Virology
Abstract
The protective human antibody response to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus focuses on the spike (S) protein which decorates the virion surface and mediates cell binding and entry. Most SARS-CoV-2 protective antibodies target the receptor-binding domain or a single dominant epitope (‘supersite’) on the N terminal domain (NTD). Here, using the single B cell technology LIBRA-seq, we isolated a large panel of NTD-reactive and SARS-CoV-2 neutralizing antibodies from an individual who had recovered from COVID-19. We found that neutralizing antibodies to the NTD supersite commonly are encoded by the IGHV1-24 gene, forming a genetic cluster that represents a public B cell clonotype. However, we also discovered a rare human antibody, COV2-3434, that recognizes a site of vulnerability on the SARS-CoV-2 S protein in the trimer interface and possesses a distinct class of functional activity. COV2-3434 disrupted the integrity of S protein trimers, inhibited cell-to-cell spread of virus in culture, and conferred protection in human ACE2 transgenic mice against SARS-CoV-2 challenge. This study provides insight about antibody targeting of the S protein trimer interface region, suggesting this region may be a site of virus vulnerability.
Authors
Naveenchandra Suryadevara, Andrea R. Shiakolas, Laura A. VanBlargan, Elad Binshtein, Rita E. Chen, James Brett Case, Kevin J. Kramer, Erica C. Armstrong, Luke Myers, Andrew Trivette, Christopher Gainza, Rachel S. Nargi, Christopher N. Selverian, Edgar Davidson, Benjamin J. Doranz, Summer M. Diaz, Laura S Handal, Robert H. Carnahan, Michael S. Diamond, Ivelin S. Georgiev, James E. Crowe Jr.
Abstract
BACKGROUND. Cytomegalovirus (CMV) is the most common intrauterine infection, leading to infant brain damage. Prognostic assessment of CMV-infected fetuses has remained an ongoing challenge in prenatal care, in the absence of established prenatal biomarkers of congenital CMV (cCMV) infection severity. We aimed to identify prognostic biomarkers of cCMV-related fetal brain injury. METHODS. Global proteome analysis was performed in mid-gestation amniotic fluid samples, comparing fetuses with severe cCMV to asymptomatic CMV-infected fetuses. The levels of selected differentially-excreted proteins were further determined by specific immunoassays. RESULTS. Employing unbiased proteome analysis in a discovery cohort, we identified amniotic fluid proteins related to inflammation and neurological disease pathways, which demonstrated distinct abundance in fetuses with severe cCMV. Amniotic fluid levels of two of these proteins - the immunomodulatory proteins chemerin and galectin-3-binding-protein - were highly predictive of the severity of cCMV in an independent validation cohort, differentiating between fetuses with severe (N=17) and asymptomatic (N=26) cCMV, with 100-93.8% positive predictive value, and 92.9-92.6% negative predictive value (for chemerin - galectin-3-binding-protein, respectively). CONCLUSION. Analysis of chemerin and galectin-3-binding-protein in mid-gestation amniotic fluids could be employed in the clinical setting to profoundly improve the prognostic assessment of CMV-infected fetuses. TRIAL REGISTRATION. NA FUNDING. Israel Science Foundation; Research Fund - Hadassah Medical Organization.
Authors
Olesya Vorontsov, Lorinne Levitt, Daniele Lilleri, Gilad W. Vainer, Orit Caplan, Licita Schreiber, Alessia Arossa, Arsenio Spinillo, Milena Furione, Or Alfi, Esther Oiknine-Djian, Meital Kupervaser, Yuval Nevo, Sharona Elgavish, Moran Yassour, Maurizio Zavattoni, Tali Bdolah-Abram, Fausto Baldanti, Miriam Geal-Dor, Zichria Zakay-Rones, Nili Yanai, Simcha Yagel, Amos Panet, Dana G. Wolf
Abstract
BACKGROUND. It is unclear whether the level of serum hepatitis B virus (HBV) DNA at baseline impacts the on-treatment risk of hepatocellular carcinoma (HCC) in HBeAg positive, non-cirrhotic patients with chronic hepatitis B (CHB). METHODS. We conducted a multicenter cohort study including 2,073 entecavir- or tenofovir-treated, HBeAg-positive, non-cirrhotic, adult CHB patients with baseline HBV DNA levels ≥5.00 log10 IU/mL at three centers in Korea between January 2007 and December 2016. We evaluated the on-treatment incidence rate of HCC by baseline HBV DNA levels. RESULTS. During a median 5.7 years of continuous antiviral treatment, 47 patients developed HCC (0.39 per 100 person-years). By Kaplan–Meier analysis, HCC risk was the lowest in those with baseline HBV DNA levels ≥8.00 log10 IU/mL, increased incrementally with decreasing viral load, and the highest with HBV DNA levels 5.00–5.99 log10 IU/mL (P<0.001). By multivariable analysis, baseline HBV DNA level was an independent factor that was inversely associated with HCC risk. Compared with HBV DNA ≥8.00 log10 IU/mL, the adjusted hazard ratios for HCC risk with HBV DNA 7.00–7.99 log10 IU/mL, 6.00–6.99 log10 IU/mL, and 5.00–5.99 log10 IU/mL were 2.48 (P=0.03), 3.69 (P=0.002), and 6.10 (P<0.001), respectively. CONCLUSION. On-treatment HCC risk increased incrementally with decreasing baseline HBV DNA levels in the range of ≥5.00 log10 IU/mL in HBeAg-positive, non-cirrhotic, adult patients with CHB. Early initiation of antiviral treatment with a high viral load (≥8.00 log10 IU/mL) may maintain the lowest risk of HCC in those patients. FUNDING. Korean Government.
Authors
Won-Mook Choi, Gi-Ae Kim, Jonggi Choi, Seungbong Han, Young-Suk Lim
Abstract
Replication of SARS-CoV-2 in human population is defined by distributions of mutants that are present at different frequencies within the infected host, and can be detected by ultra-deep sequencing techniques. In this study, we have examined the SARS-CoV-2 mutant spectra of amplicons from the spike (S)-coding region of five nasopharyngeal isolates derived from vaccine-breakthrough patients. Interestingly, all patients became infected with the Alpha variant but amino acid substitutions that correspond to the Delta Plus, Iota and Omicron variants were present in the mutant spectra of the resident virus. Deep sequencing analysis of SARS-CoV-2 from vaccine-breakthrough patients revealed a rich reservoir of mutant types, and may also inform of tolerated substitutions that can be represented in epidemiological dominant variants.
Authors
Brenda Martínez-González, Lucía Vázquez-Sirvent, María E. Soria, Pablo Mínguez, Llanos Salar-Vidal, Carlos García-Crespo, Isabel Gallego, Ana Ávila, Carlos Llorens, Beatriz Soriano, Ricardo Ramos-Ruiz, Jaime Esteban, Ricardo Fernandez-Roblas, Ignacio Gadea, Carmen Ayuso, Javier Ruiz-Hornillos, Concepción Pérez-Jorge, Esteban Domingo, Celia Perales
Abstract
BACKGROUND. Although recent epidemiological data suggest that pneumococci may contribute to the risk of SARS-CoV-2 disease, cases of co-infection with Streptococcus pneumoniae in COVID-19 patients during hospitalisation have been reported infrequently. This apparent contradiction may be explained by interactions of SARS-CoV-2 and pneumococcus in the upper airway, resulting in the escape of SARS-CoV-2 from protective host immune responses. METHODS. Here, we investigated the relationship of these two respiratory pathogens in two distinct cohorts of a) healthcare workers with asymptomatic or mildly symptomatic SARS-CoV-2 infection identified by systematic screening and b) patients with moderate to severe disease who presented to hospital. We assessed the effect of co-infection on host antibody, cellular and inflammatory responses to the virus. RESULTS. In both cohorts, pneumococcal colonisation was associated with diminished anti-viral immune responses, which affected primarily mucosal IgA levels among individuals with mild or asymptomatic infection and cellular memory responses in infected patients. CONCLUSION. Our findings suggest that S. pneumoniae impairs host immunity to SARS-CoV-2 and raises the question if pneumococcal carriage also enables immune escape of other respiratory viruses and facilitates reinfection occurrence. TRIALS REGISTRATION. ISRCTN89159899 for FASTER study and Clinicaltrials.gov identifier: NCT03502291 for LAIV study
Authors
Elena Mitsi, Jesús Reiné, Britta C. Urban, Carla Solorzano, Elissavet Nikolaou, Angela D. Hyder-Wright, Sherin Pojar, Ashleigh Howard, Lisa Hitchins, Sharon Glynn, Madlen C Farrar, Konstantinos Liatsikos, Andrea M. Collins, Naomi F. Walker, Helen C. Hill, Esther L. German, Katerina S. Cheliotis, Rachel L. Byrne, Christopher T Williams, Ana I. Cubas-Atienzar, Tom E. Fletcher, Emily R. Adams, Simon J. Draper, David Pulido, Rohini Beavon, Christian Theilacker, Elizabeth Begier, Luis Jodar, Bradford D. Gessner, Daniela M. Ferreira
Abstract
Human T cell leukemia virus type 1 (HTLV-1) mainly infects CD4+ T cells and induces chronic, persistent infection in infected individuals, with some developing adult T cell leukemia/lymphoma (ATL). HTLV-1 alters cellular differentiation, activation, and survival; however, it is unknown whether and how these changes contribute to the malignant transformation of infected cells. In this study, we used single-cell RNA-sequencing and T cell receptor–sequencing to investigate the differentiation and HTLV-1–mediated transformation of T cells. We analyzed 87,742 PBMCs from 12 infected and 3 uninfected individuals. Using multiple independent bioinformatics methods, we demonstrated the seamless transition of naive T cells into activated T cells, whereby HTLV-1–infected cells in an activated state further transformed into ATL cells, which are characterized as clonally expanded, highly activated T cells. Notably, the greater the activation state of ATL cells, the more they acquire Treg signatures. Intriguingly, the expression of HLA class II genes in HTLV-1–infected cells was uniquely induced by the viral protein Tax and further upregulated in ATL cells. Functional assays revealed that HTLV-1–infected cells upregulated HLA class II molecules and acted as tolerogenic antigen-presenting cells to induce anergy of antigen-specific T cells. In conclusion, our study revealed the in vivo mechanisms of HTLV-1–mediated transformation and immune escape at the single-cell level.
Authors
Benjy J.Y. Tan, Kenji Sugata, Omnia Reda, Misaki Matsuo, Kyosuke Uchiyama, Paola Miyazato, Vincent Hahaut, Makoto Yamagishi, Kaoru Uchimaru, Yutaka Suzuki, Takamasa Ueno, Hitoshi Suzushima, Hiroo Katsuya, Masahito Tokunaga, Yoshikazu Uchiyama, Hideaki Nakamura, Eisaburo Sueoka, Atae Utsunomiya, Masahiro Ono, Yorifumi Satou
Abstract
Authors
Rory D. de Vries, Marieke van der Heiden, Daryl Geers, Celine Imhof, Debbie van Baarle, RECOVAC-IR Collaborators
Abstract
The capacity of respiratory viruses to undergo evolution within the respiratory tract raises the possibility of evolution under the selective pressure of the host environment or drug treatment. Long-term infections in immunocompromised hosts are potential drivers of viral evolution and development of infectious variants. We show that intra-host evolution in chronic human parainfluenza virus 3 (HPIV3) infection in immunocompromised individuals elicited mutations that favor viral entry and persistence, suggesting that similar processes may operate across enveloped respiratory viruses. We profiled longitudinal HPIV3 infections from two immunocompromised individuals that persisted for 278 and 98 days. Mutations accrued in the HPIV3 attachment protein hemagglutinin-neuraminidase (HN), including the first in vivo mutation in HN’s receptor binding site responsible for activating the viral fusion process. Fixation of this mutation was associated with exposure to a drug that cleaves host cell sialic acid moieties. Longitudinal adaptation of HN was associated with features that promote viral entry and persistence in cells, including greater avidity for sialic acid and more active fusion activity in vitro, but not with antibody escape. Long term infection thus led to mutations promoting viral persistence, suggesting that host-directed therapeutics may support the evolution of viruses that alter their biophysical characteristics to persist in the face of these agents in vivo.
Authors
Alexander L. Greninger, Ksenia Rybkina, Michelle J. Lin, Jennifer Drew-Bear, Tara C. Marcink, Ryan C. Shean, Negar Makhsous, Michael Boeckh, Olivia Harder, Francesca Bovier, Shana R. Burstein, Stefan Niewiesk, Bert K. Rima, Matteo Porotto, Anne Moscona
Abstract
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is the cause of coronavirus disease 2019 (COVID-19). Little is known about the interplay between pre-existing immunity towards endemic seasonal coronaviruses and the development of a SARS-CoV-2-specific IgG response. We investigated the kinetics, breadth, magnitude and level of cross-reactivity of IgG antibodies against SARS-CoV-2 and heterologous seasonal and epidemic coronaviruses at the clonal level in mild and severe COVID-19 patients and disease control patients. Antibody reactivity towards nucleocapsid and spike antigens was assessed and correlated to SARS-CoV-2 neutralization. COVID-19 patients mounted a mostly type-specific SARS-CoV-2 response. Additionally, IgG clones directed against seasonal coronavirus were boosted in patients with severe COVID-19. These boosted clones showed limited cross-reactivity and did not neutralize SARS-CoV-2. These findings support a boost of poorly protective coronavirus-specific antibodies in COVID-19 patients that correlates with disease severity, revealing original antigenic sin.
Authors
Muriel Aguilar-Bretones, Brenda M. Westerhuis, Matthijs P. Raadsen, Erwin de Bruin, Felicity D. Chandler, Nisreen M.A. Okba, Bart L. Haagmans, Thomas Langerak, Henrik Endeman, Johannes P.C. van den Akker, Diederik A.M.P.J. Gommers, Eric C.M. van Gorp, Corine H. GeurtsvanKessel, Rory D. de Vries, Ron A.M. Fouchier, Barry H.G. Rockx, Marion P.G. Koopmans, Gijsbert P. van Nierop
Abstract
BACKGROUND. Clinical data to support the use of bamlanivimab for the treatment of outpatients with mild to moderate coronavirus disease-19 (COVID-19) is needed. METHODS. 2,335 patients who received single-dose bamlanivimab infusion between November 12, 2020 to February 17, 2021 were compared with a propensity-matched control of 2,335 untreated patients with mild to moderate COVID-19 at Mayo Clinic facilities across 4 states. The primary outcome was the rate of hospitalization at days 14, 21 and 28. RESULTS. The median age of the population was 63; 47.3% of the bamlanivimab-treated cohort were ≥65 years; 49.3% were female. High-risk characteristics included hypertension (54.2%), body mass index ≥35 (32.4%), diabetes mellitus (26.5%), chronic lung disease (25.1%), malignancy (16.6%), and renal disease (14.5%). Patients who received bamlanivimab had lower all-cause hospitalization rates at days 14 (1.5% vs 3.5%; Odds Ratio [OR], 0.38), 21 (1.9% vs 3.9%; OR, 0.46), and 28 (2.5% vs 3.9%; OR, 0.61). Secondary exploratory outcomes included lower intensive care unit admission rates at days 14 (0.14% vs 1%; OR, 0.12), 21 (0.25% vs 1%; OR: 0.24) and 28 (0.56% vs 1.1%; OR: 0.52), and lower all-cause mortality at days 14 (0% vs 0.33%), 21 (0.05% vs 0.4%; OR,0.08) and 28 (0.11% vs 0.44%; OR, 0.01). Adverse events were uncommon with bamlanivimab, occurring in 19/2355, most commonly fever (n=6), nausea (n=5), and lightheadedness (n=3). CONCLUSIONS. Among high-risk patients with mild to moderate COVID-19, treatment with bamlanivimab was associated with a statistically significant lower rate of hospitalization compared with usual care. FUNDING. Mayo Clinic.
Authors
Ravindra Ganesh, Colin F. Pawlowski, John C. O'Horo, Lori L. Arndt, Richard F. Arndt, Sarah Bell, Dennis M. Bierle, Molly Destro Borgen, Sara Hanson, Alexander Heyliger, Jennifer L. Larsen, Patrick J. Lenehan, Robert Orenstein, Arjun Puranik, Leigh L. Speicher, Sidna M. Tulledge-Scheitel, AJ Venkatakrishnan, Caroline G. Wilker, Andrew D. Badley, Raymund R. Razonable
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ISSN: 0021-9738 (print), 1558-8238 (online)