Biology subjects

Chentoufi, A.

Publications and source records attributed to Chentoufi, A..

3 recordsLinked to original sources

bioRxiv2025

CXCL13/CXCR5 Chemokine Axis Promotes CXCR5+CD19+ B-Cell and Follicular/Effector CXCR5+CD4+ T-Cell Responses in the Lungs Associated with Protection from Severe and Fatal COVID-19 Following Infection with Pathogenic SARS-CoV-2 Delta Variant

Chemokines play an important role in shaping lung innate and adaptive immunity to pulmonary infections and diseases. However, the role of CXC ligand 13 (CXCL13), a chemokine homeostatically produced by various lung cell types, in the protection from SARS-CoV-2 infection and disease remains controversial. Some studies reported that asymptomatic patients who survived severe COVID-19 had CXCL13-dominated mucosal immune responses in the lungs early during infection. In contrast, other studies reported that a high level of CXCL13 was associated with severity and mortality in COVID-19 patients. In this study, to determine the direct role of CXCL13 in SARS-CoV-2 infection and disease, we generated CXCL13-/-K18-hACE2 mice, that are both transgenic for ACE2 and deficient in CXCL13 and compared their infection and COVID-19-like disease symptoms with those in wild-type K18-hACE2 transgenic mouse littermates following intranasal inoculation with the pathogenic SARS-CoV-2 delta variant (B.1.617.2). Compared to age- and gender-matched SARS-CoV-2 infected wild-type K18-hACE2 mice, SARS-CoV-2 infected CXCL13-/-K18-hACE2 deficient mice exhibited (i) higher viral load in the lungs; (ii) severe COVID-19-like lung pathology; (iii) exacerbated weight loss; (iv) increased mortality. The apparent severe COVID-19-like symptoms in CXCL13-/-K18-hACE2 deficient mice were associated with: (i) significantly lower frequencies of functional lung-resident C-X-C chemokine receptor 5+ (CXCR5)+CD19+ B cells, follicular CXCR5+CD4+ helper T cells (Tfh cells), and IFN-{psi}+TNF-+GzmB+Ki67+effector CD4+ Th1 cells; and (ii) a significant reduction in the levels of SARS-CoV-2-Spike specific Th1 associated IgG1 and IgG2b antibody isotypes. These findings corroborate previous human reports suggesting a critical role of the CXCL13/CXCR5 chemokine axis in the protective B- and T-cell mucosal immunity to SARS-CoV-2 infection and disease, offering a potential new immunotherapeutic target for treatment.

immunology↗

bioRxiv2024

Tissue-Targeted Prime/Pull/Keep Therapeutic Herpes Simplex Virus Vaccine Protect Against Recurrent Ocular Herpes Diseases in HLA-A*0201 Transgenic Rabbits

Herpes Simplex Virus type 1 (HSV-1) continues to be one of the most prevalent viral infections globally, with approximately 3.72 billion individuals affected worldwide. A clinical herpes vaccine is still lacking. In the present study, a novel prime/pull/keep vaccine was tested in Human Leukocyte Antigen transgenic rabbit model of ocular herpes (HLA-A*0201 Tg rabbit). Ten asymptomatic (ASYMP) CD8+ T cell peptide epitopes and 3 CD4+ T-cell epitopes were selected from the HSV-1 glycoproteins D and B (gD and gB), viral tegument proteins (VP11/12 and VP13/14) and the DNA replication binding helicase (UL9), all preferentially recognized by CD8+ and CD4+ T-cells from "naturally protected" HSV-1-seropositive healthy ASYMP individuals (who never had recurrent corneal herpetic disease). HLA Tg rabbits were ocularly infected with HSV-1 then during latency at day 30 post-infection, the rabbits were ocularly vaccinated with a recombinant neurotropic AAV8 vector (107GC/ eye) encoding for the 10 CD8+ T cell peptide and 4 CD4+ T cells peptide (prime), T cell-attracting CXCL-11 (Pull) and T-cell keeping IL-2/IL-15 cytokines (keep). The rabbits were followed up for eye disease and viral loads in tears for 28 days. The frequency, function and protective efficacy of HSV-specific CD8+ T cells induced by the prime/pull/keep vaccine were assessed in the trigeminal ganglia (TG), cornea, Spleen, and peripheral blood. Compared to the mock group (unvaccinated), the peptides/CXCL11/IL-2/IL-15 vaccine generated frequent resident CD8+ T cells that infiltrated the TG. CD8+ T cells mobilization and retention into TG of prime/pull/keep vaccinated rabbits was associated with a significant reduction in corneal herpes infection and disease after an ocular HSV-1 challenge (McKrae). These findings draw attention to the novel prime/pull/keep therapeutic vaccine strategy to mobilize and retain anti-viral T cells into tissues protecting them against herpetic infection and disease. IMPORTANCEThere is an urgent need for a vaccine against widespread human herpes simplex virus infections. The present study demonstrates that immunization of humanized HLA-A*0201 transgenic rabbits with CD8+ and CD4+ T-cell epitope peptides (prime)/ CXCL11 (pull)/ IL-2/IL-15 (Keep) AAV8-based vaccine triggered mobilization ad retention of HSV-1-specific CD8+ T cells locally in the cornea and TG, the sites of acute and latent herpes infections. Mobilization and retention of antiviral CD8+ T cells into cornea and TG of HSV-1 infected rabbits that received the prime/pull/keep vaccine was associated with protection against ocular herpes infection and disease. These results highlight the importance of the prime/pull/keep vaccine strategy to bolster the number and function of protective CD8+ T cells within infected tissues.

immunology↗

bioRxiv2024

Dynamics of Spike-Specific Neutralizing Antibodies Across Five-Year Emerging SARS-CoV-2 Variants of Concern Reveal Conserved Epitopes that Protect Against Severe COVID-19

Since early 2020, several SARS-CoV-2 variants of concern (VOCs) continue to emerge, evading waning antibody mediated immunity produced by the current Spike-alone based COVID-19 vaccines. This caused a prolonged and persistent COVID-19 pandemic that is going to enter its fifth year. Thus, the need remains for innovative next generation vaccines that would incorporate protective Spike-derived B-cell epitopes that resist immune evasion. Towards that goal, in this study we (i) Screened the sequences of Spike among many VOCs and identified conserved and non-conserved linear B-cell epitopes; (ii) Compared titers and neutralization antibodies specific to these conserved and non-conserved B-cell epitopes from serum of symptomatic and asymptomatic COVID-19 patients that were exposed to multiple VOCs across the 5-year COVID-19 pandemic, and (iii) Compared protective efficacy of conserved versus non-conserved B-cell epitopes against the most pathogenic Delta variant in a "humanized" ACE-2/HLA transgenic mouse model. We found robust conserved B-cell epitope-specific antibody titers and neutralization in sera from asymptomatic COVID-19 patients. In contrast, sera from symptomatic patients contained weaker antibody responses specific to conserved B-cell epitopes. A multi-epitope COVID-19 vaccine that incorporated the conserved B-cell epitopes, but not the non-conserved B-cell epitopes, significantly protected the ACE2/HLA transgenic mice against infection and COVID-19 like symptoms caused by the Delta variant. These findings underscore the importance of conserved B-cell epitopes in generating robust protective immunity against severe COVID-19 symptoms caused by various VOCs, providing valuable insights for the development of broad-spectrum next generation Coronavirus vaccines capable of conferring cross-variant protective immunity. IMPORTANCEA persistent COVID-19 pandemic continues to evolve because of a continued emergence of SARS-CoV-2 variants of concern (VOCs) that escape the antibodies induced by the current Spike-alone COVID-19 vaccines. Identifying and characterizing the protective and non-protective Spike-derived B-cell epitopes that resist immune-evasion is a paramount for the development of broad-spectrum next generation Coronavirus vaccines. The present study identified Spike-derived conserved B cell epitopes that (i) are targeted by consistent and strong antibody responses in asymptomatic COVID-19 patients across the 5-year pandemic regardless of VOCs; and (ii) provided strong protection in humanized" ACE2/HLA transgenic mice against infection and COVID-19 like symptoms caused by the most pathogenic Delta variant. The findings have the potential to inform the design of next generation Coronavirus vaccines capable of conferring cross-variant protective immunity. TWEETProtective SARS-CoV-2 Conserved Linear B Cell Epitopes Identified from Spike Protein.

immunology↗