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Article ; Online: Impact of Convalescent Plasma Therapy on Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Antibody Profile in Coronavirus Disease 2019 (COVID-19) Patients.

Tang, Juanjie / Grubbs, Gabrielle / Lee, Youri / Golding, Hana / Khurana, Surender

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America

2021 Volume 74, Issue 2, Page(s) 327–334

Abstract: Convalescent plasma (CP) have been used for treatment of coronavirus disease 2019 (COVID-19), but their effectiveness varies significantly. Moreover, the impact of CP treatment on the composition of severe acute respiratory syndrome coronavirus 2 (SARS- ... ...

Abstract	Convalescent plasma (CP) have been used for treatment of coronavirus disease 2019 (COVID-19), but their effectiveness varies significantly. Moreover, the impact of CP treatment on the composition of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies in COVID-19 patients and antibody markers that differentiate between those who survive and those who succumb to the COVID-19 disease are not well understood. Herein, we performed longitudinal analysis of antibody profile on 115 sequential plasma samples from 16 hospitalized COVID-19 patients treated with either CP or standard of care, only half of them survived. Differential antibody kinetics was observed for antibody binding, immunoglobulin M/immunoglobulin G/immunoglobulin A (IgM/IgG/IgA) distribution, and affinity maturation in "survived" versus "fatal" COVID-19 patients. Surprisingly, CP treatment did not predict survival. Strikingly, marked decline in neutralization titers was observed in the fatal patients prior to death, and convalescent plasma treatment did not reverse this trend. Furthermore, irrespective of CP treatment, higher antibody affinity to the SARS-CoV-2 prefusion spike was associated with survival outcome. Additionally, sustained elevated IgA response was associated with fatal outcome in these COVID-19 patients. These findings propose that treatment of COVID-19 patients with convalescent plasma should be carefully targeted, and effectiveness of treatment may depend on the clinical and immunological status of COVID-19 patients, as well as the quality of the antibodies in the convalescent plasma.
MeSH term(s)	Antibodies, Neutralizing ; Antibodies, Viral ; COVID-19/therapy ; Humans ; Immunization, Passive ; SARS-CoV-2
Chemical Substances	Antibodies, Neutralizing ; Antibodies, Viral
Language	English
Publishing date	2021-04-16
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1099781-7
ISSN	1537-6591 ; 1058-4838
ISSN (online)	1537-6591
ISSN	1058-4838
DOI	10.1093/cid/ciab317
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Article ; Online: Systemic and mucosal immune profiling in asymptomatic and symptomatic SARS-CoV-2-infected individuals reveal unlinked immune signatures.

Ravichandran, Supriya / Grubbs, Gabrielle / Tang, Juanjie / Lee, Youri / Huang, Chang / Golding, Hana / Khurana, Surender

Science advances

2021 Volume 7, Issue 42, Page(s) eabi6533

Abstract: Mucosal immunity plays a key role in prevention of SARS-CoV-2 virus spread to the lungs. In this study, we evaluated systemic and mucosal immune signatures in asymptomatic SARS-CoV-2–infected versus symptomatic COVID-19 adults compared with RSV-infected ... ...

Abstract	Mucosal immunity plays a key role in prevention of SARS-CoV-2 virus spread to the lungs. In this study, we evaluated systemic and mucosal immune signatures in asymptomatic SARS-CoV-2–infected versus symptomatic COVID-19 adults compared with RSV-infected adults. Matched serum and nasal wash pairs were subjected to cytokine/chemokine analyses and comprehensive antibody profiling including epitope repertoire analyses, antibody kinetics to SARS-CoV-2 prefusion spike and spike RBD mutants, and neutralization of SARS-CoV-2 variants of concern. The data suggest independent evolution of antibody responses in the mucosal sites as reflected in differential IgM/IgG/IgA epitope repertoire compared with serum. Antibody affinity against SARS-CoV-2 prefusion spike for both serum and nasal washes was significantly higher in asymptomatic adults compared with symptomatic COVID-19 patients. Last, the cytokine/chemokine responses in the nasal washes were more robust than in serum. These data underscore the importance of evaluating mucosal immune responses for better therapeutics and vaccines against SARS-CoV-2.
Language	English
Publishing date	2021-10-13
Publishing country	United States
Document type	Journal Article
ZDB-ID	2810933-8
ISSN	2375-2548 ; 2375-2548
ISSN (online)	2375-2548
ISSN	2375-2548
DOI	10.1126/sciadv.abi6533
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Article ; Online: Protective antigenic sites identified in respiratory syncytial virus fusion protein reveals importance of p27 domain

Jeehyun Lee / Youri Lee / Laura Klenow / Elizabeth M Coyle / Juanjie Tang / Supriya Ravichandran / Hana Golding / Surender Khurana

EMBO Molecular Medicine, Vol 14, Iss 1, Pp n/a-n/a (2022)

2022

Abstract: Abstract Respiratory syncytial virus (RSV) vaccines primarily focused on surface fusion (F) protein are under development. Therefore, to identify RSV‐F protective epitopes, we evaluated 14 antigenic sites recognized following primary human RSV infection. ...

Abstract	Abstract Respiratory syncytial virus (RSV) vaccines primarily focused on surface fusion (F) protein are under development. Therefore, to identify RSV‐F protective epitopes, we evaluated 14 antigenic sites recognized following primary human RSV infection. BALB/c mice were vaccinated with F peptides, F proteins, or RSV‐A2, followed by rA2‐Line19F challenge. F peptides generated binding antibodies with minimal in vitro neutralization titers. However, several F peptides (including Site II) reduced lung viral loads and lung pathology scores in animals, suggesting partial protection from RSV disease. Interestingly, animals vaccinated with peptides (aa 101–121 and 110–136) spanning the F‐p27 sequence, which is only present in unprocessed F0 protein, showed control of viral loads with significantly reduced pathology compared with mock‐vaccinated controls. Furthermore, we observed F‐p27 expression on the surface of RSV‐infected cells as well as lungs from RSV‐infected mice. The anti‐p27 antibodies demonstrated antibody‐dependent cellular cytotoxicity (ADCC) of RSV‐infected A549 cells. These findings suggest that p27‐mediated immune response may play a role in control of RSV disease in vivo, and F‐p27 should be considered for inclusion in an effective RSV vaccine.
Keywords	epitope ; F protein ; neutralization ; RSV ; vaccine ; Medicine (General) ; R5-920 ; Genetics ; QH426-470
Language	English
Publishing date	2022-01-01T00:00:00Z
Publisher	Wiley
Document type	Article ; Online
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Article ; Online: Systemic and Lower Respiratory Tract Immunity to SARS-CoV-2 Omicron and Variants in Pediatric Severe COVID-19 and Mis-C

Juanjie Tang / Adrienne G. Randolph / Tanya Novak / Tracie C. Walker / Laura L. Loftis / Matt S. Zinter / Katherine Irby / Surender Khurana

Vaccines, Vol 10, Iss 270, p

2022 Volume 270

Abstract: Mucosal immunity plays an important role in the control of viral respiratory infections like SARS-CoV-2. While systemic immune responses against the SARS-2-CoV-2 have been studied in children, there is no information on mucosal antibody response, ... ...

Abstract	Mucosal immunity plays an important role in the control of viral respiratory infections like SARS-CoV-2. While systemic immune responses against the SARS-2-CoV-2 have been studied in children, there is no information on mucosal antibody response, especially in the lower respiratory tract of children coronavirus disease 2019 (COVID-19) and post-infectious multisystem inflammatory syndrome in children (MIS-C) against emerging SARS-CoV-2 variants. Therefore, we evaluated neutralizing antibody responses in paired plasma and endotracheal aspirates of pediatric severe, acute COVID-19 or MIS-C patients against SARS-CoV-2 WA1/2020, as well as against variants of concern (VOCs). Neutralizing antibody responses against the SARS-CoV-2 WA1/2020 strain in pediatric plasma were 2-fold or 35-fold higher compared with the matched endotracheal aspirate in COVID-19 or MIS-C patients, respectively. In contrast to plasma, neutralizing antibody responses against the VOCs and variants of interest (VOIs) in endotracheal aspirates were lower, with only one endotracheal aspirate demonstrating neutralizing titers against the Iota, Kappa, Beta, Gamma, and Omicron variants. In conclusion, our findings suggest that children and adolescents with severe COVID-19 or MIS-C have weak mucosal neutralizing antibodies in the trachea against circulating SARS-CoV-2 Omicron and other VOCs, which may have implications for recovery and for re-infection with emerging SARS-CoV-2 variants.
Keywords	SARS-CoV-2 ; COVID-19 ; pediatric ; MIS-C ; mucosal immunity ; neutralization ; Medicine ; R
Subject code	572
Language	English
Publishing date	2022-02-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
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Article: Systemic and Lower Respiratory Tract Immunity to SARS-CoV-2 Omicron and Variants in Pediatric Severe COVID-19 and Mis-C.

Tang, Juanjie / Randolph, Adrienne G / Novak, Tanya / Walker, Tracie C / Loftis, Laura L / Zinter, Matt S / Irby, Katherine / Khurana, Surender

Vaccines

2022 Volume 10, Issue 2

Abstract	Mucosal immunity plays an important role in the control of viral respiratory infections like SARS-CoV-2. While systemic immune responses against the SARS-2-CoV-2 have been studied in children, there is no information on mucosal antibody response, especially in the lower respiratory tract of children coronavirus disease 2019 (COVID-19) and post-infectious multisystem inflammatory syndrome in children (MIS-C) against emerging SARS-CoV-2 variants. Therefore, we evaluated neutralizing antibody responses in paired plasma and endotracheal aspirates of pediatric severe, acute COVID-19 or MIS-C patients against SARS-CoV-2 WA1/2020, as well as against variants of concern (VOCs). Neutralizing antibody responses against the SARS-CoV-2 WA1/2020 strain in pediatric plasma were 2-fold or 35-fold higher compared with the matched endotracheal aspirate in COVID-19 or MIS-C patients, respectively. In contrast to plasma, neutralizing antibody responses against the VOCs and variants of interest (VOIs) in endotracheal aspirates were lower, with only one endotracheal aspirate demonstrating neutralizing titers against the Iota, Kappa, Beta, Gamma, and Omicron variants. In conclusion, our findings suggest that children and adolescents with severe COVID-19 or MIS-C have weak mucosal neutralizing antibodies in the trachea against circulating SARS-CoV-2 Omicron and other VOCs, which may have implications for recovery and for re-infection with emerging SARS-CoV-2 variants.
Language	English
Publishing date	2022-02-10
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2703319-3
ISSN	2076-393X
ISSN	2076-393X
DOI	10.3390/vaccines10020270
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Article ; Online: Increased Antibody Avidity and Cross-Neutralization of Severe Acute Respiratory Syndrome Coronavirus 2 Variants by Hyperimmunized Transchromosomic Bovine-Derived Human Immunoglobulins for Treatment of Coronavirus Disease 2019.

Tang, Juanjie / Grubbs, Gabrielle / Lee, Youri / Wu, Hua / Luke, Thomas C / Egland, Kristi A / Bausch, Christoph L / Sullivan, Eddie J / Khurana, Surender

The Journal of infectious diseases

2022 Volume 226, Issue 4, Page(s) 655–663

Abstract: Passive antibody immunotherapeutics directed against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are promising countermeasures for protection and treatment of coronavirus disease 2019 (COVID-19). SARS-CoV-2 variants of concern (VOCs) and ...

Abstract	Passive antibody immunotherapeutics directed against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are promising countermeasures for protection and treatment of coronavirus disease 2019 (COVID-19). SARS-CoV-2 variants of concern (VOCs) and variants of interest (VOIs) can impact the clinical efficacy of immunotherapeutics. A fully human polyclonal antibody immunotherapeutic purified from plasma of transchromosomic (Tc) bovines hyperimmunized with SARS-CoV-2 WA-1 spike (SAB-185) is being assessed for efficacy in a phase 2/3 clinical trial when different circulating SARS-CoV-2 variants predominated. We evaluated antibody binding, avidity maturation, and SARS-CoV-2 VOCs/VOIs virus-neutralizing capacity of convalescent plasma compared with different lots of SAB-185 and individual Tc bovine sera sequentially obtained after each vaccination against Alpha, Epsilon, Iota, Gamma, Beta, Kappa, and Delta variants. In contrast to convalescent plasma, sera and SAB-185 derived from hyperimmunized Tc bovines demonstrated higher antibody avidity and more potent cross-neutralizing activity of VOCs/VOIs. Thus, SAB-185 is a potential promising therapeutic candidate for the treatment of patients infected with SARS-CoV-2 variants.
MeSH term(s)	Animals ; Antibodies, Neutralizing ; Antibodies, Viral ; Antibody Affinity ; COVID-19/therapy ; Cattle ; Humans ; Immunization, Passive ; Immunoglobulin G ; Neutralization Tests ; SARS-CoV-2 ; Spike Glycoprotein, Coronavirus
Chemical Substances	Antibodies, Neutralizing ; Antibodies, Viral ; Immunoglobulin G ; Spike Glycoprotein, Coronavirus ; spike protein, SARS-CoV-2 ; SAB-185 (GZH7FFK82R)
Language	English
Publishing date	2022-02-02
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	3019-3
ISSN	1537-6613 ; 0022-1899
ISSN (online)	1537-6613
ISSN	0022-1899
DOI	10.1093/infdis/jiac031
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Article ; Online: Antibody affinity maturation and plasma IgA associate with clinical outcome in hospitalized COVID-19 patients

Juanjie Tang / Supriya Ravichandran / Youri Lee / Gabrielle Grubbs / Elizabeth M. Coyle / Laura Klenow / Hollie Genser / Hana Golding / Surender Khurana

Nature Communications, Vol 12, Iss 1, Pp 1-

2021 Volume 13

Abstract: SARS-CoV2 infection has been linked to a wide range of clinical severities and the immunopathology is still under intense scrutiny. Here, the authors uncover an association of antibody affinity maturation and plasma IgA levels with clinical outcome in ... ...

Abstract	SARS-CoV2 infection has been linked to a wide range of clinical severities and the immunopathology is still under intense scrutiny. Here, the authors uncover an association of antibody affinity maturation and plasma IgA levels with clinical outcome in patients with COVID-19 disease.
Keywords	Science ; Q
Language	English
Publishing date	2021-02-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: D-dimer and CoV-2 spike-immune complexes contribute to the production of PGE2 and proinflammatory cytokines in monocytes.

Yun-Jong Park / David Acosta / Russell Vassell / Juanjie Tang / Surender Khurana / Carol D Weiss / Hana Golding / Marina Zaitseva

PLoS Pathogens, Vol 18, Iss 4, p e

2022 Volume 1010468

Abstract: An overreactive inflammatory response and coagulopathy are observed in patients with severe form of COVID-19. Since increased levels of D-dimer (DD) are associated with coagulopathy in COVID-19, we explored whether DD contributes to the aberrant cytokine ...

Abstract	An overreactive inflammatory response and coagulopathy are observed in patients with severe form of COVID-19. Since increased levels of D-dimer (DD) are associated with coagulopathy in COVID-19, we explored whether DD contributes to the aberrant cytokine responses. Here we show that treatment of healthy human monocytes with DD induced a dose dependent increase in production of pyrogenic mediator, Prostaglandin E2 (PGE2) and inflammatory cytokines, IL-6 and IL-8. The DD-induced PGE2 and inflammatory cytokines were enhanced significantly by co-treatment with immune complexes (IC) of SARS CoV-2 recombinant S protein or of pseudovirus containing SARS CoV-2 S protein (PVCoV-2) coated with spike-specific chimeric monoclonal antibody (MAb) containing mouse variable and human Fc regions. The production of PGE2 and cytokines in monocytes activated with DD and ICs was sensitive to the inhibitors of β2 integrin and FcγRIIa, and to the inhibitors of calcium signaling, Mitogen-Activated Protein Kinase (MAPK) pathway, and tyrosine-protein kinase. Importantly, strong increase in PGE2 and in IL-6/IL-8/IL-1β cytokines was observed in monocytes activated with DD in the presence of IC of PVCoV-2 coated with plasma from hospitalized COVID-19 patients but not from healthy donors. The IC of PVCoV-2 with convalescent plasma induced much lower levels of PGE2 and cytokines compared with plasma from hospitalized COVID-19 patients. PGE2 and IL-6/IL-8 cytokines produced in monocytes activated with plasma-containing IC, correlated well with the levels of spike binding antibodies and not with neutralizing antibody titers. Our study suggests that a combination of high levels of DD and high titers of spike-binding antibodies that can form IC with SARS CoV-2 viral particles might accelerate the inflammatory status of lung infiltrating monocytes leading to increased lung pathology in patients with severe form of COVID-19.
Keywords	Immunologic diseases. Allergy ; RC581-607 ; Biology (General) ; QH301-705.5
Subject code	610
Language	English
Publishing date	2022-04-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
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Article ; Online: D-dimer and CoV-2 spike-immune complexes contribute to the production of PGE2 and proinflammatory cytokines in monocytes.

Park, Yun-Jong / Acosta, David / Vassell, Russell / Tang, Juanjie / Khurana, Surender / Weiss, Carol D / Golding, Hana / Zaitseva, Marina

PLoS pathogens

2022 Volume 18, Issue 4, Page(s) e1010468

Abstract	An overreactive inflammatory response and coagulopathy are observed in patients with severe form of COVID-19. Since increased levels of D-dimer (DD) are associated with coagulopathy in COVID-19, we explored whether DD contributes to the aberrant cytokine responses. Here we show that treatment of healthy human monocytes with DD induced a dose dependent increase in production of pyrogenic mediator, Prostaglandin E2 (PGE2) and inflammatory cytokines, IL-6 and IL-8. The DD-induced PGE2 and inflammatory cytokines were enhanced significantly by co-treatment with immune complexes (IC) of SARS CoV-2 recombinant S protein or of pseudovirus containing SARS CoV-2 S protein (PVCoV-2) coated with spike-specific chimeric monoclonal antibody (MAb) containing mouse variable and human Fc regions. The production of PGE2 and cytokines in monocytes activated with DD and ICs was sensitive to the inhibitors of β2 integrin and FcγRIIa, and to the inhibitors of calcium signaling, Mitogen-Activated Protein Kinase (MAPK) pathway, and tyrosine-protein kinase. Importantly, strong increase in PGE2 and in IL-6/IL-8/IL-1β cytokines was observed in monocytes activated with DD in the presence of IC of PVCoV-2 coated with plasma from hospitalized COVID-19 patients but not from healthy donors. The IC of PVCoV-2 with convalescent plasma induced much lower levels of PGE2 and cytokines compared with plasma from hospitalized COVID-19 patients. PGE2 and IL-6/IL-8 cytokines produced in monocytes activated with plasma-containing IC, correlated well with the levels of spike binding antibodies and not with neutralizing antibody titers. Our study suggests that a combination of high levels of DD and high titers of spike-binding antibodies that can form IC with SARS CoV-2 viral particles might accelerate the inflammatory status of lung infiltrating monocytes leading to increased lung pathology in patients with severe form of COVID-19.
MeSH term(s)	Animals ; Antigen-Antibody Complex ; COVID-19/therapy ; Cytokines/metabolism ; Dinoprostone/metabolism ; Fibrin Fibrinogen Degradation Products ; Humans ; Immunization, Passive ; Immunologic Factors/metabolism ; Interleukin-6/metabolism ; Interleukin-8/metabolism ; Mice ; Monocytes ; Spike Glycoprotein, Coronavirus/metabolism ; COVID-19 Serotherapy
Chemical Substances	Antigen-Antibody Complex ; Cytokines ; Fibrin Fibrinogen Degradation Products ; Immunologic Factors ; Interleukin-6 ; Interleukin-8 ; Spike Glycoprotein, Coronavirus ; fibrin fragment D ; spike protein, SARS-CoV-2 ; Dinoprostone (K7Q1JQR04M)
Language	English
Publishing date	2022-04-06
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	2205412-1
ISSN	1553-7374 ; 1553-7374
ISSN (online)	1553-7374
ISSN	1553-7374
DOI	10.1371/journal.ppat.1010468
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Article ; Online: The PPR domain of mitochondrial RNA polymerase is an exoribonuclease required for mtDNA replication in Drosophila melanogaster.

Liu, Yi / Chen, Zhe / Wang, Zong-Heng / Delaney, Katherine M / Tang, Juanjie / Pirooznia, Mehdi / Lee, Duck-Yeon / Tunc, Ilker / Li, Yuesheng / Xu, Hong

Nature cell biology

2022 Volume 24, Issue 5, Page(s) 757–765

Abstract: Mitochondrial DNA (mtDNA) replication and transcription are of paramount importance to cellular energy metabolism. Mitochondrial RNA polymerase is thought to be the primase for mtDNA replication. However, it is unclear how this enzyme, which normally ... ...

Abstract	Mitochondrial DNA (mtDNA) replication and transcription are of paramount importance to cellular energy metabolism. Mitochondrial RNA polymerase is thought to be the primase for mtDNA replication. However, it is unclear how this enzyme, which normally transcribes long polycistronic RNAs, can produce short RNA oligonucleotides to initiate mtDNA replication. We show that the PPR domain of Drosophila mitochondrial RNA polymerase (PolrMT) has 3'-to-5' exoribonuclease activity, which is indispensable for PolrMT to synthesize short RNA oligonucleotides and prime DNA replication in vitro. An exoribonuclease-deficient mutant, PolrMT
MeSH term(s)	Animals ; DNA Replication/genetics ; DNA, Mitochondrial/genetics ; DNA, Mitochondrial/metabolism ; Drosophila melanogaster/genetics ; Drosophila melanogaster/metabolism ; Exoribonucleases/genetics ; Mitochondrial Proteins/metabolism ; Oligonucleotides ; RNA/genetics ; RNA, Mitochondrial/genetics
Chemical Substances	DNA, Mitochondrial ; Mitochondrial Proteins ; Oligonucleotides ; RNA, Mitochondrial ; RNA (63231-63-0) ; Exoribonucleases (EC 3.1.-)
Language	English
Publishing date	2022-04-21
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Intramural
ZDB-ID	1474722-4
ISSN	1476-4679 ; 1465-7392
ISSN (online)	1476-4679
ISSN	1465-7392
DOI	10.1038/s41556-022-00887-y
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