Infectious disease
Abstract
Chronic hepatitis B (CHB) infection is rarely eradicated by current antiviral nucleos(t)ide analogues. We found that α2,6-biantennary sialoglycans of HBV surface antigen (HBsAg) bound human SIGLEC-3 (CD33) by IP and ELISA, and the binding affinity between SIGLEC-3 and α2,6-biantennary sialoglycans was determined by biolayer interferometry (equilibrium dissociation constant [KD]: 1.95 × 10–10 ± 0.21 × 10–10 M). Moreover, HBV activated SIGLEC-3 on myeloid cells and induced immunosuppression by stimulating immunoreceptor tyrosine-based inhibitory motif phosphorylation and SHP-1/-2 recruitment via α2,6-biantennary sialoglycans on HBsAg. An antagonistic anti–SIGLEC-3 mAb reversed this effect and enhanced cytokine production in response to TLR-7 agonist GS-9620 in PBMCs from CHB patients. Moreover, anti–SIGLEC-3 mAb alone was able to upregulate the expression of molecules involved in antigen presentation, such as CD80, CD86, CD40, MHC-I, MHC-II, and PD-L1 in CD14+ cells. Furthermore, SIGLEC-3 SNP rs12459419 C, which expressed a higher amount of SIGLEC-3, was associated with increased risk of hepatocellular carcinoma (HCC) in CHB patients (HR: 1.256, 95% CI: 1.027–1.535, P = 0.0266). Thus, blockade of SIGLEC-3 is a promising strategy to reactivate host immunity to HBV and lower the incidence of HCC in the CHB patient population.
Authors
Tsung-Yu Tsai, Ming-Ting Huang, Pei-Shan Sung, Cheng-Yuan Peng, Mi-Hua Tao, Hwai-I Yang, Wei-Chiao Chang, An-Suei Yang, Chung-Ming Yu, Ya-Ping Lin, Ching-Yu Bau, Chih-Jen Huang, Mei-Hung Pan, Chung-Yi Wu, Chwan-Deng Hsiao, Yi-Hung Yeh, Shiteng Duan, James C Paulson, Shie-Liang Hsieh
Abstract
A recent report found that rare predicted loss-of-function (pLOF) variants across 13 candidate genes in TLR3- and IRF7-dependent type I IFN pathways explain up to 3.5% of severe COVID-19 cases. We performed whole-exome or whole-genome sequencing of 1,934 COVID-19 cases (713 with severe and 1,221 with mild disease) and 15,251 ancestry-matched population controls across four independent COVID-19 biobanks. We then tested if rare pLOF variants in these 13 genes were associated with severe COVID-19. We identified only one rare pLOF mutation across these genes amongst 713 cases with severe COVID-19 and observed no enrichment of pLOFs in severe cases compared to population controls or mild COVID-19 cases. We find no evidence of association of rare loss-of-function variants in the proposed 13 candidate genes with severe COVID-19 outcomes.
Authors
Gundula Povysil, Guillaume Butler-Laporte, Ning Shang, Chen Wang, Atlas Khan, Manal Alaamery, Tomoko Nakanishi, Sirui Zhou, Vincenzo Forgetta, Robert J. M. Eveleigh, Mathieu Bourgey, Naveed Aziz, Steven J.M. Jones, Bartha Knoppers, Stephen W. Scherer, Lisa J. Strug, Pierre Lepage, Jiannis Ragoussis, Guillaume Bourque, Jahad Alghamdi, Nora Aljawini, Nour Albesher, Hani M. Al-Afghani, Bader Alghamdi, Mansour S. Almutair, Ebrahim Sabri Mahmoud, Leen Abu-Safieh, Hadeel El Bardisy, Fawz S. Al Harthi, Abdulraheem Alshareef, Bandar Ali Suliman, Saleh A. Alqahtani, Abdulaziz Almalik, May M. Alrashed, Salam Massadeh, Vincent Mooser, Mark Lathrop, Mohamed Fawzy, Yaseen M. Arabi, Hamdi Mbarek, Chadi Saad, Wadha Al-Muftah, Junghyun Jung, Serghei Mangul, Radja Badji, Asma Al Thani, Said I. Ismail, Ali G. Gharavi, Malak S. Abedalthagafi, J Brent Richards, David B. Goldstein, Krzysztof Kiryluk
Abstract
The upper respiratory tract is compromised in the early period of COVID-19, but SARS-CoV-2 tropism at the cellular level is not fully defined. Unlike recent single cell RNA-sequencing analyses indicating uniformly low mRNA expression of SARS-CoV-2 entry-related host molecules in all nasal epithelial cells, we show that the protein levels are relatively high and their localizations are restricted to the apical side of multiciliated epithelial cells. In addition, we provide evidence in COVID-19 patients that SARS-CoV-2 is massively detected and replicated within the multiciliated cells. We observed these findings during the early stage of COVID-19, when infected ciliated cells are rapidly replaced by differentiating precursor cells. Moreover, our analyses reveal that SARS-CoV-2 cellular tropism is restricted to the nasal ciliated versus oral squamous epithelium. These results imply that targeting ciliated cells of the nasal epithelium during the early stage of COVID-19 could be an ideal strategy to prevent SARS-CoV-2 propagation.
Authors
Ji Hoon Ahn, JungMo Kim, Seon Pyo Hong, Sung Yong Choi, Myung Jin Yang, Young Seok Ju, Young Tae Kim, Ho Min Kim, MD Tazikur Rahman, Man Ki Chung, Sang Duk Hong, Hosung Bae, Chang-Seop Lee, Gou Young Koh
Abstract
Sepsis survivors exhibit impaired responsiveness to antigen (Ag) challenge associated with increased mortality from infection. The contribution of follicular dendritic cells (FDCs) in the impaired humoral response in sepsis-surviving mice is investigated in this study. We demonstrated that mice subjected to sepsis from cecal ligation and puncture (CLP) have reduced NP-specific high-affinity class-switched Ig antibodies compared to sham control mice following immunization with the T-dependent Ag, NP-CGG. NP-specific germinal center (GC) B cells in CLP mice exhibited reduced TNFα and AID mRNA expression compared to sham mice. CLP mice showed a reduction in FDC clusters, a reduced binding of immune complexes on FDCs, and reduced mRNA expression of CR2, ICAM-1, VCAM-1, FcγRIIB, TNFR1, IKK2 and LTbR compared to sham mice. Adoptive transfer studies showed there was no B cell-intrinsic defect. In summary, our data suggest that the reduced Ag-specific antibody response in CLP mice is secondary to a disruption in FDC and GC B cell function.
Authors
Minakshi Rana, Andrea La Bella, Rivka Lederman, Bruce T. Volpe, Barbara Sherry, Betty Diamond
Abstract
Disrupting transmission of Borrelia burgdorferi (B. burgdorferi ) from infected ticks to humans is one strategy to prevent the significant morbidity from Lyme disease. We have previously shown that an anti-OspA human monoclonal antibody, 2217, prevents transmission of B. burgdorferi from infected ticks in animal models. Maintenance of a protective plasma concentration of a human monoclonal antibody for tick season presents a significant challenge for a pre-exposure prophylaxis strategy. Here, we describe the optimization of 2217 by amino acid substitutions (LS, M428L and N434S) into the Fc domain. The LS mutation led to a twofold-increase in half-life in cynomolgus monkeys. In a rhesus macaque model, 2217LS protected animals from tick transmission of spirochetes at a dose of 3 mg/kg. Crystallographic analysis of Fab in complex with OspA reveals that 2217 binds a novel epitope that is highly conserved among the B. burgdorferi, B. garinii, and B. afzelii species. Unlike most vaccines that may require boosters to achieve protection, our work supports the development of 2217LS as an effective pre-exposure prophylaxis in Lyme-endemic regions with a single dose at the beginning of tick season offering immediate protection that remains for the duration of exposure risk.
Authors
Zachary A. Schiller, Michael J. Rudolph, Jacqueline R. Toomey, Monir Ejemel, Alan LaRochelle, Simon A. Davis, Havard S. Lambert, Aurélie Kern, Amanda C. Tardo, Colby A. Souders, Eric Peterson, Rebecca D. Cannon, Chandrashekar Ganesa, Frank Fazio, Nicholas J. Mantis, Lisa A. Cavacini, John Sullivan-Bolyai, Linden T. Hu, Monica E. Embers, Mark S. Klempner, Yang Wang
Abstract
T cell immunity is essential for the control of tuberculosis (TB), an important disease of the lung, and is generally studied in humans using peripheral blood cells. Mounting evidence, however, indicates that tissue resident memory T cells (Trm) are superior at controlling many pathogens, including Mycobacterium tuberculosis (Mtb), and can be quite different from those in circulation. Using freshly resected lung tissue, from individuals with active or previous TB, we identified distinct CD4 and CD8 Trm-like clusters within TB diseased lung tissue that were functional and enriched for IL-17 producing cells. Mtb-specific CD4 T cells producing TNF-α, IL-2 and IL-17 were highly expanded in the lung compared to matched blood samples, in which IL-17+ cells were largely absent. Strikingly, the frequency of Mtb-specific lung T cells making IL-17, but not other cytokines, inversely correlated with the plasma IL-1β levels, suggesting a potential link with disease severity. Using a human granuloma model, we showed the addition of either exogenous IL-17 or IL-2 enhanced immune control of Mtb and was associated with increased NO production. Taken together, these data support an important role for Mtb-specific Trm-like IL-17 producing cells in the immune control of Mtb in the human lung.
Authors
Paul Ogongo, Liku B. Tezera, Amanda Ardain, Shepherd Nhamoyebonde, Duran Ramsuran, Alveera Singh, Abigail Ngoepe, Farina Karim, Taryn Naidoo, Khadija Khan, Kaylesh J. Dullabh, Michael Fehlings, Boon Heng Lee, Alessandra Nardin, Cecilia S. Lindestam Arlehamn, Alessandro Sette, Samuel M. Behar, Adrie J.C. Steyn, Rajhmun Madansein, Henrik N. Kløverpris, Paul T. Elkington, Alasdair Leslie
Abstract
Drugs targeting host proteins can act prophylactically to reduce viral burden early in disease and limit morbidity, even with antivirals and vaccination. Transmembrane serine protease 2 (TMPRSS2) is a human protease required for SARS-CoV-2 viral entry and may represent such a target. We hypothesized that drugs selected from proteins related by their tertiary structure, rather than their primary structure, were likely to interact with TMPRSS2. We created a structure-based phylogenetic computational tool named 3DPhyloFold to systematically identify structurally similar serine proteases with known therapeutic inhibitors and demonstrated effective inhibition of SARS-CoV-2 infection in vitro and in vivo. Several candidate compounds, Avoralstat, PCI-27483, Antipain, and Soybean-Trypsin-Inhibitor, inhibited TMPRSS2 in biochemical and cell infection assays. Avoralstat, a clinically tested Kallikrein-related B1 inhibitor, inhibited SARS-CoV-2 entry and replication in human airway epithelial cells. In an in vivo proof of principle, Avoralstat significantly reduced lung tissue titers and mitigated weight-loss when administered prophylactically to SARS-CoV-2 susceptible mice indicating its potential to be repositioned for COVID-19 prophylaxis in humans.
Authors
Young Joo Sun, Gabriel Velez, Dylan E. Parsons, Kun Li, Miguel E. Ortiz, Shaunik Sharma, Paul B. McCray Jr., Alexander G. Bassuk, Vinit B. Mahajan
Abstract
Tissue-based T cells are important effectors in the prevention and control of mucosal viral infections – less is known about tissue-based B cells. We demonstrate that B cells and antibody-secreting cells (ASCs) are present in inflammatory infiltrates in skin biopsies of persons during symptomatic HSV2 reactivation and early healing. Both CD20+ B cells, most of which are antigen-inexperienced by co-expression of IgD, and ASCs, characterized by dense IgG RNA expression in combination with CD138, IRF4 and Blimp1 RNA, are seen in association with T cells. ASCs are found clustered with CD4+ T cells, suggesting potential for crosstalk. HSV2-specific antibodies to virus surface antigens are also present in tissue and increase in concentration during HSV2 reactivation and healing, unlike in serum where concentrations remain static over time. B cells, ASCs, and HSV-specific antibody were rarely detected in biopsies of unaffected skin. Evaluation of serial biopsies demonstrate that B cells and ASCs follow a more migratory than resident pattern of infiltration in HSV-affected genital skin, in contrast to T cells. Together, these observations suggest distinct phenotypes of B cells in HSV-affected tissue; dissecting their role in reactivation may reveal new therapeutic avenues to control these infections.
Authors
Emily S. Ford, Anton M. Sholukh, RuthMabel Boytz, Savanna S. Carmack, Alexis Klock, Khamsone Phasouk, Danica Shao, Raabya Rossenkhan, Paul T. Edlefsen, Tao Peng, Christine Johnston, Anna Wald, Jia Zhu, Lawrence Corey
Abstract
A(H3N2) Influenza vaccine effectiveness (VE) were low during 2016-2019 seasons and varied by age. We analyzed neutralizing antibody responses to egg- and cell-propagated vaccine and circulating viruses following vaccination in 375 individuals (aged 7 months to 82 years) across all vaccine eligible age groups in 3 influenza seasons. Antibody responses to cell- compared to egg-propagated vaccine viruses were significantly reduced due to egg-adapted changes T160K, D225G, and L194P in the vaccine hemagglutinins. Vaccine egg-adaptation had differential impact on antibody responses across different age groups. Immunologically naive children immunized with egg-adapted vaccines mostly mounted antibodies targeting egg-adapted epitopes, whereas those previously primed with infection produced broader responses even when vaccinated with egg-based vaccines. In elderly, repeated boost of vaccine egg-adapted epitopes significantly reduced antibody responses to the wild type cell-grown viruses. Analysis with reverse genetics viruses suggested that the response to each egg-adapted substitution varied by age. Antibody responses did not differ in male versus female vaccinees. Here, the combination of age-specific responses to vaccine egg-adapted substitutions, diverse host immune priming histories and virus antigenic drift impacted antibody responses following vaccination and may have led to the low and variable VE against A(H3N2) viruses across different age groups.
Authors
Feng Liu, F. Liaini Gross, Stacie N. Jefferson, Crystal Holiday, Yaohui Bai, Li Wang, Bin Zhou, Min Z. Levine
Abstract
COVID-19 convalescent plasma, particularly plasma with high-titer SARS-CoV-2 (CoV2) antibodies, is one of the leading treatments for individuals with early COVID-19 infection. The functionality of convalescent plasma varies greatly, but the association of antibody epitope specificities with plasma functionality remains uncharacterized. We assessed antibody functionality and reactivities to peptides across the CoV2 and the four endemic human coronavirus (HCoV) genomes in 126 COVID-19 convalescent plasma donations. We found strong correlation between plasma functionality and polyclonal antibody targeting of CoV2 spike protein peptides. Antibody reactivity to many HCoV spike peptides also displayed strong correlation with plasma functionality, including pan-coronavirus cross-reactive epitopes located in a conserved region of the fusion peptide. After accounting for antibody cross-reactivity, we identified an association between greater alphacoronavirus NL63 antibody responses and development of highly neutralizing antibodies to SARS-CoV-2. We also found that plasma preferentially reactive to the CoV2 spike receptor binding domain (RBD), versus the betacoronavirus HKU1 RBD, had higher neutralizing titer. Finally, we developed a two-peptide serosignature that identifies plasma donations with high anti-spike titer, but that suffer from low neutralizing activity. These results suggest that analysis of coronavirus antibody fine specificities may be useful for selecting therapeutic plasma with desired functionalities.
Authors
William R. Morgenlander, Stephanie N. Henson, Daniel R. Monaco, Athena Chen, Kirsten Littlefield, Evan M. Bloch, Eric Fujimura, Ingo Ruczinski, Andrew R. Crowley, Harini Natarajan, Savannah E. Butler, Joshua A. Weiner, Mamie Z. Li, Tania S. Bonny, Sarah E. Benner, Ashwin Balagopal, David Sullivan, Shmuel Shoham, Thomas C. Quinn, Susan Eshleman, Arturo Casadevall, Andrew D. Redd, Oliver Laeyendecker, Margaret E. Ackerman, Andrew Pekosz, Stephen J. Elledge, Matthew L. Robinson, Aaron A.R. Tobian, H. Benjamin Larman
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Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)