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The Journal of clinical investigation
2022 Mar 01
Harper, J;Ribeiro, SP;Chan, CN;Aid, M;Deleage, C;Micci, L;Pino, M;Cervasi, B;Raghunathan, G;Rimmer, E;Ayanoglu, G;Wu, G;Shenvi, N;Barnard, RJ;Del Prete, GQ;Busman-Sahay, K;Silvestri, G;Kulpa, DA;Bosinger, SE;Easley, K;Howell, BJ;Gorman, D;Hazuda, DJ;Estes, JD;Sekaly, RP;Paiardini, M;
PMID: 35230978 | DOI: 10.1172/JCI155251
Interleukin (IL)-10 is an immunosuppressive cytokine that signals through STAT3 to regulate T follicular helper cell (TFH) differentiation and germinal center formation. In SIV-infected macaques, levels of IL-10 in plasma and lymph node (LN) were induced by infection and not normalized with ART. During chronic infection, plasma IL-10 and transcriptomic signatures of IL-10 signaling were correlated with the cell-associated SIV-DNA content within LN CD4+ memory subsets, including TFH, and predicted the frequency of CD4+ TFH and their cell-associated SIV-DNA content during ART, respectively. In ART-treated RMs, cells harboring SIV-DNA by DNAscope were preferentially found in the LN B-cell follicle in proximity to IL-10. Finally, we demonstrated that the in vivo neutralization of soluble IL-10 in ART-treated, SIV-infected macaques reduced B cell follicle maintenance and by extension LN memory CD4+ T-cells, including TFH and those expressing PD-1 and CTLA-4. Thus, these data support a role for IL-10 in maintaining a pool of target cells in lymphoid tissue that serve as a niche for viral persistence. Targeting IL-10 signaling to impair CD4+ T-cell survival and improve antiviral immune responses may represent a novel approach to limit viral persistence in ART-suppressed people living with HIV.
BMC immunol
2020 Feb 03
Amemiya K, Dankmeyer JL, Bearss JJ, Zeng X, Stonier SW, Soffler C, Cote CK, Welkos SL, Fetterer DP, Chance TB, Trevino SR, Worsham PL, Waag DM
PMID: 32013893 | DOI: 10.1186/s12865-020-0333-9
BACKGROUND:
Melioidosis is endemic in Southeast Asia and Northern Australia and is caused by the Gram-negative, facultative intracellular pathogen Burkholderia pseudomallei. Diagnosis of melioidosis is often difficult because of the protean clinical presentation of the disease, and it may mimic other diseases, such as tuberculosis. There are many different strains of B. pseudomallei that have been isolated from patients with melioidosis, but it was not clear if they could cause a similar disease in a chronic BALB/c murine model of melioidosis. Hence, we wanted to examine chronically infected mice exposed to different strains of B. pseudomallei to determine if there were differences in the host immune response to the pathogen.
RESULTS:
We identified common host immune responses exhibited in chronically infected BALB/c mice, although there was some heterogeneity in the host response in chronically infected mice after exposure to different strains of B. pseudomallei. They all displayed pyogranulomatous lesions in their spleens with a large influx of monocytes/macrophages, NK cells, and neutrophils identified by flow cytometry. Sera from chronically infected mice by ELISA exhibited elevated IgG titers to the pathogen, and we detected by Luminex micro-bead array technology a significant increase in the expression of inflammatory cytokines/chemokines, such as IFN-?, IL-1?, IL-1?, KC, and MIG. By immunohistochemical and in situ RNA hybridization analysis we found that the increased expression of proinflammatory cytokines (IL-1?, IL-1?, TNF-?, IFN-?) was confined primarily to the area with the pathogen within pyogranulomatous lesions. We also found that cultured splenocytes from chronically infected mice could express IFN-?, TNF-?, and MIP-1? ex vivo without the need for additional exogenous stimulation. In addition by flow cytometry, we detected significant amounts of intracellular expression of TNF-? and IFN-? without a protein transport blocker in monocytes/macrophages, NK cells, and neutrophils but not in CD4+ or CD8+ T cells in splenocytes from chronically infected mice.
CONCLUSION:
Taken together the common features we have identified in chronically infected mice when 10 different human clinical strains of B. pseudomallei were examined could serve as biomarkers when evaluating potential therapeutic agents in mice for the treatment of chronic melioidosis in humans
Science immunology
2023 Mar 17
Bao, C;Chen, O;Sheng, H;Zhang, J;Luo, Y;Hayes, BW;Liang, H;Liedtke, W;Ji, RR;Abraham, SN;
PMID: 36930731 | DOI: 10.1126/sciimmunol.adc9417
IgE-mediated anaphylaxis is an acute life-threatening systemic reaction to allergens, including certain foods and venoms. Anaphylaxis is triggered when blood-borne allergens activate IgE-bound perivascular mast cells (MCs) throughout the body, causing an extensive systemic release of MC mediators. Through precipitating vasodilatation and vascular leakage, these mediators are believed to trigger a sharp drop in blood pressure in humans and in core body temperature in animals. We report that the IgE/MC-mediated drop in body temperature in mice associated with anaphylaxis also requires the body's thermoregulatory neural circuit. This circuit is activated when granule-borne chymase from MCs is deposited on proximal TRPV1+ sensory neurons and stimulates them via protease-activated receptor-1. This triggers the activation of the body's thermoregulatory neural network, which rapidly attenuates brown adipose tissue thermogenesis to cause hypothermia. Mice deficient in either chymase or TRPV1 exhibited limited IgE-mediated anaphylaxis, and, in wild-type mice, anaphylaxis could be recapitulated simply by systemically activating TRPV1+ sensory neurons. Thus, in addition to their well-known effects on the vasculature, MC products, especially chymase, promote IgE-mediated anaphylaxis by activating the thermoregulatory neural circuit.
Journal of immunology (Baltimore, Md. : 1950)
2022 Jul 22
Lai, CW;Bagadia, P;Barisas, DAG;Jarjour, NN;Wong, R;Ohara, T;Muegge, BD;Lu, Q;Xiong, S;Edelson, BT;Murphy, KM;Stappenbeck, TS;
PMID: 35868637 | DOI: 10.4049/jimmunol.2200278
The local microenvironment shapes macrophage differentiation in each tissue. We hypothesized that in the peritoneum, local factors in addition to retinoic acid can support GATA6-driven differentiation and function of peritoneal large cavity macrophages (LCMs). We found that soluble proteins produced by mesothelial cells lining the peritoneal cavity maintained GATA6 expression in cultured LCMs. Analysis of global gene expression of isolated mesothelial cells highlighted mesothelin (Msln) and its binding partner mucin 16 (Muc16) as candidate secreted ligands that potentially regulate GATA6 expression in peritoneal LCMs. Mice deficient for either of these molecules showed diminished GATA6 expression in peritoneal and pleural LCMs that was most prominent in aged mice. The more robust phenotype in older mice suggested that monocyte-derived macrophages were the target of Msln and Muc16. Cell transfer and bone marrow chimera experiments supported this hypothesis. We found that lethally irradiated Msln-/- and Muc16-/- mice reconstituted with wild-type bone marrow had lower levels of GATA6 expression in peritoneal and pleural LCMs. Similarly, during the resolution of zymosan-induced inflammation, repopulated peritoneal LCMs lacking expression of Msln or Muc16 expressed diminished GATA6. These data support a role for mesothelial cell-produced Msln and Muc16 in local macrophage differentiation within large cavity spaces such as the peritoneum. The effect appears to be most prominent on monocyte-derived macrophages that enter into this location as the host ages and also in response to infection.
The induction of preterm labor in rhesus macaques is determined by the strength of immune response to intrauterine infection
PLoS biology
2021 Sep 01
Cappelletti, M;Presicce, P;Feiyang, M;Senthamaraikannan, P;Miller, LA;Pellegrini, M;Sim, MS;Jobe, AH;Divanovic, S;Way, SS;Chougnet, CA;Kallapur, SG;
PMID: 34495952 | DOI: 10.1371/journal.pbio.3001385
Intrauterine infection/inflammation (IUI) is a major contributor to preterm labor (PTL). However, IUI does not invariably cause PTL. We hypothesized that quantitative and qualitative differences in immune response exist in subjects with or without PTL. To define the triggers for PTL, we developed rhesus macaque models of IUI driven by lipopolysaccharide (LPS) or live Escherichia coli. PTL did not occur in LPS challenged rhesus macaques, while E. coli-infected animals frequently delivered preterm. Although LPS and live E. coli both caused immune cell infiltration, E. coli-infected animals showed higher levels of inflammatory mediators, particularly interleukin 6 (IL-6) and prostaglandins, in the chorioamnion-decidua and amniotic fluid (AF). Neutrophil infiltration in the chorio-decidua was a common feature to both LPS and E. coli. However, neutrophilic infiltration and IL6 and PTGS2 expression in the amnion was specifically induced by live E. coli. RNA sequencing (RNA-seq) analysis of fetal membranes revealed that specific pathways involved in augmentation of inflammation including type I interferon (IFN) response, chemotaxis, sumoylation, and iron homeostasis were up-regulated in the E. coli group compared to the LPS group. Our data suggest that the intensity of the host immune response to IUI may determine susceptibility to PTL.
The active human immunodeficiency virus reservoir during antiretroviral therapy: emerging players in viral persistence
Current opinion in HIV and AIDS
2021 Jul 01
Astorga-Gamaza, A;Buzon, MJ;
PMID: 33973900 | DOI: 10.1097/COH.0000000000000685
To discuss the role of CD4+ T cells with active Human immunodeficiency virus (HIV), meaning infected cells with transcriptional and/or translational viral activity during antiretroviral therapy (ART), focusing on new technologies for its detection, potential cell markers for its characterization, and evidences on the contribution of the active HIV reservoir to long-term viral persistence.HIV-infected cells expressing viral ribonucleic acid are systematically detected in subjects on long-term ART. In recent years, powerful new tools have provided significant insights into the nature, quantification, and identification of cells with active HIV, including the identification of new cell markers, and the presence of viral activity in specific cell populations located in different cellular and anatomical compartments. Moreover, studies on viral sequence integrity have identified cell clones with intact viral genomes and active viral transcription that could potentially persist for years. Together, new investigations support the notion that the active reservoir could represent a relevant fraction of long-term infected cells, and therefore, the study of its cell sources and mechanisms of maintenance could represent a significant advance in our understanding of viral persistence and the development of new curative strategies.The presence of HIV-infected cells with viral expression during ART has been traditionally overlooked for years. Based on recent investigations, this active viral reservoir could play an important role in HIV persistence.
Vaccines
2023 Jun 19
Parish, LA;Stavale, EJ;Houchens, CR;Wolfe, DN;
PMID: 37376509 | DOI: 10.3390/vaccines11061120
Outbreaks of viral hemorrhagic fever caused by filoviruses have become more prevalent in recent years, with outbreaks of Ebola virus (EBOV), Sudan virus (SUDV), and Marburg virus (MARV) all occurring in 2022 and 2023. While licensed vaccines are now available for EBOV, vaccine candidates for SUDV and MARV are all in preclinical or early clinical development phases. During the recent outbreak of SUDV virus disease, the Biomedical Advanced Research and Development Authority (BARDA), as part of the Administration for Strategic Preparedness and Response within the U.S. Department of Health and Human Services, implemented key actions with our existing partners to advance preparedness and enable rapid response to the outbreak, while also aligning with global partners involved in the implementation of clinical trials in an outbreak setting. Beyond pre-existing plans prior to the outbreak, BARDA worked with product sponsors to expedite manufacturing of vaccine doses that could be utilized in clinical trials. While the SUDV outbreak has since ended, a new outbreak of MARV disease has emerged. It remains critical that we continue to advance a portfolio of vaccines against SUDV and MARV while also expediting manufacturing activities ahead of, or in parallel if needed, outbreaks.
eLife
2023 Jan 17
Caetano, AJ;Redhead, Y;Karim, F;Dhami, P;Kannambath, S;Nuamah, R;Volponi, AA;Nibali, L;Booth, V;D'Agostino, EM;Sharpe, PT;
PMID: 36648332 | DOI: 10.7554/eLife.81525
The interplay among different cells in a tissue is essential for maintaining homeostasis. Although disease states have been traditionally attributed to individual cell types, increasing evidence and new therapeutic options have demonstrated the primary role of multicellular functions to understand health and disease, opening new avenues to understand pathogenesis and develop new treatment strategies. We recently described the cellular composition and dynamics of the human oral mucosa; however, the spatial arrangement of cells is needed to better understand a morphologically complex tissue. Here, we link single-cell RNA sequencing, spatial transcriptomics, and high-resolution multiplex fluorescence in situ hybridisation to characterise human oral mucosa in health and oral chronic inflammatory disease. We deconvolved expression for resolution enhancement of spatial transcriptomic data and defined highly specialised epithelial and stromal compartments describing location-specific immune programs. Furthermore, we spatially mapped a rare pathogenic fibroblast population localised in a highly immunogenic region, responsible for lymphocyte recruitment through CXCL8 and CXCL10 and with a possible role in pathological angiogenesis through ALOX5AP. Collectively, our study provides a comprehensive reference for the study of oral chronic disease pathogenesis.
Nature immunology
2023 May 01
Swanson, RV;Gupta, A;Foreman, TW;Lu, L;Choreno-Parra, JA;Mbandi, SK;Rosa, BA;Akter, S;Das, S;Ahmed, M;Garcia-Hernandez, ML;Singh, DK;Esaulova, E;Artyomov, MN;Gommerman, J;Mehra, S;Zuniga, J;Mitreva, M;Scriba, TJ;Rangel-Moreno, J;Kaushal, D;Khader, SA;
PMID: 37012543 | DOI: 10.1038/s41590-023-01476-3
Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is a global cause of death. Granuloma-associated lymphoid tissue (GrALT) correlates with protection during TB, but the mechanisms of protection are not understood. During TB, the transcription factor IRF4 in T cells but not B cells is required for the generation of the TH1 and TH17 subsets of helper T cells and follicular helper T (TFH)-like cellular responses. A population of IRF4+ T cells coexpress the transcription factor BCL6 during Mtb infection, and deletion of Bcl6 (Bcl6fl/fl) in CD4+ T cells (CD4cre) resulted in reduction of TFH-like cells, impaired localization within GrALT and increased Mtb burden. In contrast, the absence of germinal center B cells, MHC class II expression on B cells, antibody-producing plasma cells or interleukin-10-expressing B cells, did not increase Mtb susceptibility. Indeed, antigen-specific B cells enhance cytokine production and strategically localize TFH-like cells within GrALT via interactions between programmed cell death 1 (PD-1) and its ligand PD-L1 and mediate Mtb control in both mice and macaques.
bioRxiv : the preprint server for biology
2023 Jan 20
Florsheim, EB;Bachtel, ND;Cullen, J;Lima, BGC;Godazgar, M;Zhang, C;Carvalho, F;Gautier, G;Launay, P;Wang, A;Dietrich, MO;Medzhitov, R;
PMID: 36712030 | DOI: 10.1101/2023.01.19.524823
In addition to its canonical function in protecting from pathogens, the immune system can also promote behavioural alterations 1â€"3 . The scope and mechanisms of behavioural modifications by the immune system are not yet well understood. Using a mouse food allergy model, here we show that allergic sensitization drives antigen-specific behavioural aversion. Allergen ingestion activates brain areas involved in the response to aversive stimuli, including the nucleus of tractus solitarius, parabrachial nucleus, and central amygdala. Food aversion requires IgE antibodies and mast cells but precedes the development of gut allergic inflammation. The ability of allergen-specific IgE and mast cells to promote aversion requires leukotrienes and growth and differentiation factor 15 (GDF15). In addition to allergen-induced aversion, we find that lipopolysaccharide-induced inflammation also resulted in IgE-dependent aversive behaviour. These findings thus point to antigen-specific behavioural modifications that likely evolved to promote niche selection to avoid unfavourable environments.
iScience
2023 Apr 01
Song, J;Deshpande, T;Zhang, X;Hannocks, M;Lycke, N;Cardell, S;Sorokin, L;
| DOI: 10.1016/j.isci.2023.106753
Germinal centre (GC) formation and antibody production in lymph node follicles require coordinated interactions between B-cells, T-cells and dendritic cells (DCs), orchestrated by the extracellular matrix-rich reticular fibre (RF) network. We describe a unique laminin 523-containing RF network around and between follicles that associates with PDGFrec highCCL19lowgp38low fibroblastic reticular cells (FRC). In the absence of FRC expression of laminin 5 (pdgfrb-cre:Lama5fl/fl), pre-Tfh-cells, B-cells and DCs are displaced from follicle borders, correlating with fewer Tfh-cells and GC B-cells. Total DCs are not altered in pdgfrb-cre:Lama5fl/fl mice, but cDC2s, which localize to laminin 5 in RFs at follicle borders, are reduced. Additionally, PDGFrec highCCL19lowgp38low FRCs show lower Ch25h expression, required for 7,25-dihydroxycholesterol synthesis that attracts pre-Tfh-cells, B-cells and DCs to follicle borders. We propose that RF basement membrane components represent a type of tissue memory, that guides the localization and differentiation of both specialized FRC and DC populations, required for normal lymph node function.
Frontiers in Immunology
2023 Jun 19
Primard, C;Monchâtre-Leroy, E;Del Campo, J;Valsesia, S;Nikly, E;Chevandier, M;Boué, F;Servat, A;Wasniewski, M;Picard-Meyer, E;Courant, T;Collin, N;Salguero, F;Le Vert, A;Guyon-Gellin, D;Nicolas, F;
| DOI: 10.3389/fimmu.2023.1188605
Spike-based COVID-19 vaccines induce potent neutralizing antibodies but their efficacy against SARS-CoV-2 variants decreases. OVX033 is a recombinant protein composed of the full-length nucleocapsid (N) protein of SARS-CoV-2 genetically fused to oligoDOM , a self-assembling domain which improves antigen immunogenicity. OVX033 including N as an antigenic target is proposed as new vaccine candidate providing broad-spectrum protection against sarbecoviruses. OVX033 demonstrated its ability to trigger cross-reactive T cell responses and cross-protection against three variants of SARS-CoV-2 (B.1 Europe, Delta B.1.617.2, and Omicron B.1.1.529) in a hamster challenge model, as evidenced by lower weight loss, lower lung viral loads, and reduced lung histopathological lesions.
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| Description | ||
|---|---|---|
| sense Example: Hs-LAG3-sense | Standard probes for RNA detection are in antisense. Sense probe is reverse complent to the corresponding antisense probe. | |
| Intron# Example: Mm-Htt-intron2 | Probe targets the indicated intron in the target gene, commonly used for pre-mRNA detection | |
| Pool/Pan Example: Hs-CD3-pool (Hs-CD3D, Hs-CD3E, Hs-CD3G) | A mixture of multiple probe sets targeting multiple genes or transcripts | |
| No-XSp Example: Hs-PDGFB-No-XMm | Does not cross detect with the species (Sp) | |
| XSp Example: Rn-Pde9a-XMm | designed to cross detect with the species (Sp) | |
| O# Example: Mm-Islr-O1 | Alternative design targeting different regions of the same transcript or isoforms | |
| CDS Example: Hs-SLC31A-CDS | Probe targets the protein-coding sequence only | |
| EnEm | Probe targets exons n and m | |
| En-Em | Probe targets region from exon n to exon m | |
| Retired Nomenclature | ||
| tvn Example: Hs-LEPR-tv1 | Designed to target transcript variant n | |
| ORF Example: Hs-ACVRL1-ORF | Probe targets open reading frame | |
| UTR Example: Hs-HTT-UTR-C3 | Probe targets the untranslated region (non-protein-coding region) only | |
| 5UTR Example: Hs-GNRHR-5UTR | Probe targets the 5' untranslated region only | |
| 3UTR Example: Rn-Npy1r-3UTR | Probe targets the 3' untranslated region only | |
| Pan Example: Pool | A mixture of multiple probe sets targeting multiple genes or transcripts | |
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