Medical Microbiology Commons^™

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

Microbiology, Immunology, and Molecular Genetics Faculty Publications

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

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

Microbiology, Immunology, and Molecular Genetics Faculty Publications

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

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

Microbiology, Immunology, and Molecular Genetics Faculty Publications

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

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

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

Microbiology, Immunology, and Molecular Genetics Faculty Publications

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

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

Microbiology, Immunology, and Molecular Genetics Faculty Publications

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

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

Microbiology, Immunology, and Molecular Genetics Faculty Publications

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

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

Microbiology, Immunology, and Molecular Genetics Faculty Publications

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

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

Microbiology, Immunology, and Molecular Genetics Faculty Publications

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

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

Microbiology, Immunology, and Molecular Genetics Faculty Publications

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

Correlates Of Sars-Cov-2 Anti-Rbd Igg Antibody Titers Among Persons Experiencing Homelessness In Los Angeles, Adeline Nyamathi, Sanghyuk S. Shin, Brianna M. Doratt, Alexandria Jones-Patten, Benissa Salem, Lillian Gelberg, Darlene Lee, Dana Garfin, Kartik Yadav, Alicia H. Chang, Kathryn White, Nicholas Arce, Ilhem Messaoudi

Microbiology, Immunology, and Molecular Genetics Faculty Publications

Objectives: People experiencing homelessness (PEH) have been especially impacted by the COVID-19 pandemic, likely due to increased vulnerabilities stemming from chronic diseases, substance use, and mental health conditions.

Design: A case–control study to assess the presence of antibodies against SARS-CoV-2 among PEH and associations with key variables.

Sample: A convenience sample of 97 PEH in Skid Row, Los Angeles.

Measurements: A structured questionnaire assessing socio-demographic, mental health, drug and alcohol use, health care access, pandemic stress, and other COVID-19-specific questions.

Results: We found high anti-receptor binding domain (RBD) IgG titers among five of 15 PEH who reported no prior COVID-19 …

Maternal Obesity Blunts Antimicrobial Responses In Fetal Monocytes, Suhas Sureshchandra, Brianna M. Doratt, Norma Mendza, Oleg Varlamov, Monica Rincon, Nicole E. Marshall, Ilhem Messaoudi

Microbiology, Immunology, and Molecular Genetics Faculty Publications

Maternal pre-pregnancy (pregravid) obesity is associated with adverse outcomes for both mother and offspring. Amongst the complications for the offspring is increased susceptibility and severity of neonatal infections necessitating admission to the intensive care unit, notably bacterial sepsis and enterocolitis. Previous studies have reported aberrant responses to LPS and polyclonal stimulation by umbilical cord blood monocytes that were mediated by alterations in the epigenome. In this study, we show that pregravid obesity dysregulates umbilical cord blood monocyte responses to bacterial and viral pathogens. Specifically, interferon-stimulated gene expression and inflammatory responses to respiratory syncytial virus (RSV) and E. coli were significantly …

Sars-Cov-2 Infection And Seroconversion Rates In Healthcare Providers Prior To Covid-19 Vaccine Rollout, Sanghyuk S. Shin, Miriam Bender, Delphine C. Malherbe, Hannah Vasquez, Brianna M. Doratt, Ilhem Messaoudi

Microbiology, Immunology, and Molecular Genetics Faculty Publications

Objective: A 6-month longitudinal surveillance study of asymptomatic healthcare providers (HCP) was carried out at a large urban academic medical center in the United States to assess whether their job occupation with higher exposure risks to SARS-CoV-2 would equate with higher risk of contracting COVID-19 at the beginning of the pandemic before COVID-19 vaccines were available.

Methods: A longitudinal cohort study design was used to collect and analyze immunological and virological monitoring data and self-report survey assessments of personal protective equipment (PPE) availability, adherence to infection control guidelines, and time spent on COVID-19 wards.

Results: Among 289 eligible participants, SARS-CoV-2 …

Single-Dose Vsv-Based Vaccine Protects Cynomolgus Macaques From Disease After Taï Forest Virus Infection, Paige Fletcher, Kyle L. O'Donnell, Brianna M. Doratt, Delphine C. Malherbe, Chad S. Clancy, Joseph F. Rhoderick, Friederike Feldmann, Patrick W. Hanley, Thomas G. Ksiazek, Thomas W. Geisbert, Ilhem Messaoudi, Andrea Marzi

Microbiology, Immunology, and Molecular Genetics Faculty Publications

Taï Forest virus (TAFV) is a lesser-known ebolavirus that causes lethal infections in chimpanzees and is responsible for a single human case. Limited research has been done on this human pathogen; however, with the recent emergence of filoviruses in West Africa, further investigation and countermeasure development against this virus is warranted. We developed a vesicular stomatitis virus (VSV)-based vaccine expressing the TAFV glycoprotein as the viral antigen and assessed it for protective efficacy in nonhuman primates (NHPs). Following a single high-dose vaccination, NHPs developed antigen-specific binding and neutralizing antibodies as well as modest T cell responses. Importantly, all vaccinated NHPs …

Transcriptional Profiling Of Immune Responses In Nhps After Low-Dose, Vsv-Based Vaccination Against Marburg Virus, Cecilia A. Prator, Brianna M. Doratt, Kyle L. O'Donnell, Justin Lack, Amanda N. Pinski, Stacy M. Ricklefs, Craig A. Martens, Ilhem Messaoudi, Andrea Marzi

Microbiology, Immunology, and Molecular Genetics Faculty Publications

Infection with Marburg virus (MARV), the causative agent of Marburg virus disease (MVD), results in haemorrhagic disease and high case fatality rates (>40%) in humans. Despite its public health relevance, there are no licensed vaccines or therapeutics to prevent or treat MVD. A vesicular stomatitis virus (VSV)-based vaccine expressing the MARV glycoprotein (VSV-MARV) is currently in clinical development. Previously, a single 10 million PFU dose of VSV-MARV administered 1–5 weeks before lethal MARV challenge conferred uniform protection in nonhuman primates (NHPs), demonstrating fast-acting potential. Additionally, our group recently demonstrated that even a low dose VSV-MARV (1000 PFU) protected NHPs …

Loss Of Ubiquitin-Specific Peptidase 18 Destabilizes 14-3-3Ζ Protein And Represses Lung Cancer Metastasis, Zibo Chen, Lin Zheng, Yulong Chen, Xiuxia Liu, Masanori Kawakami, Lisa Maria Mustachio, Jason Roszik, Katherine V Ferry-Galow, Ralph E Parchment, Xin Liu, Thorkell Andresson, Gerard Duncan, Jonathan M Kurie, Jaime Rodriguez-Canales, Xi Liu, Ethan Dmitrovsky

Faculty, Staff and Student Publications

Cancer metastasis is a major cause of cancer-related mortality. Strategies to reduce metastases are needed especially in lung cancer, the most common cause of cancer mortality. We previously reported increased ubiquitin-specific peptidase 18 (USP18) expression in lung and other cancers. Engineered reduction of USP18 expression repressed lung cancer growth and promoted apoptosis. This deubiquitinase (DUB) stabilized targeted proteins by removing the complex interferon-stimulated gene 15 (ISG15). This study explores if the loss of USP18 reduced lung cancer metastasis. USP18 knock-down in lung cancer cells was independently achieved using small hairpin RNAs (shRNAs) and small interfering RNAs (siRNAs). USP18 knock-down reduced …

Role Of Adenylyl Cyclase Type 7 In Functions Of Bv-2 Microglia, Yawen Hu, Rebecca A. Hill, Masami Yoshimura

School of Medicine Faculty Publications

To assess the role of adenylyl cyclase type 7 (AC7) in microglia’s immune function, we generated AC7 gene knockout (AC7 KO) clones from a mouse microglial cell line, BV-2, using the CRISPR-Cas9 gene editing system. The ability of BV-2 cells to generate cAMP and their innate immune functions were examined in the presence or absence of ethanol. The parental BV-2 cells showed robust cAMP production when stimulated with prostaglandin-E1 (PGE1) and ethanol increased cAMP production in a dose-dependent manner. AC7 KO clones of BV-2 cells showed diminished and ethanol-insensitive cAMP production. The phagocytic activity of the parental BV-2 cells was …

Interferon Partly Dictates A Divergent Transcriptional Response In Poxvirus-Infected And Bystander Inflammatory Monocytes, Carolina R Melo-Silva, Marisa I Roman, Cory J Knudson, Lingjuan Tang, Ren-Huan Xu, Michel Tassetto, Patrick Dolan, Raul Andino, Luis J. Sigal

Department of Microbiology and Immunology Faculty Papers

Inflammatory monocytes (iMOs) and B cells are the main targets of the poxvirus ectromelia virus (ECTV) in the lymph nodes of mice and play distinct roles in surviving the infection. Infected and bystander iMOs control ECTV's systemic spread, preventing early death, while B cells make antibodies that eliminate ECTV. Our work demonstrates that within an infected animal that survives ECTV infection, intrinsic and bystander infection of iMOs and B cells differentially control the transcription of genes important for immune cell function and, perhaps, cell identity. Bystander cells upregulate metabolism, antigen presentation, and interferon-stimulated genes. Infected cells downregulate many cell-type-specific genes …

Human Dectin-1 Deficiency Impairs Macrophage-Mediated Defense Against Phaeohyphomycosis, Rebecca A. Drummond, Jigar V. Desai, Amy P. Hsu, Vasileios Oikonomou, Donald C. Vinh, Joshua A. Acklin, Michael S. Abers, Magdalena A. Walkiewicz, Sarah L. Anzick, Muthulekha Swamydas, Simon Vautier, Mukil Natarajan, Andrew J. Oler, Daisuke Yamanaka, Katrin D. Mayer-Barber, Yoichiro Iwakura, David Bianchi, Brian Driscoll, Ken Hauck, Ahnika Kline, Nicholas S.P. Viall, Christa S. Zerbe, Elise M.N. Ferré, Monica M. Schmitt, Tom Dimaggio, Stefania Pittaluga, John A. Butman, Adrian M. Zelazny, Yvonne R. Shea, Cesar A. Arias, Cameron Ashbaugh, Maryam Mahmood, Zelalem Temesgen, Alexander G. Theofiles, Masayuki Nigo, Varsha Moudgal, Karen C. Bloch, Sean G. Kelly, M. Suzanne Whitworth, Ganesh Rao, Cindy J. Whitener, Neema Mafi, Juan Gea-Banacloche, Lawrence C. Kenyon, William R. Miller, Katia Boggian, Andrea Gilbert, Matthew Sincock, Alexandra F. Freeman, John E. Bennett, Rodrigo Hasbun, Constantinos M. Mikelis, Kyung J. Kwon-Chung, Yasmine Belkaid, Gordon D. Brown, Jean K. Lim, Douglas B. Kuhns, Steven M. Holland, Michail S. Lionakis

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Subcutaneous phaeohyphomycosis typically affects immunocompetent individuals following traumatic inoculation. Severe or disseminated infection can occur in CARD9 deficiency or after transplantation, but the mechanisms protecting against phaeohyphomycosis remain unclear. We evaluated a patient with progressive, refractory Corynespora cassiicola phaeohyphomycosis and found that he carried biallelic deleterious mutations in CLEC7A encoding the CARD9-coupled, β-glucan-binding receptor, Dectin-1. The patient's PBMCs failed to produce TNF-α and IL-1β in response to β-glucan and/or C. cassiicola. To confirm the cellular and molecular requirements for immunity against C. cassiicola, we developed a mouse model of this infection. Mouse macrophages required Dectin-1 and CARD9 for IL-1β and …

Caspase-8 Inactivation Drives Autophagy-Dependent Inflammasome Activation In Myeloid Cells., Yung-Hsuan Wu, Shu-Ting Mo, I-Ting Chen, Fu-Yi Hsieh, Shie-Liang Hsieh, Jianke Zhang, Ming-Zong Lai

Department of Microbiology and Immunology Faculty Papers

Caspase-8 activity controls the switch from cell death to pyroptosis when apoptosis and necroptosis are blocked, yet how caspase-8 inactivation induces inflammasome assembly remains unclear. We show that caspase-8 inhibition via IETD treatment in Toll-like receptor (TLR)-primed Fadd-/-Ripk3-/- myeloid cells promoted interleukin-1β (IL-1β) and IL-18 production through inflammasome activation. Caspase-8, caspase-1/11, and functional GSDMD, but not NLRP3 or RIPK1 activity, proved essential for IETD-triggered inflammasome activation. Autophagy became prominent in IETD-treated Fadd-/-Ripk3-/- macrophages, and inhibiting it attenuated IETD-induced cell death and IL-1β/IL-18 production. In contrast, inhibiting GSDMD or autophagy did not prevent IETD-induced septic …

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 …

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 …

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 …

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 …

Is Strongyloides Stercoralis Hyperinfection Induced By Gglucocorticoids A Result Of Both Suppressed Host Immunity And Altered Parasite Genetics?, De'broski R Herbert, Jonathan D C Stoltzfus, Heather L Rossi, David Abraham

Department of Microbiology and Immunology Faculty Papers

The gastrointestinal (GI) nematode Strongyloides stercoralis (S.s.) causes human strongyloidiasis, a potentially life-threatening disease that currently affects over 600 million people globally. The uniquely pernicious aspect of S.s. infection, as compared to all other GI nematodes, is its autoinfective larval stage (L3a) that maintains a low-grade chronic infection, allowing undetectable persistence for decades. Infected individuals who are administered glucocorticoid therapy can develop a rapid and often lethal hyperinfection syndrome within days. Hyperinfection patients often present with dramatic increases in first- and second-stage larvae and L3a in their GI tract, with L3a widely disseminating throughout host organs leading to sepsis. How …

Microbiome Dynamics During Chemoradiation Therapy For Anal Cancer, Daniel Lin, Molly B. El Alam, Joseph Abi Jaoude, Ramez Kouzy, Jae L. Phan, Jacob H. Elnaggar, Brianna Resendiz, Andrea Y.Delgado Medrano, Erica J. Lynn, Nicholas D. Nguyen, Sonal S. Noticewala, Geena G. Mathew, Emma B. Holliday, Bruce D. Minsky, Prajnan Das, Van K. Morris, Cathy Eng, Melissa P. Mezzari, Joseph F. Petrosino, Nadim J. Ajami, Ann H. Klopp, Cullen M. Taniguchi, Lauren E. Colbert

School of Graduate Studies Faculty Publications

Purpose: Patients with localized squamous cell carcinoma of the anus (SCCA) who experience treatment toxicity or recurrences have few therapeutic options. Investigation into the microbiome's influence on treatment toxicity and its potential use as a predictive biomarker could improve these patients’ outcomes. Our study presents the first longitudinal characterization of the SCCA tumor microbiome and its associations with treatment-related toxicities. Methods and Materials: This prospective cohort study included patients with nonmetastatic SCCA receiving standard-of-care chemoradiation therapy. Anorectal swabs of the tumor site were collected before, during, and after treatment. Patient-reported quality-of-life metrics were collected at similar time points. 16S rRNA …

Homeostasis Of Cell Wall Integrity Pathway Phosphorylation Is Required For The Growth And Pathogenicity Of Magnaporthe Oryzae, Yongchao Cai, Xinyu Liu, Lingbo Shen, Nian Wang, Yangjie He, Haifeng Zhang, Ping Wang, Zhengguang Zhang

School of Graduate Studies Faculty Publications

The cell wall provides a crucial barrier to stress imposed by the external environment. In the rice blast fungus Magnaporthe oryzae, this stress response is mediated by the cell wall integrity (CWI) pathway, consisting of a well-characterized protein phosphorylation cascade. However, other regulators that maintain CWI phosphorylation homeostasis, such as protein phosphatases (PPases), remain unclear. Here, we identified two PPases, MoPtc1 and MoPtc2, that function as negative regulators of the CWI pathway. MoPtc1 and MoPtc2 interact with MoMkk1, one of the key components of the CWI pathway, and are crucial for the vegetative growth, conidial formation, and virulence of M. …

"Don't Look Up" Your Science-Herd Immunity Or Herd Mentality?, Botond Z Igyártó

Department of Microbiology and Immunology Faculty Papers

This analysis piece will attempt to examine some of the critical pandemic-related measures implemented in the United States from an immunological perspective and pinpoint caveats that should have been considered before their implementation. I also discuss alternative measures grounded in scientific data that were not thoroughly explored and likely could have helped fight the pandemic.

Solid-State Nmr Analysis Of Unlabeled Fungal Cell Walls From Aspergillus And Candida Species, Liyanage D. Fernando, Malitha C. Dickwella Widanage, S. Chandra Shekar, Frederic Mentink-Vigier, Ping Wang, Sungsool Wi, Tuo Wang

School of Medicine Faculty Publications

Fungal infections cause high mortality in immunocompromised individuals, which has emerged as a significant threat to human health. The efforts devoted to the development of antifungal agents targeting the cell wall polysaccharides have been hindered by our incomplete picture of the assembly and remodeling of fungal cell walls. High-resolution solid-state nuclear magnetic resonance (ss NMR) studies have substantially revised our understanding of the polymorphic structure of polysaccharides and the nanoscale organization of cell walls in Aspergillus fumigatus and multiple other fungi. However, this approach requires 13C/15N-enrichment of the sample being studied, severely restricting its application. Here we employ the dynamic …

Genomic Features Underlie The Co-Option Of Sva Transposons As Cis-Regulatory Elements In Human Pluripotent Stem Cells, Samantha M Barnada, Andrew Isopi, Daniela Tejada-Martinez, Clément Goubert, Sruti Patoori, Luca Pagliaroli, Mason Tracewell, Marco Trizzino

Department of Biochemistry and Molecular Biology Faculty Papers

Domestication of transposable elements (TEs) into functional cis-regulatory elements is a widespread phenomenon. However, the mechanisms behind why some TEs are co-opted as functional enhancers while others are not are underappreciated. SINE-VNTR-Alus (SVAs) are the youngest group of transposons in the human genome, where ~3,700 copies are annotated, nearly half of which are human-specific. Many studies indicate that SVAs are among the most frequently co-opted TEs in human gene regulation, but the mechanisms underlying such processes have not yet been thoroughly investigated. Here, we leveraged CRISPR-interference (CRISPRi), computational and functional genomics to elucidate the genomic features that underlie SVA domestication …