Postdoc Listing

Grad Listing

Total Submitted Abstracts: 17

Submitted for: Postdoc Presentation Okay to Post to Web: Yes


  Tumor-associated B cells: Friends or Foes?

  Presenter: Lloyd Bod
  All Authors:Lloyd Bod, Lloyd Bod, Jingwen Shi, Elena Torlai Triglia, Alexandra Schnell, Yoon-Chul Kye, Johannes Fessler, Juhi R. Kuchroo, Rocky M. Barilla, Sarah Zaghouani, Elena Christian, Toni Marie Delorey, Kanishka Mohib, Sheng Xiao, David M. Rothstein, Orit Rozenblatt-Rosen, Arlene H. Sharpe, Lionel Apetoh, Aviv Regev, Vijay K. Kuchroo
  Harvard Medical School and Brigham and Women's Hospital

As one of the main populations of the immune system, B cells exert a key role in both the innate and adaptive branches of immunity. Depending on the context, different specialized B cell subsets are solicited and engage a various range of responses. Beyond their ability to mediate humoral response, B cells are potent antigen presenting cells and could provide co-stimulatory or co-inhibitory signals and secrete cytokines modulating the immune responses. In cancer, B cells represent the second most abundant tumor-infiltrating lymphocyte and therefore might play an important role in modulating the immune response to cancer. However, it remains ambiguous how B cells orient the anti-tumor immunity, indicated by divergent conclusions in studies addressing this question. A better understanding of the tumor-infiltrating B cell subsets remains essential to dissect how they influence cancer immunity. Using both bulk and single-cell RNA sequencing (scRNAseq) technologies combined with high-throughput flow cytometry, we investigated tumor-associated B cell diversity and potential role on tumor progression. Our goal is to better identify pro- and anti- tumor B cells to design therapies targeting one of these subsets and improve clinical outcome.


Submitted for: Graduate Student Presentation Okay to Post to Web: Yes


  Early Life Inflammation Primes a Th2-Fibroblast Niche in Skin

  Presenter: Ian Boothby
  All Authors:Ian Boothby, Maxime J. Kinet, Devi P. Boda, Elaine Y. Kwan, Sean Clancy, Jarish N. Cohen, Ireneusz Habrylo, Margaret M. Lowe, Mariela Pauli, Ashley E. Yates, Jamie D. Chan, Hobart W. Harris, Isaac M. Neuhaus, Timothy H. McCalmont, Ari B. Molofsky, and Michael D. Rosenblum

Inflammation early in life can prime the local immune milieu of peripheral tissues, causing lasting changes in immunologic tone that confer disease protection or susceptibility. The cellular and molecular mechanisms that incite changes in immune tone in many nonlymphoid tissues remain largely unknown. We find that time-limited neonatal inflammation induced by transient reduction of neonatal regulatory T cells (Tregs) causes a dramatic dysregulation of subcutaneous tissue in murine skin, accompanied by the selective accumulation of Th2 cells within a distinct microanatomic niche. Th2 cells are maintained into adulthood through interactions with a fibroblast population in skin fascia that we refer to as Th2-interacting fascial fibroblasts (TIFFs), which expand in response to Th2 cytokines to form subcutaneous fibrous bands. Activation of the Th2-TIFF niche by neonatal inflammation primes skin for altered reparative responses to wounding. We further identify fibroblasts in healthy human skin expressing the TIFF transcriptional signature and find these cells at high levels in eosinophilic fasciitis, an orphan disease characterized by inflammation and fibrosis of the skin fascia. Taken together, these data define a novel Th2 niche in skin, functionally characterize a disease-associated fibroblast population, and suggest a mechanism of immunologic priming whereby inflammation early in life creates networks between adaptive immune cells and stromal cells, establishing an immunological set-point in tissues that is maintained throughout life.


Submitted for: Graduate Student Presentation Okay to Post to Web: Yes


  The Vγ9Vδ2 T cell response is modulated by inhibitory receptors with MHC-I ligands

  Presenter: Perri Callaway
  All Authors:Perri Callaway, Lila Farrington, Justine Levan, Felistas Nankya, Kate Naluwu, Kenneth Musinguzi, Emmanuel Arinaitwe, Moses Kamya, Grant Dorsey, Margaret Feeney
  UCSF/UC Berkeley

Vγ9Vδ2 T cells (Vδ2s) are a subset of γδ T cells that are important in their response to both microbes and to malignant cells. In particular, Vδ2s are intrinsically reactive to the phosphoantigen HMBPP produced by P. falciparum, the causative agent of malaria. HMBPP is taken up by host cells and binds intracellularly to the molecules BTN2a1 and BTN3a1, which in turn causes conformational shifts that are recognized by the Vδ2 TCR, leading to Vδ2 degranulation and cytokine production. We have previously shown that chronic P. falciparum exposure leads to a decrease in the overall frequency of Vδ2s and TCR responsiveness but an increase in their expression of a number of different NK receptors, including CD16 and KIRs. Here we expand these studies to other NK receptors and show that blocking MHC-I, the ligand not only for KIRs but also LILRB1 and NKG2a, increased overall Vδ2 activation. We further show that LILRB1 expression on Vδ2s is elevated in individuals with chronic malaria exposure but that NKG2a is not. LILRB1 is also more likely to be expressed on CD16+ Vδ2s while NKG2a has a uniform distribution across Vδ2 subsets. Together, these results suggest that LILRB1 on Vδ2s is modulated by repeated P. falciparum exposure in a similar manner to CD16 and KIRs but that NKG2a is independent of these changes. These results also have implications for the field of immuno-oncology where Vδ2s are being investigated as cell therapies and monoclonal antibodies against KIRs, LILRB1 and NKG2a are being developed as checkpoint inhibitors.


Submitted for: Graduate Student Presentation Okay to Post to Web: Yes


  The role of temperature on macrophage functional activity in young and aged mice.

  Presenter: Intisar Hassan
  All Authors:Intisar Hassan , Allison Strope, Satyajit Rath, Jeannine M Durdik
  University of Arkansas

Fever responses provide a survival advantage. Macrophages function under a range of temperatures experienced by the core and extremities and at the elevated body temperatures of fever. We examined the effect of temperature on the in vitro immune response of young and aged mouse macrophages. Macrophages isolated from young (4-6 months) and old (18-24 months) mice and activated with lipopolysaccharide (LPS) or IFN-g or both. Stimulated mouse bone marrow-derived macrophage (BMDM) and splenic macrophage (SM) cells from young mice show increased NO production and protein synthesis at 39°C compared to 37°C. At fever temperature, BMDM from aged mice had even higher levels of NO in response to LPS and IFN-g than young at 37 and 39°C. Stimulated SM cells from aged did not further increase NO or protein synthesis at 39°C over 37°C. Peritoneal resident macrophage (PRM) from aged mice produced less NO at both 37°C and 39°C compared to those from young mice in spite of an increased in the number of PRM present in aged mice. PRM from young mice tested higher for protein synthesis at 39°C compared to 37°C. The unstimulated PRM from aged mice protein synthesis was higher than unstimulated young and showed some increase with LPS at 39°C but at a lesser increment than the young. Our findings suggest that increasing host body temperature can enhance macrophage function over a narrow range of temperatures and that this function is dependent upon the age and inflammatory state of the host and the local tissue environment.


Submitted for: Faculty Presentation Okay to Post to Web: Yes


  A non-canonical, interferon-independent signaling activity of cGAMP triggers DNA damage response signaling

  Presenter: Nagaraj Kerur
  All Authors:Nagaraj Kerur, Daipayan Banerjee, Kurt Langberg, Salar Abbas, Eric Odermatt, Praveen Yerramothu, Martin Volaric, Matthew A. Reidenbach, Kathy J. Krentz, C. Dustin Rubinstein, David L. Brautigan, Tarek Abbas, Bradley D. Gelfand, Jayakrishna Ambati, Nagaraj Kerur
  The Ohio State University

Cyclic guanosine monophosphate-adenosine monophosphate (cGAMP), produced by cyclic GMP-AMP synthase (cGAS), stimulates the production of type I interferons (IFN). Here we show that cGAMP activates DNA damage response (DDR) signaling independently of its canonical IFN pathways. Loss of cGAS dampens DDR signaling induced by genotoxic insults. Mechanistically, cGAS activates DDR in a STING-TBK1-dependent manner, wherein TBK1 stimulates the autophosphorylation of the DDR kinase ATM, with the consequent activation of the CHK2-p53-p21 signal transduction pathway and the induction of G1 cell cycle arrest. Despite its stimulatory activity on ATM, cGAMP suppresses homology-directed repair (HDR) through the inhibition of polyADP-ribosylation (PARylation). Finally, we show that cGAMP also activates DDR signaling in invertebrate species lacking IFN (Crassostrea virginica and Nematostella vectensis), suggesting that the genome surveillance mechanism of cGAS predates metazoan interferon-based immunity.


Submitted for: Other Presentation Okay to Post to Web: Yes


  TGFß-dependent LRRC15+ myofibroblasts dictate the tumor fibroblast setpoint to promote cancer immunotherapy resistance

  Presenter: Akshay Krishnamurty
  All Authors:Akshay Krishnamurty, Minh Thai, Justin Shyer, Matthew B. Buechler, Yeqing Angela Yang, Rachana N. Pradhan, Amber W. Wang, Patricia L. Sanchez, Yan Qu, Cécile Chalouni, Debra Dunlap, James Ziai, Lucinda Tam, Merone Roose-Girma, Zora Modrusan, Sören Müller*, Shannon J. Turley*

Single cell transcriptomics has led to the generation of large-scale atlases to understand cellular heterogeneity across both healthy and diseased tissues at the highest resolution. Such atlases have allowed for in silico inferences of fibroblast ontogeny and function, but without in vivo substantiation are limited in their utility to inspire novel fibroblast-directed therapies to improve disease outcome. In cancer, single-cell studies identified the emergence of a myofibroblast population, in both mice and humans, uniquely marked by a highly restricted leucine rich repeat containing protein, LRRC15. However, the molecular signals underlying development of LRRC15+ cancer associated fibroblasts (CAFs) and their direct impact on anti-tumor immunity remain uncharacterized. In a mouse model of pancreatic cancer, we provide in vivo genetic evidence that TGFßR2 signaling in healthy Dermatopontin (DPT)+ universal fibroblasts is essential for development of tumor-associated LRRC15+ myofibroblasts. Analysis of tumors from 159 patients across 13 indications revealed a conserved axis from universal fibroblasts to LRRC15+ myofibroblasts. This axis is the predominant driver of fibroblast lineage diversity in human cancers. Using a newly developed Lrrc15-Diphtheria toxin receptor knock-in mouse model that enables selective depletion of LRRC15+ CAFs, we show loss of this population markedly reduced total tumor fibroblast content and recalibrated the CAF composition towards universal fibroblasts. In turn, tumor regression in response to anti-PD-L1 immune checkpoint blockade and expansion of polyfunctional effector CD8 T cells were significantly augmented upon ablation. Collectively, these findings demonstrate that TGFß-dependent LRRC15+ CAFs dictate the tumor-fibroblast setpoint to promote tumor growth, suppress CD8+ T cell functionality, and limit responsiveness to checkpoint blockade. Development of treatments that restore the homeostatic fibroblast setpoint by diminishing pro-disease LRRC15+ myofibroblasts may improve patient survival and response to immunotherapy.


Submitted for: Graduate Student Presentation Okay to Post to Web: No


  Disrupted X chromosome inactivation (XCI) maintenance in B lymphocytes predisposes female mice to lupus-like disease

  Presenter: Claudia Lovell
  All Authors:Claudia Lovell, Claudia Lovell, Montserrat Anguera
  University of Pennsylvania

90% of individuals diagnosed with the autoimmune disease systemic lupus erythematosus (SLE) are women, but the mechanisms that govern sex bias in immunologic pathology are not well understood. Susceptibility to SLE increases with the number of X chromosomes carried by an individual. This suggests that having more than one X chromosome, which contains numerous immune-regulatory genes, may contribute to sex-biased risk for developing autoimmune disease. The dosage of X-linked gene expression in mammals with more than one X chromosome is balanced by X-Chromosome Inactivation (XCI). XCI is maintained in somatic cells by association of the long non-coding RNA Xist with the inactive X chromosome (Xi), along with heterochromatic repressive marks. Our lab discovered that mouse and human naïve B cells contain no visualizable Xist RNA or have dispersed Xist RNA signal in the nucleus. Upon B cell stimulation, Xist RNA and heterochromatic modifications re-localize to the Xi. This dynamic XCI maintenance is disrupted in B cells from SLE patients and mouse models of SLE, with incomplete re-localization of silencing marks to the Xi upon stimulation. Furthermore, B cells from SLE patients exhibit increased expression of X-linked genes, including some immune-related genes, likely due to incomplete XCI maintenance. To determine whether impaired localization of Xist RNA to the Xi impacts B cell biology and increases predisposition to autoimmune disease, we leverage a B-cell specific conditional knockout of Xist using an mb1-cre driven system. Female Mb1-cre Xist cKO/cKO (“Xist cKO”) mice are viable, have no survival deficits, and exhibit minimal changes in B cell subsets compared to age-matched wild type mice. Strikingly, in a chemically induced model of SLE, Xist cKO mice develop and maintain higher levels of anti-double stranded DNA autoantibodies earlier than wild type counterparts. These findings suggest that loss of Xist RNA in B lymphocytes and subsequent perturbed XCI maintenance leads to sex biased development of chemically-induced SLE. Investigating the epigenetic mechanisms of XCI maintenance in B cells will reveal how genetic contributions from the X are critical for B cell function, and will unveil an X-chromosome based mechanism that contributes to female-biased autoimmunity.


Submitted for: Postdoc Presentation Okay to Post to Web: Yes


  The role of cross-reactive CD4+ T cells in immune responses upon SARS-CoV-2 infection and vaccination

  Presenter: Lucie Loyal
  All Authors:Lucie Loyal, Lucie Loyal, Julian Braun, Larissa Henze, Lil Meyer-Arndt, Andreas Thiel, Claudia Giesecke-Thiel
  Si-M / “Der Simulierte Mensch” a science framework of Technische Universität Berlin and Charité - Universitätsmedizin Berlin, Berlin, Germany; Berlin Institute of Health at Charité - Universitätsmedizin Berlin, BIH Center for Regenerative Therapies, Berlin (BCRT), Germany

The newly emerged coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), caused a global pandemic challenging economy and health systems. Initially, it was assumed that SARS-CoV-2 encountered an immunologically unprotected population, however, SARS-CoV-2 displays considerable homologies with endemic, seasonal common cold endemic coronaviruses (HCoVs). We and others could demonstrate the existence of cellular and humoral cross-reactivity to SARS-CoV-2, still the role of cross-reactive immunity in SARS-CoV-2 infection and vaccination is under debate. We comprehensively determined HCoV-reactivity and SARS-CoV-2-cross-reactivity in unexposed individuals and COVID-19 convalescents. HCoV reactive CD4+ T cells were ubiquitous, but their presence decreased with age, paralleled by a decrease in SARS-CoV-2 cross-reactive CD4+ T cells. Pre-existing cross-reactive memory T cells were efficiently recruited into mild SARS-CoV-2 infections and their abundance correlated with higher S1 IgG and neutralising antibodies titers. Importantly, the cells were also reactivated after primary BNT162b2 COVID-19 mRNA vaccination in which their kinetics resembled that of secondary immune responses. Our results highlight the functional importance of pre-existing spike-cross-reactive T cells in SARS-CoV-2 infection and vaccination. Cross-reactive immunity may account for the unexpectedly rapid induction of immunity following primary SARS-CoV-2 immunisation and the high rate of asymptomatic/mild COVID-19 disease courses.


Submitted for: Graduate Student Presentation Okay to Post to Web: Yes


  Imaging the lung microenvironment during Coccidioidomycosis

  Presenter: Nadia Miranda
  All Authors:Nadia Miranda, Anh Diep, Susana Tejeda-Garibay, Dr. Katrina K Hoyer
  UC Merced

Valley fever is a respiratory disease caused by the fungal pathogen Coccidioides. Very little is known about how the fungus interacts with the immune system and the lung microenvironment, hampering vaccine and therapy development. There is a critical need to identify which immune cells are interacting with the fungus in the lungs and how these cells control infection. Granulomas form within the lung to control infection, but the formation, maintenance, and molecular and immune players in these processes are largely unexplored. Granuloma cell mass can be identified in X-rays and MRI scans only to be misdiagnosed for tumors, until a lung biopsy is analyzed. To investigate immune cells present in Coccidioides granulomas, we utilized tissue immunohistochemistry via fixed-formalin paraffin-embedded (FFPE) and fresh frozen embedded samples to assess immune cell and Coccidioides interactions. Various labeling methods have been investigated using infected mouse lungs to optimize procedures before switching to patient samples. Hematoxylin and eosin (H&E) staining combined with periodic acid–Schiff (PAS) identifies Coccidioides spread within the lung following fungal inhalation in mice. Lung imaging challenges include the presence of endogenous peroxidases that cause non-specific antibody binding. Antigen retrieval following paraffin embedding, have now been optimized to fit the lung and specific to the antibody that is being used. Here we highlight various troubleshooting methods with successful immunofluorescence FFPE lung imaging.


Submitted for: Postdoc Presentation Okay to Post to Web: Yes


  Regulatory T cells promote inflammation after skin injury

  Presenter: Joshua Moreau
  All Authors:Joshua Moreau, Miqdad Dhariwala, Victoire Gouirand, Devi Boda, Ian Boothby, Margaret Lowe, Jarish Cohen, Courtney Macon, John Leech, Lokesh Kalekar, Tiffany Scharschmidt, Michael Rosenblum
  University of California, San Francisco

Regulatory T cells (Tregs) potently attenuate inflammation to prevent autoimmunity. However, Tregs in peripheral barrier tissues have additional specialized functions. In the skin, Tregs promote wound healing, suppress dermal fibrosis, facilitate epidermal regeneration, and augment hair follicle cycling. Here, we report that skin Tregs are transcriptionally attuned to interact with their local tissue environment through increased expression of integrin and TGF-β pathway genes that influence epithelial cell biology. Tregs localizing to the skin epithelium are specifically enriched in these transcriptional pathways. We identify a molecular circuit where skin Tregs license keratinocytes to promote neutrophilic inflammation after injury to the skin barrier. Combining single-cell transcriptomic discovery approaches with Treg lineage specific loss of function experiments, we uncovered preferential expression and activity of the integrin αvβ8 on skin Tregs. Upon skin injury, Tregs utilize this integrin to activate latent TGF-ß, which induces CXCL5 production from epithelial cells to promote neutrophil recruitment. Induction of this pathway delayed epidermal regeneration but provided protection from Staphylococcus aureus infection across a compromised barrier. Thus, αvβ8-expressing Tregs in the skin, somewhat paradoxical to their canonical immunosuppressive functions, facilitate inflammation acutely after loss of barrier integrity to finely balance tissue repair with anti-microbial defense.


Submitted for: Postdoc Presentation Okay to Post to Web: Yes


  Complement C5a induces the formation of neutrophil extracellular traps by myeloid-derived suppressor cells to promote metastasis

  Presenter: Sergio Ortiz-Espinosa (1,2,3)
  All Authors:Sergio Ortiz-Espinosa (1,2,3), Xabier Morales(1,3,4), Yaiza Senent(1,2,3), Diego Alignani(3,5,6), Beatriz Tavira(1,3), Irati Macaya(1), Borja Ruiz(1), Haritz Moreno(1), Ana Remirez(1,3,6), Cristina Sainz(1,3,6), Alejandro Rodriguez-Pena(1,3,4), Alvaro Oyarbide(1,3,4), Mikel Ariz(1,3,4), Maria P Andueza(7), Karmele Valencia(1,2,3,6), Alvaro Teijeira(8), Kai Hoehlig(9), Axel Vater(9), Barbara Rolfe(10), Trent M Woodruff(10), Jose Maria Lopez-Picazo(3,7), Silvestre Vicent(1,3,6,11), Grazyna Kochan(3,12), David Escors(3,12), Ignacio Gil-Bazo(1,3,6,7), Jose Luis Perez-Gracia(3,6,7), Luis M Montuenga(1,3,6,11), John D Lambris(13), Carlos Ortiz de Solorzano(1,3,4,6), Fernando Lecanda(1,3,6), Daniel Ajona(1,2,3,6), Ruben Pio(1,2,3,6)
  (1) Program in Solid Tumors, Cima-University of Navarra, Pamplona, Spain. (2) Department of Biochemistry and Genetics, School of Sciences, University of Navarra, Pamplona, Spain. (3) Navarra’s Health Research Institute (IDISNA), Pamplona, Spain. (4) Imaging Platform, CIMA, Pamplona, Spain. (5) Cytometry Unit, Cima-University of Navarra, Pamplona, Spain. (6) Centro de Investigación Biomédica en Red Cáncer (CIBERONC), Madrid, Spain. (7) Department of Oncology, Clínica Universidad de Navarra, Pamplona, Spain. (8) Program in Immunology and Immunotherapy, Cima-University of Navarra, Pamplona, Spain. (9) Aptarion biotech, Berlin, Germany. (10) School of Biomedical Sciences, Faculty of Medicine, University of Queensland, Queensland, Australia. (11) Department of Pathology, Anatomy and Physiology, School of Medicine, University of Navarra, Pamplona, Spain. (12) Immunomodulation Group, Navarrabiomed-Biomedical Research Center, Pamplona, Spain.(13) Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Myeloid-derived suppressor cells (MDSCs) play a major role in cancer progression. We investigated the mechanisms by which complement C5a increases the capacity of polymorphonuclear MDSCs (PMN-MDSCs) to promote tumor growth and metastatic spread. PMN-MDSCs stimulated with C5a favored the invasion of cancer cells via a process dependent on the formation of neutrophil extracellular traps (NETs). NETosis was dependent on the production of high mobility group box 1 (HMGB1) by cancer cells. Moreover, C5a induced the surface expression of the HMGB1 receptors TLR4 and RAGE in PMN-MDSCs. In an in vivo lung metastasis model, inhibition of C5a, C5a receptor-1 (C5aR1), or treatment with NETosis inhibitors reduced the number of circulating-tumor cells, the NETosis in primary tumors and the metastatic burden. In support of the translational relevance of these findings, C5a was also able to stimulate NETosis in PMN-MDSCs obtained from lung cancer patients. Furthermore, myeloperoxidase (MPO)-DNA complexes, as markers of NETosis, were elevated in lung cancer patients and significantly correlated with C5a levels. In conclusion, C5a induces the formation of NETs from PMN-MDSCs in the presence of cancer cells, which may facilitate cancer cell dissemination and metastasis.


Submitted for: Postdoc Presentation Okay to Post to Web: Yes


  Single cell immune profiling of convalescent COVID-19 patients identifies long-lasting changes in T cell and monocyte subsets and CD9 expression which correlate with disease severity

  Presenter: William Pandori
  All Authors:William Pandori, Lindsey E. Padgett, Norma A. Gutierrez, Ahmad Alimadadi, Huy Q. Dinh, Serena J. Chee, Claire E. Olingy, Runpei Wu, Daniel J. Araujo, Pandurangan Vijayanand, Christian H. Ottensmeier, and Catherine C. Hedrick
  La Jolla Institute for Immunology

Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 infection is associated with wide immune system dysfunction which can result in severe symptoms, hospitalization and death. While some recover quickly, a substantial population develop long-haul COVID-19 and continue to experience symptoms months after infection. Although significant progress has been made in understanding the adaptive immune response to SARS-CoV-2 during acute infection, gaps still remain in our understanding of how innate immune cells may change across time after SARS-CoV-2 infection. We hypothesized that by using cytometry by time of flight (CyTOF) to analyze PBMCS from healthy and infected subjects, we would identify new cell surface markers and subsets of innate immune cells that change in COVID-19 patients and correlate with clinical parameters associated with COVID-19 severity. In this pursuit, we analyzed PBMCs from 8 healthy, 7 non-hospitalized and 20 hospitalized blood donors and identified monocyte and dendritic cell subsets that changed in frequency during acute SARS-CoV-2 infection and were correlated with clinical parameters of disease severity. The tetraspanin CD9, CD163 and PD-L2 were the only markers that significantly increased in expression in infected subjects. We also found that after approximately 3 months, CD9+ monocytes remained significantly increased and nonclassical monocytes remained significantly decreased in hospitalized subjects’ PBMCs. These data identify new monocyte subsets present in the blood of acute COVID-19 patients, and mark CD9, for the first time, as an important cell surface marker that may influence COVID-19 severity. Also, our data suggest that SARS-CoV-2 infection can induce long-lasting changes in the myeloid cell compartment, which could be related to complications observed in long-haul COVID-19.


Submitted for: Graduate Student Presentation Okay to Post to Web: Yes


  Intestinal and tracheal microbiomes inhibit in vitro growth of Coccidioides immitis

  Presenter: Susana Tejeda-Garibay
  All Authors:Susana Tejeda-Garibay, Anh L. Diep, Katrina K. Hoyer
  University of California Merced

Valley fever is a disease caused by Coccidioides, a fungal pathogen, and is frequently misdiagnosed as community acquired bacterial pneumonia and treated with several rounds of antibiotics prior to accurate diagnosis. Antibiotic treatment changes the microbiome repertoire and host immunity; the impact of these microenvironmental changes on Coccidioides invasiveness is unknown. A soil microbial antagonist related to Bacillus subtilis inhibits in vitro growth of Coccidioides immitis through a clear zone of inhibition between fungi and bacteria. Whether host microbiota also could inhibit Coccidioides is unknown. To assess whether the host microbiota has inhibition capabilities against Coccidioides, we performed two types of inhibition assays. A 50/50 inhibition assay was performed in which the host microbiota and Coccidioides were placed in direct competition simultaneously on agar plates. A spike in inhibition assay was also performed in which the host microbiota was allowed to reach ~80% confluency, to mimic an established in vivo microbiome, before spiking in Coccidioides. The area of growth was observed and measured at day 4, 7, and 11. Our in vitro data indicate that specific intestinal and tracheal host microbiome species inhibit Coccidioides growth. To assess if partial in vitro depletion of host microbiota allows greater Coccidioides growth, antibiotic disc diffusion assays were performed. Our data suggests that depleting commensal microbiomes, allows a niche for Coccidioides growth. These in vitro findings could have clinical relevance and shape the way physicians assess prescription of antibiotics and coccidioidomycosis diagnosis. Experiments to identify the inhibitory microbiota and proteomic interactions are ongoing.


Submitted for: Graduate Student Presentation Okay to Post to Web: Yes



  Presenter: Test Test
  All Authors:Test Test, Test



Submitted for: Graduate Student Presentation Okay to Post to Web: No


  Basal-flux cGAS-STING signaling and touchless activation through post Golgi trafficking interruption

  Presenter: Xintao Tu
  All Authors:Xintao Tu, Ting-ting Chu, Devon Jeltema, Kennady Abbott, Kun Yang, Nicole Dobbs, Jie Han, Nan Yan
  UT Southwestern Medical Center

The cGAS-STING pathway activation is traditionally considered as a “trigger-release” mechanism where detection microbial ligands set off the type I interferon (IFN) response. Here, we performed a spatial and temporal mass spec screening of STING trafficking regulators using proximity labelling. We found that STING post-Golgi trafficking is mediated by several post-Golgi cofactors, and their lost-of-function activates tonic IFN signaling. We demonstrate a new “basal-flux” mechanism in which cGAS actively drives STING trafficking and signaling at homeostasis to maintain a basal state of immune defense. cGas-/- lowers the immune state and post-Golgi trafficking blockade extends STING Golgi-dwell time, resulting in elevated immune signaling. Mice which are deficient in the post Golgi regulator of STING develop moderate serologic autoimmunity. Cancer cells which lack these post-Golgi regulators of STING induce T-cell- and IFN-dependent anti-tumor immunity in mice. Together, our data reveal a “basal-flux” mechanism for cGAS-STING signaling that can be activated by blocking a previously enigmatic post-Golgi phase of STING trafficking.


Submitted for: Postdoc Presentation Okay to Post to Web: No


  Early life interactions between commensal bacteria and dermal CD301b+ cDC2s facilitate long-term immune tolerance to the skin microbiome

  Presenter: Antonin Weckel
  All Authors:Antonin Weckel, Julianne Riggs, Geil Merana, Jeanmarie Gonzalez, Joy Okoro, Miqdad Dariwhala, Yosuke Kumamoto , Tiffany Scharschmidt
  University of California San Francisco

Tolerance to commensal bacteria is critical for skin immune homeostasis. We have previously shown that tolerance to skin commensals is preferentially established in neonatal life and supported by generation of commensal-specific regulatory T cells (Tregs). Here, we set out to identify how dendritic cell (DC) interactions with bacteria in neonatal skin facilitate commensal-specific Treg formation. Colonization of neonatal mice with fluorescent Staphylococcus epidermidis (SE) demonstrated that type 2 conventional DCs (cDC2s), particularly those expressing the C-type lectin CD301b, are the primary DC subset to phagocytose and traffic SE to the skin-draining lymph node. CITE-seq revealed that CD301b marks a subset of dermal cDC2s enriched for phagocytic and antigen presentation pathways. Notably, SE phagocytosis prompts neonatal CD301b+ cDC2s to increase expression of both maturation and regulatory molecules indicative of a mature regulatory DC (mregDC) program, which has been linked to Treg generation in other contexts. Using in vitro SE-DC-T cell co-cultures, we find that CD301b+ cDC2s preferentially drive commensal-specific CD4+ proliferation and Treg generation. Depleting this subset in neonatal Mgl2DTR mice substantially prevented accumulation of SE-specific Tregs in vivo. When CD301b+ DCs are transiently depleted during the neonatal period, reduction of the SE-specific Treg compartment persists into adulthood, and adult re-exposure to SE in the context of skin barrier disruption causes heightened Th17-polarized skin inflammation. Lastly, we utilize a novel human skin explant system that enables bacterial colonization of human foreskin to demonstrate that SE colonization also causes human skin cDC2s to adopt an mregDC phenotype. Taken together, our results identify CD301b+ cDC2s and their polarization into mreg DCs as critical for the neonatal establishment of long-term tolerance to skin commensals.


Submitted for: Postdoc Presentation Okay to Post to Web: Yes


  Costimulation of TLR8 responses by CXCL4 in Human Monocytes Mediated by TBK1-IRF5 Signaling and Epigenomic Remodeling

  Presenter: CHAO YANG
  All Authors:CHAO YANG, Mahesh Bachu, Caroline Brauner, Ruoxi Yuan, Yong Du, Marie Dominique Ah Kioon, Giancarlo Chesi, Franck J. Barrat, Lionel B. Ivashkiv
  Hospital for Special Surgery

CXCL4 regulates responses of immune cells to endosomal TLRs and has been implicated in the pathogenesis of inflammatory and fibrotic diseases. However, mechanisms by which CXCL4 modulates TLR responses, and its functions in monocytes/macrophages, are still unclear. Here we report that CXCL4 changes the profile of the TLR8 response in human monocytes by selectively and dramatically amplifying inflammatory gene transcription and IL-1? production while partially attenuating the IFN response. Mechanistically, costimulation by CXCL4 and TLR8 synergistically activated TBK1/IKK? and repurposed these kinases towards an inflammatory response via coupling with IRF5, and by activating the NLRP3 inflammasome without the need for a second signal. CXCL4 strongly induced chromatin remodeling in a cooperative and synergistic manner with TLR8 signaling, inducing de novo enhancers associated with inflammatory genes. These findings identify signaling and epigenomic mechanisms that underly synergistic activation of inflammatory genes by CXCL4 and TLR8, provide a new paradigm for modulation of TLR responses that is relevant for cytokine storm, and suggest targeting the TBK1/IKK?-IRF5 axis may be beneficial in inflammatory diseases.