Immunopathology Commons^™

Decline In Amphibian Health In Local Stream, Elyse Vetter, Elise Dearment, Colton Russell, Audrey Fontes, Lee Kats

Seaver College Research And Scholarly Achievement Symposium

Many local streams of the Santa Monica Mountains are populated by the native California Newt, Taricha torosa, a species of special concern. Arroyo Sequit is one of these streams, the upper and lower portions of which are split by a culvert and the Mulholland Highway. This stream and the surrounding areas burned during the Woolsey fire of 2018. Since the fire, construction has been ongoing in and around the stream. Two years post-fire (during the summer of 2020) significantly more newts were found in the stream than years prior. A large proportion of these newts were unhealthy in appearance, presenting ...

Lung Epithelial Cell Transcriptional Regulation As A Factor In Covid-19 Associated Coagulopathies, Ethan S. Fitzgerald, Yongzhi Chen, Katherine A. Fitzgerald, Amanda M. Jamieson

COVID-19 Publications by UMMS Authors

SARS-CoV-2 has rapidly become a global pandemic. In addition to the acute pulmonary symptoms of COVID-19 (the disease associated with SARS-CoV-2 infection), pulmonary and distal coagulopathies have caused morbidity and mortality in many patients. Currently, the molecular pathogenesis underlying COVID-19 associated coagulopathies are unknown. Identifying the molecular basis of how SARS-CoV-2 drives coagulation is essential to mitigating short and long term thrombotic risks of sick and recovered COVID-19 patients. We aimed to perform coagulation focused transcriptome analysis of in vitro infected primary respiratory epithelial cells, patient derived bronchial alveolar lavage (BALF) cells, and circulating immune cells during SARS-CoV-2 infection. Our ...

Cnbp, Rel, And Bhlhe40 Variants Are Associated With Il-12 And Il-10 Responses And Tuberculosis Risk [Preprint], Javeed A. Shah, Christopher M. Sassetti, Katherine A. Fitzgerald

University of Massachusetts Medical School Faculty Publications

Rationale: The major human genes regulating M. tuberculosis (Mtb)-induced immune responses and tuberculosis (TB) susceptibility are poorly understood. Although IL-12 and IL-10 are critical for TB pathogenesis, the genetic factors that regulate their expression are unknown. CNBP, REL, and BHLHE40 are master regulators of IL-12 and IL-10 signaling.

Objectives: To determine whether common human genetic variation in CNBP, REL and BHLHE40 is associated with IL-12 and IL-10 expression, adaptive immune responses to mycobacteria, and susceptibility to TB.

Methods and Main Measurements: We characterized the association between common variants in CNBP, REL, and BHLHE40 and innate immune responses in dendritic ...

Human Antibody Immune Responses Are Personalized By Selective Removal Of Mhc-Ii Peptide Epitopes [Preprint], Matias Gutiérrez-González, Padma P. Nanaware, Liying Lu, Lawrence J. Stern, Brandon J. Dekosky

University of Massachusetts Medical School Faculty Publications

Human antibody responses are established by the generation of combinatorial sequence diversity in antibody variable domains, followed by iterative rounds of mutation and selection via T cell recognition of antigen peptides presented on MHC-II. Here, we report that MHC-II peptide epitope deletion from B cell receptors (BCRs) correlates with antibody development in vivo. Large-scale antibody sequence analysis and experimental validation of peptide binding revealed that MHC-II epitope removal from BCRs is linked to genetic signatures of T cell help, and donor-specific antibody repertoire modeling demonstrated that somatic hypermutation selectively targets the personalized MHC-II epitopes in antibody variable regions. Mining of ...

Innate Lymphoid Cells And Disease Tolerance In Sars-Cov-2 Infection [Preprint], Noah J. Silverstein, Yetao Wang, Zachary Manickas-Hill, Claudia C. Carbone, Ann Dauphin, Mgh Covid-19 Collection & Processing Team, Jonathan Z. Li, Bruce D. Walker, Xu G. Yu, Jeremy Luban

University of Massachusetts Medical School Faculty Publications

BACKGROUND: Risk of severe coronavirus disease 2019 (COVID-19) increases with age, is greater in males, and is associated with decreased numbers of blood lymphoid cells. Though the reasons for these robust associations are unclear, effects of age and sex on innate and adaptive lymphoid subsets, including on homeostatic innate lymphoid cells (ILCs) implicated in disease tolerance, may underlie the effects of age and sex on COVID-19 morbidity and mortality.

METHODS: Flow cytometry was used to quantitate subsets of blood lymphoid cells from people infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), comparing those hospitalized with severe COVID-19 (n=40 ...

The Intestinal And Oral Microbiomes Are Robust Predictors Of Covid-19 Severity The Main Predictor Of Covid-19-Related Fatality [Preprint], Doyle V. Ward, Shakti Bhattarai, Mayra Rojas-Correa, Ayan Purkayastha, Devon Holler, Ming Da Qu, William G. Mitchell, Jason D. Yang, Samuel Fountain, Abigail Zeamer, Catherine Forconi, Gavin Fujimori, Boaz Odwar, Caitlin Cawley, Beth A. Mccormick, Ann M. Moormann, Mireya Wessolossky, Vanni Bucci, Ana Maldonado-Contreras

University of Massachusetts Medical School Faculty Publications

The reason for the striking differences in clinical outcomes of SARS-CoV-2 infected patients is still poorly understood. While most recover, a subset of people become critically ill and succumb to the disease. Thus, identification of biomarkers that can predict the clinical outcomes of COVID-19 disease is key to help prioritize patients needing urgent treatment. Given that an unbalanced gut microbiome is a reflection of poor health, we aim to identify indicator species that could predict COVID-19 disease clinical outcomes. Here, for the first time and with the largest COVID-19 patient cohort reported for microbiome studies, we demonstrated that the intestinal ...

T Cells In The Brain Enhance Neonatal Mortality During Peripheral Lcmv Infection, Laurie L. Kenney, Erik P. Carter, Anna Gil, Liisa K. Selin

Open Access Publications by UMMS Authors

In adult mice the severity of disease from viral infections is determined by the balance between the efficiency of the immune response and the magnitude of viral load. Here, the impact of this dynamic is examined in neonates. Newborns are highly susceptible to infections due to poor innate responses, lower numbers of T cells and Th2-prone immune responses. Eighty-percent of 7-day old mice, immunologically equivalent to human neonates, succumbed to extremely low doses (5 PFU) of the essentially non-lethal lymphocytic choriomeningitis virus (LCMV-Armstrong) given intraperitoneally. This increased lethality was determined to be dependent upon poor early viral control, as well ...

Morphological Changes In Dorsal Root Ganglia Macrophages Associated With Neuropathic Pain Mechanisms Suggest A Novel Target For Chronic Pain Therapy, Emily Kussick

CMC Senior Theses

The present study examined morphological changes in the dorsal root ganglia (DRG) following an innate immune stimulus. The importance of the DRG has increasingly become recognized in pain processing as more than just the home of primary afferent cell bodies. All sensory information passes through the DRG via the primary afferents, and on to the spinal cord. The primary afferents synapse with second-order neurons in the spinal cord that ascend towards the brain, where they transmit the pain signal to the limbic forebrain and/or the somatosensory cortex for processing. The DRG is an interesting niche to study at as ...

Case Series: Gene Expression Analysis In Canine Vogt-Koyanagi-Harada/Uveodermatologic Syndrome And Vitiligo Reveals Conserved Immunopathogenesis Pathways Between Dog And Human Autoimmune Pigmentary Disorders, Ista A. Egbeto, Colton J. Garelli, Cesar Piedra-Mora, Neil B. Wong, Clement N. David, Nicholas A. Robinson, Jillian M. Richmond

Open Access Publications by UMMS Authors

Vogt-Koyanagi-Harada syndrome (VKH) and vitiligo are autoimmune diseases that target melanocytes. VKH affects several organs such as the skin, hair follicle, eyes, ears, and meninges, whereas vitiligo is often limited to the skin and mucosa. Many studies have identified immune genes, pathways and cells that drive the pathogeneses of VKH and vitiligo, including interleukins, chemokines, cytotoxic T-cells, and other leukocytes. Here, we present case studies of 2 canines with VKH and 1 with vitiligo, which occurred spontaneously in client-owned companion dogs. We performed comparative transcriptomics and immunohistochemistry studies on lesional skin biopsies from these cases in order to determine if ...

Host-Pathogen Genetic Interactions Underlie Tuberculosis Susceptibility In Genetically Diverse Mice [Preprint], Clare M. Smith, Richard E. Baker, Megan K. Proulx, Bibhuti B. Mishra, Jarukit E. Long, Michael C. Kiritsy, Michelle Bellerose, Andrew J. Olive, Kenan C. Murphy, Kadamba Papavinasasundaram, Frederick Boehm, Charlotte Reames, Christopher M. Sassetti

University of Massachusetts Medical School Faculty Publications

The outcome of an encounter with Mycobacterium tuberculosis (Mtb) depends on the pathogen’s ability to adapt to the heterogeneous immune response of the host. Understanding this interplay has proven difficult, largely because experimentally tractable small animal models do not recapitulate the heterogenous disease observed in natural infections. We leveraged the genetically diverse Collaborative Cross (CC) mouse panel in conjunction with a library of Mtb mutants to associate bacterial genetic requirements with host genetics and immunity. We report that CC strains vary dramatically in their susceptibility to infection and represent reproducible models of qualitatively distinct immune states. Global analysis of ...

Mitochondrial Respiration Contributes To The Interferon Gamma Response In Antigen Presenting Cells [Preprint], Michael C. Kiritsy, Daniel Mott, Samuel M. Behar, Christopher M. Sassetti, Andrew J. Olive

University of Massachusetts Medical School Faculty Publications

The immunological synapse allows antigen presenting cells (APC) to convey a wide array of functionally distinct signals to T cells, which ultimately shape the immune response. The relative effect of stimulatory and inhibitory signals is influenced by the activation state of the APC, which is determined by an interplay between signal transduction and metabolic pathways. While toll-like receptor ligation relies on glycolytic metabolism for the proper expression of inflammatory mediators, little is known about the metabolic dependencies of other critical signals such as interferon gamma (IFNγ). Using CRISPR-Cas9, we performed a series of genome-wide knockout screens in macrophages to identify ...

Epidemiology And Pathophysiology Of Common Skin Diseases In West Africa: An Immunodermatological Framework, Osazomon Imarenezor

All HCAS Student Capstones, Theses, and Dissertations

This capstone reviews the common skin diseases on a global scale. With these dermatoses being further funneled into Africa and then magnified into common West African dermatoses, the meta-analyses of literature available paints a clear picture of the epidemiological & pathological factors and their contribution to the skin disease. Each article analysed in this analysis was taken from a 20-year span of January 2000 to December 2019. The selection of articles was fine-tuned by identifying the distribution of skin disease, revealing the populations affected (age, gender, ethnicity, etc), the main causes, country of origin, the prognosis of disease, and the pathology ...

The Tec Kinase Itk Differentially Optimizes Nfat, Nf-Κb, And Mapk Signaling During Early T Cell Activation To Regulate Graded Gene Induction [Preprint], Michael P. Gallagher, James M. Conley, Pranitha Vangala, Andrea Reboldi, Manuel Garber, Leslie J. Berg

University of Massachusetts Medical School Faculty Publications

The strength of peptide:MHC interactions with the T cell receptor (TCR) is correlated with the time to first cell division, the relative scale of the effector cell response, and the graded expression of activation-associated proteins like IRF4. To regulate T cell activation programming, the TCR and the TCR proximal kinase ITK simultaneously trigger many biochemically separate TCR signaling cascades. T cells lacking ITK exhibit selective impairments in effector T cell responses after activation, but under the strongest signaling conditions ITK activity is dispensable. To gain insight into whether TCR signal strength and ITK activity tune observed graded gene expression ...

Deep Gene Sequence Cluster Analyses Of Multi-Virus Infected Mucosal Tissue Reveal Enhanced Transmission Of Acute Hiv-1, Katja Klein, Nicholas J. Hathaway, Eric J. Arts

Open Access Publications by UMMS Authors

Exposure of the genital mucosa to a genetically diverse viral swarm from the donor HIV-1 can result in breakthrough and systemic infection by a single transmitted/founder (TF) virus in the recipient. The highly diverse HIV-1 envelope (Env) in this inoculating viral swarm may have critical role in transmission and subsequent immune response. Thus, chronic (Envchronic) and acute (Envacute) Env chimeric HIV-1 were tested using multi-virus competition assays in human mucosal penile and cervical tissues. Viral competition analysis revealed that Envchronic viruses resided and replicated mainly in the tissue while Envacute viruses penetrated the human tissue and established infection of ...

A Natural Polymorphism Of Mycobacterium Tuberculosis In The Esxh Gene Disrupts Immunodomination By The Tb10.4-Specific Cd8 T Cell Response, Rujapak Sutiwisesak, Nathan D. Hicks, Shayla Boyce, Kenan C. Murphy, Kadamba Papavinasasundaram, Stephen M. Carpenter, Julie Boucau, Neelambari Joshi, Sylvie Le Gall, Sarah M. Fortune, Christopher M. Sassetti, Samuel M. Behar

Open Access Publications by UMMS Authors

CD8 T cells provide limited protection against Mycobacterium tuberculosis (Mtb) infection in the mouse model. As Mtb causes chronic infection in mice and humans, we hypothesize that Mtb impairs T cell responses as an immune evasion strategy. TB10.4 is an immunodominant antigen in people, nonhuman primates, and mice, which is encoded by the esxH gene. In C57BL/6 mice, 30-50% of pulmonary CD8 T cells recognize the TB10.44-11 epitope. However, TB10.4-specific CD8 T cells fail to recognize Mtb-infected macrophages. We speculate that Mtb elicits immunodominant CD8 T cell responses to antigens that are inefficiently presented by infected ...

Peptidylarginine Deiminase 2 Has Potential As Both A Biomarker And Therapeutic Target Of Sepsis, Yuzi Tian, Santanu Mondal, Paul R. Thompson, Yongqing Li

Open Access Publications by UMMS Authors

Peptidylarginine deiminases (PADs) are a family of calcium-dependent enzymes that are involved in a variety of human disorders, including cancer and autoimmune diseases. Although targeting PAD4 has shown no benefit in sepsis, the role of PAD2 remains unknown. Here, we report that PAD2 is engaged in sepsis and sepsis-induced acute lung injury in both human patients and mice. Pad2-/- or selective inhibition of PAD2 by a small molecule inhibitor increased survival and improved overall outcomes in mouse models of sepsis. Pad2 deficiency decreased neutrophil extracellular trap (NET) formation. Importantly, Pad2 deficiency inhibited Caspase-11-dependent pyroptosis in vivo and in vitro. Suppression ...

Is Smaller Better? Vaccine Targeting Recombinant Receptor-Binding Domain Might Hold The Key For Mass Production Of Effective Prophylactics To Fight The Covid-19 Pandemic, Manish Muhuri, Guangping Gao

COVID-19 Publications by UMMS Authors

A recent report by Yang et al. published in Nature reported a recombinant vaccine utilizing recombinant receptor-binding domain (RBD) of SARS-CoV-2 Spike Protein.This vaccine candidate successfully induced potent functional antibody responses in the immunized mice, rabbits, and non-human primates. The study highlights the critical role of the immunogenicity of the RBD domain upon SARS-CoV-2 infection and the alternate vaccine designs that could serve as effective prophylactics against the pandemic.

An In-Depth Investigation Of The Safety And Immunogenicity Of An Inactivated Sars-Cov-2 Vaccine [Preprint], Jing Pu, Shan Lu, Qihan Li

University of Massachusetts Medical School Faculty Publications

BACKGROUND: 50 In-depth investigations of the safety and immunogenicity of inactivated SARS-CoV-2 vaccines 51 are needed. 52

METHOD: 53 In a phase I randomized, double-blinded, and placebo-controlled trial involving 192 healthy 54 adults 18-59 years of age, two injections of three different doses (50 EU, 100 EU and 150 EU) 55 of an inactivated SARS-CoV-2 vaccine or the placebo were administered intramuscularly with 56 a 2- or 4-week interval between the injections. The safety and immunogenicity of the vaccine 57 were evaluated within 28 days. 58

FINDING: 59 In this study, 191 subjects assigned to three doses groups or the ...

An Approach For The In-Vivo Characterization Of Brain And Heart Inflammation In Duchenne Muscular Dystrophy, Joanne Tang

Electronic Thesis and Dissertation Repository

Duchenne muscular dystrophy (DMD) is a neuromuscular disorder caused by dystrophin loss—notably within muscles and CNS neurons. DMD presents as cognitive weakness, progressive skeletal and cardiac muscle degeneration until pre-mature death from cardiac or respiratory failure. Innovative therapies improved life expectancy, but this is accompanied by increased late-onset heart failure and emergent cognitive degeneration. Thus, there is an increasing need to both better understand and track disease pathophysiology in the dystrophic heart and brain prior to onset of severe degenerative symptoms. Chronic inflammation is strongly associated with skeletal and cardiac muscle degeneration, however chronic neuroinflammation’s role is largely ...

Seroprevalence Of Sars-Cov-2-Specific Igg Antibodies Among Adults Living In Connecticut: Post-Infection Prevalence (Pip) Study [Preprint], Shiwani Mahajan, Lokinendi V. Rao, Harlan M. Krumholz

University of Massachusetts Medical School Faculty Publications

Background: A seroprevalence study can estimate the percentage of people with SARS-CoV-2 antibodies in the general population, however, most existing reports have used a convenience sample, which may bias their estimates.

Methods: We sought a representative sample of Connecticut residents, aged ≥18 years and residing in non-congregate settings, who completed a survey between June 4 and June 23, 2020 and underwent serology testing for SARS-CoV-2-specific IgG antibodies between June 10 and July 29, 2020. We also oversampled non-Hispanic Black and Hispanic subpopulations. We estimated the seroprevalence of SARS-CoV-2-specific IgG antibodies and the prevalence of symptomatic illness and self-reported adherence to ...