scholarly journals Estimating biologically relevant parameters under uncertainty for experimental within-host murine West Nile virus infection

2016 ◽  
Vol 13 (117) ◽  
pp. 20160130 ◽  
Author(s):  
Soumya Banerjee ◽  
Jeremie Guedj ◽  
Ruy M. Ribeiro ◽  
Melanie Moses ◽  
Alan S. Perelson
Keyword(s):  
Immune Response ◽  
West Nile Virus ◽  
Humoral Immune Response ◽  
Basic Reproductive Number ◽  
Response Model ◽  
Wild Type ◽  
West Nile ◽  
Humoral Immune ◽  
Infectious Virion ◽  
The Mean

West Nile virus (WNV) is an emerging pathogen that has decimated bird populations and caused severe outbreaks of viral encephalitis in humans. Currently, little is known about the within-host viral kinetics of WNV during infection. We developed mathematical models to describe viral replication, spread and host immune response in wild-type and immunocompromised mice. Our approach fits a target cell-limited model to viremia data from immunocompromised knockout mice and an adaptive immune response model to data from wild-type mice. Using this approach, we first estimate parameters governing viral production and viral spread in the host using simple models without immune responses. We then use these parameters in a more complex immune response model to characterize the dynamics of the humoral immune response. Despite substantial uncertainty in input parameters, our analysis generates relatively precise estimates of important viral characteristics that are composed of nonlinear combinations of model parameters: we estimate the mean within-host basic reproductive number, R 0 , to be 2.3 (95% of values in the range 1.7–2.9); the mean infectious virion burst size to be 2.9 plaque-forming units (95% of values in the range 1.7–4.7); and the average number of cells infected per infectious virion to be between 0.3 and 0.99. Our analysis gives mechanistic insights into the dynamics of WNV infection and produces estimates of viral characteristics that are difficult to measure experimentally. These models are a first step towards a quantitative understanding of the timing and effectiveness of the humoral immune response in reducing host viremia and consequently the epidemic spread of WNV.

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 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 Humoral immune response in inactivated SARS-CoV-2 vaccine: When should a booster dose be administered?

2021 ◽  
Author(s):  
Ertan Kara ◽  
Ferdi Tanir ◽  
Hakan Demirhindi ◽  
Burak Mete ◽  
Filiz Kibar ◽  
...  
Keyword(s):  
Immune Response ◽  
Humoral Immune Response ◽  
Health Workers ◽  
Plasma Concentrations ◽  
Test Method ◽  
Inactivated Vaccine ◽  
Igg Antibodies ◽  
Igg Antibody ◽  
Humoral Immune ◽  
The Mean

Background: For a sustained and essential protective antibody response, it is important to understand how long the humoral immune response induced by the SARS-CoV-2 inactivated vaccine persists. Aims: This study aimed to detect the first and third-month concentrations and seroconversion rates of the antibodies induced by the inactivated vaccine. Study Design: This is a vaccine efficacy study. Methods: The study included 272 health workers who were vaccinated at days 0 and 28 by the inactivated SARS-CoV-2 vaccine (3µg/0.5ml). Anti-S-RBD-IgG and total anti-spike/anti-nucleocapsid-IgG antibody concentrations and seroconversion rates were examined in vaccinated health workers at the 1st and 3rd months after the vaccination. The test method used for the qualitative detection and differentiation of IgG antibodies (indirect method) to SARS-CoV-2 is a chemiluminescence reaction (CLIA). Results: The mean age of the health workers was 38.93±10.59 (min:21-max:64). A total of 45(16.5%) participants declared to have had COVID-19 before the first dose of the inactivated vaccine. The participants were found to be reactive for anti-S-RBD-IgG antibodies by 98.2% and 97.8% at the first and third months, respectively, after the administration of the second dose. The decrease in the mean plasma concentrations of anti-S-RBD IgG was observed as 56.7% in the cohort with only two doses of the vaccine (1st month:42.4AU/ml versus 3rd month: 18.2AU/ml). In the cohort with a history of COVID-19 prior to the vaccination, the decrease was observed as 25.1% (1st month:58.29 versus 3rd month:43.64 AU/ml) and at a mean of 57.4 (0-90) days prior to vaccination, the decrease was of 43.1% (1st month:55.05 AU/ml versus 3rd month:31.28 AU/ml), keeping more stable in participants infected at a mean of 183.1 (91-330) days prior to vaccination (a decrease of 5.2%; with 62.34 AU/ml at 1st and 59.08 AU/ml at 3rd months). Anti-S-RBD concentrations were observed to increase 10-fold (30.44 AU/ml at 1st and 310.64 AU/ml at 3rd months) in participants infected after the vaccination and to decrease among people aged 50 years and older. Conclusion: Antibody concentrations at the 1st and 3rd months after the vaccination with two doses of the inactivated SARS-CoV-2 vaccine were found to be decreased, but still detectable (except in one participant). As participants who had COVID-19 at a mean of 181 (90-330) days before the vaccination presented with a more stable antibody level, it can be concluded that a booster at months 6-12, resulting in a schedule of 0-1-6 months, is recommended for the inactive SARS-CoV-2 vaccination. Keywords: Humoral immune response, vaccines, SARS-CoV-2, booster, inactive vaccine

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.

scholarly journals Sensitivity of two SARS-CoV-2 variants with spike protein mutations to neutralising antibodies

Virus Genes ◽  
2021 ◽  
Author(s):  
Katharina Müller ◽  
Philipp Girl ◽  
Andreas Giebl ◽  
Stefanie Gruetzner ◽  
Markus Antwerpen ◽  
...  
Keyword(s):  
Immune Response ◽  
Humoral Immune Response ◽  
Point Of View ◽  
Spike Protein ◽  
Wild Type ◽  
Serum Samples ◽  
Antibody Treatment ◽  
Neutralising Antibodies ◽  
Humoral Immune ◽  
Protein Mutations

AbstractSARS-CoV-2 infections elicit a humoral immune response capable of neutralising the virus. However, multiple variants have emerged with mutations in the spike protein amongst others, the key target of neutralising antibodies. We evaluated the neutralising efficacy of 89 serum samples from patients, infected with SARS-CoV-2 in the beginning of 2020, against two virus variants isolated from acutely infected patients and harbouring spike protein mutations. One isolate was assigned to lineage B.1.351 (MUC-IMB-B.1.351) whilst the other (MUC-484) was isolated from an immunocompromised patient, sharing some but not all mutations with B.1.351 and representing a transitional variant. Both variants showed a significant reduction in neutralisation sensitivity compared to wild-type SARS-CoV-2 with MUC-IMB-B.1.351 being almost completely resistant to neutralisation. The observed reduction in neutralising activity of wild-type-specific antibodies against both variants suggests that individual mutations in the spike protein are sufficient to confer a potent escape from the humoral immune response. In addition, the effect of escape mutations seems to accumulate, so that more heavily mutated variants show a greater loss of sensitivity to neutralisation up to complete insensitivity as observed for MUC-IMB-B.1.351. From a clinical point of view, this might affect the efficacy of (monoclonal) antibody treatment of patients with prolonged infections as well as patients infected with variants other than the donor. At the same, this could also negatively influence the efficacy of current vaccines (as they are based on wild-type spike protein) emphasising the need to thoroughly surveil the emergence and distribution of variants and adapt vaccines and therapeutics accordingly.

scholarly journals A Comparative Study of the Innate Humoral Immune Response to Avian Influenza Virus in Wild and Domestic Mallards

2020 ◽  
Vol 11 ◽  
Author(s):  
Jacintha G. B. van Dijk ◽  
Josanne H. Verhagen ◽  
Arne Hegemann ◽  
Conny Tolf ◽  
Jenny Olofsson ◽  
...  
Keyword(s):  
Immune Response ◽  
Avian Influenza ◽  
Immune Function ◽  
Innate Immune Response ◽  
Acute Phase ◽  
Humoral Immune Response ◽  
Innate Immune ◽  
Wild Type ◽  
Free Living ◽  
Humoral Immune

Domestic mallards (Anas platyrhynchos domesticus) are traditionally used as a model to investigate infection dynamics and immune responses to low pathogenic avian influenza viruses (LPAIVs) in free-living mallards. However, it is unclear whether the immune response of domestic birds reflects the response of their free-living counterparts naturally exposed to these viruses. We investigated the extent to which the innate humoral immune response was similar among (i) wild-type domestic mallards in primary and secondary infection with LPAIV H4N6 in a laboratory setting (laboratory mallards), (ii) wild-type domestic mallards naturally exposed to LPAIVs in a semi-natural setting (sentinel mallards), and (iii) free-living mallards naturally exposed to LPAIVs. We quantified innate humoral immune function by measuring non-specific natural antibodies (agglutination), complement activity (lysis), and the acute phase protein haptoglobin. We demonstrate that complement activity in the first 3 days after LPAIV exposure was higher in primary-exposed laboratory mallards than in sentinel and free-living mallards. LPAIV H4N6 likely activated the complement system and the acute phase response in primary-exposed laboratory mallards, as lysis was higher and haptoglobin lower at day 3 and 7 post-exposure compared to baseline immune function measured prior to exposure. There were no differences observed in natural antibody and haptoglobin concentrations among laboratory, sentinel, and free-living mallards in the first 3 days after LPAIV exposure. Our study demonstrates that, based on the three innate humoral immune parameters measured, domestic mallards seem an appropriate model to investigate innate immunology of their free-living counterparts, albeit the innate immune response of secondary-LPAIV exposed mallards is a better proxy for the innate immune response in pre-exposed free-living mallards than that of immunologically naïve mallards.

scholarly journals MAVS regulates the quality of the antibody response to West-Nile Virus

2020 ◽  
Vol 16 (10) ◽  
pp. e1009009
Author(s):  
Marvin O’Ketch ◽  
Spencer Williams ◽  
Cameron Larson ◽  
Jennifer L. Uhrlaub ◽  
Rachel Wong ◽  
...  
Keyword(s):  
Immune Response ◽  
West Nile Virus ◽  
Antibody Response ◽  
Adaptive Immunity ◽  
Viral Infections ◽  
Adaptive Immune Response ◽  
Neutralizing Antibody ◽  
West Nile ◽  
Humoral Immune

A key difference that distinguishes viral infections from protein immunizations is the recognition of viral nucleic acids by cytosolic pattern recognition receptors (PRRs). Insights into the functions of cytosolic PRRs such as the RNA-sensing Rig-I-like receptors (RLRs) in the instruction of adaptive immunity are therefore critical to understand protective immunity to infections. West Nile virus (WNV) infection of mice deficent of RLR-signaling adaptor MAVS results in a defective adaptive immune response. While this finding suggests a role for RLRs in the instruction of adaptive immunity to WNV, it is difficult to interpret due to the high WNV viremia, associated exessive antigen loads, and pathology in the absence of a MAVS-dependent innate immune response. To overcome these limitations, we have infected MAVS-deficient (MAVSKO) mice with a single-round-of-infection mutant of West Nile virus. We show that MAVSKO mice failed to produce an effective neutralizing antibody response to WNV despite normal antibody titers against the viral WNV-E protein. This defect occurred independently of antigen loads or overt pathology. The specificity of the antibody response in infected MAVSKO mice remained unchanged and was still dominated by antibodies that bound the neutralizing lateral ridge (LR) epitope in the DIII domain of WNV-E. Instead, MAVSKO mice produced IgM antibodies, the dominant isotype controlling primary WNV infection, with lower affinity for the DIII domain. Our findings suggest that RLR-dependent signals are important for the quality of the humoral immune response to WNV.

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