Immunology of Infectious Disease Commons^™

Factors Associated With Severe Illness In Patients Aged <21 Years Hospitalized For Covid-19, Rewa Choudhary, Bryant J Webber, Lindsay S Womack, Hannah K Dupont, Sophia K Chiu, Valentine Wanga, Megan E Gerdes, Sophia Hsu, Dallas S Shi, Theresa M Dulski, Osatohamwen I Idubor, Arthur M Wendel, Nickolas T Agathis, Kristi Anderson, Tricia Boyles, Eleanor S Click, Juliana Da Silva, Mary E Evans, Jeremy A W Gold, Julia C Haston, Pamela Logan, Susan A Maloney, Marisol Martinez, Pavithra Natarajan, Kevin B Spicer, Mark Swancutt, Valerie A Stevens, Jessica Rogers-Brown, Gyan Chandra, Megan Light, Frederick E Barr, Jessica Snowden, Larry K Kociolek, Matthew Mchugh, David L Wessel, Joelle N Simpson, Kathleen C Gorman, Kristen A Breslin, Roberta L Debiasi, Aaron Thompson, Mark W Kline, Julie A Boom, Ila R Singh, Michael Dowlin, Mark Wietecha, Beth Schweitzer, Sapna Bamrah Morris, Emilia H Koumans, Jean Y Ko, David A Siegel, Anne A Kimball

Faculty, Staff and Students Publications

OBJECTIVES: To describe coronavirus disease 2019 (COVID-19)-related pediatric hospitalizations during a period of B.1.617.2 (Δ) variant predominance and to determine age-specific factors associated with severe illness.

METHODS: We abstracted data from medical charts to conduct a cross-sectional study of patients agedchildren's hospitals from July to August 2021 for COVID-19 or with an incidental positive severe acute respiratory syndrome coronavirus 2 test. Among patients with COVID-19, we assessed factors associated with severe illness by calculating age-stratified prevalence ratios (PR). We defined severe illness as receiving high-flow nasal cannula, positive airway pressure, or invasive mechanical ventilation.

RESULTS: Of 947 hospitalized patients, 759 …

Performance Evaluation Of The Xt Microslide Assay Pairs On The Vitros Xt 7600 Compared To Vitros Single Microslide Assays On Vitros 5600, Lily Olayinka, Estella Tam, Sridevi Devaraj

Faculty, Staff and Students Publications

OBJECTIVES: Pediatric hospitals are always challenged by specimen volumes and thus any innovation in this realm is very welcome. With the introduction of Microslide assay pairs, we aimed to evaluate the analytical performance of the Vitros XT MicroSlide assay pairs on the Vitros XT 7600 compared to single MicroSlides.

DESIGN: Performance characteristics included within-run precision, analytical measurable range, method comparison, and interference verification. We compared six XT MicroSlide pairs on the Vitros XT 7600 with twelve corresponding single slide assays on the Vitros 5600 system.

RESULTS: The XT MicroSlides on Vitros XT 7600 demonstrated excellent precision, equivalent analytical measurable range, …

Conventional And Advanced Mr Imaging Findings In A Cohort Of Pathology-Proven Dermoid Cysts Of The Pediatric Scalp And Skull, Bettina L Serrallach, Gunes Orman, M John Hicks, Nilesh Desai, Stephen Kralik, Thierry Agm Huisman

Faculty, Staff and Students Publications

BACKGROUND: In the pediatric population, dermoid cysts are among the most frequent lesions of the scalp and skull. Imaging plays a key role in characterizing scalp and skull lesions in order to narrow the differential diagnoses. In general, dermoids are described as heterogeneous T1-/T2-hypo- to hyperintense lesions on magnetic resonance imaging.

METHODS: The goal of this retrospective study is to evaluate the diffusion weighted imaging findings while reviewing the conventional T1-/T2-/T1+C-weighted MR characteristics in a pathology-proven series of 14 dermoids of the pediatric scalp and skull.

RESULTS: In our pediatric cohort (eight boys, six girls, age range 3-95 months), half …

The Testis-Specific E3 Ubiquitin Ligase Rnf133 Is Required For Fecundity In Mice, Kaori Nozawa, Yoshitaka Fujihara, Darius J Devlin, Ricardo E Deras, Katarzyna Kent, Irina V Larina, Kohei Umezu, Zhifeng Yu, Courtney M Sutton, Qiuji Ye, Laura K Dean, Chihiro Emori, Masahito Ikawa, Thomas X Garcia, Martin M Matzuk

Faculty, Staff and Students Publications

BACKGROUND: Ubiquitination is a post-translational modification required for a number of physiological functions regulating protein homeostasis, such as protein degradation. The endoplasmic reticulum (ER) quality control system recognizes and degrades proteins no longer needed in the ER through the ubiquitin-proteasome pathway. E2 and E3 enzymes containing a transmembrane domain have been shown to function in ER quality control. The ER transmembrane protein UBE2J1 is a E2 ubiquitin-conjugating enzyme reported to be essential for spermiogenesis at the elongating spermatid stage. Spermatids from Ube2j1 KO male mice are believed to have defects in the dislocation step of ER quality control. However, associated …

Systemic Ablation Of Camkk2 Impairs Metastatic Colonization And Improves Insulin Sensitivity In Tramp Mice: Evidence For Cancer Cell-Extrinsic Camkk2 Functions In Prostate Cancer, Thomas L Pulliam, Dominik Awad, Jenny J Han, Mollianne M Murray, Jeffrey J Ackroyd, Pavithr Goli, Jonathan S Oakhill, John W Scott, Michael M Ittmann, Daniel E Frigo

Faculty, Staff and Students Publications

Despite early studies linking calcium-calmodulin protein kinase kinase 2 (CAMKK2) to prostate cancer cell migration and invasion, the role of CAMKK2 in metastasis in vivo remains unclear. Moreover, while CAMKK2 is known to regulate systemic metabolism, whether CAMKK2's effects on whole-body metabolism would impact prostate cancer progression and/or related comorbidities is not known. Here, we demonstrate that germline ablation of

Peppermint Oil Effects On The Gut Microbiome In Children With Functional Abdominal Pain, Santosh Thapa, Ruth Ann Luna, Bruno P Chumpitazi, Numan Oezguen, Susan M Abdel-Rahman, Uttam Garg, Salma Musaad, James Versalovic, Gregory L Kearns, Robert J Shulman

Faculty, Staff and Students Publications

Peppermint oil (PMO) is effective in the treatment of functional abdominal pain disorders, but its mechanism of action is unclear. Evidence suggests PMO has microbicidal activity. We investigated the effect of three different doses of PMO on gut microbiome composition. Thirty children (7-12 years of age) with functional abdominal pain provided a baseline stool sample prior to randomization to 180, 360, or 540 mg of enteric coated PMO (10 participants per dose). They took their respective dose of PMO (180 mg once, 180 mg twice, or 180 mg thrice daily) for 1 week, after which the stool collection was repeated. …

Novel Role Of Ghrelin Receptor In Gut Dysbiosis And Experimental Colitis In Aging, Ji Yeon Noh, Chia-Shan Wu, Jennifer A A Deluca, Sridevi Devaraj, Arul Jayaraman, Robert C Alaniz, Xiao-Di Tan, Clinton D Allred, Yuxiang Sun

Faculty, Staff and Students Publications

Chronic low-grade inflammation is a hallmark of aging, which is now coined as inflamm-aging. Inflamm-aging contributes to many age-associated diseases such as obesity, type 2 diabetes, cardiovascular disease, and inflammatory bowel disease (IBD). We have shown that gut hormone ghrelin, via its receptor growth hormone secretagogue receptor (GHS-R), regulates energy metabolism and inflammation in aging. Emerging evidence suggests that gut microbiome has a critical role in intestinal immunity of the host. To determine whether microbiome is an integral driving force of GHS-R mediated immune-metabolic homeostasis in aging, we assessed the gut microbiome profiles of young and old GHS-R global knockout …

Repair-Assisted Damage Detection Reveals Biological Disparities In Prostate Cancer Between African Americans And European Americans, Kimiko L Krieger, Jie H Gohlke, Kevin J Lee, Danthasinghe Waduge Badrajee Piyarathna, Patricia D Castro, Jeffrey A Jones, Michael M Ittmann, Natalie R Gassman, Arun Sreekumar

Faculty, Staff and Students Publications

African Americans (AA) are two times more likely to be diagnosed with and succumb to prostate cancer (PCa) compared to European Americans (EA). There is mounting evidence that biological differences in these tumors contribute to disparities in patient outcomes. Our goal was to examine the differences in DNA damage in AA and EA prostate tissues. Tissue microarrays with matched tumor-benign adjacent pairs from 77 AA and EA PCa patients were analyzed for abasic sites, oxidative lesions, crosslinks, and uracil content using the Repair Assisted Damage Detection (RADD) assay. Our analysis revealed that AA PCa, overall, have more DNA damage than …

Sars-Cov-2 Anti-Spike Antibodies After Vaccination In Pediatric Heart Transplantation: A First Report, Joseph A Spinner, Christopher L Julien, Lily Olayinka, William J Dreyer, Claire E Bocchini, Flor M Munoz, Sridevi Devaraj

Faculty, Staff and Students Publications

BACKGROUND: BACKGROUND: There is a paucity of data regarding the antibody response to SARS-CoV-2 vaccination in children after solid organ transplant.

METHODS: We retrospectively reviewed the SARS-CoV-2 Anti-Spike IgG antibodies measured following SARS-CoV-2 vaccination at our pediatric heart transplant (HTx) center.

RESULTS: Among patients (median age 17.1 years) in whom antibody testing was performed (median 118 days post-vaccine completion), a SARS-CoV-2 Anti-Spike IgG antibody was detected in 28 of 40 (70%) post-HTx recipients (median antibody level 10.9 AU/ml). Neutropenia, diabetes mellitus, and previous use of rituximab were associated with absence of a detectable antibody. All 7 post-HTx patients with a …

Fecal Microbiota Transplantation Commonly Failed In Children With Co-Morbidities, Richard Kellermayer, Qinglong Wu, Dorottya Nagy-Szakal, Karen Queliza, Faith D Ihekweazu, Claire E Bocchini, Abria R Magee, Numan Oezguen, Jennifer K Spinler, Emily B Hollister, Robert J Shulman, James Versalovic, Ruth Ann Luna, Tor C Savidge

Faculty, Staff and Students Publications

OBJECTIVES: Fecal microbiota transplantation (FMT) is arguably the most effective treatment for recurrent Clostridioides difficile infection (rCDI). Clinical reports on pediatric FMT have not systematically evaluated microbiome restoration in patients with co-morbidities. Here, we determined whether FMT recipient age and underlying co-morbidity influenced clinical outcomes and microbiome restoration when treated from shared fecal donor sources.

METHODS: Eighteen rCDI patients participating in a single-center, open-label prospective cohort study received fecal preparation from a self-designated (single case) or two universal donors. Twelve age-matched healthy children and four pediatric ulcerative colitis (UC) cases from an independent serial FMT trial, but with a shared …

Maternal Lactobacillus Reuteri Supplementation Shifts The Intestinal Microbiome In Mice And Provides Protection From Experimental Colitis In Female Offspring, Mahesh Krishna, Melinda Engevik, Karen Queliza, Savini Britto, Rajesh Shah, Wenly Ruan, Hongtao Wang, James Versalovic, Richard Kellermayer

Faculty, Staff and Students Publications

The purpose of our experiment was to explore how stochastic (inter-individual variation) gut microbiome composition may link to inflammatory bowel disease (IBD) susceptibility and guide the development of a perinatal preventative probiotic. Dextran sodium sulfate (DSS) was introduced to C57BL/BJ mice to induce acute colitis as a model of IBD. Potentially protective bacteria were identified using a discovery-validation cohort approach toward stochastic DSS susceptibility.

Metabolism Of A Selective Serotonin And Norepinephrine Reuptake Inhibitor Duloxetine In Liver Microsomes And Mice, Xuan Qin, John M Hakenjos, Kevin R Mackenzie, Mercedes Barzi, Hemantkumar Chavan, Pranavanand Nyshadham, Jin Wang, Sung Yun Jung, Joie Z Guner, Si Chen, Lei Guo, Partha Krishnamurthy, Karl-Dimiter Bissig, Stephen Palmer, Martin M Matzuk, Feng Li

Faculty, Staff and Students Publications

Duloxetine (DLX) is a dual serotonin and norepinephrine reuptake inhibitor, widely used for the treatment of major depressive disorder. Although DLX has shown good efficacy and safety, serious adverse effects (e.g., liver injury) have been reported. The mechanisms associated with DLX-induced toxicity remain elusive. Drug metabolism plays critical roles in drug safety and efficacy. However, the metabolic profile of DLX in mice is not available, although mice serve as commonly used animal models for mechanistic studies of drug-induced adverse effects. Our study revealed 39 DLX metabolites in human/mouse liver microsomes and mice. Of note, 13 metabolites are novel, including five …

Reduced Pro-Inflammatory Dendritic Cell Phenotypes Are A Potential Indicator Of Successful Peanut Oral Immunotherapy, Sara Anvari, Levi B Watkin, Charles G Minard, Kimberly Schuster, Oluwatomi Hassan, Aikaterini Anagnostou, Jordan S Orange, David B Corry, Carla M Davis

Faculty, Staff and Students Publications

Dendritic cells are important mediators in the early presentation of antigen and regulation of the differentiation of T cells. Peanut oral immunotherapy (POIT) results in desensitization in most peanut allergic individuals (responders), but not in others due to allergic reactions (non-responders). Delineation of early immunologic changes contributing to desensitization would help clarify the POIT mechanism of action. We analyzed dendritic cells in 15 pediatric subjects (5-12 years) undergoing a phase 1 single-center POIT study. We examined dendritic cells at baseline, 6-, 12-, 18- and 24-weeks after initiation of POIT and responders of therapy were compared to non-responders and healthy controls. …

Sarscov-2 Serostatus Amongst Vaccinated Employees At A Pediatric Hospital System, Sridevi Devaraj, Izmarie Poventud-Fuentes, Matthew Girotto, Jermaine Monroe, Julie Boom, George Delclos, James Versalovic

Faculty, Staff and Students Publications

To gain insights on the heterogeneity of immune responses to vaccination against SARS-CoV-2 and to identify factors that could make individuals vulnerable to infection due to lack of response to vaccination, our hospital started offering free voluntary post-antibody testing against the spike protein IgG for all fully vaccinated employees.

Post-vaccination response against SARS-CoV-2 was assessed using the FDA-EUA approved VITROS anti-SARS-CoV-2 IgG immunometric assay specific to the spike protein.

Out of a total of 3266 antibody tests performed in fully vaccinated Texas Children’s, 99.4% had a positive antibody response to the spike protein. From the 21 employees (0.6%) that had …

Urine Alcam, Pf4 And Vcam-1 Surpass Conventional Metrics In Identifying Nephritis Disease Activity In Childhood-Onset Systemic Lupus Erythematosus, Samar A Soliman, Anam Haque, Kamala Vanarsa, Ting Zhang, Faten Ismail, Kyung Hyun Lee, Claudia Pedroza, Larry A Greenbaum, Sherene Mason, M John Hicks, Scott E Wenderfer, Chandra Mohan

Faculty, Staff and Students Publications

OBJECTIVES: Serial kidney biopsy for repeat evaluation and monitoring of lupus nephritis (LN) in childhood-onset Systemic Lupus Erythematosus (cSLE) remains challenging, thus non-invasive biomarkers are needed. Here, we evaluate the performance of ten urine protein markers of diverse nature including cytokines, chemokines, and adhesion molecules in distinguishing disease activity in cSLE.

METHODS: Eighty-four pediatric patients meeting ≥4 ACR criteria for SLE were prospectively enrolled for urine assay of 10 protein markers normalized to urine creatinine, namely ALCAM, cystatin-C, hemopexin, KIM-1, MCP-1, NGAL, PF-4, Timp-1, TWEAK, and VCAM-1 by ELISA. Samples from active renal (LN) and active non-renal SLE patients were …

Crispr/Cas9-Mediated Genome Editing Reveals 12 Testis-Enriched Genes Dispensable For Male Fertility In Mice, Yuki Oyama, Haruhiko Miyata, Keisuke Shimada, Yoshitaka Fujihara, Keizo Tokuhiro, Thomas X Garcia, Martin M Matzuk, Masahito Ikawa

Faculty, Staff and Students Publications

Gene expression analyses suggest that more than 1000-2000 genes are expressed predominantly in mouse and human testes. Although functional analyses of hundreds of these genes have been performed, there are still many testis-enriched genes whose functions remain unexplored. Analyzing gene function using knockout (KO) mice is a powerful tool to discern if the gene of interest is essential for sperm formation, function, and male fertility in vivo. In this study, we generated KO mice for 12 testis-enriched genes, 1700057G04Rik, 4921539E11Rik, 4930558C23Rik, Cby2, Ldhal6b, Rasef, Slc25a2, Slc25a41, Smim8, Smim9, Tmem210, and Tomm20l, using the clustered regularly interspaced short palindromic repeats /CRISPR-associated …

Loss Of H2r Signaling Disrupts Neutrophil Homeostasis And Promotes Inflammation-Associated Colonic Tumorigenesis In Mice, Zhongcheng Shi, Yuko Mori-Akiyama, Wa Du, Robert Fultz, Yanling Zhao, Wenly Ruan, Susan Venable, Melinda A Engevik, James Versalovic

Faculty, Staff and Students Publications

BACKGROUND & AIMS: We previously showed that histamine suppressed inflammation-associated colonic tumorigenesis through histamine type 2 receptor (H2R) signaling in mice. This study aimed to precisely elucidate the downstream effects of H2R activation in innate immune cells.

METHODS: Analyses using online databases of single-cell RNA sequencing of intestinal epithelial cells in mice and RNA sequencing of mouse immune cells were performed to determine the relative abundances of 4 histamine receptors among different cell types. Mouse neutrophils, which expressed greater amounts of H2R, were collected from the peritoneum of wild-type and H2R-deficient mice, of which low-density and high-density neutrophils were extracted …

Enhancement Of Hiv Persistence By Adipose Tissue, Jacob Couturier

Dissertations and Theses (Open Access)

A major challenge for HIV eradication is the persistence of cellular and anatomic viral reservoirs. The primary cellular reservoirs for HIV, memory CD4 T cells and macrophages, traffic into various tissues where most viral replication occurs, or in the case of virally-suppressed antiretroviral-treated patients, the virus becomes dormant and protected from drugs and immune responses. The major tissue reservoirs for HIV include lymphoid tissues such as lymph nodes, bone marrow, and gastrointestinal lymphoid tissues, but adipose tissues could potentially harbor HIV as well. Adipose tissues are ubiquitous connective tissues and major sites of infiltration and immune activity by T cells …

The Effect Of Activation Induced Cytidine Deaminase Phosphorylation And Herpes Virus Uracil Dna Glycosylase On Antibody Diversification, Marc Macaluso

Dissertations and Theses (Open Access)

Activation-induced cytidine deaminase (AID) is a mutagenic enzyme that is expressed in mammalian B-cells and initiates the antibody diversification processes of somatic hypermuntation (SHM) and isotype class switch recombination (CSR). AID is targeted to the immunoglobulin gene locus where it deaminates cytosines to generate uracil residues in DNA. This generates guanine-uracil (U:G) mismatch lesion which are recognized by uracil DNA glycosylase (UNG), a DNA repair enzyme that removes uracil from DNA and triggers downstream repair of the lesion. While UNG is a ubiquitously expressed DNA repair enzyme, its recognition and removal of AID introduced uracils is essential in both SHM …

Selection Methods For Genetically-Modified T Cells: In Support Of Translational Therapy, David Rushworth

Dissertations and Theses (Open Access)

T cells are blood cells which organize the immune system of the host. These cells are necessary for the host to respond appropriately to threats from foreign organisms and cancerous growth. However, in the case of certain infections and cancer, T cells are unable to respond appropriately to a threat and establish immunity. This leads to disease when the infection or cancer is not sufficiently eliminated. On the other hand, T cells can lack tolerance for healthy tissue and perceive healthy tissue as infected. The ensuing over-reactive immune response also leads to disease. A delicate balance must exist between immunity …

The Role Of Dual Specificity Phosphatase -11 In Innate And Adaptive Immune Responses, Kalyan Chakravarthy Nallaparaju

Dissertations and Theses (Open Access)

THE ROLE OF DUAL SPECIFICITY PHOSPHATASE -11 IN INNATE AND ADAPTIVE IMMUNE RESPONSES

Kalyan Chakravarthy Nallaparaju, M.S.

Supervisory Professor: Chen Dong, Ph.D.

Dual-specificity phosphatases (DUSPs) constitute a subfamily of protein tyrosine phosphatases characterized by their ability to dephosphorylate both phosphotyrosine and phosphoserine/phosphothreonine residues within a substrate, typically among members of the MAP kinase family. DUSPs have been shown to play a critical role in the regulation of various cellular processes including signal transduction, cell cycle regulation and cellular proliferation via modulation of MAP kinase activities. Also, many members of this family have been demonstrated to be potent immune regulators. …

The Role Of The C5a Receptor In Host Defense Against Listeria Monocytogenes, Daniel Calame

Dissertations and Theses (Open Access)

Listeria monocytogenes (Lm) is a major cause of mortality resulting from food poisoning in the United States. While the complement component C5 is known to be protective in listeriosis, it is unknown how its cleavage fragment C5a participates. Here we show in a model of systemic Lm infection that the C5a receptor is essential for host defense. C5aR-/- mice have reduced survival and increased bacterial burden in the liver and spleen in comparison to WT mice. Surprisingly, C5aR-/- mice also have a dramatic reduction in splenocyte numbers resulting from elevated cell death as indicated by TUNEL staining and caspase 3 …

C-Jun N-Terminal Kinases Regulate Adenovirus-Mediated Autophagy And Antigen Presentation, Sarah R. Klein

Dissertations and Theses (Open Access)

Targeted immunotherapy with recombinant, oncolytic adenoviruses is under investigation for the treatment of cancer. Evidence indicates adenoviruses induce autophagy that is required for oncolysis, but the molecular regulation of autophagy in infected cells remains under investigation. Our data suggested the canonical pathway regulating starvation-induced autophagy was not implemented in adenovirus-induced autophagy; however, adenovirus infection triggered phosphorylation of c-Jun N-terminal kinases (JNK) that was essential for autophagy. Adenoviral replication within the host cell elicited JNK pathway activation leading to B cell lymphoma-2 (Bcl-2) phosphorylation. JNK-dependent Bcl-2 phosphorylation stimulated the dissociation of Bcl-2/beclin 1 heterodimers, enabling beclin 1 to initiate autophagy. Moreover, …

Regulation Of To Xin Synthesis By Clostridium Difficile, Charles Darkoh

Dissertations and Theses (Open Access)

Clostridium difficile is the leading definable cause of nosocomial diarrhea worldwide due to its virulence, multi-drug resistance, spore-forming ability, and environmental persistence. The incidence of C. difficile infection (CDI) has been increasing exponentially in the last decade. Virulent strains of C. difficile produce either toxin A and/or toxin B, which are essential for the pathogenesis of this bacterium. Current methods for diagnosing CDI are mostly qualitative tests that detect the bacterium, the toxins, or the toxin genes. These methods do not differentiate virulent C. difficile strains that produce active toxins from non-virulent strains that do not produce toxins or produce …

Role Of Vitamin-D3 And Retinoic Acid In A Human Thp-1 Macrophage Model Of Mycobacterium Tuberculosis Infection, Jaymie L. Estrella

Dissertations and Theses (Open Access)

Mycobacterium tuberculosis (Mtb) replicates within the human macrophages and we investigated the activating effects of retinoic acid (RA) and vitamin D3 (VD) on macrophages in relation to the viability of Mtb. A combination of these vitamins (RAVD) enhanced the receptors on THP-1 macrophage (Mannose receptor and DC-SIGN) that increased mycobacterial uptake but inhibited the
subsequent intracellular growth of Mtb by inducing reactive oxygen species (ROS) and autophagy. RAVD also enhanced antigen presenting and homing receptors in THPs that suggested an activated phenotype for THPs following RAVD treatment. RAVD mediated activation was also associated with a marked phenotypic change in Mtb …

The Role Of Mucosal Epithelial Cells In Hiv-1 Infection, Danielle Fontenot

Dissertations and Theses (Open Access)

The predominant route of human immunodeficiency virus type 1 (HIV-1) transmission is infection across the vaginal mucosa. Epithelial cells, which form the primary barrier of protection against pathogens, are the first cell type at these mucosal tissues to encounter the virus but their role in HIV infection has not been clearly elucidated. Although mucosal epithelial cells express only low levels of the receptors required for successful HIV infection, productive infection does occur at these sites. The present work provides evidence to show that HIV exposure, without the need for productive infection, induces human cervical epithelial cells to produce Thymic Stromal …