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Infectious disease

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Mycobacterium tuberculosis hijacks the UBE2O pathway to regulate host iron homeostasis
Tran Xuan Ngoc Huy, Huynh Tan Hop
Tran Xuan Ngoc Huy, Huynh Tan Hop
Published May 1, 2025
Citation Information: J Clin Invest. 2025;135(9):e184095. https://doi.org/10.1172/JCI184095.
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Mycobacterium tuberculosis hijacks the UBE2O pathway to regulate host iron homeostasis

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Abstract

Authors

Tran Xuan Ngoc Huy, Huynh Tan Hop

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Widespread distribution of transcriptionally active, clonally expanded, HIV-1 proviruses despite suppressive antiretroviral therapy
Hiromi Imamichi, … , Kanal Singh, H. Clifford Lane
Hiromi Imamichi, … , Kanal Singh, H. Clifford Lane
Published April 29, 2025
Citation Information: J Clin Invest. 2025. https://doi.org/10.1172/JCI190824.
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Widespread distribution of transcriptionally active, clonally expanded, HIV-1 proviruses despite suppressive antiretroviral therapy

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Abstract

The rapid viral rebound observed following treatment interruption, despite prolonged time on antiretroviral therapy with plasma HIV-RNA levels <40 copies/mL, suggests persistent HIV-1 reservoir(s) outside of the blood. Studies of HIV-1 proviruses in autopsy tissue samples have hinted at their persistence. However, their distribution across different anatomical compartments and their transcriptional activity within tissues remains unclear. The present study has examined molecular DNA and RNA reservoirs of HIV-1 in autopsy samples from 13 individuals with HIV-1 infection. Of the 13, 5 had detectable levels of HIV-1 RNA in plasma while 8 did not. Cell associated HIV-RNA was detected in 12 out of 13 donors and in 27 of the 30 different tissues examined. HIV-specific DNA and RNA were widely distributed and predominantly associated with clonal expansions. No significant differences were noted between the groups and no tissues were preferentially affected. These data imply that a substantial seeding of tissues with cells harboring transcriptionally active proviral DNA can be seen in the setting of HIV-1 infection despite ART and highlight one of the challenges in achieving an HIV-1 cure.

Authors

Hiromi Imamichi, Ven Natarajan, Francesca Scrimieri, Mindy Smith, Yunden Badralmaa, Marjorie Bosche, Jack M. Hensien, Thomas Buerkert, Weizhong Chang, Brad T. Sherman, Kanal Singh, H. Clifford Lane

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Antimicrobial Peptide Developed with Machine Learning Sequence Optimization Targets Drug Resistant Staphylococcus aureus in Mice
Biswajit Mishra, … , Paul P. Sotiriadis, Eleftherios Mylonakis
Biswajit Mishra, … , Paul P. Sotiriadis, Eleftherios Mylonakis
Published April 22, 2025
Citation Information: J Clin Invest. 2025. https://doi.org/10.1172/JCI185430.
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Antimicrobial Peptide Developed with Machine Learning Sequence Optimization Targets Drug Resistant Staphylococcus aureus in Mice

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As antimicrobial resistance rises, new antibacterial candidates are urgently needed. Using sequence space information from over 14,743 functional antimicrobial peptides (AMPs), we improved the antimicrobial properties of citropin 1.1, an AMP with weak anti-methicillin resistant Staphylococcus aureus (MRSA) activity, producing a short and potent anti-staphylococcal peptide, CIT-8 (13 residues). At 40 μg/ml, CIT-8 eradicated 1 × 108 drug-resistant MRSA and VRSA (vancomycin resistant S. aureus) persister cells within 30 mins of exposure and reduced the number of viable biofilm cells of MRSA and VRSA by 3 log10 and 4 log10 in established biofilms, respectively. CIT-8 (at 32 μg/ml) depolarized and permeated the S. aureus MW2 membrane. In a mouse model of MRSA skin infection, CIT-8 (2% w/w in petroleum jelly) significantly reduced the bacterial burden by 2.3 log10 (p < 0.0001). Our methodology accelerates AMP design by combining traditional peptide design strategies, such as truncation, substitution, and structure-guided alteration, with machine learning (ML)-backed sequence optimization.

Authors

Biswajit Mishra, Anindya Basu, Fadi Shehadeh, LewisOscar Felix, Sai Sundeep Kollala, Yashpal Singh Chhonker, Mandar T. Naik, Charilaos Dellis, Liyang Zhang, Narchonai Ganesan, Daryl J. Murry, Jianhua Gu, Michael B. Sherman, Frederick M. Ausubel, Paul P. Sotiriadis, Eleftherios Mylonakis

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Colistin exerts potent activity against mcr+ Enterobacteriaceae via synergistic interactions with the host defense
Monika Kumaraswamy, … , George Sakoulas, Victor Nizet
Monika Kumaraswamy, … , George Sakoulas, Victor Nizet
Published April 22, 2025
Citation Information: J Clin Invest. 2025. https://doi.org/10.1172/JCI170690.
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Colistin exerts potent activity against mcr+ Enterobacteriaceae via synergistic interactions with the host defense

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Abstract

Colistin (COL) is a cationic cyclic peptide that disrupts negatively-charged Gram-negative bacterial cell membranes and frequently serves as an antibiotic of last resort to combat multidrug-resistant Gram-negative bacterial infections. Emergence of the horizontally transferable plasmid-borne mobilized colistin resistance (mcr) determinant and its spread to Gram-negative strains harboring extended-spectrum β-lactamase and carbapenemase resistance genes threatens futility of our chemotherapeutic arsenal. COL is widely regarded to have zero activity against mcr+ strains based on standard antimicrobial susceptibility testing (AST) performed in enriched bacteriological growth media; consequently, the drug is withheld from patients with mcr+ infections. However, these standard testing media poorly mimic in vivo physiology and omit host immune factors. Here we observed that COL exhibits bactericidal activities against mcr+ isolates of Escherichia coli, Klebsiella pneumoniae, and Salmonella enterica in tissue culture media containing the physiological buffer bicarbonate. Moreover, COL promoted serum complement deposition on the mcr-1+ Gram-negative bacterial surface and synergized potently with active human serum in pathogen killing. At COL concentrations readily achievable with standard dosing, the peptide antibiotic killed mcr-1+ E. coli, K. pneumoniae, and S. enterica in freshly isolated human blood and proved effective as monotherapy in a murine model of E. coli bacteremia. Our results suggest that COL, currently ignored as a treatment option based on traditional AST, may in fact benefit patients with mcr-1+ Gram negative infections based on evaluations performed in a more physiologic context. These concepts warrant careful consideration in the clinical microbiology laboratory and for future clinical investigation of their merits in high-risk patients with limited therapeutic options.

Authors

Monika Kumaraswamy, Angelica Riestra, Anabel Flores, Samira Dahesh, Fatemeh Askarian, Satoshi Uchiyama, Jonathan Monk, Sean Jung, Gunnar Bondsäter, Victoria Nilsson, Melanie Chang, Jürgen B Bulitta, Yinzhi Lang, Armin Kousha, Elisabet Bjånes, Natalie Chavarria, Ty'Tianna Clark, Hideya Seo, George Sakoulas, Victor Nizet

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SLAMF7 and SLAMF8 receptors shape human plasmacytoid dendritic cell responses to intracellular bacteria
Joaquín Miguel Pellegrini, … , Sylvie Mémet, Jean-Pierre Gorvel
Joaquín Miguel Pellegrini, … , Sylvie Mémet, Jean-Pierre Gorvel
Published April 15, 2025
Citation Information: J Clin Invest. 2025;135(8):e182467. https://doi.org/10.1172/JCI182467.
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SLAMF7 and SLAMF8 receptors shape human plasmacytoid dendritic cell responses to intracellular bacteria

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Plasmacytoid dendritic cells (pDCs), professional type I IFN–producing cells, have been implicated in host responses against bacterial infections. However, their role in host defense is debated, and the operating molecular mechanisms are unknown. Certain signaling lymphocyte activation molecule family (SLAMF) members act as microbial sensors and modulate immune functions in response to infection. Here, human blood transcriptomic analyses reveal the involvement of SLAMF7 and SLAMF8 in many infectious diseases, with elevated levels associated with type I IFN responses in salmonellosis and brucellosis patients. We further identify SLAMF7 and SLAMF8 as key regulators of human pDC function. They activate pDC maturation and cytokine production during infection with bacteria that induce acute (Salmonella) or chronic (Brucella) inflammation. SLAMF7 and SLAMF8 signal through NF-κB, IRF7, and STAT-1, and limit mitochondrial ROS accumulation upon Salmonella infection. Remarkably, this SLAMF7/8-dependent control of mitochondrial ROS levels favors bacterial persistence and NF-κB activation. Overall, our results unravel essential shared multifaceted roles of SLAMF7 and SLAMF8 in finely tuning human pDC responses to intracellular bacterial infections with potential for future diagnostic and therapeutic applications.

Authors

Joaquín Miguel Pellegrini, Anne Keriel, Laurent Gorvel, Sean Hanniffy, Vilma Arce-Gorvel, Mile Bosilkovski, Javier Solera, Stéphane Méresse, Sylvie Mémet, Jean-Pierre Gorvel

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Virus-associated inflammation imprints an inflammatory profile on monocyte-derived macrophages in the human liver
Juan Diego Sanchez Vasquez, … , Harry L.A. Janssen, Adam J. Gehring
Juan Diego Sanchez Vasquez, … , Harry L.A. Janssen, Adam J. Gehring
Published April 15, 2025
Citation Information: J Clin Invest. 2025;135(8):e175241. https://doi.org/10.1172/JCI175241.
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Virus-associated inflammation imprints an inflammatory profile on monocyte-derived macrophages in the human liver

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Abstract

Chronic liver injury triggers the activation and recruitment of immune cells, causing antigen-independent tissue damage and liver disease progression. Tissue inflammation can reshape macrophage composition through monocyte replacement. Replacement of tissue macrophages with monocytes differentiating in an inflammatory environment can potentially imprint a phenotype that switches the liver from an immune-tolerant organ to one predisposed to tissue damage. We longitudinally sampled the liver of patients with chronic hepatitis B who had active liver inflammation and were starting antiviral therapy. Antiviral therapy suppressed viral replication and liver inflammation, which coincided with decreased myeloid activation markers. Single-cell RNA-Seq mapped peripheral inflammatory markers to a monocyte-derived macrophage population, distinct from Kupffer cells, with an inflammatory transcriptional profile. The inflammatory macrophages (iMacs) differentiated from blood monocytes and were unique from macrophage found in healthy or cirrhotic liver. iMacs retained their core transcriptional signature after inflammation resolved, indicating inflammation-mediated remodeling of the macrophage population in the human liver that may affect progressive liver disease and immunotherapy.

Authors

Juan Diego Sanchez Vasquez, Shirin Nkongolo, Daniel Traum, Valentin Sotov, Samuel C. Kim, Deeqa Mahamed, Aman Mehrotra, Anjali Patel, Diana Y. Chen, Scott Fung, Anuj Gaggar, Jordan J. Feld, Kyong-Mi Chang, Jeffrey J. Wallin, Ben X. Wang, Harry L.A. Janssen, Adam J. Gehring

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Bacterial vaginosis associates with dysfunctional T cells and altered soluble immune factors in the cervicovaginal tract
Finn MacLean, … , Jairam R. Lingappa, Jennifer M. Lund
Finn MacLean, … , Jairam R. Lingappa, Jennifer M. Lund
Published March 25, 2025
Citation Information: J Clin Invest. 2025. https://doi.org/10.1172/JCI184609.
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Bacterial vaginosis associates with dysfunctional T cells and altered soluble immune factors in the cervicovaginal tract

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Background: Bacterial vaginosis (BV) is a dysbiosis of the vaginal microbiome that is prevalent among reproductive-age females worldwide. Adverse health outcomes associated with BV include an increased risk of sexually-acquired HIV, yet the immunological mechanisms underlying this association are not well understood. Methods: To investigate BV-driven changes to cervicovaginal tract (CVT) and circulating T cell phenotypes, Kinga Study participants with or without BV provided vaginal tract (VT) and ectocervical (CX) tissue biopsies and PBMC samples. Results: High-parameter flow cytometry revealed an increased frequency of cervical conventional CD4+ T cells (Tconv) expressing CCR5. However, we found no difference in number of CD3+CD4+CCR5+ cells in the CX or VT of BV+ versus BV- individuals, suggesting that BV-driven increased HIV susceptibility may not be solely attributed to increased CVT HIV target cell abundance. Flow cytometry also revealed that individuals with BV have an increased frequency of dysfunctional CX and VT CD39+ Tconv and CX tissue-resident CD69+CD103+ Tconv, reported to be implicated in HIV acquisition risk and replication. Many soluble immune factor differences in the CVT further support that BV elicits diverse and complex CVT immune alterations. Conclusion: Our comprehensive analysis expands on potential immunological mechanisms that may underlie the adverse health outcomes associated with BV including increased HIV susceptibility.

Authors

Finn MacLean, Adino Tesfahun Tsegaye, Jessica B. Graham, Jessica L. Swarts, Sarah C. Vick, Nicole B. Potchen, Irene Cruz Talavera, Lakshmi Warrier, Julien Dubrulle, Lena K. Schroeder, Ayumi Saito, Corinne Mar, Katherine K. Thomas, Matthias Mack, Michelle C. Sabo, Bhavna H. Chohan, Kenneth Ngure, Nelly Rwamba Mugo, Jairam R. Lingappa, Jennifer M. Lund

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IL33 protects from recurrent C. difficile infection by restoration of humoral immunity
Farha Naz, … , Gregory R. Madden, William A. Petri Jr.
Farha Naz, … , Gregory R. Madden, William A. Petri Jr.
Published March 6, 2025
Citation Information: J Clin Invest. 2025. https://doi.org/10.1172/JCI184659.
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IL33 protects from recurrent C. difficile infection by restoration of humoral immunity

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Clostridioides difficile infection (CDI) recurs in one of five patients. Monoclonal antibodies targeting the virulence factor TcdB reduce disease recurrence, suggesting that an inadequate anti-TcdB response to CDI leads to recurrence. In patients with CDI, we discovered that IL33 measured at diagnosis predicts future recurrence, leading us to test the role of IL33 signaling in the induction of humoral immunity during CDI. Using a mouse recurrence model, IL33 was demonstrated to be integral for anti-TcdB antibody production. IL33 acted via ST2+ ILC2 cells, facilitating germinal center T follicular helper (GC-Tfh) cell generation of antibodies. IL33 protection from reinfection was antibody-dependent, as mMT KO mice and mice treated with anti-CD20 mAb were not protected. These findings demonstrate the critical role of IL33 in generating humoral immunity to prevent recurrent CDI.

Authors

Farha Naz, Md Jashim Uddin, Nicholas M. Hagspiel, Mary K. Young, David Tyus, Rachel Boone, Audrey C. Brown, Girija Ramakrishnan, Isaura Rigo, Claire Fleming, Gregory R. Madden, William A. Petri Jr.

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CRISPR-mediated detection of Pneumocystis transcripts in bronchoalveolar, oropharyngeal, and serum specimens for Pneumocystis pneumonia diagnosis
Brady M. Youngquist, … , Jay K. Kolls, Tony Y. Hu
Brady M. Youngquist, … , Jay K. Kolls, Tony Y. Hu
Published March 3, 2025
Citation Information: J Clin Invest. 2025. https://doi.org/10.1172/JCI177241.
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CRISPR-mediated detection of Pneumocystis transcripts in bronchoalveolar, oropharyngeal, and serum specimens for Pneumocystis pneumonia diagnosis

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BACKGROUND.Pneumocystis jirovecii pneumonia (PCP) is a leading cause of fungal pneumonia, but its diagnosis primarily relies on invasive bronchoalveolar lavage (BAL) specimens that are difficult to obtain. Oropharyngeal swabs and serum could improve the PCP diagnostic workflow, and we hypothesized that CRISPR could enhance assay sensitivity to allow robust P. jirovecii diagnosis using swabs and serum. Herein we describe the development of an ultrasensitive RT-PCR-coupled CRISPR assay with high active-infection specificity in infant swabs and adult BAL and serum. METHODS. Mouse analyses employed an RT-PCR CRISPR assay to analyze P. murina transcripts in wild-type and Rag2–/– mouse lung RNA, BAL, and serum at 2-, 4-, and 6-weeks post-infection. Human studies used an optimized RT-PCR CRISPR assay to detect P. jirovecii transcripts in infant oropharyngeal swab samples, adult serum, and adult BAL specimens from P. jirovecii-infected and P. jirovecii-non-infected patients. RESULTS. The P. murina assays sensitively detected Pneumocystis RNA in the serum of infected mice throughout infection. Oropharyngeal swab CRISPR assay results identified infants infected with P. jirovecii with greater sensitivity (96.3% vs. 66.7%) and specificity (100% vs. 90.6%) than RT-qPCR compared to mtLSU standard marker, and CRISPR results achieved higher sensitivity than RT-qPCR results (93.3% vs. 26.7%) in adult serum specimens. CONCLUSION. Since swabs are routinely collected in pediatric pneumonia patients and serum is easier to obtain than BAL, this assay approach could improve the accuracy and timing of pediatric and adult Pneumocystis diagnosis by achieving specificity for active infection and potentially avoiding the requirement for BAL specimens.

Authors

Brady M. Youngquist, Ayanda Trevor Mnguni, Dora Pungan, Rachel P.J. Lai, Guixiang Dai, Chun Fai Ng, Amy Samson, Yasmean Abdelgaliel, Christopher J. Lyon, Bo Ning, Shahid Husain, Sean Wasserman, Jay K. Kolls, Tony Y. Hu

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The role of TREM2 in sepsis
Jiejie Zhu, … , Tianyin Sun, Hanren Dai
Jiejie Zhu, … , Tianyin Sun, Hanren Dai
Published February 17, 2025
Citation Information: J Clin Invest. 2025;135(4):e188895. https://doi.org/10.1172/JCI188895.
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The role of TREM2 in sepsis

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Abstract

Authors

Jiejie Zhu, Tianyin Sun, Hanren Dai

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