Medical Microbiology Commons^™

The Temporal Impulse Response Function In Infantile Nystagmus, Gal Avital, Felicia Kuperwaser, Andrew W Pountain, Keenan A Lacey, Erin E Zwack, Magdalena Podkowik, Bo Shopsin, Victor J Torres, Itai Yanai

Faculty, Staff and Student Publications

Innate immune recognition of bacterial pathogens is a key determinant of the ensuing systemic response, and host or pathogen heterogeneity in this early interaction can impact the course of infection. To gain insight into host response heterogeneity, we investigate macrophage inflammatory dynamics using primary human macrophages infected with Group B Streptococcus. Transcriptomic analysis reveals discrete cellular states within responding macrophages, one of which consists of four sub-states, reflecting inflammatory activation. Infection with six additional bacterial species—Staphylococcus aureus, Listeria monocytogenes, Enterococcus faecalis, Yersinia pseudotuberculosis, Shigella flexneri, and Salmonella enterica—recapitulates these states, though at …

Maternal Gut Microbiota Mediate Intergenerational Effects Of High-Fat Diet On Descendant Social Behavior, Claudia M Di Gesù, Lisa M Matz, Ian J Bolding, Robert Fultz, Kristi L Hoffman, Antonella Marino Gammazza, Joseph F Petrosino, Shelly A Buffington

Faculty, Staff and Students Publications

Dysbiosis of the maternal gut microbiome during pregnancy is associated with adverse neurodevelopmental outcomes. We previously showed that maternal high-fat diet (MHFD) in mice induces gut dysbiosis, social dysfunction, and underlying synaptic plasticity deficits in male offspring (F1). Here, we reason that, if HFD-mediated changes in maternal gut microbiota drive offspring social deficits, then MHFD-induced dysbiosis in F1 female MHFD offspring would likewise impair F2 social behavior. Metataxonomic sequencing reveals reduced microbial richness among female F1 MHFD offspring. Despite recovery of microbial richness among MHFD-descendant F2 mice, they display social dysfunction. Post-weaning Limosilactobacillus reuteri treatment increases the abundance of short-chain …

Associated Risk Of Blastocystis Infection In Colorectal Cancer, Lena Abdulbaset Labania

Theses

Blastocystis species is an anaerobic intestinal protozoan seen in humans and a wide range of animals. Only nine Blastocystis subtypes are seen in humans. The pathogenicity of Blastocystis spp. has long been controversial. Recently, a subtype-dependent association between Blastocystis spp. and colorectal cancer (CRC) is being debated. Thus, this thesis aims to assess the possible association between Blastocystis spp. infection and CRC condition compared to cancer outside the gastrointestinal tract (COGT) and a cancer-free control (CF) group. This study is the first of its kind in the UAE. Participants were divided into two groups; cancer patients and CF participants. The …

Investigating The Role Of Natural Killer (Nk) Cells In Ozanimod-Mediated Remission In Experimental Autoimmune Encephalomyelitis (Eae) In C57bl/6 Mice, Doua Youssef Kamyan

Theses

Experimental autoimmune encephalomyelitis (EAE) is an important model of multiple sclerosis (MS) in rodents. The disease is characterized by axonal damages mediated by activated autoreactive T lymphocytes, microglia, and macrophages. Ozanimod (RPC1063) is an immunomodulator that has been recently approved by the FDA for the treatment of relapsing-remitting multiple sclerosis (2020) and ulcerative colitis (2021). It is a selective agonist of the sphingosine1-phophate receptors (1 and 5) involved in lymphocyte trafficking and expressed on naïve and central memory T and B cells as well as NK cells. Ozanimod acts by inducing internalization and degradation of the S1PR which in turn …

Oxidation Of Two Cysteines Within Yeast Hsp70 Impairs Proteostasis While Directly Triggering An Hsf1-Dependent Cytoprotective Response, Alec Santiago, Kevin A Morano

Faculty, Staff and Student Publications

Neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's diseases affect millions of Americans every year. One factor linked to the formation of aggregates associated with these diseases is damage sustained to proteins by oxidative stress. Management of protein misfolding by the ubiquitous Hsp70 chaperone family can be modulated by modification of two key cysteines in the ATPase domain by oxidizing or thiol-modifying compounds. To investigate the biological consequences of cysteine modification on the Hsp70 Ssa1 in budding yeast, we generated cysteine null (cysteine to serine) and oxidomimetic (cysteine to aspartic acid) mutant variants of both C264 and C303 and demonstrate …

Wellness In The Face Of Frailty Among Older Adults In First Nations Communities, Morgan Slater, Gabrielle Bruser, Roseanne Sutherland, Melissa K Andrew, Wayne Warry, Kristen M Jacklin, Jennifer D Walker

Faculty, Staff and Student Publications

OBJECTIVES: First Nations people report high levels of wellness despite high rates of chronic illness. Our goal was to understand the factors associated with wellness among First Nations adults in Ontario who were considered frail.

METHODS: Using the First Nations Regional Health Survey, we created a profile of First Nations adults (aged 45+) who were categorized as "frail" (weighted sample size = 8121). We used multivariate logistic regression to determine associations between wellness (as measured by self-reported physical, emotional, mental, and spiritual balance) and determinants of health.

RESULTS: Rates of reported wellness were high among those who were frail, ranging …

Discovery Of An Orally Active Benzoxaborole Prodrug Effective In The Treatment Of Chagas Disease In Non-Human Primates, Angel M Padilla, Wei Wang, Tsutomu Akama, David S Carter, Eric Easom, Yvonne Freund, Jason S Halladay, Yang Liu, Sarah A Hamer, Carolyn L Hodo, Gregory K Wilkerson, Dylan Orr, Brooke White, Arlene George, Huifeng Shen, Yiru Jin, Michael Zhuo Wang, Susanna Tse, Robert T Jacobs, Rick L Tarleton

Faculty, Staff and Student Publications

Trypanosoma cruzi, the agent of Chagas disease, probably infects tens of millions of people, primarily in Latin America, causing morbidity and mortality. The options for treatment and prevention of Chagas disease are limited and underutilized. Here we describe the discovery of a series of benzoxaborole compounds with nanomolar activity against extra- and intracellular stages of T. cruzi. Leveraging both ongoing drug discovery efforts in related kinetoplastids, and the exceptional models for rapid drug screening and optimization in T. cruzi, we have identified the prodrug AN15368 that is activated by parasite carboxypeptidases to yield a compound that targets the messenger RNA …

Exploring The Dynamics Of Primary Epsteinbarr Virus Infection Using A Novel Rabbit, Narendran Reguraman

Dissertations

Epstein-Barr virus (EBV) is a common herpesvirus asymptomatically carried by over 90% of the world population. However, in certain circumstances, the virus can lead to life-threatening diseases. Although the virus was isolated over 55 years ago, several fundamental aspects of the biology of EBV and the mechanism by which this virus induces pathology remain unknown. One major obstacle has been the lack of a suitable small animal model for EBV infection. We have recently shown that healthy rabbits are susceptible to EBV infection, and the virus establishes long-term latent infection typically seen in humans. The main objective of this dissertation …

Characteristics Of Community-Acquired Carbapenem-Resistant Enterobacterales, Rima Shrestha, Courtney L Luterbach, Weixiao Dai, Lauren Komarow, Michelle Earley, Gregory Weston, Erica Herc, Jesse T Jacob, Robert Salata, Darren Wong, Deverick Anderson, Kirsten B Rydell, Cesar A Arias, Liang Chen, David Van Duin, Mdro Investigators

Faculty, Staff and Student Publications

BACKGROUND: Community-acquired carbapenem-resistant Enterobacterales (CA-CRE) are an important threat.

METHODS: In CRACKLE-2, we defined patients with CA-CRE as admitted from home, without pre-existing conditions, and a positive culture within 48 h of admission. Healthcare-associated CRE (HA-CRE) were those with the lowest likelihood of community acquisition, not admitted from home and cultured >48 h after admission. Specific genetic markers in carbapenemase-producing Klebsiella pneumoniae were evaluated through random forest modelling.

RESULTS: CA-CRE and HA-CRE were detected in 83 (10%) and 208 (26%) of 807 patients. No significant differences were observed in bacterial species or strain type distribution. K. pneumoniae (204/291, 70%) was …

Identification Of An Early Survival Prognostic Gene Signature For Localized Osteosarcoma Patients, Harry Mackay, Chathura J Gunasekara, Kit-Yi Yam, Dollada Srisai, Hari Krishna Yalamanchili, Yumei Li, Rui Chen, Cristian Coarfa, Robert A Waterland

Faculty, Staff and Students Publications

Recent genome-wide association studies corroborate classical research on developmental programming indicating that obesity is primarily a neurodevelopmental disease strongly influenced by nutrition during critical ontogenic windows. Epigenetic mechanisms regulate neurodevelopment; however, little is known about their role in establishing and maintaining the brain's energy balance circuitry. We generated neuron and glia methylomes and transcriptomes from male and female mouse hypothalamic arcuate nucleus, a key site for energy balance regulation, at time points spanning the closure of an established critical window for developmental programming of obesity risk. We find that postnatal epigenetic maturation is markedly cell type and sex specific and …

Plasma Protein Biomarkers For Primary Graft Dysfunction After Lung Transplantation: A Single-Center Cohort Analysis, Lourdes Chacon-Alberty, Rupa S Kanchi, Shengbin Ye, Camila Hochman-Mendez, Daoud Daoud, Cristian Coarfa, Meng Li, Sandra L Grimm, Maher Baz, Ivan Rosas, Gabriel Loor

Faculty, Staff and Students Publications

The clinical use of circulating biomarkers for primary graft dysfunction (PGD) after lung transplantation has been limited. In a prospective single-center cohort, we examined the use of plasma protein biomarkers as indicators of PGD severity and duration after lung transplantation. The study comprised 40 consecutive lung transplant patients who consented to blood sample collection immediately pretransplant and at 6, 24, 48, and 72 h after lung transplant. An expert grader determined the severity and duration of PGD and scored PGD at T0 (6 h after reperfusion), T24, T48, and T72 h post-reperfusion using the 2016 ISHLT consensus guidelines. A bead-based …

Overlapping And Distinct Functions Of The Paralogous Pagr Regulators Of Bacillus Anthracis, Ileana D Corsi, Theresa M Koehler

Faculty, Staff and Student Publications

The Bacillus anthracis pagA gene, encoding the protective antigen component of anthrax toxin, is part of a bicistronic operon on pXO1 that codes for its own repressor, PagR1. In addition to the pagAR1 operon, PagR1 regulates sap and eag, two chromosome genes encoding components of the surface layer, a mounting structure for surface proteins involved in virulence. Genomic studies have revealed a PagR1 paralog, PagR2, encoded by a gene on pXO2. The amino acid sequences of the paralogues are 71% identical and show similarity to the ArsR family of transcription regulators. We determined that the expression of either rPagR1 …

Pathogenesis Of Tobacco-Associated Lung Adenocarcinoma Is Closely Coupled With Changes In The Gut And Lung Microbiomes, Casey T Finnicum, Zahraa Rahal, Maya Hassane, Warapen Treekitkarnmongkol, Ansam Sinjab, Rhiannon Morris, Yuejiang Liu, Elizabeth L Tang, Sarah Viet, Jason L Petersen, Philip L Lorenzi, Lin Tan, Joseph Petrosino, Kristi L Hoffman, Junya Fujimoto, Seyed Javad Moghaddam, Humam Kadara

Faculty, Staff and Students Publications

Microbial dysbiosis has emerged as a modulator of oncogenesis and response to therapy, particularly in lung cancer. Here, we investigate the evolution of the gut and lung microbiomes following exposure to a tobacco carcinogen. We performed 16S rRNA-Seq of fecal and lung samples collected prior to and at several timepoints following (nicotine-specific nitrosamine ketone/NNK) exposure in Gprc5a^−/− mice that were previously shown to exhibit accelerated lung adenocarcinoma (LUAD) development following NNK exposure. We found significant progressive changes in human-relevant gut and lung microbiome members (e.g., Odoribacter, Alistipes, Akkermansia, and Ruminococus) that are closely associated with …

Novel Technologies To Characterize And Engineer The Microbiome In Inflammatory Bowel Disease, Alba Boix-Amorós, Hilarly Monaco, Elisa Sambataro, Jose C. Clemente

Publications and Research

We present an overview of recent experimental and computational advances in technology used to characterize the microbiome, with a focus on how these developments improve our understanding of inflammatory bowel disease (IBD). Specifically, we present studies that make use of flow cytometry and metabolomics assays to provide a functional characterization of microbial communities. We also describe computational methods for strain-level resolution, temporal series, myco - biome and virome data, co-occurrence networks, and compositional data analysis. In addition, we review novel techniques to therapeutically manipulate the microbiome in IBD. We discuss the benefits and drawbacks of these technologies to increase awareness …

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

Department of Medicine Faculty Papers

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

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

Rothman Institute Papers

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

Comparative Analysis Of Co-Cultured Amniotic Cell-Conditioned Media With Cell-Free Amniotic Fluid Reveals Differential Effects On Epithelial-Mesenchymal Transition And Myofibroblast Activation, Naiyou Liu, Charles M Bowen, Mohammadali M Shoja, Karen Larissa Castro De Pereira, Laxmi Priya Dongur, Antonio Saad, William K Russell, Thomas Christopher Broderick, Jeffrey H Fair, William Samuel Fagg

Faculty, Staff and Student Publications

Myofibroblast activation is a cellular response elicited by a variety of physiological or pathological insults whereby cells initiate a coordinated response intended to eradicate the insult and then revert back to a basal state. However, an underlying theme in various disease states is persistent myofibroblast activation that fails to resolve. Based on multiple observations, we hypothesized that the secreted factors harvested from co-culturing amniotic stem cells might mimic the anti-inflammatory state that cell-free amniotic fluid (AF) elicits. We optimized an amnion epithelial and amniotic fluid cell co-culture system, and tested this hypothesis in the context of myofibroblast activation. However, we …

Pre-Exposure To Mrna-Lnp Inhibits Adaptive Immune Responses And Alters Innate Immune Fitness In An Inheritable Fashion, Zhen Qin, Aurélie Bouteau, Christopher Herbst, Botond Z. Igyártó

Department of Microbiology and Immunology Faculty Papers

Hundreds of millions of SARS-CoV-2 mRNA-LNP vaccine doses have already been administered to humans. However, we lack a comprehensive understanding of the immune effects of this platform. The mRNA-LNP-based SARS-CoV-2 vaccine is highly inflammatory, and its synthetic ionizable lipid component responsible for the induction of inflammation has a long in vivo half-life. Since chronic inflammation can lead to immune exhaustion and non-responsiveness, we sought to determine the effects of pre-exposure to the mRNA-LNP on adaptive immune responses and innate immune fitness. We found that pre-exposure to mRNA-LNPs or LNP alone led to long-term inhibition of the adaptive immune response, which …

Mab21l4 Deficiency Drives Squamous Cell Carcinoma Via Activation Of Ret, Ankit Srivastava, Cristina Tommasi, Dane Sessions, Angela Mah, Tomas Bencomo, Jasmine M Garcia, Tiffany Jiang, Michael Lee, Joseph Y Shen, Lek Wei Seow, Audrey Nguyen, Kimal Rajapakshe, Cristian Coarfa, Kenneth Y Tsai, Vanessa Lopez-Pajares, Carolyn S Lee

Faculty, Staff and Students Publications

UNLABELLED: Epithelial squamous cell carcinomas (SCC) most commonly originate in the skin, where they display disruptions in the normally tightly regulated homeostatic balance between keratinocyte proliferation and terminal differentiation. We performed a transcriptome-wide screen for genes of unknown function that possess inverse expression patterns in differentiating keratinocytes compared with cutaneous SCC (cSCC), leading to the identification of MAB21L4 (C2ORF54) as an enforcer of terminal differentiation that suppresses carcinogenesis. Loss of MAB21L4 in human cSCC organoids increased expression of RET to enable malignant progression. In addition to transcriptional upregulation of RET, deletion of MAB21L4 preempted recruitment of the CacyBP-Siah1 E3 ligase …

Ppm1d In Solid And Hematologic Malignancies: Friend And Foe?, Linda Zhang, Joanne I Hsu, Margaret A Goodell

Faculty, Staff and Students Publications

In the face of constant genomic insults, the DNA damage response (DDR) is initiated to preserve genome integrity; its disruption is a classic hallmark of cancer. Protein phosphatase Mg2+/Mn2+-dependent 1D (PPM1D) is a central negative regulator of the DDR that is mutated or amplified in many solid cancers. PPM1D overexpression is associated with increased proliferative and metastatic behavior in multiple solid tumor types and patients with PPM1D-mutated malignancies have poorer prognoses. Recent findings have sparked an interest in the role of PPM1D in hematologic malignancies. Acquired somatic mutations may provide hematopoietic stem cells with a competitive advantage, leading to a …