Infectious disease
Abstract
Systemic sclerosis (SSc) is characterized by immune system failure, vascular insult, autoimmunity, and tissue fibrosis. Transforming growth factor-beta (TGF-β) is a crucial mediator of persistent myofibroblast activation and aberrant extracellular matrix production in SSc. The factors responsible for this are unknown. By amplifying pattern recognition receptor signaling, Triggering Receptor Expressed on Myeloid Cells 1 (TREM-1) is implicated in multiple inflammatory conditions. In this study, we used novel ligand-independent TREM-1 inhibitors in order to investigate the pathogenic role of TREM-1 in SSc, using preclinical models of fibrosis, and explanted SSc skin fibroblasts. Selective pharmacological TREM-1 blockade prevented and reversed skin fibrosis induced by bleomycin in mice and mitigated constitutive collagen synthesis and myofibroblast features in SSc fibroblasts in vitro. Our results implicate aberrantly activated TREM-1 signaling in SSc pathogenesis, identify a unique approach to TREM-1 blockade, and suggest a potential therapeutic benefit for TREM-1 inhibition.
Authors
Swarna Bale, Priyanka Verma, Bharath Yalavarthi, Matija Bajželj, Syed A.M. Hasan, Jenna N. Silverman, Katherine Broderick, Kris A. Shah, Timothy Hamill, Dinesh Khanna, Alexander B. Sigalov, Swati Bhattacharyya, John Varga
Abstract
Daptomycin is a last resort lipopeptide antibiotic that disrupts cell membrane (CM) and peptidoglycan homeostasis. Enterococcus faecalis has developed a sophisticated mechanism to avoid daptomycin killing by re-distributing CM anionic phospholipids away from the septum. The CM changes are orchestrated by a three-component regulatory system, designated LiaFSR, with a possible contribution of cardiolipin synthase (Cls). However, the mechanism by which LiaFSR controls the CM response and the role of Cls are unknown. Here, we show that cardiolipin synthase activity is essential for anionic phospholipid redistribution and daptomycin resistance since deletion of the two genes (cls1 and cls2) encoding Cls abolished CM remodeling. We identified LiaY, a transmembrane protein regulated by LiaFSR, and Cls1 as important mediators of CM remodeling required for re-distribution of anionic phospholipid microdomains. Together, our insights provide a mechanistic framework on the enterococcal response to cell envelope antibiotics that could be exploited therapeutically.
Authors
April H. Nguyen, Truc T. Tran, Diana Panesso, Kara S. Hood, Vinathi Polamraju, Rutan Zhang, Ayesha Khan, William R. Miller, Eugenia Mileykovskaya, Yousif Shamoo, Libin Xu, Heidi Vitrac, Cesar A. Arias
Abstract
BACKGROUND Congenital cytomegalovirus (cCMV) infection can cause developmental impairment and sensorineural hearing loss (SNHL). To determine the relationship between immune responses to cCMV infection and neurologic sequelae, T cell responses were compared for their connection to clinical symptoms at birth and neurodevelopmental outcomes.METHODS Thirty cCMV-infected and 15 uninfected infants were enrolled in a single-center prospective observational case-control study. T cell pp65-specific cytokine responses; CD57, CD28, and PD-1 expression; and memory subsets were compared.RESULTS Infected neonates (73% symptomatic at birth) lacked pp65-specific cytokine-secreting T cells, with elevated frequencies of CD57+, CD28–, and PD-1+CD8+ T cells and effector memory subsets. Though frequencies overlapped between cCMV symptom groups, asymptomatic infants had higher frequencies of CD57+PD-1+CD8+ T cells. Neonates with subsequent developmental delay lacked detectable CMV-specific T cell responses, with patterns resembling those of uninfected infants. Two children with progressive SNHL had high frequencies of PD-1+CD8+ T cells over the first year compared with children without progressive SNHL.CONCLUSION Similar to published reports, neonatal viral antigen–specific cytokine-secreting T cell responses were not detected, but overall patterns indicate that globally differentiated memory CD8+ T cell populations were induced by cCMV infection, with higher frequencies of terminally differentiated PD-1+CD8+ T cells potentially associated with asymptomatic infection. In this cohort, a lack of in utero T cell differentiation was associated with developmental delay, and high frequencies of PD-1+CD8+ T cells persisted only in children with progressive SNHL. Further work is needed to define the specificity of these T cells and their mechanistic connection to these outcomes.FUNDING This study was funded through an intramural research award at Nationwide Children’s Hospital, the Pediatric Infectious Disease Society Fellowship Award funded by Stanley and Susan Plotkin and Sanofi Pasteur, the Abigail Wexner Research Institute at Nationwide Children’s Hospital, and the Pichichero Family Foundation Vaccines for Children Initiative Research Award from the Pediatric Infectious Diseases Society Foundation.
Authors
Alexandra K. Medoro, Ravi Dhital, Pablo J. Sánchez, Kaitlyn Flint, Brianna Graber, Traci Pifer, Rachelle Crisan, William C. Ray, Christopher C. Phelps, Jonathan R. Honegger, Jing Peng, Ursula Findlen, Prashant Malhotra, Oliver Adunka, Masako Shimamura
Abstract
Vaginal infections in women of reproductive age represent a clinical dilemma with significant socio-economic implications. The understanding of mucosal immunity failure during early pathogenic invasions that allow the pathogen to grow and thrive is far from complete. Neutrophils infiltrate most tissues following circadian patterns as part of normal repair, regulation of microbiota, or immune surveillance and become more numerous after infection. Neutrophils are responsible for maintaining vaginal immunity. Specific to the vagina, neutrophils continuously infiltrate at high levels, although during ovulation they retreat to avoid sperm damage and permit reproduction. Here we show that after ovulation, progesterone promotes resident vaginal macrophage-neutrophils crosstalk by up-regulating Yolk sac and early fetal organs (Folr2+ (folate receptor 2)) macrophage Cxcl2 expression, in a Tnfa-monocyte-derived macrophage (Cx3cr1hi MHCIIhi) mediated manner, to activate neutrophils' capacity to eliminate sex-transmitted and opportunistic microorganisms. Indeed, progesterone plays an essential role in conciliating the balance between the commensal microbiota, sperm, and the threat of pathogens: because progesterone not only promotes a flurry of neutrophils but also increases neutrophilic fury to restore immunity after ovulation to thwart pathogenic invasion post-intercourse. Therefore, modest progesterone dysregulations could lead to a suboptimal neutrophilic response, resulting in insufficient mucosal defense and recurrent unresolved infections.
Authors
Carla Gómez-Oro, Maria C. Latorre, Patricia Arribas-Poza, Alexandra Ibáñez-Escribano, Katia R. Baca-Cornejo, Jorge Gallego-Valle, Natalia López-Escobar, Mabel Mondéjar-Palencia, Marjorie Pion, Luis A. López-Fernández, Enrique Mercader-Cidoncha, Federico Pérez-Milán, Miguel Relloso
Abstract
Epstein Barr virus (EBV) contributes to around 2% of all tumors worldwide. Simultaneously, more than 90% of healthy human adults persistently carry EBV without clinical symptoms. In most EBV carriers it is thought that virus-induced tumorigenesis is prevented by cell-mediated immunity. Specifically, memory CD8+ T cells recognize EBV-infected cells during latent and lytic infection. Using a symptomatic primary infection model, similar to infectious mononucleosis (IM), we found EBV-induced CD8+ tissue-resident memory T cells (TRMs) in mice with a humanized immune system. These human TRMs were preferentially established after intranasal EBV infection in nasal-associated lymphoid tissues (NALT), equivalent to tonsils, the primary site of EBV infection in humans. They expressed canonical TRM markers, including CD69, CD103, and BLIMP-1, as well as Granzyme B, CD107a and CCL5. Despite cytotoxic activity and cytokine production ex vivo, these TRMs demonstrated reduced CD27 expression and proliferation and failed to control EBV viral loads in the NALT during infection although effector memory T cells (TEMs) controlled viral titers in spleen and blood. Overall, TRMs are established in mucosal lymphoid tissues by EBV infection, but primarily systemic CD8+ T cell expansion seems to control viral loads in the context of IM-like infection.
Authors
Daniel Kirchmeier, Yun Deng, Lisa Rieble, Michelle Böni, Fabienne Läderach, Patrick Schuhmachers, Alma Delia Valencia-Camargo, Anita Murer, Nicole Caduff, Bithi Chatterjee, Obinna Chijioke, Kyra Zens, Christian Münz
Abstract
In humans, lymph nodes are the primary site of measles virus (MeV) replication. To understand the immunological events that occur at this site, we infected human lymphoid tissue explants using a pathogenic strain of MeV that expresses GFP. We found that MeV infected 5%–15% of cells across donors. Using single-cell RNA-Seq and flow cytometry, we found that while most of the 29 cell populations identified in the lymphoid culture were susceptible to MeV, there was a broad preferential infection of B cells and reduced infection of T cells. Further subsetting of T cells revealed that this reduction may be driven by the decreased infection of naive T cells. Transcriptional changes in infected B cells were dominated by an interferon-stimulated gene (ISG) signature. To determine which of these ISGs were most substantial, we evaluated the proteome of MeV-infected Raji cells by mass spectrometry. We found that IFIT1, IFIT2, IFIT3, ISG15, CXCL10, MX2, and XAF1 proteins were the most highly induced and positively correlated with their expression in the transcriptome. These data provide insight into the immunological events that occur in lymph nodes during infection and may lead to the development of therapeutic interventions.
Authors
Joshua A. Acklin, Aum R. Patel, Andrew P. Kurland, Shu Horiuchi, Arianna S. Moss, Emma J. DeGrace, Satoshi Ikegame, Jillian Carmichael, Shreyas Kowdle, Patricia A. Thibault, Naoko Imai, Hideki Ueno, Benjamin Tweel, Jeffrey R. Johnson, Brad R. Rosenberg, Benhur Lee, Jean K. Lim
Abstract
Melioidosis, a neglected tropical infection caused by Burkholderia pseudomallei, commonly presents as pneumonia or sepsis with mortality rates up to 50% despite appropriate treatment. A better understanding of the early host immune response to melioidosis may lead to new therapeutic interventions and prognostication strategies to reduce disease burden. Whole blood transcriptomic signatures in 164 melioidosis patients and 70 patients with other infections hospitalized in northeastern Thailand enrolled within 24 hours following hospital admission were studied. Key findings were validated in an independent melioidosis cohort. Melioidosis was characterized by upregulation of interferon signaling responses compared to other infections. Mortality in melioidosis was associated with excessive inflammation, up-regulated type 2 immune responses and a dramatic decrease in T cell-mediated immunity compared to survivors. We identified and independently confirmed a five-gene predictive set classifying fatal melioidosis (validation cohort: an area under the receiver operating characteristic curve 0.83, 95% CI: 0.67–0.99). In conclusion, this study highlights the intricate balance between innate and adaptive immunity during fatal melioidosis and can inform future precision medicine strategies for targeted therapies and prognostication in this severe infection.
Authors
Patpong Rongkard, Lu Xia, Barbara Kronsteiner, Thatcha Yimthin, Rungnapa Phunpang, Adul Dulsuk, Viriya Hantrakun, Gumphol Wongsuvan, Parinya Chamnan, Lara Lovelace-Macon, Emanuele Marchi, Nicholas P.J. Day, Ali Shojaie, Direk Limmathurotsakul, Narisara Chantratita, Paul Klenerman, Susanna J. Dunachie, T. Eoin West, Sina A. Gharib
Abstract
Chronic immune activation promotes tuberculosis (TB) reactivation in the macaque Mycobacterium tuberculosis (M. tuberculosis)/SIV coinfection model. Initiating combinatorial antiretroviral therapy (cART) early lowers the risk of TB reactivation, but immune activation persists. Studies of host-directed therapeutics (HDTs) that mitigate immune activation are, therefore, required. Indoleamine 2,3, dioxygenase (IDO), a potent immunosuppressor, is one of the most abundantly induced proteins in NHP and human TB granulomas. Inhibition of IDO improves immune responses in the lung, leading to better control of TB, including adjunctive to TB chemotherapy. The IDO inhibitor D-1 methyl tryptophan (D1MT) is, therefore, a bona fide TB HDT candidate. Since HDTs against TB are likely to be deployed in an HIV coinfection setting, we studied the effect of IDO inhibition in M. tuberculosis/SIV coinfection, adjunctive to cART. D1MT is safe in this setting, does not interfere with viral suppression, and improves the quality of CD4+ and CD8+ T cell responses, including reconstitution, activation and M. tuberculosis–specific cytokine production, and access of CD8+ T cells to the lung granulomas; it reduces granuloma size and necrosis, type I IFN expression, and the recruitment of inflammatory IDO+ interstitial macrophages (IMs). Thus, trials evaluating the potential of IDO inhibition as HDT in the setting of cART in M. tuberculosis/HIV coinfected individuals are warranted.
Authors
Bindu Singh, Riti Sharan, Gayathri Ravichandran, Ruby Escobedo, Vinay Shivanna, Edward J. Dick Jr., Shannan Hall-Ursone, Garima Arora, Xavier Alvarez, Dhiraj K. Singh, Deepak Kaushal, Smriti Mehra
Abstract
Cytomegalovirus (CMV)-specific T-cells, NK cells, and neutralizing antibodies (nAb) were assessed in a randomized trial of CMV prevention with preemptive antiviral therapy (PET) vs. prophylactic antiviral therapy (PRO) in donor seropositive/recipient seronegative (D+R-) liver transplant recipients (LTxR), at 100 days (end of intervention), and at 6 and 12 months post-transplant. The PET group had significantly increased numbers of circulating polyfunctional T-cells, NK cells, and nAb compared to the PRO group at day 100 and several CMV immune parameters remained significantly higher by 12 months post-transplant. Among PET recipients, preceding CMV viremia (vs. no preceding viremia) was associated with significantly higher levels of most CMV immune parameters at day 100. Higher numbers of CMV-specific polyfunctional T-cells and NKG2C+ NK cells at day 100 were associated with a decreased incidence of CMV disease in multivariable Cox regression. The strongest associations with protection against CMV disease were with increased numbers of CMV-specific polyfunctional CD4 T-cells, CD3negCD56dimCD57negNKG2Cpos, and CD3negCD56dimCD57posNKG2Cpos NK cells. PET is superior to PRO for CMV disease prevention by allowing low-level CMV replication and associated antigen exposure that is promptly controlled by antiviral therapy and facilitates enhanced CMV protective immunity in D+R- LTxR.
Authors
Danniel Zamora, Sayan Dasgupta, Terry Stevens-Ayers, Bradley Edmison, Drew J. Winston, Raymund R. Razonable, Aneesh K. Mehta, G. Marshall Lyon, Michael Boeckh, Nina Singh, David M. Koelle, Ajit P. Limaye
Abstract
Rift Valley fever (RVF) is an emerging arboviral disease affecting both humans and livestock. In humans, RVF displays a spectrum of clinical manifestations, including encephalitis. To date, there are no FDA-approved vaccines or therapeutics for human use, although several are in pre-clinical development. Few small animal models of RVF encephalitis exist, further complicating countermeasure assessment. Human mAbs RVFV-140, RVFV-268 and RVFV-379 are recombinant potently neutralizing antibodies that prevent infection by binding the RVFV surface glycoproteins. Previous studies showed that both RVFV-268 and RVFV-140 improve survival in a lethal mouse model of disease, and RVFV-268 has prevented vertical transmission in a pregnant rat model of infection. Despite these successes, evaluation of mAbs in the context of brain disease has been limited. This is the first study to assess neutralizing antibodies for prevention of RVF neurologic disease using a rat model. Administration of RVFV-140, RVFV-268, or RVFV-379 twenty-four hours prior to aerosol exposure to the virulent ZH501 strain of RVFV results in substantially enhanced survival and lack of neurological signs of disease. These results using a stringent and highly lethal aerosol infection model supports the potential use of human mAbs to prevent the development of RVF encephalitis.
Authors
Kaleigh A. Connors, Nathaniel S. Chapman, Cynthia M. McMillen, Ryan M. Hoehl, Jackson J. McGaughey, Zachary D. Frey, Morgan Midgett, Connor Williams, Douglas S. Reed, James E. Crowe Jr., Amy L. Hartman
No posts were found with this tag.
