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Article ; Online: Gut Microbiome Homeostasis and the CD4 T- Follicular Helper Cell IgA Axis in Human Immunodeficiency Virus Infection.

Onabajo, Olusegun O / Mattapallil, Joseph J

2021 Volume 12, Page(s) 657679

Abstract: Human Immunodeficiency Virus (HIV) and Simian Immunodeficiency Virus (SIV) are associated with severe perturbations in the gut mucosal environment characterized by massive viral replication and depletion of CD4 T cells leading to dysbiosis, breakdown of ... ...

Abstract	Human Immunodeficiency Virus (HIV) and Simian Immunodeficiency Virus (SIV) are associated with severe perturbations in the gut mucosal environment characterized by massive viral replication and depletion of CD4 T cells leading to dysbiosis, breakdown of the epithelial barrier, microbial translocation, immune activation and disease progression. Multiple mechanisms play a role in maintaining homeostasis in the gut mucosa and protecting the integrity of the epithelial barrier. Among these are the secretory IgA (sIgA) that are produced daily in vast quantities throughout the mucosa and play a pivotal role in preventing commensal microbes from breaching the epithelial barrier. These microbe specific, high affinity IgA are produced by IgA+ plasma cells that are present within the Peyer's Patches, mesenteric lymph nodes and the isolated lymphoid follicles that are prevalent in the lamina propria of the gastrointestinal tract (GIT). Differentiation, maturation and class switching to IgA producing plasma cells requires help from T follicular helper (Tfh) cells that are present within these lymphoid tissues. HIV replication and CD4 T cell depletion is accompanied by severe dysregulation of Tfh cell responses that compromises the generation of mucosal IgA that in turn alters barrier integrity leading to commensal bacteria readily breaching the epithelial barrier and causing mucosal pathology. Here we review the effect of HIV infection on Tfh cells and mucosal IgA responses in the GIT and the consequences these have for gut dysbiosis and mucosal immunopathogenesis.
MeSH term(s)	Animals ; B-Lymphocyte Subsets/immunology ; B-Lymphocyte Subsets/metabolism ; Cell Communication/immunology ; Gastrointestinal Microbiome/immunology ; HIV/immunology ; HIV Infections/immunology ; HIV Infections/metabolism ; HIV Infections/virology ; Homeostasis/immunology ; Host-Pathogen Interactions/immunology ; Humans ; Immunity, Mucosal ; Immunoglobulin A/immunology ; Immunoglobulin A, Secretory/immunology ; Intestinal Mucosa/immunology ; Intestinal Mucosa/metabolism ; Intestinal Mucosa/microbiology ; Plasma Cells/immunology ; Plasma Cells/metabolism ; Signal Transduction ; Simian Immunodeficiency Virus/immunology ; T-Lymphocytes, Helper-Inducer/immunology ; T-Lymphocytes, Helper-Inducer/metabolism
Chemical Substances	Immunoglobulin A ; Immunoglobulin A, Secretory
Language	English
Publishing date	2021-03-19
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2021.657679
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Article ; Online: GALT CD4

Onabajo, Olusegun O / Lewis, Mark G / Mattapallil, Joseph J

Cellular immunology

2021 Volume 366, Page(s) 104396

Abstract: Human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) infections are characterized by dramatic alterations in the mucosal CD4 T cell compartment. Though viremia is effectively suppressed, and peripheral CD4 T cell numbers recover to ... ...

Abstract	Human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) infections are characterized by dramatic alterations in the mucosal CD4 T cell compartment. Though viremia is effectively suppressed, and peripheral CD4 T cell numbers recover to near healthy levels after highly active anti-retroviral therapy (HAART), some of the dysfunctional consequences of HIV infection continue to persist during therapy. We hypothesized that CD4 T follicular helper (Tfh) cell deficiencies may play a role in this process. Using the macaque model we show that SIV infection was associated with a significant loss of Tfh cells in the GALT that drain the mesentery lining the gastrointestinal tract (GIT). Loss of Tfh cells significantly correlated with the depletion of the overall memory CD4 T cell compartment; most Tfh cells in the GALT expressed a CD95+CD28+ memory phenotype suggesting that infection of the memory compartment likely drives the loss of GALT Tfh cells during infection. Continuous anti-retroviral therapy (cART) was accompanied by a significant repopulation of Tfh cells in the GALT to levels similar to those of uninfected animals. Repopulating Tfh cells displayed significantly higher capacity to produce IL-21 as compared to SIV infected animals suggesting that cART fully restores Tfh cells that are functionally capable of supporting GC reactions in the GALT.
MeSH term(s)	Animals ; Antiretroviral Therapy, Highly Active/methods ; CD4-Positive T-Lymphocytes/drug effects ; CD4-Positive T-Lymphocytes/immunology ; Cell Movement ; Disease Models, Animal ; Germinal Center/immunology ; HIV Infections/drug therapy ; HIV Infections/immunology ; HIV-1/physiology ; Humans ; Immunologic Memory ; Interleukins/metabolism ; Intestines/immunology ; Lymphoid Tissue/immunology ; Lymphopenia ; Macaca ; Programmed Cell Death 1 Receptor/metabolism ; Simian Acquired Immunodeficiency Syndrome/drug therapy ; Simian Acquired Immunodeficiency Syndrome/immunology ; Simian Immunodeficiency Virus/physiology
Chemical Substances	Interleukins ; Programmed Cell Death 1 Receptor ; interleukin-21 (MKM3CA6LT1)
Language	English
Publishing date	2021-06-16
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	80094-6
ISSN	1090-2163 ; 0008-8749
ISSN (online)	1090-2163
ISSN	0008-8749
DOI	10.1016/j.cellimm.2021.104396
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Article ; Online: The IFN-λ4 Conundrum: When a Good Interferon Goes Bad.

Onabajo, Olusegun O / Muchmore, Brian / Prokunina-Olsson, Ludmila

Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research

2019 Volume 39, Issue 10, Page(s) 636–641

Abstract: Since its discovery in 2013, interferon lambda 4 (IFN-λ4) has received a reputation as a paradoxical type III IFN. Difficulties in detecting IFN-λ4, especially in secreted form even led to questions about its existence. However, the genetic ability to ... ...

Abstract	Since its discovery in 2013, interferon lambda 4 (IFN-λ4) has received a reputation as a paradoxical type III IFN. Difficulties in detecting IFN-λ4, especially in secreted form even led to questions about its existence. However, the genetic ability to generate IFN-λ4, determined by the presence of the rs368234815-ΔG allele, is the strongest predictor of impaired clearance of hepatitis C virus (HCV) infection in humans. Significant modulation of IFN-λ4 activity by a genetic variant (P70S) supports IFN-λ4, and not other type III IFNs encoded in the same genomic locus, as the primary functional cause of the association with HCV clearance. Although the ability to produce IFN-λ4 is associated with decreased HCV clearance, the recombinant IFN-λ4 is active against HCV and other viruses. These observations present an apparent conundrum-when and how does a presumably good IFN, with anti-HCV activity, interfere with the ability to clear HCV? In this review, we discuss findings that suggest potential mechanisms for explaining this conundrum.
MeSH term(s)	Hepacivirus/genetics ; Hepacivirus/metabolism ; Hepatitis C/genetics ; Hepatitis C/metabolism ; Hepatitis C/pathology ; Humans ; Interleukins/genetics ; Interleukins/metabolism ; Polymorphism, Genetic
Chemical Substances	IFNL4 protein, human ; Interleukins
Language	English
Publishing date	2019-06-26
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Intramural ; Review
ZDB-ID	1226675-9
ISSN	1557-7465 ; 1079-9907
ISSN (online)	1557-7465
ISSN	1079-9907
DOI	10.1089/jir.2019.0044
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Zs.A 1748: Show issues

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Article ; Online: Transcriptomic and proteomic assessment of tocilizumab response in a randomized controlled trial of patients hospitalized with COVID-19.

Shivram, Haridha / Hackney, Jason A / Rosenberger, Carrie M / Teterina, Anastasia / Qamra, Aditi / Onabajo, Olusegun / McBride, Jacqueline / Cai, Fang / Bao, Min / Tsai, Larry / Regev, Aviv / Rosas, Ivan O / Bauer, Rebecca N

iScience

2023 Volume 26, Issue 9, Page(s) 107597

Abstract: High interleukin (IL)-6 levels are associated with greater COVID-19 severity. IL-6 receptor blockade by tocilizumab (anti-IL6R; Actemra) is used globally for the treatment of severe COVID-19, yet a molecular understanding of the therapeutic benefit ... ...

Abstract	High interleukin (IL)-6 levels are associated with greater COVID-19 severity. IL-6 receptor blockade by tocilizumab (anti-IL6R; Actemra) is used globally for the treatment of severe COVID-19, yet a molecular understanding of the therapeutic benefit remains unclear. We characterized the immune profile and identified cellular and molecular pathways modified by tocilizumab in peripheral blood samples from patients enrolled in the COVACTA study, a phase 3, randomized, double-blind, placebo-controlled trial of the efficacy and safety of tocilizumab in hospitalized patients with severe COVID-19. We identified markers of inflammation, lymphopenia, myeloid dysregulation, and organ injury that predict disease severity and clinical outcomes. Proteomic analysis confirmed a pharmacodynamic effect for tocilizumab and identified novel pharmacodynamic biomarkers. Transcriptomic analysis revealed that tocilizumab treatment leads to faster resolution of lymphopenia and myeloid dysregulation associated with severe COVID-19, indicating greater anti-inflammatory activity relative to placebo and potentially leading to faster recovery in patients hospitalized with COVID-19.
Language	English
Publishing date	2023-08-11
Publishing country	United States
Document type	Journal Article
ISSN	2589-0042
ISSN (online)	2589-0042
DOI	10.1016/j.isci.2023.107597
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Article ; Online: Chronic simian immunodeficiency virus infection is associated with contrasting phenotypes of dysfunctional Bcl6

Onabajo, Olusegun O / Lewis, Mark G / Mattapallil, Joseph J

Journal of cellular and molecular medicine

2018 Volume 22, Issue 11, Page(s) 5682–5687

Abstract: Human immunodeficiency virus (HIV) infection is characterized by dysfunctional B cell responses. Here we show that chronic simian immunodeficiency virus (SIV) infection is characterized by an expansion of either lymph node germinal center (GC) B cells ... ...

Abstract	Human immunodeficiency virus (HIV) infection is characterized by dysfunctional B cell responses. Here we show that chronic simian immunodeficiency virus (SIV) infection is characterized by an expansion of either lymph node germinal center (GC) B cells that co-express Bcl6, Ki-67 and IL-21R and correlate with expanded T follicular helper (Tfh) cells or B cells that lack Bcl6, Ki-67 and IL-21R but express high levels of anti-apoptotic Bcl2 that negatively correlate with Tfh cells. The lack of Tfh cells likely contributes to persistence of dysfunctional non-proliferating B cells during chronic infection. These findings have implications for protective immunity in HIV-infected individuals who harbour low frequencies of Tfh cells.
MeSH term(s)	Animals ; B-Lymphocytes/immunology ; B-Lymphocytes/pathology ; Cell Differentiation/immunology ; Germinal Center/immunology ; Germinal Center/virology ; HIV Infections/genetics ; HIV Infections/immunology ; HIV Infections/pathology ; HIV Infections/virology ; Humans ; Lymph Nodes/immunology ; Lymph Nodes/pathology ; Macaca mulatta/immunology ; Phenotype ; Proto-Oncogene Proteins c-bcl-2/genetics ; Proto-Oncogene Proteins c-bcl-6/genetics ; Simian Acquired Immunodeficiency Syndrome/genetics ; Simian Acquired Immunodeficiency Syndrome/immunology ; Simian Acquired Immunodeficiency Syndrome/pathology ; Simian Acquired Immunodeficiency Syndrome/virology ; Simian Immunodeficiency Virus/genetics ; Simian Immunodeficiency Virus/immunology ; Simian Immunodeficiency Virus/pathogenicity ; T-Lymphocytes, Helper-Inducer/immunology ; T-Lymphocytes, Helper-Inducer/pathology
Chemical Substances	Proto-Oncogene Proteins c-bcl-2 ; Proto-Oncogene Proteins c-bcl-6
Language	English
Publishing date	2018-09-06
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2074559-X
ISSN	1582-4934 ; 1582-4934 ; 1582-1838
ISSN (online)	1582-4934
ISSN	1582-4934 ; 1582-1838
DOI	10.1111/jcmm.13844
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Zs.A 5752: Show issues

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Article ; Online: Direct intranodal tonsil vaccination with modified vaccinia Ankara vaccine protects macaques from highly pathogenic SIVmac251.

Mattathil, Jeffy G / Volz, Asisa / Onabajo, Olusegun O / Maynard, Sean / Bixler, Sandra L / Shen, Xiaoying X / Vargas-Inchaustegui, Diego / Robert-Guroff, Marjorie / Lebranche, Celia / Tomaras, Georgia / Montefiori, David / Sutter, Gerd / Mattapallil, Joseph J

Nature communications

2023 Volume 14, Issue 1, Page(s) 1264

Abstract: Human immunodeficiency virus (HIV) is a mucosally transmitted virus that causes immunodeficiency and AIDS. Developing efficacious vaccines to prevent infection is essential to control the epidemic. Protecting the vaginal and rectal mucosa, the primary ... ...

Abstract	Human immunodeficiency virus (HIV) is a mucosally transmitted virus that causes immunodeficiency and AIDS. Developing efficacious vaccines to prevent infection is essential to control the epidemic. Protecting the vaginal and rectal mucosa, the primary routes of HIV entry has been a challenge given the significant compartmentalization between the mucosal and peripheral immune systems. We hypothesized that direct intranodal vaccination of mucosa associated lymphoid tissue (MALT) such as the readily accessible palatine tonsils could overcome this compartmentalization. Here we show that rhesus macaques primed with plasmid DNA encoding SIVmac251-env and gag genes followed by an intranodal tonsil MALT boost with MVA encoding the same genes protects from a repeated low dose intrarectal challenge with highly pathogenic SIVmac251; 43% (3/7) of vaccinated macaques remained uninfected after 9 challenges as compared to the unvaccinated control (0/6) animals. One vaccinated animal remained free of infection even after 22 challenges. Vaccination was associated with a ~2 log decrease in acute viremia that inversely correlated with anamnestic immune responses. Our results suggest that a combination of systemic and intranodal tonsil MALT vaccination could induce robust adaptive and innate immune responses leading to protection from mucosal infection with highly pathogenic HIV and rapidly control viral breakthroughs.
MeSH term(s)	Animals ; Humans ; Female ; Vaccinia ; Palatine Tonsil ; Macaca mulatta ; Vaccinia virus ; Vaccination ; Lymphoma, B-Cell, Marginal Zone ; HIV Infections
Language	English
Publishing date	2023-03-07
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-023-36907-0
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Article ; Online: Expansion or depletion of T follicular helper cells during HIV infection: consequences for B cell responses.

Onabajo, Olusegun O / Mattapallil, Joseph J

Current HIV research

2014 Volume 11, Issue 8, Page(s) 595–600

Abstract: HIV infection is characterized by aberrant B cell responses and B cell dysfunction. These dysfunctional responses have been extensively documented in peripheral blood and organized lymphoid tissues such as the lymph nodes. Though the loss of CD4 T cell ... ...

Abstract	HIV infection is characterized by aberrant B cell responses and B cell dysfunction. These dysfunctional responses have been extensively documented in peripheral blood and organized lymphoid tissues such as the lymph nodes. Though the loss of CD4 T cell help has been thought to play a key role in dysfunctional B cell responses, recent studies have implicated a subset of CD4 T helper cells called the T follicular helper (Tfh) cells in this process. Tfh cells interact with B cells and play a key role in mediating the germinal center reaction, and driving the differentiation and maturation of B cells. Why Tfh expands in some HIV infected individuals as compared to their loss in others is still not clear. Here we review some of the recent developments in the field and discuss the implications of Tfh cell dysregulation on B cell responses during HIV infection.
MeSH term(s)	B-Lymphocytes/physiology ; CD4-Positive T-Lymphocytes/physiology ; Cell Differentiation/physiology ; HIV Infections/immunology ; Humans ; Lymphocyte Depletion ; T-Lymphocytes, Helper-Inducer/physiology
Language	English
Publishing date	2014-02-25
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	2192348-6
ISSN	1873-4251 ; 1570-162X
ISSN (online)	1873-4251
ISSN	1570-162X
DOI	10.2174/1570162x12666140225153552
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Zs.A 6102: Show issues

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Article ; Online: Comparative Functional Analysis of 12 Mammalian IFN-λ4 Orthologs.

Paquin, Ashley / Onabajo, Olusegun O / Tang, Wei / Prokunina-Olsson, Ludmila

Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research

2016 Volume 36, Issue 1, Page(s) 30–36

Abstract: IFN-λ4 is a novel type-III interferon with strong clinical significance in humans. Only a subset of individuals--up to 10% of Asians, 50% of Europeans, and 90% of Africans--carry the ΔG allele of a genetic variant rs368234815-TT/ΔG and are genetically ... ...

Abstract	IFN-λ4 is a novel type-III interferon with strong clinical significance in humans. Only a subset of individuals--up to 10% of Asians, 50% of Europeans, and 90% of Africans--carry the ΔG allele of a genetic variant rs368234815-TT/ΔG and are genetically able to produce IFN-λ4 protein. Carriers of the ΔG allele have impaired ability to clear infection with hepatitis C virus (HCV). IFN-λ4 is also predicted to exist and be functionally important in several nonhuman mammals. In this study, we present the first comparative analysis of 12 mammalian IFN-λ4 orthologs in a human hepatic cell line, HepG2, which supports signaling of the human IFN-λ4. We show that despite differences in protein sequences, functional properties of the recombinant human and nonhuman IFN-λ4 proteins are comparable-they are all expressed as predominantly cytoplasmic proteins that are biologically active for induction of interferon signaling. We show that several IFN-λ4 orthologs can be detected by Western blotting, flow cytometry, and confocal imaging using a monoclonal antibody developed for the human IFN-λ4. Studies of IFN-λ4 in animals should help improve our understanding of the biology of this novel clinically important interferon in normal and disease conditions.
MeSH term(s)	Amino Acid Sequence ; Animals ; Cytosol/immunology ; Cytosol/metabolism ; Gene Expression ; Genes, Reporter ; Hep G2 Cells ; Humans ; Interleukins/genetics ; Interleukins/immunology ; Luciferases/genetics ; Luciferases/immunology ; Molecular Sequence Data ; Plasmids/chemistry ; Plasmids/metabolism ; Recombinant Proteins/genetics ; Recombinant Proteins/immunology ; Sequence Alignment ; Sequence Homology, Amino Acid ; Species Specificity ; Transfection
Chemical Substances	IFNL4 protein, human ; Interleukins ; Recombinant Proteins ; Luciferases (EC 1.13.12.-)
Keywords	covid19
Language	English
Publishing date	2016-01
Publishing country	United States
Document type	Comparative Study ; Journal Article ; Research Support, N.I.H., Intramural
ZDB-ID	1226675-9
ISSN	1557-7465 ; 1079-9907
ISSN (online)	1557-7465
ISSN	1079-9907
DOI	10.1089/jir.2015.0096
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Article ; Online: Intracellular Accumulation of IFN-λ4 Induces ER Stress and Results in Anti-Cirrhotic but Pro-HCV Effects.

Onabajo, Olusegun O / Wang, Fang / Lee, Mei-Hsuan / Florez-Vargas, Oscar / Obajemu, Adeola / Tanikawa, Chizu / Vargas, Joselin M / Liao, Shu-Fen / Song, Ci / Huang, Yu-Han / Shen, Chen-Yang / Banday, A Rouf / O'Brien, Thomas R / Hu, Zhibin / Matsuda, Koichi / Prokunina-Olsson, Ludmila

Frontiers in immunology

2021 Volume 12, Page(s) 692263

Abstract: ... IFNL3/ ... ...

Abstract	IFNL3/IFNL4
MeSH term(s)	Adult ; Apoptosis ; Carcinoma, Hepatocellular/genetics ; Carcinoma, Hepatocellular/metabolism ; Carcinoma, Hepatocellular/virology ; Case-Control Studies ; Cell Proliferation ; Databases, Factual ; Endoplasmic Reticulum Stress ; Female ; Genetic Predisposition to Disease ; Hep G2 Cells ; Hepatitis C/genetics ; Hepatitis C/metabolism ; Hepatitis C/virology ; Humans ; Interferons/genetics ; Interleukins/genetics ; Interleukins/metabolism ; Japan ; Liver/metabolism ; Liver/pathology ; Liver Cirrhosis/genetics ; Liver Cirrhosis/metabolism ; Liver Cirrhosis/prevention & control ; Liver Cirrhosis/virology ; Liver Neoplasms/genetics ; Liver Neoplasms/metabolism ; Liver Neoplasms/virology ; Male ; Middle Aged ; Phenotype ; Polymorphism, Genetic ; Protective Factors ; Risk Assessment ; Risk Factors ; Taiwan
Chemical Substances	interferon-lambda, human ; IFNL4 protein, human ; Interleukins ; Interferons (9008-11-1)
Language	English
Publishing date	2021-08-23
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Intramural ; Research Support, Non-U.S. Gov't ; Video-Audio Media
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2021.692263
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Article ; Online: Tocilizumab treatment leads to early resolution of myeloid dysfunction and lymphopenia in patients hospitalized with COVID-19

Shivram, Haridha / Hackney, Jason A. / Rosenberger, Carrie M / Teterina, Anastasia / Qamra, Aditi / Onabajo, Olusegun / McBride, Jacqueline / Cai, Fang / Bao, Min / Tsai, Larry / Regev, Aviv / Rosas, Ivan O. / Bauer, Rebecca N.

bioRxiv

Abstract: Tocilizumab, an anti-interleukin-6 receptor inhibitor, is recommended in global treatment guidelines for patients hospitalized with severe COVID-19. Using proteomic and transcriptomic analysis, we characterized the immune profile and identified cellular ... ...

Abstract	Tocilizumab, an anti-interleukin-6 receptor inhibitor, is recommended in global treatment guidelines for patients hospitalized with severe COVID-19. Using proteomic and transcriptomic analysis, we characterized the immune profile and identified cellular and molecular pathways directly modified by tocilizumab in peripheral blood samples collected from patients enrolled in the COVACTA study, a phase 3, randomized, double-blind, placebo-controlled trial, to assess the efficacy and safety of tocilizumab in hospitalized patients with severe COVID-19 pneumonia. We identified factors predicting disease severity and clinical outcomes, including markers of inflammation, lymphopenia, myeloid dysfunction, and organ injury. Proteomic analysis confirmed a pharmacodynamic effect for tocilizumab. Transcriptomic analysis revealed that tocilizumab treatment leads to faster resolution of lymphopenia and myeloid dysfunction associated with severe COVID-19, thus defining an anti-inflammatory mechanism of action for the beneficial effects of tocilizumab in patients hospitalized with COVID-19.
Keywords	covid19
Language	English
Publishing date	2022-10-28
Publisher	Cold Spring Harbor Laboratory
Document type	Article ; Online
DOI	10.1101/2022.10.27.514096
Database	COVID19

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