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Article ; Online: Structural Cells as Key Regulators of Organ-specific Immunity.

Rybkina, Ksenia / Farber, Donna L

2021 Volume 105, Issue 6, Page(s) 1137–1139

MeSH term(s)	Immunity, Innate
Language	English
Publishing date	2021-05-28
Publishing country	United States
Document type	Journal Article ; Comment
ZDB-ID	208424-7
ISSN	1534-6080 ; 0041-1337
ISSN (online)	1534-6080
ISSN	0041-1337
DOI	10.1097/TP.0000000000003572
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Article ; Online: Tissue immunity to SARS-CoV-2: Role in protection and immunopathology.

Rybkina, Ksenia / Davis-Porada, Julia / Farber, Donna L

Immunological reviews

2022 Volume 309, Issue 1, Page(s) 25–39

Abstract: The SARS-CoV-2 pandemic has demonstrated the importance of studying antiviral immunity within sites of infection to gain insights into mechanisms for immune protection and disease pathology. As SARS-CoV-2 is tropic to the respiratory tract, many studies ... ...

Abstract	The SARS-CoV-2 pandemic has demonstrated the importance of studying antiviral immunity within sites of infection to gain insights into mechanisms for immune protection and disease pathology. As SARS-CoV-2 is tropic to the respiratory tract, many studies of airway washes, lymph node aspirates, and postmortem lung tissue have revealed site-specific immune dynamics that are associated with the protection or immunopathology but are not readily observed in circulation. This review summarizes the growing body of work identifying immune processes in tissues and their interplay with immune responses in circulation during acute SARS-CoV-2 infection, severe disease, and memory persistence. Establishment of tissue resident immunity also may have implications for vaccination and the durability of immune memory and protection.
MeSH term(s)	COVID-19 ; Humans ; Lung ; Pandemics ; SARS-CoV-2 ; Vaccination
Language	English
Publishing date	2022-06-25
Publishing country	England
Document type	Journal Article ; Review ; Research Support, N.I.H., Extramural
ZDB-ID	391796-4
ISSN	1600-065X ; 0105-2896
ISSN (online)	1600-065X
ISSN	0105-2896
DOI	10.1111/imr.13112
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Article ; Online: Genetic diversity and molecular epidemiology of respiratory syncytial virus circulated in Antananarivo, Madagascar, from 2011 to 2017: Predominance of ON1 and BA9 genotypes.

Razanajatovo Rahombanjanahary, Norosoa Harline / Rybkina, Ksenia / Randriambolamanantsoa, Tsiry Hasina / Razafimanjato, Helisoa / Heraud, Jean-Michel

Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology

2020 Volume 129, Page(s) 104506

Abstract: Background: Respiratory syncytial virus is the main cause of acute respiratory infections leading to a considerable morbidity and mortality among under-5 years children. A comprehensive scheme of RSV virus evolution is of great value in implementing ... ...

Abstract	Background: Respiratory syncytial virus is the main cause of acute respiratory infections leading to a considerable morbidity and mortality among under-5 years children. A comprehensive scheme of RSV virus evolution is of great value in implementing effective universal RSV vaccine. Objective: We investigated the clinical spectrum and molecular characteristics of detected RSV over a period of seven years (January 2011 to June 2017) in Antananarivo, the capital city of Madagascar. Study design: 671 nasopharyngeal samples taken from children aged less than 5 years suffered from ARI were screened for RSV by real-time PCR. Clinical data were retrieved from case report forms. Genotype identification was performed by reverse-transcription PCR and sequencing of the second hyper variable region (HVR2) of the G glycoprotein. Results: Amongst samples tested, 292 (43.5 %) were found positive for RSV. RSV A predominated during the study period which accounted for 62.3 % (182/292) of positive samples while RSV B represented 37.0 % (108/292). Phylogenetic analyses identified NA1 and ON1 genotypes among RSV A. Though NA1 widespread from 2011 to 2013, ON1 became prevalent during the following years. Among RSV B, THB, CB1 and BA9 genotypes were detected. A co-circulation of THB and CB1 strains occurred during the 2011 season that was substituted by the BA9 from 2012. Malagasy ON1 strains carried some characteristic amino acid substitutions that distinguish them from the worldwide ON1 strains. By analyzing clinical spectrum, ON1 and BA genotypes seemed to prevail in mild infections compared to NA1. Conclusion: Results obtained here will have its implication in predicting temporal evolution of RSV at the local level. Considering the insularity of the country, information obtained should help in comparative analysis with global RSV strains to optimize vaccine efficacy.
MeSH term(s)	Child ; Genetic Variation ; Genotype ; Humans ; Infant ; Madagascar ; Molecular Epidemiology ; Phylogeny ; Respiratory Syncytial Virus Infections ; Respiratory Syncytial Virus, Human/genetics
Language	English
Publishing date	2020-06-13
Publishing country	Netherlands
Document type	Journal Article ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	1446080-4
ISSN	1873-5967 ; 1386-6532
ISSN (online)	1873-5967
ISSN	1386-6532
DOI	10.1016/j.jcv.2020.104506
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Article ; Online: Inhibition of Measles Viral Fusion Is Enhanced by Targeting Multiple Domains of the Fusion Protein.

Bovier, Francesca T / Rybkina, Ksenia / Biswas, Sudipta / Harder, Olivia / Marcink, Tara C / Niewiesk, Stefan / Moscona, Anne / Alabi, Christopher A / Porotto, Matteo

ACS nano

2021 Volume 15, Issue 8, Page(s) 12794–12803

Abstract: Measles virus (MeV) infection remains a significant public health threat despite ongoing global efforts to increase vaccine coverage. As eradication of MeV stalls, and vulnerable populations expand, effective antivirals against MeV are in high demand. ... ...

Abstract	Measles virus (MeV) infection remains a significant public health threat despite ongoing global efforts to increase vaccine coverage. As eradication of MeV stalls, and vulnerable populations expand, effective antivirals against MeV are in high demand. Here, we describe the development of an antiviral peptide that targets the MeV fusion (F) protein. This antiviral peptide construct is composed of a carbobenzoxy-d-Phe-l-Phe-Gly (fusion inhibitor peptide; FIP) conjugated to a lipidated MeV F C-terminal heptad repeat (HRC) domain derivative. Initial in vitro testing showed high antiviral potency and specific targeting of MeV F-associated cell plasma membranes, with minimal cytotoxicity. The FIP and HRC-derived peptide conjugates showed synergistic antiviral activities when administered individually. However, their chemical conjugation resulted in markedly increased antiviral potency. In vitro mechanistic experiments revealed that the FIP-HRC lipid conjugate exerted its antiviral activity predominantly through stabilization of the prefusion F, while HRC-derived peptides alone act predominantly on the F protein after its activation. Coupled with in vivo experiments showing effective prevention of MeV infection in cotton rats, FIP-HRC lipid conjugates show promise as potential MeV antivirals via specific targeting and stabilization of the prefusion MeV F structure.
MeSH term(s)	Humans ; Measles virus ; Viral Fusion Proteins ; Measles ; Antiviral Agents/pharmacology ; Antiviral Agents/chemistry ; Peptides/pharmacology ; Peptides/chemistry ; Lipids/pharmacology
Chemical Substances	Viral Fusion Proteins ; Antiviral Agents ; Peptides ; Lipids
Language	English
Publishing date	2021-07-22
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ISSN	1936-086X
ISSN (online)	1936-086X
DOI	10.1021/acsnano.1c02057
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Article ; Online: SARS-CoV-2 infection and recovery in children: Distinct T cell responses in MIS-C compared to COVID-19.

Rybkina, Ksenia / Bell, Joseph N / Bradley, Marissa C / Wohlbold, Teddy / Scafuro, Marika / Meng, Wenzhao / Korenberg, Rebecca C / Davis-Porada, Julia / Anderson, Brett R / Weller, Rachel J / Milner, Joshua D / Moscona, Anne / Porotto, Matteo / Luning Prak, Eline T / Pethe, Kalpana / Connors, Thomas J / Farber, Donna L

The Journal of experimental medicine

2023 Volume 220, Issue 8

Abstract: SARS-CoV-2 infection for most children results in mild or minimal symptoms, though in rare cases severe disease can develop, including a multisystem inflammatory syndrome (MIS-C) with myocarditis. Here, we present longitudinal profiling of immune ... ...

Abstract	SARS-CoV-2 infection for most children results in mild or minimal symptoms, though in rare cases severe disease can develop, including a multisystem inflammatory syndrome (MIS-C) with myocarditis. Here, we present longitudinal profiling of immune responses during acute disease and following recovery in children who developed MIS-C, relative to children who experienced more typical symptoms of COVID-19. T cells in acute MIS-C exhibited transient signatures of activation, inflammation, and tissue residency which correlated with cardiac disease severity, while T cells in acute COVID-19 upregulated markers of follicular helper T cells for promoting antibody production. The resultant memory immune response in recovery showed increased frequencies of virus-specific memory T cells with pro-inflammatory functions in children with prior MIS-C compared to COVID-19 while both cohorts generated comparable antibody responses. Together our results reveal distinct effector and memory T cell responses in pediatric SARS-CoV-2 infection delineated by clinical syndrome, and a potential role for tissue-derived T cells in the immune pathology of systemic disease.
MeSH term(s)	Humans ; Child ; COVID-19 ; SARS-CoV-2 ; Inflammation ; Severity of Illness Index
Language	English
Publishing date	2023-05-03
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	218343-2
ISSN	1540-9538 ; 0022-1007
ISSN (online)	1540-9538
ISSN	0022-1007
DOI	10.1084/jem.20221518
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Article ; Online: Inactivated and live-attenuated seasonal influenza vaccines boost broadly neutralizing antibodies in children.

Yegorov, Sergey / Celeste, Daniel B / Gomes, Kimberly Braz / Ang, Jann C / Vandenhof, Colin / Wang, Joanne / Rybkina, Ksenia / Tsui, Vanessa / Stacey, Hannah D / Loeb, Mark / Miller, Matthew S

Cell reports. Medicine

2022 Volume 3, Issue 2, Page(s) 100509

Abstract: The induction of broadly neutralizing antibodies (bNAbs) that target the hemagglutinin stalk domain is a promising strategy for the development of "universal" influenza virus vaccines. bNAbs can be boosted in adults by sequential exposure to ... ...

Abstract	The induction of broadly neutralizing antibodies (bNAbs) that target the hemagglutinin stalk domain is a promising strategy for the development of "universal" influenza virus vaccines. bNAbs can be boosted in adults by sequential exposure to heterosubtypic viruses through natural infection or vaccination. However, little is known about if or how bNAbs are induced by vaccination in more immunologically naive children. Here, we describe the impact of repeated seasonal influenza vaccination and vaccine type on induction of bNAbs against group 1 influenza viruses in a pediatric cohort enrolled in randomized controlled trials of seasonal influenza vaccination. Repeated seasonal vaccination results in significant boosting of a durable bNAb response. Boosting of serological bNAb titers is comparable within inactivated and live attenuated (LAIV) vaccinees and declines with age. These data provide insights into vaccine-elicited bNAb induction in children, which have important implications for the design of universal influenza vaccine modalities in this critical population.
MeSH term(s)	Adult ; Broadly Neutralizing Antibodies ; Child ; Humans ; Influenza Vaccines ; Influenza, Human/prevention & control ; Seasons ; Vaccines, Attenuated
Chemical Substances	Broadly Neutralizing Antibodies ; Influenza Vaccines ; Vaccines, Attenuated
Language	English
Publishing date	2022-02-03
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2666-3791
ISSN (online)	2666-3791
DOI	10.1016/j.xcrm.2022.100509
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Article ; Online: Induction of bronchus-associated lymphoid tissue is an early life adaptation for promoting human B cell immunity.

Nature immunology

2023 Volume 24, Issue 8, Page(s) 1370–1381

Abstract: Infants and young children are more susceptible to common respiratory pathogens than adults but can fare better against novel pathogens like severe acute respiratory syndrome coronavirus 2. The mechanisms by which infants and young children mount ... ...

Abstract	Infants and young children are more susceptible to common respiratory pathogens than adults but can fare better against novel pathogens like severe acute respiratory syndrome coronavirus 2. The mechanisms by which infants and young children mount effective immune responses to respiratory pathogens are unknown. Through investigation of lungs and lung-associated lymph nodes from infant and pediatric organ donors aged 0-13 years, we show that bronchus-associated lymphoid tissue (BALT), containing B cell follicles, CD4
MeSH term(s)	Adult ; Infant ; Humans ; Child ; Child, Preschool ; Lymphoid Tissue ; Bronchi/pathology ; COVID-19/pathology ; B-Lymphocytes ; Lymph Nodes
Language	English
Publishing date	2023-07-17
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2016987-5
ISSN	1529-2916 ; 1529-2908
ISSN (online)	1529-2916
ISSN	1529-2908
DOI	10.1038/s41590-023-01557-3
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Article ; Online: Site-specific development and progressive maturation of human tissue-resident memory T cells over infancy and childhood.

Immunity

2023 Volume 56, Issue 8, Page(s) 1894–1909.e5

Abstract: Infancy and childhood are critical life stages for generating immune memory to protect against pathogens; however, the timing, location, and pathways for memory development in humans remain elusive. Here, we investigated T cells in mucosal sites, ... ...

Abstract	Infancy and childhood are critical life stages for generating immune memory to protect against pathogens; however, the timing, location, and pathways for memory development in humans remain elusive. Here, we investigated T cells in mucosal sites, lymphoid tissues, and blood from 96 pediatric donors aged 0-10 years using phenotypic, functional, and transcriptomic profiling. Our results revealed that memory T cells preferentially localized in the intestines and lungs during infancy and accumulated more rapidly in mucosal sites compared with blood and lymphoid organs, consistent with site-specific antigen exposure. Early life mucosal memory T cells exhibit distinct functional capacities and stem-like transcriptional profiles. In later childhood, they progressively adopt proinflammatory functions and tissue-resident signatures, coincident with increased T cell receptor (TCR) clonal expansion in mucosal and lymphoid sites. Together, our findings identify staged development of memory T cells targeted to tissues during the formative years, informing how we might promote and monitor immunity in children.
MeSH term(s)	Child ; Humans ; Infant ; CD8-Positive T-Lymphocytes ; Immunologic Memory ; Lymphoid Tissue/metabolism ; Memory T Cells ; Mucous Membrane ; Receptors, Antigen, T-Cell/genetics ; Receptors, Antigen, T-Cell/metabolism ; Infant, Newborn ; Child, Preschool
Chemical Substances	Receptors, Antigen, T-Cell
Language	English
Publishing date	2023-07-07
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1217235-2
ISSN	1097-4180 ; 1074-7613
ISSN (online)	1097-4180
ISSN	1074-7613
DOI	10.1016/j.immuni.2023.06.008
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Article ; Online: Human parainfluenza virus evolution during lung infection of immunocompromised individuals promotes viral persistence.

Greninger, Alexander L / Rybkina, Ksenia / Lin, Michelle J / Drew-Bear, Jennifer / Marcink, Tara C / Shean, Ryan C / Makhsous, Negar / Boeckh, Michael / Harder, Olivia / Bovier, Francesca / Burstein, Shana R / Niewiesk, Stefan / Rima, Bert K / Porotto, Matteo / Moscona, Anne

The Journal of clinical investigation

2021 Volume 131, Issue 23

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 ... ...

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 showed that intrahost evolution in chronic human parainfluenza virus 3 (HPIV3) infection in immunocompromised individuals elicited mutations that favored viral entry and persistence, suggesting that similar processes may operate across enveloped respiratory viruses. We profiled longitudinal HPIV3 infections from 2 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.
MeSH term(s)	Adult ; Binding Sites ; DNA Mutational Analysis ; Female ; Gene Frequency ; Graft vs Host Disease/drug therapy ; HEK293 Cells ; Humans ; Immunocompromised Host ; Leukemia, Myeloid, Acute ; Lung/virology ; Lung Diseases/virology ; Mutation ; Mycophenolic Acid/administration & dosage ; N-Acetylneuraminic Acid/chemistry ; Parainfluenza Virus 3, Human/genetics ; Parainfluenza Virus 3, Human/metabolism ; Paramyxoviridae Infections/metabolism ; Paramyxoviridae Infections/virology ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/complications ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapy ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/virology ; Receptors, Virus/metabolism ; Sirolimus/administration & dosage ; Viral Fusion Proteins/genetics ; Viral Fusion Proteins/metabolism ; Virus Internalization ; Young Adult
Chemical Substances	Receptors, Virus ; Viral Fusion Proteins ; N-Acetylneuraminic Acid (GZP2782OP0) ; Mycophenolic Acid (HU9DX48N0T) ; Sirolimus (W36ZG6FT64)
Language	English
Publishing date	2021-10-05
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	3067-3
ISSN	1558-8238 ; 0021-9738
ISSN (online)	1558-8238
ISSN	0021-9738
DOI	10.1172/JCI150506
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Article ; Online: Analysis of a Subacute Sclerosing Panencephalitis Genotype B3 Virus from the 2009-2010 South African Measles Epidemic Shows That Hyperfusogenic F Proteins Contribute to Measles Virus Infection in the Brain.

Angius, Fabrizio / Smuts, Heidi / Rybkina, Ksenia / Stelitano, Debora / Eley, Brian / Wilmshurst, Jo / Ferren, Marion / Lalande, Alexandre / Mathieu, Cyrille / Moscona, Anne / Horvat, Branka / Hashiguchi, Takao / Porotto, Matteo / Hardie, Diana

Journal of virology

2019 Volume 93, Issue 4

Abstract: During a measles virus (MeV) epidemic in 2009 in South Africa, measles inclusion body encephalitis (MIBE) was identified in several HIV-infected patients. Years later, children are presenting with subacute sclerosing panencephalitis (SSPE). To ... ...

Abstract	During a measles virus (MeV) epidemic in 2009 in South Africa, measles inclusion body encephalitis (MIBE) was identified in several HIV-infected patients. Years later, children are presenting with subacute sclerosing panencephalitis (SSPE). To investigate the features of established MeV neuronal infections, viral sequences were analyzed from brain tissue samples of a single SSPE case and compared with MIBE sequences previously obtained from patients infected during the same epidemic. Both the SSPE and the MIBE viruses had amino acid substitutions in the ectodomain of the F protein that confer enhanced fusion properties. Functional analysis of the fusion complexes confirmed that both MIBE and SSPE F protein mutations promoted fusion with less dependence on interaction by the viral receptor-binding protein with known MeV receptors. While the SSPE F required the presence of a homotypic attachment protein, MeV H, in order to fuse, MIBE F did not. Both F proteins had decreased thermal stability compared to that of the corresponding wild-type F protein. Finally, recombinant viruses expressing MIBE or SSPE fusion complexes spread in the absence of known MeV receptors, with MIBE F-bearing viruses causing large syncytia in these cells. Our results suggest that alterations to the MeV fusion complex that promote fusion and cell-to-cell spread in the absence of known MeV receptors is a key property for infection of the brain.
MeSH term(s)	Amino Acid Substitution ; Animals ; Brain/virology ; Cell Adhesion Molecules/metabolism ; Chlorocebus aethiops ; Epidemics ; Female ; Genotype ; Giant Cells/virology ; HEK293 Cells ; Humans ; Male ; Measles/epidemiology ; Measles/metabolism ; Measles/virology ; Measles virus/genetics ; Mutation ; Neurons/virology ; South Africa ; Subacute Sclerosing Panencephalitis/genetics ; Subacute Sclerosing Panencephalitis/virology ; Vero Cells ; Viral Fusion Proteins/genetics ; Viral Fusion Proteins/metabolism
Chemical Substances	Cell Adhesion Molecules ; Viral Fusion Proteins
Language	English
Publishing date	2019-02-05
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	80174-4
ISSN	1098-5514 ; 0022-538X
ISSN (online)	1098-5514
ISSN	0022-538X
DOI	10.1128/JVI.01700-18
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