Farrugia, Madhusudan Grover, Mauro D'Amato

Faculty, Staff and Students Publications

BACKGROUND: Gastroparesis (GP) is characterized by delayed gastric emptying in the absence of mechanical obstruction.

OBJECTIVE: Genetic predisposition may play a role; however, investigation at the genome-wide level has not been performed.

METHODS: We carried out a genome-wide association study (GWAS) meta-analysis on (i) 478 GP patients from the National Institute of Diabetes and Digestive and Kidney Diseases Gastroparesis Clinical Research Consortium (GpCRC) compared to 9931 population-based controls from the University of Michigan Health and Retirement Study; and (ii) 402 GP cases compared to 48,340 non-gastroparesis controls from the Michigan Genomics Initiative. Associations for 5,811,784 high-quality SNPs were tested on …