TLR4 regulates rabies virus-induced humoral immunity through recruitment of cDC2 to lymph organs

2021 ◽  
Author(s):  
Chen Chen ◽  
Chengguang Zhang ◽  
Haoqi Li ◽  
Zongmei Wang ◽  
Yueming Yuan ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune Responses ◽  
Rabies Virus ◽  
Humoral Immunity ◽  
Humoral Immune Response ◽  
Critical Role ◽  
Wild Type ◽  
Humoral Immune ◽  
Specific Igg ◽  
Molecular Patterns

Rabies, caused by rabies virus (RABV), is fatal to both humans and animals around the world. Effective clinical therapy for rabies has not been achieved, and vaccination is the most effective means of preventing and controlling rabies. Although different vaccines, such as live attenuated and inactivated vaccines, can induce different immune responses, different expression of pattern recognition receptors (PRRs) also causes diverse immune responses. Toll-like receptor 4 (TLR4) is a pivotal PRR that induces cytokine production and bridges innate and adaptive immunity. Importantly, TLR4 recognizes various virus-derived pathogen-associated molecular patterns (PAMPs) and virus-induced damage-associated molecular patterns (DAMPs), usually leading to the activation of immune cells. However, the role of TLR4 in the humoral immune response induced by RABV has not been revealed yet. Based on TLR4-deficient ( TLR4 -/- ) and wild-type (WT) mouse models, we report that TLR4-dependent recruitment of the conventional type-2 dendritic cells (CD8α - CD11b + cDC2) into secondary lymph organs (SLOs) is critical for antigen presentation. cDC2-initiated differentiation of Tfh cells promotes the proliferation of germinal centre (GC) B cells, the formation of GCs, and the production of plasma cells (PCs), all of which contribute to the production of RABV-specific IgG and virus-neutralizing antibodies (VNAs). Collectively, our work demonstrates that TLR4 is necessary for the recruitment of cDC2 and for the induction of RABV-induced humoral immunity, which is regulated by the cDC2-Tfh-GC B axis. IMPORTANCE Vaccination is the most efficient method to prevent rabies. TLR4, a well-known immune sensor, plays a critical role in initiating innate immune response. Here, we found that TLR4 deficiency ( TLR4 -/- ) mice suppressed the induction of humoral immune response after immunization with rabies virus (RABV), including reduced production of VNAs and RABV-specific IgG, compared with that occurred in wild-type (WT) mice. As a consequence, TLR4 -/- mice exhibited higher mortality than WT mice after challenge with virulent RABV. Importantly, further investigation found that TLR4 signaling promoted the recruitment of cDC2 (CD8α + CD11b - ), a subset of cDCs known to induce CD4 + T cell immunity through their MHC-II presentation machinery. Our results imply that TLR4 is indispensable for an efficient humoral response to rabies vaccine, which provides new insight into the development of novel rabies vaccines.

scholarly journals Characterization of SARS-CoV-2-specific humoral immunity and its potential applications and therapeutic prospects

2021 ◽  
Author(s):  
Jiaxin Zheng ◽  
Yingying Deng ◽  
Zhenyu Zhao ◽  
Binli Mao ◽  
Mengji Lu ◽  
...  
Keyword(s):  
Immune Response ◽  
Humoral Immunity ◽  
Humoral Immune Response ◽  
Vaccine Development ◽  
Control Strategies ◽  
Critical Role ◽  
Neutralizing Antibody ◽  
Antibody Testing ◽  
Humoral Immune ◽  
Potential Applications

AbstractCoronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is an ongoing pandemic that poses a great threat to human health worldwide. As the humoral immune response plays essential roles in disease occurrence and development, understanding the dynamics and characteristics of virus-specific humoral immunity in SARS-CoV-2-infected patients is of great importance for controlling this disease. In this review, we summarize the characteristics of the humoral immune response after SARS-CoV-2 infection and further emphasize the potential applications and therapeutic prospects of SARS-CoV-2-specific humoral immunity and the critical role of this immunity in vaccine development. Notably, serological antibody testing based on the humoral immune response can guide public health measures and control strategies; however, it is not recommended for population surveys in areas with very low prevalence. Existing evidence suggests that asymptomatic individuals have a weaker immune response to SARS-CoV-2 infection, whereas SARS-CoV-2-infected children have a more effective humoral immune response than adults. The correlations between antibody (especially neutralizing antibody) titers and protection against SARS-CoV-2 reinfection should be further examined. In addition, the emergence of cross-reactions among different coronavirus antigens in the development of screening technology and the risk of antibody-dependent enhancement related to SARS-CoV-2 vaccination should be given further attention.

scholarly journals EFFECT OF BACILLUS OF CALMETTE-GUÉRIN, AVRIDINE AND Propionibacterium acnes AS IMMUNOMODULATORS ON RABIES IN MICE

1999 ◽  
Vol 41 (2) ◽  
pp. 107-114 ◽  
Author(s):  
J. MEGID ◽  
M.T.S. PERAÇOLI ◽  
P.R. CURI ◽  
C.R. ZANETTI ◽  
W.H. CABRERA ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune Responses ◽  
Rabies Virus ◽  
Cellular Immune Response ◽  
Propionibacterium Acnes ◽  
Inoculation Test ◽  
Humoral Immune ◽  
Humoral Immune Responses ◽  
Cellular Immune

The cellular and humoral immune responses of mice inoculated with rabies virus and treated with the Bacillus of Calmette-Guérin, Avridine and Propionibacterium acnes were evaluated in this paper. There was a higher percentage of surviving mice in groups submitted to P. acnes treatment. Lower levels of interferon-<FONT FACE="Symbol">g</font> (IFN-<FONT FACE="Symbol">g</font>) were found in infected mice. The intra-pad inoculation test (IPI) was not effective to detect cellular immune response, contrary to the results found in MIF reaction. The survival of mice did not present correlation with the levels of antirabies serum neutralizing (SN) antibodies titers, IFN-<FONT FACE="Symbol">g</font> concentration and MIF response.

A New Vaccine Paradigm To Break Tolerance with Potential Applications for the Immunotherapy of B Cell Lymphoma.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1411-1411
Author(s):  
Ronald P. Taylor ◽  
Emily C. Whipple ◽  
Margaret A. Lindorfer ◽  
Andrew H. Ditto ◽  
Ryan S. Shanahan
Keyword(s):  
Flow Cytometry ◽  
Immune Response ◽  
B Cells ◽  
B Cell ◽  
Humoral Immune Response ◽  
Critical Role ◽  
B Cell Lymphoma ◽  
Breakdown Product ◽  
Humoral Immune ◽  
Mouse Igg2a

Abstract Complement (C) plays a critical role in the immune response by opsonizing immune complexes (IC) and thymus-independent type 2 antigens with C3 breakdown product C3dg. We investigated the in vivo fate and handling in mice of anti-CR1/CR2 mAb 7G6. We used this rat IgG mAb as a surrogate for C3dg-opsonized IC; mAb 7G6 binds to CR1/CR2 with high affinity, blocks C3dg binding and saturates mouse B cell CR2 at inputs of only 2 ug. RIA, flow cytometry, and fluorescence immunohistochemistry were used to examine the disposition of 0.5–2 ug quantities of mAb 7G6 infused i.v. in mice. The mAb binds to circulating B cells and in the spleen binds preferentially to marginal zone (MZ) B cells. However, within 24 h MZ B cells relocate and transfer the mAb to regions rich in follicular dendritic cells (FDC). Localization of intact antigen to FDC should induce a substantial immune response, and therefore we immunized mice and monkeys i.v. with low doses (1–20 ug/kg) of prototype antigens constructed with anti-CR1/2 mAb 7G6 or anti-CR2 mAb HB135, respectively. We observed a strong immune response characterized by early development of IgG antibodies and long-lasting immunity extending out to at least one year. We applied our immunization paradigm to mouse IgG idiotypes, based on i.v. infusion of mouse IgG2a mAbs which were cross-linked with mAb 7G6. The purpose of these experiments was to determine if tolerance can be broken in order to develop a more powerful vaccine strategy to induce a cytotoxic humoral immune response to malignant B cells based on targeting the idiotype of immunoglobulin molecules expressed on their surfaces. I.V. immunization with the constructs indeed generated a mouse IgG1 immune response to two different mouse IgG2a mAbs, as demonstrated by ELISA. The immune response was idiotype specific, but some anti-isotype antibodies were also detected. Moreover, sera from immunized mice immunoprecipitated the specific radiolabeled mouse mAbs in the presence of 7.5% polyethylene glycol. This humoral immune response was also demonstrable in flow cytometry assays in which IgG1 in sera of immunized mice bound to erythrocytes opsonized with bispecific mAb constructs consisting of the IgG2a mAb crosslinked with an anti-CR1 mAb. The present approach, based on coupling the targeted immunoglobulin to an anti-CR2 mAb for delivery to FDC, may lead to a more effective immunotherapeutic vaccine compared to methods currently in clinical trials which require use of glutaraldehyde to effect crosslinking of the targeted immunoglobulin to KLH.

scholarly journals Role of Bordetella bronchisepticaFimbriae in Tracheal Colonization and Development of a Humoral Immune Response

2000 ◽  
Vol 68 (4) ◽  
pp. 2024-2033 ◽  
Author(s):  
Seema Mattoo ◽  
Jeff F. Miller ◽  
Peggy A. Cotter
Keyword(s):  
Immune Response ◽  
Humoral Immune Response ◽  
Limit Of Detection ◽  
Immunoglobulin M ◽  
Tissue Culture Cell ◽  
Wild Type ◽  
Humoral Immune ◽  
Tract Infections

ABSTRACT Fimbriae are filamentous, cell surface structures which have been proposed to mediate attachment of Bordetella species to respiratory epithelium. Bordetella bronchiseptica has four known fimbrial genes: fim2, fim3,fimX, and fimA. While these genes are unlinked on the chromosome, their protein products are assembled and secreted by a single apparatus encoded by the fimBCD locus. ThefimBCD locus is embedded within the fha operon, whose genes encode another putative adhesin, filamentous hemagglutinin (FHA). We have constructed a Fim− B. bronchiseptica strain, RB63, by introducing an in-frame deletion extending from fimB through fimD. Western blot analysis showed that RB63 is unable to synthesize fimbriae but is unaffected for FHA expression. Using this mutant, we assessed the role of fimbriae in pathogenesis in vitro and in vivo in natural animal hosts. Although RB63 was not significantly defective in its ability to adhere to various tissue culture cell lines, including human laryngeal HEp-2 cells, it was considerably altered in its ability to cause respiratory tract infections in rats. The number of ΔfimBCD bacteria recovered from the rat trachea at 10 days postinoculation was significantly decreased compared to that of wild-type B. bronchiseptica and was below the limit of detection at 30 and 60 days postinoculation. The number of bacteria recovered from the nasal cavity and larynx was not significantly different between RB63 and the wild-type strain at any time point. The ability of fimbriae to mediate initial attachment to tracheal tissue was tested in an intratracheal inoculation assay. Significantly fewer RB63 than wild-type bacteria were recovered from the tracheas at 24 h after intratracheal inoculation. These results demonstrate that fimbriae are involved in enhancing the ability of B. bronchiseptica to establish tracheal colonization and are essential for persistent colonization at this site. Interestingly, anti-Bordetella serum immunoglobulin M (IgM) levels were significantly lower in animals infected with RB63 than in animals infected with wild-type B. bronchiseptica at 10 days postinoculation. Even at 30 days postinoculation, RB63-infected animals had lower serum anti-Bordetella antibody titers in general. This disparity in antibody profiles suggests that fimbriae are also important for the induction of a humoral immune response.

scholarly journals Recombinant Mycobacterium paragordonae Expressing SARS-CoV-2 Receptor-Binding Domain as a Vaccine Candidate Against SARS-CoV-2 Infections

2021 ◽  
Vol 12 ◽  
Author(s):  
Byoung-Jun Kim ◽  
Hyein Jeong ◽  
Hyejun Seo ◽  
Mi-Hyun Lee ◽  
Hyun Mu Shin ◽  
...  
Keyword(s):  
Immune Response ◽  
Single Dose ◽  
Immune Responses ◽  
Receptor Binding ◽  
Humoral Immune Response ◽  
Vaccine Candidate ◽  
Binding Domain ◽  
Receptor Binding Domain ◽  
Live Virus ◽  
Humoral Immune

At present, concerns that the recent global emergence of SARS-CoV-2 variants could compromise the current vaccines have been raised, highlighting the urgent demand for new vaccines capable of eliciting T cell-mediated immune responses, as well as B cell-mediated neutralizing antibody production. In this study, we developed a novel recombinant Mycobacterium paragordonae expressing the SARS-CoV-2 receptor-binding domain (RBD) (rMpg-RBD-7) that is capable of eliciting RBD-specific immune responses in vaccinated mice. The potential use of rMpg-RBD-7 as a vaccine for SARS-CoV-2 infections was evaluated in in vivo using mouse models of two different modules, one for single-dose vaccination and the other for two-dose vaccination. In a single-dose vaccination model, we found that rMpg-RBD-7 versus a heat-killed strain could exert an enhanced cell-mediated immune (CMI) response, as well as a humoral immune response capable of neutralizing the RBD and ACE2 interaction. In a two-dose vaccination model, rMpg-RBD-7 in a two-dose vaccination could also exert a stronger CMI and humoral immune response to neutralize SARS-CoV-2 infections in pseudoviral or live virus infection systems, compared to single dose vaccinations of rMpg-RBD or two-dose RBD protein immunization. In conclusion, our data showed that rMpg-RBD-7 can lead to an enhanced CMI response and humoral immune responses in mice vaccinated with both single- or two-dose vaccination, highlighting its feasibility as a novel vaccine candidate for SARS-CoV-2. To the best of our knowledge, this study is the first in which mycobacteria is used as a delivery system for a SARS-CoV-2 vaccine.

scholarly journals Association between Reactogenicity and Immunogenicity after Vaccination with BNT162b2

Vaccines ◽  
2021 ◽  
Vol 9 (10) ◽  
pp. 1089
Author(s):  
Stilla Bauernfeind ◽  
Bernd Salzberger ◽  
Florian Hitzenbichler ◽  
Karolina Scigala ◽  
Sebastian Einhauser ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cell ◽  
Immune Responses ◽  
Humoral Immune Response ◽  
Adverse Reactions ◽  
Medical Center ◽  
Neutralization Activity ◽  
Humoral Immune ◽  
Cell Mediated Immune Response ◽  
Severe Adverse Reactions

It is not clear whether there is an association between adverse reactions and immune response after vaccination. Seven hundred and thirty-five vaccinees from our University Medical Center vaccination clinic provided information about sex, age and adverse reactions after first and second vaccination with BNT162b2. Adverse reactions were categorized into three groups: no or minor on the injection side, moderate (not further classified) and severe—defined as any symptom(s) resulting in sick leave. We chose 38 vaccinees with the most severe adverse reactions and compared their humoral and T-cell-mediated immune responses after second vaccination with those of 38 sex and age matched controls without or only minor injection-side related adverse reactions. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) anti-receptor binding domain (RBD) IgG titers were detectable in all participants (median 5528; range 958–26,285). Men with severe adverse reactions had 1.5-fold higher median SARS-CoV-2 RBD IgG titers compared to men without adverse reactions (median 7406 versus 4793; p < 0.001). Similarly; neutralization activity was significantly higher in men with severe adverse reactions (half maximal inhibitory concentrations (IC50) median 769 versus 485; p < 0.001). Reactogenicity did not influence humoral immune response in women nor T-cell-mediated immune response in any sex. To conclude; adverse reactions after vaccination with BNT162b2 do influence humoral immune response yet only in men and are not a prerequisite for a robust antibody response.

scholarly journals Reduced schedule of human anti rabies immunization with Fuenzalida & Palacios vaccine

1989 ◽  
Vol 31 (1) ◽  
pp. 23-27 ◽  
Author(s):  
Carlos Roberto Zanetti ◽  
Silvana Regina Favoretto ◽  
Milene Silva Tino ◽  
Avelino Albas ◽  
Elizabeth Juliana G. Valentini ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune Responses ◽  
Humoral Immune Response ◽  
The Other ◽  
Double Dose ◽  
Humoral Immune ◽  
Cellular Immune Responses ◽  
Lymphoblastic Transformation ◽  
Cellular Immune

The present study evaluates the humoral and cellular immune responses in 35 volunteers submited to short antirabies vaccination schedules with the Fuenzalida & Palacios vaccine based on the administration of doses on non consecutive days. The volunteers were divided into two groups. The first group received a total number of five doses given on days 0, 4, 7, 20 and 35. The other group received four doses, the first one being a double dose given on day 0 and than three other single doses on days 7, 20 and 35. The evaluation of humoral immune response was carried out by serum neutralization (SN) and indirect immunofluorescense (IIF) tests, while the cellular immune response was evaluated by lymphoblastic transformation assay (LTA) and skin test (ST). According to our results these reduced schedules elicited early and effective humoral and cellulafimmune responses to rabies antigen suggesting that new reduced schedules should be extensively studied in order to give the proper bases to the proposition of changes in the current long-term schedule.

scholarly journals COVID-ONE-humoral immune: The One-stop Database for COVID-19-specific Antibody Responses and Clinical Parameters

2021 ◽  
Author(s):  
Zhaowei Xu ◽  
Yang Li ◽  
Qing Lei ◽  
Likun Huang ◽  
Dan-yun Lai ◽  
...  
Keyword(s):  
Immune Responses ◽  
Humoral Immunity ◽  
Clinical Parameters ◽  
Single Group ◽  
Analysis Pipeline ◽  
Humoral Immune ◽  
Start Button ◽  
One Stop ◽  
Specific Igg ◽  
The One

Coronavirus disease 2019 (COVID-19), which is caused by SARS-CoV-2, varies with regard to symptoms and mortality rates among populations. Humoral immunity plays critical roles in SARS-CoV-2 infection and recovery from COVID-19. However, differences in immune responses and clinical features among COVID-19 patients remain largely unknown. Here, we report a database for COVID-19-specific IgG/IgM immune responses and clinical parameters (COVID-ONE humoral immune). COVID-ONE humoral immunity is based on a dataset that contains the IgG/IgM responses to 21 of 28 known SARS-CoV-2 proteins and 197 spike protein peptides against 2,360 COVID-19 samples collected from 783 patients. In addition, 96 clinical parameters for the 2,360 samples and information for the 783 patients are integrated into the database. Furthermore, COVID-ONE humoral immune provides a dashboard for defining samples and a one-click analysis pipeline for a single group or paired groups. A set of samples of interest is easily defined by adjusting the scale bars of a variety of parameters. After the START button is clicked, one can readily obtain a comprehensive analysis report for further interpretation. COVID-ONE-humoral immune is freely available at www.COVID-ONE.cn.

scholarly journals Antibody Responses 3-5 Months Post-Vaccination with mRNA-1273 or BNT163b2 in Nursing Home Residents

2021 ◽  
Author(s):  
Jessica A. Breznik ◽  
Ali Zhang ◽  
Angela Huynh ◽  
Matthew S. Miller ◽  
Ishac Nazy ◽  
...  
Keyword(s):  
Immune Response ◽  
Nursing Home ◽  
Humoral Immune Response ◽  
Type Strain ◽  
Wild Type Strain ◽  
Nursing Home Residents ◽  
Wild Type ◽  
Humoral Immune ◽  
Fold Reduction ◽  
Antibody Levels

AbstractNursing home residents often fail to mount robust responses to vaccinations and recent reports of breakthrough infections, particularly from variants of concern, raise questions about whether vaccination regimens elicit a sufficient humoral immune response or if booster doses are warranted. We examined SARS-CoV-2 antibody levels and neutralizing capacity in nursing home residents 3-5 months after 2 doses of mRNA-1273 or BNT163b2 vaccination as per recommended schedules.Nursing home residents were recruited from eight long-term care homes in Ontario, Canada, between March and July 2021. Antibody levels and neutralization capacity from a previously published convalescent cohort were used as a comparator. Serum SARS-CoV-2 IgA/G/M against spike (S) protein and its receptor-binding domain (RBD) were measured by validated ELISA, with assay cut-off at the mean and 3 standard deviations of a pre-COVID-19 population from the same geographic region. Antibody neutralization was measured against the wild-type strain of SARS-CoV-2 and the beta variant of concern (B.1.351).No neutralizing antibodies were detected in ∼20% of residents to the wild-type virus (30/155; 19%) or beta variant (27/134; 20%). Residents that received BNT163b2 had a ∼4-fold reduction in neutralization to the wild-type strain, and a ∼2-fold reduction in neutralization to the beta variant relative to those who received mRNA-1273.Current mRNA SARS-CoV-2 vaccine regimens may not have equivalent efficacy in nursing home residents. Our findings imply that differences in the humoral immune response may contribute to breakthrough infections, and suggest that consideration of the type of vaccine administered to older adults will have a positive impact on the generation of protective immunity.

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