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Infectious disease

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Transcription of hepatitis B surface antigen shifts from cccDNA to integrated HBV DNA during treatment
Maraake Taddese, … , Chloe L. Thio, Ashwin Balagopal
Maraake Taddese, … , Chloe L. Thio, Ashwin Balagopal
Published February 3, 2025
Citation Information: J Clin Invest. 2025. https://doi.org/10.1172/JCI184243.
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Transcription of hepatitis B surface antigen shifts from cccDNA to integrated HBV DNA during treatment

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Abstract

The cornerstone of functional cure for chronic hepatitis B (CHB) is hepatitis B surface antigen (HBsAg) loss from blood. HBsAg is encoded by covalently closed circular DNA (cccDNA) and HBV DNA integrated into the host genome (iDNA). Nucleos(t)ide analogues (NUCs), the mainstay of CHB treatment, rarely lead to HBsAg loss, which we hypothesized was due to continued iDNA transcription despite decreased cccDNA transcription. To test this, we applied a novel multiplex droplet digital PCR that identifies the dominant source of HBsAg mRNAs to 3436 single cells from paired liver biopsies from ten people with CHB and HIV receiving NUCs. With increased NUC duration, cells producing HBsAg mRNAs shifted from chiefly cccDNA to chiefly iDNA. This shift was due to both a reduction in the number of cccDNA-containing cells and diminished cccDNA-derived transcription per cell; furthermore, it correlated with reduced detection of proteins deriving from cccDNA but not iDNA. Despite this shift in the primary source of HBsAg, rare cells remained with detectable cccDNA-derived transcription, suggesting a source for maintaining the replication cycle. Functional cure must address both iDNA and residual cccDNA transcription. Further research is required to understand the significance of HBsAg when chiefly derived from iDNA.

Authors

Maraake Taddese, Tanner Grudda, Giulia Belluccini, Mark Anderson, Gavin Cloherty, Hyon S. Hwang, Monika Mani, Che-Min Lo, Naomi Esrig, Mark S. Sulkowski, Richard K. Sterling, Yang Zhang, Ruy M. Ribeiro, David L. Thomas, Chloe L. Thio, Ashwin Balagopal

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Mycobacterium tuberculosis resisters despite HIV exhibit activated T cells and macrophages in their pulmonary alveoli
Monica Dallmann-Sauer, … , Nelita Du Plessis, Erwin Schurr
Monica Dallmann-Sauer, … , Nelita Du Plessis, Erwin Schurr
Published January 21, 2025
Citation Information: J Clin Invest. 2025. https://doi.org/10.1172/JCI188016.
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Mycobacterium tuberculosis resisters despite HIV exhibit activated T cells and macrophages in their pulmonary alveoli

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Abstract

Natural resistance to Mycobacterium tuberculosis (Mtb) infection in some people with HIV (PWH) is unexplained. We performed single cell RNA-sequencing of bronchoalveolar lavage cells, unstimulated or ex vivo stimulated with Mtb, for 7 PWH who were TST & IGRA positive (called LTBI) and 6 who were persistently TST & IGRA negative (called resisters). Alveolar macrophages (AM) from resisters displayed a baseline M1 macrophage phenotype while AM from LTBI did not. Resisters displayed alveolar lymphocytosis, with enrichment of all T cell subpopulations including IFNG-expressing cells. In both groups, mycobactericidal granulysin was expressed almost exclusively by a T cell subtype that co-expressed granzyme B, perforin and NK cell receptors. These poly-cytotoxic T lymphocytes (CTL) over-expressed activating NK cell receptors and were increased in resister BAL. Following challenge with Mtb, only Intraepithelial Lymphocytes-like cells from LTBI participants responded with increased transcription of IFNG. AM from resisters responded with a stronger TNF signature at 6h post-infection while at 24h post-infection AM from LTBI displayed a stronger IFN-γ signature. Conversely, at 24h post-infection only AM from resisters displayed a significant upregulation of MICA transcripts which encode an activating ligand for poly-CTL. These results suggest that poly-CTL and AM mediate the resister phenotype in PWH.

Authors

Monica Dallmann-Sauer, Vinicius M. Fava, Stephanus T. Malherbe, Candice E. MacDonald, Marianna Orlova, Elouise E. Kroon, Aurélie Cobat, Stéphanie Boisson-Dupuis, Eileen G. Hoal, Laurent Abel, Marlo Möller, Jean-Laurent Casanova, Gerhard Walzl, Nelita Du Plessis, Erwin Schurr

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CXCL12 ameliorates neutrophilia and disease severity in SARS-CoV-2 infection
Jian Zheng, … , Jun Yan, Stanley Perlman
Jian Zheng, … , Jun Yan, Stanley Perlman
Published January 7, 2025
Citation Information: J Clin Invest. 2025. https://doi.org/10.1172/JCI188222.
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CXCL12 ameliorates neutrophilia and disease severity in SARS-CoV-2 infection

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Abstract

Neutrophils, particularly low-density neutrophils (LDNs), are believed to contribute to acute COVID-19 severity. Here, we showed that neutrophilia can be detected acutely and even months after SARS-CoV-2 infection in patients and mice, while neutrophil depletion reduced disease severity in mice. A key factor in neutrophilia and severe disease in infected mice was traced to the chemokine CXCL12 secreted by bone marrow cells and unexpectedly, endothelial cells. CXCL12 levels were negatively correlated with LDN numbers in longitudinal analyses of patient blood samples. CXCL12 blockade in SARS-CoV-2-infected mice increased blood/lung neutrophil numbers thereby accelerating disease progression without changing lung virus titers. The exaggerated mortality caused by CXCL12 blockade can be reversed by neutrophil depletion. In addition, blocking interactions between SARS-CoV-2 and Angiotensin-Converting Enzyme 2 (ACE2) reduced CXCL12 levels, suggesting a signal transduction from virus-mediated ACE2 ligation to increased CXCL12 secretion. Collectively, these results demonstrate a previously unappreciated role of CXCL12 in diminishing neutrophilia, including low density neutrophilia, and its deleterious effects in SARS-CoV-2 infections. The results also support the involvement of SARS-CoV-2-endothelial cell interactions in viral pathogenesis.

Authors

Jian Zheng, Hima Dhakal, Enya Qing, Rejeena Shrestha, Anne E. Geller, Samantha M. Morrissey, Divyasha Saxena, Xiaoling Hu, Hong Li, Haiyan Li, Kevin Wilhelmsen, Linder H. Wendt, Klaus Klumpp, Patrick S. Hume, William J. Janssen, Rachel Brody, Kenneth E. Palmer, Silvia M. Uriarte, Patrick P. Ten Eyck, David K. Meyerholz, Michael L. Merchant, Kenneth McLeish, Tom Gallagher, Jiapeng Huang, Jun Yan, Stanley Perlman

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Preexisting vaccine-primed heterosubtypic T cell immunity protects the maternal-fetal unit from adverse influenza outcomes in mice
Valeria Flores Malavet, … , K. Kai McKinstry, Tara M. Strutt
Valeria Flores Malavet, … , K. Kai McKinstry, Tara M. Strutt
Published January 2, 2025
Citation Information: J Clin Invest. 2025;135(1):e179230. https://doi.org/10.1172/JCI179230.
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Preexisting vaccine-primed heterosubtypic T cell immunity protects the maternal-fetal unit from adverse influenza outcomes in mice

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Abstract

The risk of severe outcomes of influenza increases during pregnancy. Whether vaccine-induced T cell memory–primed prepregnancy retains the ability to mediate protection during pregnancy, when systemic levels of several hormones with putative immunomodulatory functions are increased, is unknown. Here, using murine adoptive transfer systems and a translationally relevant model of cold-adapted live-attenuated influenza A virus vaccination, we show that preexisting virus-specific memory T cell responses are largely unaltered and highly protective against heterotypic viral challenges during pregnancy. Expression of the transcription factor T-bet, which is upregulated in antiviral T cells responding in pregnant mice, is critical in preventing hormone-associated gain of detrimental T helper type 2 (TH2) attributes reported in other settings. Beyond antiviral effects, preexisting vaccine-primed T cell immunity prevents metabolic dysfunction in gravid dams and adverse neonatal outcomes often associated with maternal influenza infection. These results demonstrate robust protection of the maternal-fetal unit from severe consequences of respiratory virus infection by preexisting T cell immunity.

Authors

Valeria Flores Malavet, Kunal Dhume, Ali Satchmei, Andrea C. Arvelo, Aaron J. Beaird, Siva N. Annamalai, Lauren A. Kimball, K. Kai McKinstry, Tara M. Strutt

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A conserved human CD4+ T cell subset recognizing the mycobacterial adjuvant, trehalose monomycolate
Yuki Sakai, … , Go Hirai, Sho Yamasaki
Yuki Sakai, … , Go Hirai, Sho Yamasaki
Published December 24, 2024
Citation Information: J Clin Invest. 2024. https://doi.org/10.1172/JCI185443.
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A conserved human CD4+ T cell subset recognizing the mycobacterial adjuvant, trehalose monomycolate

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Abstract

Mycobacterium tuberculosis causes human tuberculosis. As mycobacteria are protected by thick lipid cell wall, humans have developed immune responses against diverse mycobacterial lipids. Most of these immunostimulatory lipids are known as adjuvants acting through innate immune receptors, such as C-type lectin receptors. Although a few mycobacterial lipid antigens activate unconventional T cells, antigenicity of most adjuvantic lipids are unknown. Here, we identified that trehalose monomycolate (TMM), an abundant mycobacterial adjuvant, activates human T cells bearing a unique ɑβTCR. This recognition was restricted by CD1b, a monomorphic antigen-presenting molecule conserved in primates but not mice. Single-cell TCR-RNA sequencing using newly established CD1b-TMM tetramers revealed that TMM-specific T cells are present as CD4+ effector memory T cells in the periphery of uninfected donors, but express IFNγ, TNF and anti-mycobacterial effectors upon TMM stimulation. TMM-specific T cells are detected in cord blood and PBMCs of non-BCG-vaccinated donors, but are expanded in active tuberculosis patients. A cryo-electron microscopy study of CD1b-TMM-TCR complexes revealed unique antigen recognition by conserved features of TCRs, positively-charged CDR3ɑ and long CDR3β regions. These results indicate that humans have a commonly-shared and pre-formed CD4+ T cell subset recognizing a typical mycobacterial adjuvant as an antigen. Furthermore, the dual role of TMM justifies reconsideration of the mechanism of action of adjuvants.

Authors

Yuki Sakai, Minori Asa, Mika Hirose, Wakana Kusuhara, Nagatoshi Fujiwara, Hiroto Tamashima, Takahiro Ikazaki, Shiori Oka, Kota Kuraba, Kentaro Tanaka, Takashi Yoshiyama, Masamichi Nagae, Yoshihiko Hoshino, Daisuke Motooka, Ildiko Van Rhijn, Xiuyuan Lu, Eri Ishikawa, D. Branch Moody, Takayuki Kato, Shinsuke Inuki, Go Hirai, Sho Yamasaki

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Long COVID is associated with lower percentages of mature, cytotoxic NK cell phenotypes
Tasha Tsao, … , Oscar A. Aguilar, Timothy J. Henrich
Tasha Tsao, … , Oscar A. Aguilar, Timothy J. Henrich
Published December 17, 2024
Citation Information: J Clin Invest. 2024. https://doi.org/10.1172/JCI188182.
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Long COVID is associated with lower percentages of mature, cytotoxic NK cell phenotypes

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Abstract

Authors

Tasha Tsao, Amanda M. Buck, Lilian Grimbert, Brian H. LaFranchi, Belen Altamirano Poblano, Emily A. Fehrman, Thomas Dalhuisen, Priscilla Y. Hsue, J. Daniel Kelly, Jeffrey N. Martin, Steven G. Deeks, Peter W. Hunt, Michael J. Peluso, Oscar A. Aguilar, Timothy J. Henrich

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Pathobiont-driven antibody sialylation through IL-10 undermines vaccination
Chih-Ming Tsai, … , Nathan E. Lewis, George Y. Liu
Chih-Ming Tsai, … , Nathan E. Lewis, George Y. Liu
Published December 16, 2024
Citation Information: J Clin Invest. 2024;134(24):e179563. https://doi.org/10.1172/JCI179563.
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Pathobiont-driven antibody sialylation through IL-10 undermines vaccination

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Abstract

The pathobiont Staphylococcus aureus (Sa) induces nonprotective antibody imprints that underlie ineffective staphylococcal vaccination. However, the mechanism by which Sa modifies antibody activity is not clear. Herein, we demonstrate that IL-10 is the decisive factor that abrogates antibody protection in mice. Sa-induced B10 cells drive antigen-specific vaccine suppression that affects both recalled and de novo developed B cells. Released IL-10 promotes STAT3 binding upstream of the gene encoding sialyltransferase ST3gal4 and increases its expression by B cells, leading to hyper-α2,3sialylation of antibodies and loss of protective activity. IL-10 enhances α2,3sialylation on cell-wall–associated IsdB, IsdA, and MntC antibodies along with suppression of the respective Sa vaccines. Consistent with mouse findings, human anti-Sa antibodies as well as anti-pseudomonal antibodies from cystic fibrosis subjects (high IL-10) are hypersialylated, compared with anti–Streptococcus pyogenes and pseudomonal antibodies from normal individuals. Overall, we demonstrate a pathobiont-centric mechanism that modulates antibody glycosylation through IL-10, leading to loss of staphylococcal vaccine efficacy.

Authors

Chih-Ming Tsai, Irshad A. Hajam, J.R. Caldera, Austin W.T. Chiang, Cesia Gonzalez, Xin Du, Biswa Choudhruy, Haining Li, Emi Suzuki, Fatemeh Askarian, Ty’Tianna Clark, Brian Lin, Igor H. Wierzbicki, Angelica M. Riestra, Douglas J. Conrad, David J. Gonzalez, Victor Nizet, Nathan E. Lewis, George Y. Liu

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Clinical tolerance but no protective efficacy in a placebo-controlled trial of repeated controlled schistosome infection
Jan Pieter R. Koopman, … , Cornelis H. Hokke, Meta Roestenberg
Jan Pieter R. Koopman, … , Cornelis H. Hokke, Meta Roestenberg
Published December 12, 2024
Citation Information: J Clin Invest. 2024. https://doi.org/10.1172/JCI185422.
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Clinical tolerance but no protective efficacy in a placebo-controlled trial of repeated controlled schistosome infection

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BACKGROUND. Partial protective immunity to schistosomiasis develops over time, following repeated praziquantel treatment. Moreover, animals develop protective immunity after repeated immunisation with irradiated cercariae. Here, we evaluated development of natural immunity through consecutive exposure-treatment cycles with Schistosoma mansoni (Sm) in healthy, Schistosoma-naïve participants using single-sex controlled human Sm infection. METHODS. Twenty-four participants were randomised double-blind (1:1) to either the reinfection group, which received three exposures (week 0,9,18) to 20 male cercariae or the infection control group, which received two mock exposures with water (week 0,9) prior to cercariae exposure (week 18). Participants were treated with praziquantel (or placebo) at week 8, 17 and 30. Attack rates after the final exposure (week 19-30) using serum circulating anodic antigen (CAA) positivity were compared between groups. Adverse events were collected for safety. RESULTS. Twenty-three participants completed follow-up. No protective efficacy was seen, given 82% (9/11) attack rate after the final exposure in the reinfection group and 92% (11/12) in the infection control group (protective efficacy 11%; 95% CI -24% to 35%; p =0.5). Related adverse events were higher after the first infection (45%), compared to the second (27%) and third infection (28%). Severe acute schistosomiasis was observed after the first infections only (2/12 in reinfection group and 2/12 in infection control group). CONCLUSION. Repeated Schistosoma exposure and treatment cycles resulted in apparent clinical tolerance, with fewer symptoms reported with subsequent infections, but did not result in protection against reinfection. TRIAL REGISTRATION. ClinicalTrials.gov NCT05085470. FUNDING. ERC Starting grant (no. 101075876).

Authors

Jan Pieter R. Koopman, Emma L. Houlder, Jacqueline J. Janse, Olivia A.C. Lamers, Geert V.T. Roozen, Jeroen C. Sijtsma, Miriam Casacuberta-Partal, Stan T. Hilt, M.Y. Eileen C. van der Stoep, Inge M. van Amerongen-Westra, Eric A.T. Brienen, Linda J. Wammes, Lisette van Lieshout, Govert J. van Dam, Paul L.A.M. Corstjens, Angela van Diepen, Maria Yazdanbakhsh, Cornelis H. Hokke, Meta Roestenberg

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Ferumoxytol nanozymes effectively target chronic biofilm infections in apical periodontitis
Alaa Babeer, … , Chider Chen, Hyun Koo
Alaa Babeer, … , Chider Chen, Hyun Koo
Published November 26, 2024
Citation Information: J Clin Invest. 2024. https://doi.org/10.1172/JCI183576.
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Ferumoxytol nanozymes effectively target chronic biofilm infections in apical periodontitis

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Abstract

Bacterial biofilms are pervasive and recalcitrant to current antimicrobials, causing numerous infections. Iron oxide-nanozymes, including an FDA-approved formulation (ferumoxytol, FMX), show potential against biofilm infections via catalytic activation of hydrogen peroxide (H2O2). However, clinical evidence on its efficacy and therapeutic mechanisms is lacking. Here, we investigate whether FMX-nanozymes can treat chronic biofilm infections and compare their bioactivity to gold-standard sodium hypochlorite (NaOCl), a potent but caustic disinfectant. Clinical performance was assessed in patients with apical periodontitis, an intractable endodontic infection affecting half of the global adult population. Data show robust antibiofilm activity by a single application of FMX with H2O2 achieving results comparable to NaOCl without adverse effects. FMX binds efficiently to bacterial pathogens Enterococcus faecalis and Fusobacterium nucleatum and remains catalytically active without being affected by dental tissues. This allows for effective eradication of endodontic biofilms via on-site free-radical generation without inducing cytotoxicity. Unexpectedly, FMX promotes growth of stem cells of apical papilla (SCAP), with transcriptomic analyses revealing upregulation of proliferation-associated pathways and downregulation of cell-cycle suppressor genes. Notably, FMX activates SCAP pluripotency and WNT/NOTCH signaling that induces its osteogenic capacity. Together, we show FMX nanozymes are clinically effective against severe chronic biofilm infection with pathogen targeting and unique stem cell-stimulatory properties, offering a regenerative approach to antimicrobial therapy.

Authors

Alaa Babeer, Yuan Liu, Zhi Ren, Zhenting Xiang, Min Jun Oh, Nil Kanatha Pandey, Aurea Simon-Soro, Ranran Huang, Bekir Karabucak, David P. Cormode, Chider Chen, Hyun Koo

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Neisseria gonorrhoeae induces local secretion of IL-10 at the human cervix to promote colonization
Yiwei Dai, … , Daniel C. Stein, Wenxia Song
Yiwei Dai, … , Daniel C. Stein, Wenxia Song
Published November 25, 2024
Citation Information: J Clin Invest. 2024. https://doi.org/10.1172/JCI183331.
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Neisseria gonorrhoeae induces local secretion of IL-10 at the human cervix to promote colonization

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Abstract

Gonorrhea, caused by the human-restricted pathogen Neisseria gonorrhoeae, is a commonly reported sexually transmitted infection. Since most infections in women are asymptomatic, the true number of infections is likely much higher than reported. How gonococci (GC) colonize women’s cervixes without triggering symptoms remains elusive. Using a human cervical tissue explant model, we found that GC inoculation increased the local secretion of both pro- (IL-1β and TNF-α) and anti-inflammatory (IL-10) cytokines during the first 24-h. Cytokine induction required GC expression of Opa isoforms that bind the host receptors carcinoembryonic antigen-related cell adhesion molecules (CEACAMs). GC inoculation induced NF-κB activation in both cervical epithelial and subepithelial cells. However, inhibition of NF-κB activation, which reduced GC-induced IL-1β and TNF-α, did not affect GC colonization. Neutralizing IL-10 or blocking IL-10 receptors by antibodies reduced GC colonization by increasing epithelial shedding and epithelial cell-cell junction disassembly. Inhibition of the CEACAM downstream signaling molecule SHP1/2, which reduced GC colonization and increased epithelial shedding, decreased GC-induced IL-10 secretion. These results show that GC induce local secretion of IL-10, a potent anti-inflammatory cytokine, at the cervix by engaging the host CEACAMs to prevent GC-colonizing epithelial cells from shedding, providing a potential mechanism for GC asymptomatic colonization in women.

Authors

Yiwei Dai, Vonetta L. Edwards, Qian Yu, Hervé Tettelin, Daniel C. Stein, Wenxia Song

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