Secondary infections are frequent complications of viral respiratory infections but the potential consequence of SARS-CoV-2 co-infection with common pulmonary pathogens is poorly understood. We report that co-infection of human ACE2 transgenic mice with sublethal doses of SARS-CoV-2 and Streptococcus pneumoniae results in synergistic lung inflammation and lethality. Mortality was observed regardless of whether SARS-CoV-2 challenge occurred before or after establishment of sublethal pneumococcal infection. Increased bacterial levels following co-infection were associated with alveolar macrophage depletion and treatment with murine GM-CSF reduced lung bacteria numbers and pathology, and partially protected from death. However, therapeutic targeting of interferons, an approach that is effective against influenza co-infections, failed to increase survival. Combined vaccination against both SARS-CoV-2 and pneumococci resulted in 100% protection against subsequent co-infection. The results indicate that when seasonal respiratory infections return to pre-pandemic levels, they could lead to an increased incidence of lethal COVID-19 superinfections, especially among the unvaccinated population.
Tarani Kanta Barman, Amit K. Singh, Jesse L. Bonin, Tanvir N. Nafiz, Sharon L. Salmon, Dennis W. Metzger
Hvcn1 is a voltage-gated proton channel, which reduces cytosol acidification and facilitates the production of reactive oxygen species (ROS). The increased expression of this channel in some cancers, has led to proposing Hvcn1 antagonists as potential therapeutics.While its role in most leukocytes has been studied in-depth, the function of Hvcn1 in T-cells remains poorly defined. We show that HVCN1 plays a non-redundant role in protecting naïve T-cells from intracellular acidification during priming. Despite sharing overall functional impairment in vivo and in vitro, Hvcn1-deficient CD4+ and CD8+ T-cells display profound differences during the transition from naïve to primed T-cells, including in the preservation of TCR signaling, cellular division and death. These selective features result, at least in part, from a substantially different metabolic response to intracellular acidification associated with priming. While Hvcn1-deficient naïve CD4+ T-cells reprogram to rescue the glycolytic pathway, naïve CD8+ T-cells, which express high levels of this channel in the mitochondria, respond by metabolically compensating mitochondrial dysfunction, at least in part via AMPK activation.These observations imply heterogeneity between adaptation of naïve CD4+ and CD8+ T-cells to intracellular acidification during activation.
David Coe, Thanushiyan Poobalasingam, Hongmei Fu, Fabrizia Bonacina, Guosu Wang, Valle Morales, Annalisa Moregola, Nico Mitro, Kenneth C.P. Cheung, Eleanor J. Ward, Suchita Nadkarni, Dunja Aksentijevic, Katiuscia Bianchi, Giuseppe Danilo Norata, Melania Capasso, Federica M. Marelli-Berg
BACKGROUND. Limited information is available on the impact of immunosuppressants on COVID-19 vaccination in patients with immune-mediated inflammatory diseases (IMID). METHODS. This observational cohort study examined the immunogenicity of SARS-CoV-2 mRNA vaccines in adult patients with inflammatory bowel disease, rheumatoid arthritis, ankylosing spondylitis, or psoriatic disease, with or without maintenance immunosuppressive therapies. Antibody and T cell responses to SARS-COV-2, including neutralization against SARS-CoV-2 variants were determined before and after 1 and 2 vaccine doses. RESULTS. We prospectively followed 150 subjects, 26 healthy controls, 9 IMID patients on no treatment, 44 on anti-TNF, 16 on anti-TNF with methotrexate/azathioprine (MTX/AZA), 10 on anti-IL-23, 28 on anti-IL-12/23, 9 on anti-IL-17, and 8 on MTX/AZA. Antibody and T cell responses to SARS-CoV-2 were detected in all participants, increasing from dose 1 to dose 2 and declining 3 months later, with greater attrition in IMID patients compared to healthy controls. Antibody levels and neutralization efficacy against variants of concern were substantially lower in anti-TNF treated patients than in healthy controls and were undetectable against Omicron by 3 months after dose 2. CONCLUSIONS. Our findings support the need for a third dose of mRNA vaccine and for continued monitoring of immunity in these patient groups. FUNDING. Funded by a donation from Juan and Stefania Speck and by Canadian Institutes of Health (CIHR) /COVID-Immunity Task Force (CITF) grants VR-1 172711 and VS1-175545 (T.H.W. and A.C.G); CIHR FDN-143250 (T.H.W.), GA2- 177716 (V.C., A.C.G., T.H.W.), GA1-177703 (A.C.G.) and the CIHR rapid response network to SARS-CoV-2 variants, CoVaRR-Net (to A.C.G.).
Roya M. Dayam, Jaclyn C. Law, Rogier L. Goetgebuer, Gary Y.C. Chao, Kento T. Abe, Mitchell Sutton, Naomi Finkelstein, Joanne M. Stempak, Daniel Pereira, David Croitoru, Lily Acheampong, Saima Rizwan, Klaudia Rymaszewski, Raquel Milgrom, Darshini Ganatra, Nathalia V. Batista, Melanie Girard, Irene Lau, Ryan Law, Michelle W. Cheung, Bhavisha Rathod, Julia Kitaygorodsky, Reuben Samson, Queenie Hu, W. Rod Hardy, Nigil Haroon, Robert D. Inman, Vincent Piguet, Vinod Chandran, Mark S. Silverberg, Anne-Claude Gingras, Tania H. Watts
Inflammation of the esophageal epithelium is a hallmark of eosinophilic esophagitis (EoE), an emerging chronic allergic disease. Herein, we probed human esophageal epithelial cells at single-cell resolution during homeostasis and EoE. During allergic inflammation, the epithelial differentiation program was blocked, leading to loss of KRT6high differentiated populations and expansion of TOP2high proliferating and DSPhigh, SERPINB3high transitioning populations; however, there was stability of the stem cell–enriched PDPNhigh basal epithelial compartment. This differentiation program blockade was associated with dysregulation of transcription factors, including nuclear receptor signalers, in the most differentiated epithelial cells and altered NOTCH-related cell-to-cell communication. Each epithelial population expressed genes with allergic disease risk variants, supporting their functional interplay. The esophageal epithelium differed notably between EoE in histologic remission and controls, indicating that remission is a transitory state poised to relapse. Collectively, our data uncover the dynamic nature of the inflamed human esophageal epithelium and provide a framework to better understand esophageal health and disease.
Mark Rochman, Ting Wen, Michael Kotliar, Phillip J. Dexheimer, Netali Ben-Baruch Morgenstern, Julie M. Caldwell, Hee-Woong Lim, Marc E. Rothenberg
The RTS,S/AS01E vaccine targets the circumsporozoite protein (CSP) of the Plasmodium falciparum parasite. Using protein microarrays, levels of IgG to 1,000 P. falciparum antigens were measured in 2,138 infants (age 6-12 weeks) and children (age 5-17 months) from 6 African sites of the phase 3 trial, sampled before and at four longitudinal visits after vaccination. One month post-vaccination, IgG responses to 17% of all probed antigens showed differences between RTS,S/AS01E and comparator vaccination groups, whereas no prevaccination differences were found. A small subset of antigens presented IgG levels reaching 4- to 8 fold increases in the RTS,S/AS01E group, comparable in magnitude to anti-CSP IgG levels (~11-fold increase). They were strongly cross-correlated and correlated with anti CSP levels, waning similarly over time and re-increasing with the booster dose. Such an intriguing phenomenon may be due to cross-reactivity of anti-CSP antibodies with these antigens. RTS,S/AS01E vaccinees with strong off target IgG responses had an estimated lower clinical malaria incidence after adjusting for age group, site and post-vaccination anti-CSP levels. RTS,S/AS01E-induced IgG may bind strongly not only to CSP, but to unrelated malaria antigens, and this seems to either confer, or at least be a marker of, increased protection from clinical malaria.
Dídac Macià, Joseph J. Campo, Gemma Moncunill, Chenjerai Jairoce, Augusto J. Nhabomba, Maximilian Mpina, Hermann Sorgho, David Dosoo, Ousmane Traore, Kwadwo A. Kusi, Nana Aba Williams, Amit Oberai, Arlo Randall, Hector Sanz, Clarissa Valim, Kwaku P. Asante, Seth Owusu-Agyei, Halidou Tinto, Selidji T. Agnandji, Simon Kariuki, Ben Gyan, Claudia Daubenberger, Benjamin Mordmüller, Paula Petrone, Carlota Dobaño
Molecular signaling in the tumor microenvironment (TME) is complex, and crosstalks among various cell compartments in supporting metastasis remain poorly understood. In particular, the role of vascular pericytes, a critical cellular component in the TME, in cancer invasion and metastasis warrants further investigation. Here we report an elevation of FGF-2 signaling in both nasopharyngeal carcinoma (NPC) patient samples and xenograft mouse models promotes NPC metastasis. Mechanistically, tumor cell-derived FGF-2 strongly promoted pericyte proliferation and pericyte-specific expression of an orphan chemokine (C-X-C motif) ligand 14 (CXCL14) via FGFR1- AHR signaling. Gain and loss-of-function experiments validated that pericyte-derived CXCL14 promoted macrophage recruitment and polarization towards an M2-like phenotype. Genetic knockdown of FGF2 or genetic depletion of tumoral pericytes blocked CXCL14 expression and tumor-associated macrophage (TAM) infiltration. Pharmacological inhibition of TAMs by clodronate liposomes treatment resulted in a reduction of FGF-2-induced pulmonary metastasis. Together, these findings shed light on the inflammatory role of tumoral pericytes in promoting TAM-mediated metastasis. We provide mechanistic insight into an FGF-2-FGFR1-pericyte-CXCL14-TAM stromal communication axis in NPC and propose an effective anti-metastasis therapy concept by targeting a pericyte-derived inflammation for NPC or FGF-2-high tumors.
Yujie Wang, Qi Sun, Ying Ye, Xiaoting Sun, Sisi Xie, Yuhang Zhan, Jian Song, Xiaoqin Fan, Bin Zhang, Ming Yang, Lei Lv, Kayoko Hosaka, Yunlong Yang, Guohui Nie
T cells play a prominent role in orchestrating the adaptive immune response to viral diseases and are a key component in understanding variability in SARS-CoV-2 infection severity and immunity. How the T cell response to SARS-CoV-2 infection and vaccination relates to clinical presentation, other components of the immune response, and subsequent immunity remains poorly understood. A population-based swab survey of the municipality of Vo’, Italy, conducted after the initial SARS-CoV-2 outbreak, uncovered a high frequency of asymptomatic infected individuals and their role in transmission. We sampled the T-cell receptor repertoire structure of the entire Vo’ population 2 months after the initial survey and followed up positive cases at 9 and 15 months post infection. We found that 97.0% (98/101) of cases had elevated levels of T-cell receptors associated with SARS-CoV-2 antigens at 2 months. T-cell frequency (depth) was increased in individuals with more severe disease. Both depth and diversity (breadth) of the T-cell receptor repertoire were also positively associated with neutralizing antibody titers, driven mostly by helper CD4+ T cells directed towards antigens from spike protein. At the later time points, detection of SARS-CoV-2 associated T cells remained high, with 90.7% (78/96) and 86.2% (25/29) of individuals having detectable signal at 9 and 15 months, respectively. Notably, at 9 months, T-cell signal was detectable in 84.6% (22/26) of cases who were initially asymptomatic. Forty-three individuals had been vaccinated by month fifteen, all presenting with a positive T-cell signal and showing a significant increase in T cells, specifically directed against spike protein. Taken together, these results demonstrate the central role of the T-cell response in mounting a comprehensive immune defense against SARS-CoV-2 that persists out to 15 months.
Rachel M. Gittelman, Enrico Lavezzo, Thomas M. Snyder, H. Jabran Zahid, Cara L. Carty, Rebecca Elyanow, Sudeb C. Dalai, Ilan Kirsch, Lance Baldo, Laura Manuto, Elisa Franchin, Claudia Del Vecchio, Monia Pacenti, Caterina Boldrin, Margherita Cattai, Francesca Saluzzo, Andrea Padoan, Mario Plebani, Fabio Simeoni, Jessica Bordini, Nicola I. Lorè, Dejan Lazarević, Daniela Maria Cirillo, Paolo Ghia, Stefano Toppo, Jonathan M. Carlson, Harlan S. Robins, Andrea Crisanti, Giovanni Tonon
Tissue-resident macrophage-based immune therapies have been proposed for various diseases. However, generation of sufficient numbers that possess tissue-specific functions remains a major handicap. Here, we showed that fetal liver monocytes cultured with GM-CSF (CSF2-cFLiMo) rapidly differentiated into a long-lived, homogeneous alveolar macrophage–like population in vitro. CSF2-cFLiMo retained the capacity to develop into bona fide alveolar macrophages upon transfer into Csf2ra–/– neonates and prevented development of alveolar proteinosis and accumulation of apoptotic cells for at least 1 year in vivo. CSF2-cFLiMo more efficiently engrafted empty alveolar macrophage niches in the lung and protected mice from severe pathology induced by respiratory viral infection compared with transplantation of macrophages derived from BM cells cultured with M-CSF (CSF1-cBMM) in the presence or absence of GM-CSF. Harnessing the potential of this approach for gene therapy, we restored a disrupted Csf2ra gene in fetal liver monocytes and demonstrated their capacity to develop into alveolar macrophages in vivo. Altogether, we provide a platform for generation of immature alveolar macrophage–like precursors amenable for genetic manipulation, which will be useful to dissect alveolar macrophage development and function and for pulmonary transplantation therapy.
Fengqi Li, Katarzyna Maria Okreglicka, Federica Piattini, Lea Maria Pohlmeier, Christoph Schneider, Manfred Kopf
We investigate how myeloid subsets differentially shape immunity to pancreatic ductal adenocarcinoma (PDA). We show that tumor antigenicity sculpts myeloid cell composition and functionality. Antigenicity promotes accumulation of type 1 dendritic cells (cDC1), which is driven by Xcr1 signaling, and overcomes macrophage-mediated suppression. The therapeutic activity of adoptive T cell therapy or programmed cell death ligand 1 blockade required cDC1s, which sustained splenic Klrg1+ cytotoxic antitumor T cells and functional intratumoral T cells. KLRG1 and cDC1 genes correlated in human tumors, and PDA patients with high intratumoral KLRG1 survived longer than patients with low intratumoral KLRG1. The immunotherapy CD40 agonist also required host cDC1s for maximal therapeutic benefit. However, CD40 agonist exhibited partial therapeutic benefit in cDC1-deficient hosts and resulted in priming of tumor-specific yet atypical CD8+ T cells with a regulatory phenotype and that failed to participate in tumor control. Monocyte/macrophage depletion using clodronate liposomes abrogated T cell priming yet enhanced the antitumor activity of CD40 agonist in cDC1-deficient hosts via engagement of innate immunity. In sum, our study supports that cDC1s are essential for sustaining effective antitumor T cells and supports differential roles for cDC1s and monocytes/macrophages in instructing T cell fate and immunotherapy response.
Adam L. Burrack, Zoe C. Schmiechen, Michael T. Patterson, Ebony A. Miller, Ellen J. Spartz, Meagan R. Rollins, Jackson F. Raynor, Jason S. Mitchell, Tsuneyasu Kaisho, Brian T. Fife, Ingunn M. Stromnes
Diffuse intrinsic pontine gliomas (DIPGs) are aggressive pediatric brain tumors, and patient survival has not changed despite many therapeutic efforts, emphasizing the urgent need for effective treatments. Here, we evaluated the anti-DIPG effect of the oncolytic adenovirus Delta-24-ACT, which was engineered to express the costimulatory ligand 4-1BBL to potentiate the antitumor immune response of the virus. Delta-24-ACT induced the expression of functional 4-1BBL on the membranes of infected DIPG cells, which enhanced the costimulation of CD8+ T lymphocytes. In vivo, Delta-24-ACT treatment of murine DIPG orthotopic tumors significantly improved the survival of treated mice, leading to long-term survivors that developed immunological memory against these tumors. In addition, Delta-24-ACT was safe and caused no local or systemic toxicity. Mechanistic studies showed that Delta-24-ACT modulated the tumor-immune content, not only increasing the number, but also improving the functionality of immune cells. All of these data highlight the safety and potential therapeutic benefit of Delta-24-ACT the treatment of patients with DIPG.
Virginia Laspidea, Montserrat Puigdelloses, Sara Labiano, Lucía Marrodán, Marc Garcia-Moure, Marta Zalacain, Marisol Gonzalez-Huarriz, Naiara Martínez-Vélez, Iker Ausejo-Mauleon, Daniel de la Nava, Guillermo Herrador-Cañete, Javier Marco-Sanz, Elisabeth Guruceaga, Carlos E. de Andrea, María Villalba, Oren Becher, Massimo Squatrito, Verónica Matía, Jaime Gállego Pérez-Larraya, Ana Patiño-García, Sumit Gupta, Candelaria Gomez-Manzano, Juan Fueyo, Marta M. Alonso
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