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Article ; Online: Lymph node but not intradermal injection site macrophages are critical for germinal center formation and antibody responses to rabies vaccination.

Lytle, Andrew G / Shen, Shixue / McGettigan, James P

2015 Volume 89, Issue 5, Page(s) 2842–2848

Abstract: Unlabelled: Replication-deficient rabies virus (RABV)-based vaccines induce rapid and potent antibody responses via T cell-independent and T cell-dependent mechanisms. To further investigate early events in vaccine-induced antibody responses against ... ...

Abstract	Unlabelled: Replication-deficient rabies virus (RABV)-based vaccines induce rapid and potent antibody responses via T cell-independent and T cell-dependent mechanisms. To further investigate early events in vaccine-induced antibody responses against RABV infections, we studied the role of macrophages as mediators of RABV-based vaccine immunogenicity. In this report, we show that a recombinant matrix gene-deleted RABV-based vaccine (rRABV-ΔM) infects and activates primary murine macrophages in vitro. Immunization of mice with live RABV-based vaccines results in accumulation of macrophages at the site of immunization, which suggests that macrophages in tissues support the development of effective anti-RABV B cell responses. However, we show that draining lymph node macrophages, but not macrophages at the site of immunization, are essential for the generation of germinal center B cells, follicular T helper cells, and RABV-specific antibodies. Our findings have implications for the design of new RABV-based vaccines for which early immunological events are important for the protection against RABV in postexposure settings. Importance: More than two-thirds of the world's population live in regions where rabies is endemic. Postexposure prophylaxis is the primary means of treating humans. Identifying immunological principles that guide the development of rapid and potent antibody responses against rabies infections will greatly increase our ability to produce more-effective rabies vaccines. Here we report that macrophages in the draining lymph node, but not in the tissue at the site of immunization are important for vaccine-induced antibody responses to rabies. Information gleaned from this study may help guide the development of a single-dose vaccine against rabies infections.
MeSH term(s)	Animals ; Antibodies, Viral/blood ; Antibody Formation ; B-Lymphocytes/immunology ; Female ; Germinal Center/immunology ; Injections, Intradermal ; Lymph Nodes/immunology ; Macrophages/immunology ; Mice, Inbred C57BL ; Rabies Vaccines/administration & dosage ; Rabies Vaccines/immunology ; T-Lymphocytes, Helper-Inducer/immunology
Chemical Substances	Antibodies, Viral ; Rabies Vaccines
Language	English
Publishing date	2015-03
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	80174-4
ISSN	1098-5514 ; 0022-538X
ISSN (online)	1098-5514
ISSN	0022-538X
DOI	10.1128/JVI.03409-14
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Anemia in a young Guinean male.

Wilcox, Nicholas S / Tapé, Chantal / Cordisco, Anthony J / Than, Minh T / Zuroff, Leah / Dobkin, Jane / Massa, Ryan C / Lytle, Andrew G / Bagg, Adam / Min, Htun / Glaser, Laurel J / Kosseim, Laura M

Clinical case reports

2021 Volume 9, Issue 8, Page(s) e04593

Abstract: The etiology of anemia in adults is often multifactorial. This case highlights an uncommon combination of causes of anemia and the importance of a diagnostic workup guided by a patient's unique history, risk factors, and laboratory findings. ...

Abstract	The etiology of anemia in adults is often multifactorial. This case highlights an uncommon combination of causes of anemia and the importance of a diagnostic workup guided by a patient's unique history, risk factors, and laboratory findings.
Language	English
Publishing date	2021-08-06
Publishing country	England
Document type	Case Reports
ZDB-ID	2740234-4
ISSN	2050-0904
ISSN	2050-0904
DOI	10.1002/ccr3.4593
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Article ; Online: APRIL:TACI axis is dispensable for the immune response to rabies vaccination.

Haley, Shannon L / Tzvetkov, Evgeni P / Lytle, Andrew G / Alugupalli, Kishore R / Plummer, Joseph R / McGettigan, James P

Antiviral research

2017 Volume 144, Page(s) 130–137

Abstract: There is significant need to develop a single-dose rabies vaccine to replace the current multi-dose rabies vaccine regimen and eliminate the requirement for rabies immune globulin in post-exposure settings. To accomplish this goal, rabies virus (RABV)- ... ...

Abstract	There is significant need to develop a single-dose rabies vaccine to replace the current multi-dose rabies vaccine regimen and eliminate the requirement for rabies immune globulin in post-exposure settings. To accomplish this goal, rabies virus (RABV)-based vaccines must rapidly activate B cells to secrete antibodies which neutralize pathogenic RABV before it enters the CNS. Increased understanding of how B cells effectively respond to RABV-based vaccines may improve efforts to simplify post-exposure prophylaxis (PEP) regimens. Several studies have successfully employed the TNF family cytokine a proliferation-inducing ligand (APRIL) as a vaccine adjuvant. APRIL binds to the receptors TACI and B cell maturation antigen (BCMA)-expressed by B cells in various stages of maturation-with high affinity. We discovered that RABV-infected primary murine B cells upregulate APRIL ex vivo. Cytokines present at the time of antigen exposure affect the outcome of vaccination by influencing T and B cell activation and GC formation. Therefore, we hypothesized that the presence of APRIL at the time of RABV-based vaccine antigen exposure would support the generation of protective antibodies against RABV glycoprotein (G). In an effort to improve the response to RABV vaccination, we constructed and characterized a live recombinant RABV-based vaccine vector which expresses murine APRIL (rRABV-APRIL). Immunogenicity testing in mice demonstrated that expressing APRIL from the RABV genome does not impact the primary antibody response against RABV G compared to RABV alone. In order to evaluate the necessity of APRIL for the response to rabies vaccination, we compared the responses of APRIL-deficient and wild-type mice to immunization with rRABV. APRIL deficiency does not affect the primary antibody response to vaccination. Furthermore, APRIL expression by the vaccine did not improve the generation of long-lived antibody-secreting plasma cells (PCs) as serum antibody levels were equivalent in response to rRABV-APRIL and the vector eight weeks after immunization. Moreover, APRIL is dispensable for the long-lived antibody-secreting PC response to rRABV vaccination as anti-RABV G IgG levels were similar in APRIL-deficient and wild-type mice six months after vaccination. Mice lacking the APRIL receptor TACI demonstrated primary anti-RABV G antibody responses similar to wild-type mice following immunization with the vaccine vector indicating that this response is independent of TACI-mediated signals. Collectively, our findings demonstrate that APRIL and associated TACI signaling is dispensable for the immune response to RABV-based vaccination.
MeSH term(s)	Adjuvants, Immunologic/metabolism ; Animals ; Antibodies, Viral/blood ; Immunoglobulin G/blood ; Mice ; Mice, Knockout ; Rabies Vaccines/immunology ; Transmembrane Activator and CAML Interactor Protein/metabolism ; Tumor Necrosis Factor Ligand Superfamily Member 13/deficiency ; Tumor Necrosis Factor Ligand Superfamily Member 13/metabolism ; Vaccines, Attenuated/immunology
Chemical Substances	Adjuvants, Immunologic ; Antibodies, Viral ; Immunoglobulin G ; Rabies Vaccines ; Tnfrsf13b protein, mouse ; Tnfsf13 protein, mouse ; Transmembrane Activator and CAML Interactor Protein ; Tumor Necrosis Factor Ligand Superfamily Member 13 ; Vaccines, Attenuated
Language	English
Publishing date	2017
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	306628-9
ISSN	1872-9096 ; 0166-3542
ISSN (online)	1872-9096
ISSN	0166-3542
DOI	10.1016/j.antiviral.2017.06.004
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: B cell infection and activation by rabies virus-based vaccines.

Lytle, Andrew G / Norton, James E / Dorfmeier, Corin L / Shen, Shixue / McGettigan, James P

Journal of virology

2013 Volume 87, Issue 16, Page(s) 9097–9110

Abstract: Replication-deficient rabies viruses (RABV) are promising rabies postexposure vaccines due to their prompt and potent stimulation of protective virus neutralizing antibody titers, which are produced in mice by both T-dependent and T-independent ... ...

Abstract	Replication-deficient rabies viruses (RABV) are promising rabies postexposure vaccines due to their prompt and potent stimulation of protective virus neutralizing antibody titers, which are produced in mice by both T-dependent and T-independent mechanisms. To promote such early and robust B cell stimulation, we hypothesized that live RABV-based vaccines directly infect B cells, thereby activating a large pool of antigen-presenting cells (APCs) capable of providing early priming and costimulation to CD4(+) T cells. In this report, we show that live RABV-based vaccine vectors efficiently infect naive primary murine and human B cells ex vivo. Infection of B cells resulted in the significant upregulation of early markers of B cell activation and antigen presentation, including CD69, major histocompatibility complex class II (MHC-II), and CD40 in murine B cells or HLA-DR and CD40 in human B cells compared to mock-infected cells or cells treated with an inactivated RABV-based vaccine. Furthermore, primary B cells infected with a live RABV expressing ovalbumin were able to prime and stimulate naive CD4(+) OT-II T cells to proliferate and to secrete interleukin-2 (IL-2), demonstrating a functional consequence of B cell infection and activation by live RABV-based vaccine vectors. We propose that this direct B cell stimulation by live RABV-based vaccines is a potential mechanism underlying their induction of early protective T cell-dependent B cell responses, and that designing live RABV-based vaccines to infect and activate B cells represents a promising strategy to develop a single-dose postexposure rabies vaccine where the generation of early protective antibody titers is critical.
MeSH term(s)	Adult ; Animals ; B-Lymphocytes/immunology ; B-Lymphocytes/virology ; CD4-Positive T-Lymphocytes/immunology ; Cell Proliferation ; Cells, Cultured ; Female ; Humans ; Interleukin-2/metabolism ; Lymphocyte Activation ; Male ; Mice ; Mice, Inbred C57BL ; Rabies Vaccines/immunology ; Rabies virus/immunology ; Vaccines, Attenuated/immunology
Chemical Substances	Interleukin-2 ; Rabies Vaccines ; Vaccines, Attenuated
Language	English
Publishing date	2013-06-12
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	80174-4
ISSN	1098-5514 ; 0022-538X
ISSN (online)	1098-5514
ISSN	0022-538X
DOI	10.1128/JVI.00800-13
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Zs.A 609: Show issues

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Article ; Online: Protective vaccine-induced CD4(+) T cell-independent B cell responses against rabies infection.

Dorfmeier, Corin L / Lytle, Andrew G / Dunkel, Amber L / Gatt, Anthony / McGettigan, James P

Journal of virology

2012 Volume 86, Issue 21, Page(s) 11533–11540

Abstract: A major goal in rabies virus (RV) research is to develop a single-dose postexposure prophylaxis (PEP) that would simplify vaccination protocols, reduce costs associated with rabies prevention in humans, and save lives. Live replication-deficient RV-based ...

Abstract	A major goal in rabies virus (RV) research is to develop a single-dose postexposure prophylaxis (PEP) that would simplify vaccination protocols, reduce costs associated with rabies prevention in humans, and save lives. Live replication-deficient RV-based vaccines are emerging as promising single-dose vaccines to replace currently licensed inactivated RV-based vaccines. Nonetheless, little is known about how effective B cells develop in response to live RV-based vaccination. Understanding this fundamental property of rabies immunology may help in developing a single-dose RV vaccine. Typically, vaccines induce B cells secreting high-affinity, class-switched antibodies during germinal center (GC) reactions; however, there is a lag time between vaccination and the generation of GC B cells. In this report, we show that RV-specific antibodies are detected in mice immunized with live but not inactivated RV-based vaccines before B cells displaying a GC B cell phenotype (B220(+)GL7(hi)CD95(hi)) are formed, indicating a potential role for T cell-independent and early extrafollicular T cell-dependent antibody responses in the protection against RV infection. Using two mouse models of CD4(+) T cell deficiency, we show that B cells secreting virus-neutralizing antibodies (VNAs) are induced via T cell-independent mechanisms within 4 days postimmunization with a replication-deficient RV-based vaccine. Importantly, mice that are completely devoid of T cells (B6.129P2-Tcrβ(tm1Mom) Tcrδ(tm1Mom)/J) show protection against pathogenic challenge shortly after immunization with a live replication-deficient RV-based vaccine. We show that vaccines that can exploit early pathways of B cell activation and development may hold the key for the development of a single-dose RV vaccine wherein the rapid induction of VNA is critical.
MeSH term(s)	Animals ; Antibodies, Neutralizing/blood ; Antibodies, Viral/blood ; B-Lymphocytes/immunology ; CD4-Positive T-Lymphocytes/immunology ; Female ; Mice ; Mice, Inbred C57BL ; Rabies Vaccines/administration & dosage ; Rabies Vaccines/immunology ; Rabies virus/immunology ; Vaccines, Attenuated/administration & dosage ; Vaccines, Attenuated/immunology
Chemical Substances	Antibodies, Neutralizing ; Antibodies, Viral ; Rabies Vaccines ; Vaccines, Attenuated
Language	English
Publishing date	2012-08-15
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	80174-4
ISSN	1098-5514 ; 0022-538X
ISSN (online)	1098-5514
ISSN	0022-538X
DOI	10.1128/JVI.00615-12
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Zs.A 609: Show issues

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ab Jg. 2022: Lesesaal (EG)

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Article ; Online: ICAM-1-based rabies virus vaccine shows increased infection and activation of primary murine B cells in vitro and enhanced antibody titers in-vivo.

Norton, James E / Lytle, Andrew G / Shen, Shixue / Tzvetkov, Evgeni P / Dorfmeier, Corin L / McGettigan, James P

PloS one

2014 Volume 9, Issue 1, Page(s) e87098

Abstract: We have previously shown that live-attenuated rabies virus (RABV)-based vaccines infect and directly activate murine and human primary B cells in-vitro, which we propose can be exploited to help develop a single-dose RABV-based vaccine. Here we report on ...

Abstract	We have previously shown that live-attenuated rabies virus (RABV)-based vaccines infect and directly activate murine and human primary B cells in-vitro, which we propose can be exploited to help develop a single-dose RABV-based vaccine. Here we report on a novel approach to utilize the binding of Intracellular Adhesion Molecule-1 (ICAM-1) to its binding partner, Lymphocyte Function-associated Antigen-1 (LFA-1), on B cells to enhance B cell activation and RABV-specific antibody responses. We used a reverse genetics approach to clone, recover, and characterize a live-attenuated recombinant RABV-based vaccine expressing the murine Icam1 gene (rRABV-mICAM-1). We show that the murine ICAM-1 gene product is incorporated into virus particles, potentially exposing ICAM-1 to extracellular binding partners. While rRABV-mICAM-1 showed 10-100-fold decrease in viral titers on baby hamster kidney cells compared to the parental virus (rRABV), rRABV-mICAM-1 infected and activated primary murine B cells in-vitro more efficiently than rRABV, as indicated by significant upregulation of CD69, CD40, and MHCII on the surface of infected B cells. ICAM-1 expression on the virus surface was responsible for enhanced B cell infection since pre-treating rRABV-mICAM-1 with a neutralizing anti-ICAM-1 antibody reduced B cell infection to levels observed with rRABV alone. Furthermore, 100-fold less rRABV-mICAM-1 was needed to induce antibody titers in immunized mice equivalent to antibody titers observed in rRABV-immunized mice. Of note, only 10(3) focus forming units (ffu)/mouse of rRABV-mICAM-1 was needed to induce significant anti-RABV antibody titers as early as five days post-immunization. As both speed and potency of antibody responses are important in controlling human RABV infection in a post-exposure setting, these data show that expression of Icam1 from the RABV genome, which is then incorporated into the virus particle, is a promising strategy for the development of a single-dose RABV vaccine that requires only a minimum of virus.
MeSH term(s)	Animals ; Antibodies, Viral/biosynthesis ; B-Lymphocytes/immunology ; B-Lymphocytes/virology ; Cell Line ; Cricetinae ; Female ; Gene Expression ; Genome, Viral ; Humans ; Immunity, Humoral/drug effects ; Intercellular Adhesion Molecule-1/genetics ; Intercellular Adhesion Molecule-1/immunology ; Lymphocyte Function-Associated Antigen-1/genetics ; Lymphocyte Function-Associated Antigen-1/immunology ; Mice ; Mice, Inbred C57BL ; Rabies/immunology ; Rabies/prevention & control ; Rabies/virology ; Rabies Vaccines/administration & dosage ; Rabies Vaccines/genetics ; Rabies Vaccines/immunology ; Rabies virus/genetics ; Rabies virus/immunology ; Recombinant Fusion Proteins/genetics ; Recombinant Fusion Proteins/immunology ; Vaccines, Attenuated ; Vaccines, Synthetic ; Viral Proteins/genetics ; Viral Proteins/immunology ; Virion/genetics ; Virion/immunology
Chemical Substances	Antibodies, Viral ; Lymphocyte Function-Associated Antigen-1 ; Rabies Vaccines ; Recombinant Fusion Proteins ; Vaccines, Attenuated ; Vaccines, Synthetic ; Viral Proteins ; Intercellular Adhesion Molecule-1 (126547-89-5)
Language	English
Publishing date	2014-01-29
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0087098
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Lymph node but not intradermal injection site macrophages are critical for germinal center formation and antibody responses to rabies vaccination.

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Article: Anemia in a young Guinean male.

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Article ; Online: APRIL:TACI axis is dispensable for the immune response to rabies vaccination.

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Article ; Online: B cell infection and activation by rabies virus-based vaccines.

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Article ; Online: Protective vaccine-induced CD4(+) T cell-independent B cell responses against rabies infection.

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Article ; Online: ICAM-1-based rabies virus vaccine shows increased infection and activation of primary murine B cells in vitro and enhanced antibody titers in-vivo.

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