scholarly journals Large-Scale Structure-Based Screening of Potential T Cell Cross-Reactivities Involving Peptide-Targets From BCG Vaccine and SARS-CoV-2

2022 ◽  
Vol 12 ◽  
Author(s):  
Renata Fioravanti Tarabini ◽  
Mauricio Menegatti Rigo ◽  
André Faustino Fonseca ◽  
Felipe Rubin ◽  
Rafael Bellé ◽  
...  

Although not being the first viral pandemic to affect humankind, we are now for the first time faced with a pandemic caused by a coronavirus. The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has been responsible for the COVID-19 pandemic, which caused more than 4.5 million deaths worldwide. Despite unprecedented efforts, with vaccines being developed in a record time, SARS-CoV-2 continues to spread worldwide with new variants arising in different countries. Such persistent spread is in part enabled by public resistance to vaccination in some countries, and limited access to vaccines in other countries. The limited vaccination coverage, the continued risk for resistant variants, and the existence of natural reservoirs for coronaviruses, highlight the importance of developing additional therapeutic strategies against SARS-CoV-2 and other coronaviruses. At the beginning of the pandemic it was suggested that countries with Bacillus Calmette-Guérin (BCG) vaccination programs could be associated with a reduced number and/or severity of COVID-19 cases. Preliminary studies have provided evidence for this relationship and further investigation is being conducted in ongoing clinical trials. The protection against SARS-CoV-2 induced by BCG vaccination may be mediated by cross-reactive T cell lymphocytes, which recognize peptides displayed by class I Human Leukocyte Antigens (HLA-I) on the surface of infected cells. In order to identify potential targets of T cell cross-reactivity, we implemented an in silico strategy combining sequence-based and structure-based methods to screen over 13,5 million possible cross-reactive peptide pairs from BCG and SARS-CoV-2. Our study produced (i) a list of immunogenic BCG-derived peptides that may prime T cell cross-reactivity against SARS-CoV-2, (ii) a large dataset of modeled peptide-HLA structures for the screened targets, and (iii) new computational methods for structure-based screenings that can be used by others in future studies. Our study expands the list of BCG peptides potentially involved in T cell cross-reactivity with SARS-CoV-2-derived peptides, and identifies multiple high-density “neighborhoods” of cross-reactive peptides which could be driving heterologous immunity induced by BCG vaccination, therefore providing insights for future vaccine development efforts.

2020 ◽  
Author(s):  
Shira Weingarten-Gabbay ◽  
Susan Klaeger ◽  
Siranush Sarkizova ◽  
Leah R. Pearlman ◽  
Da-Yuan Chen ◽  
...  

ABSTRACTT cell-mediated immunity may play a critical role in controlling and establishing protective immunity against SARS-CoV-2 infection; yet the repertoire of viral epitopes responsible for T cell response activation remains mostly unknown. Identification of viral peptides presented on class I human leukocyte antigen (HLA-I) can reveal epitopes for recognition by cytotoxic T cells and potential incorporation into vaccines. Here, we report the first HLA-I immunopeptidome of SARS-CoV-2 in two human cell lines at different times post-infection using mass spectrometry. We found HLA-I peptides derived not only from canonical ORFs, but also from internal out-of-frame ORFs in Spike and Nucleoprotein not captured by current vaccines. Proteomics analyses of infected cells revealed that SARS-CoV-2 may interfere with antigen processing and immune signaling pathways. Based on the endogenously processed and presented viral peptides that we identified, we estimate that a pool of 24 peptides would provide one or more peptides for presentation by at least one HLA allele in 99% of the human population. These biological insights and the list of naturally presented SARS-CoV-2 peptides will facilitate data-driven selection of peptides for immune monitoring and vaccine development.


2009 ◽  
Vol 83 (13) ◽  
pp. 6566-6577 ◽  
Author(s):  
Katherine A. Richards ◽  
Francisco A. Chaves ◽  
Andrea J. Sant

ABSTRACT The specificity of the CD4 T-cell immune response to influenza virus is influenced by the genetic complexity of the virus and periodic encounters with variant subtypes and strains. In order to understand what controls CD4 T-cell reactivity to influenza virus proteins and how the influenza virus-specific memory compartment is shaped over time, it is first necessary to understand the diversity of the primary CD4 T-cell response. In the study reported here, we have used an unbiased approach to evaluate the peptide specificity of CD4 T cells elicited after live influenza virus infection. We have focused on four viral proteins that have distinct intracellular distributions in infected cells, hemagglutinin (HA), neuraminidase (NA), nucleoprotein, and the NS1 protein, which is expressed in infected cells but excluded from virion particles. Our studies revealed an extensive diversity of influenza virus-specific CD4 T cells that includes T cells for each viral protein and for the unexpected immunogenicity of the NS1 protein. Due to the recent concern about pandemic avian influenza virus and because CD4 T cells specific for HA and NA may be particularly useful for promoting the production of neutralizing antibody to influenza virus, we have also evaluated the ability of HA- and NA-specific CD4 T cells elicited by a circulating H1N1 strain to cross-react with related sequences found in an avian H5N1 virus and find substantial cross-reactivity, suggesting that seasonal vaccines may help promote protection against avian influenza virus.


2021 ◽  
Vol 12 ◽  
Author(s):  
Yueran Li ◽  
Pooja Deshpande ◽  
Rebecca J. Hertzman ◽  
Amy M. Palubinsky ◽  
Andrew Gibson ◽  
...  

Adverse drug reactions (ADRs) remain associated with significant mortality. Delayed hypersensitivity reactions (DHRs) that occur greater than 6 h following drug administration are T-cell mediated with many severe DHRs now associated with human leukocyte antigen (HLA) risk alleles, opening pathways for clinical prediction and prevention. However, incomplete negative predictive value (NPV), low positive predictive value (PPV), and a large number needed to test (NNT) to prevent one case have practically prevented large-scale and cost-effective screening implementation. Additional factors outside of HLA contributing to risk of severe T-cell-mediated DHRs include variation in drug metabolism, T-cell receptor (TCR) specificity, and, most recently, HLA-presented immunopeptidome-processing efficiencies via endoplasmic reticulum aminopeptidase (ERAP). Active research continues toward identification of other highly polymorphic factors likely to impose risk. These include those previously associated with T-cell-mediated HLA-associated infectious or auto-immune disease such as Killer cell immunoglobulin-like receptors (KIR), epistatically linked with HLA class I to regulate NK- and T-cell-mediated cytotoxic degranulation, and co-inhibitory signaling pathways for which therapeutic blockade in cancer immunotherapy is now associated with an increased incidence of DHRs. As such, the field now recognizes that susceptibility is not simply a static product of genetics but that individuals may experience dynamic risk, skewed toward immune activation through therapeutic interventions and epigenetic modifications driven by ecological exposures. This review provides an updated overview of current and proposed genetic factors thought to predispose risk for severe T-cell-mediated DHRs.


2021 ◽  
Vol 12 ◽  
Author(s):  
Jiaqi Xia ◽  
Peng Bai ◽  
Weiliang Fan ◽  
Qiming Li ◽  
Yongzheng Li ◽  
...  

T-cell recognition of somatic mutation-derived cancer neoepitopes can lead to tumor regression. Due to the difficulty to identify effective neoepitopes, constructing a database for sharing experimentally validated cancer neoantigens will be beneficial to precise cancer immunotherapy. Meanwhile, the routine neoepitope prediction in silico is important but laborious for clinical use. Here we present NEPdb, a database that contains more than 17,000 validated human immunogenic neoantigens and ineffective neoepitopes within human leukocyte antigens (HLAs) via curating published literature with our semi-automatic pipeline. Furthermore, NEPdb also provides pan-cancer level predicted HLA-I neoepitopes derived from 16,745 shared cancer somatic mutations, using state-of-the-art predictors. With a well-designed search engine and visualization modes, this database would enhance the efficiency of neoantigen-based cancer studies and treatments. NEPdb is freely available at http://nep.whu.edu.cn/.


2018 ◽  
Vol 92 (11) ◽  
Author(s):  
M. Justin Iampietro ◽  
Rafael A. Larocca ◽  
Nicholas M. Provine ◽  
Peter Abbink ◽  
Zi Han Kang ◽  
...  

ABSTRACT Adenovirus (Ad) vectors are being investigated as vaccine candidates, but baseline antivector immunity exists in human populations to both human Ad (HuAd) and chimpanzee Ad (ChAd) vectors. In this study, we investigated the immunogenicity and cross-reactivity of a panel of recently described rhesus adenoviral (RhAd) vectors. RhAd vectors elicited T cells with low exhaustion markers and robust anamnestic potential. Moreover, RhAd vector immunogenicity was unaffected by high levels of preexisting anti-HuAd immunity. Both HuAd/RhAd and RhAd/RhAd prime-boost vaccine regimens were highly immunogenic, despite a degree of cross-reactive neutralizing antibodies (NAbs) between phylogenetically related RhAd vectors. We observed extensive vector-specific cross-reactive CD4 T cell responses and more limited CD8 T cell responses between RhAd and HuAd vectors, but the impact of vector-specific cellular responses was far less than that of vector-specific NAbs. These data suggest the potential utility of RhAd vectors and define novel heterologous prime-boost strategies for vaccine development. IMPORTANCE To date, most adenoviral vectors developed for vaccination have been HuAds from species B, C, D, and E, and human populations display moderate to high levels of preexisting immunity. There is a clinical need for new adenoviral vectors that are not hindered by preexisting immunity. Moreover, the development of RhAd vector vaccines expands our ability to vaccinate against multiple pathogens in a population that may have received other HuAd or ChAd vectors. We evaluated the immunogenicity and cross-reactivity of RhAd vectors, which belong to the poorly described adenovirus species G. These vectors induced robust cellular and humoral immune responses and were not hampered by preexisting anti-HuAd vector immunity. Such properties make RhAd vectors attractive as potential vaccine vectors.


2021 ◽  
Vol 12 ◽  
Author(s):  
Peter J. Eggenhuizen ◽  
Boaz H. Ng ◽  
Janet Chang ◽  
Ashleigh L. Fell ◽  
Rachel M. Y. Cheong ◽  
...  

Epidemiological studies and clinical trials suggest Bacillus Calmette-Guérin (BCG) vaccine has protective effects against coronavirus disease 2019 (COVID-19). There are now over 30 clinical trials evaluating if BCG vaccination can prevent or reduce the severity of COVID-19. However, the mechanism by which BCG vaccination can induce severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific T cell responses is unknown. Here, we identify 8 novel BCG-derived peptides with significant sequence homology to either SARS-CoV-2 NSP3 or NSP13-derived peptides. Using an in vitro co-culture system, we show that human CD4+ and CD8+ T cells primed with a BCG-derived peptide developed enhanced reactivity to its corresponding homologous SARS-CoV-2-derived peptide. As expected, HLA differences between individuals meant that not all persons developed immunogenic responses to all 8 BCG-derived peptides. Nevertheless, all of the 20 individuals that were primed with BCG-derived peptides developed enhanced T cell reactivity to at least 7 of 8 SARS-CoV-2-derived peptides. These findings provide an in vitro mechanism that may account, in part, for the epidemiologic observation that BCG vaccination confers some protection from COVID-19.


Author(s):  
Vladislavs Jasinskis ◽  
Oksana Koļesova ◽  
Aleksandrs Koļesovs ◽  
Baiba Rozentāle ◽  
Inga Ažiņa ◽  
...  

Abstract Antiretroviral therapy (ART) aims at suppressing viral replication and strengthening immune system in patients with HIV-1. Human Leukocyte Antigens (HLA) are among factors responsible for effectiveness of ART. The aim of this study was to determine the effect of HLA Class II alleles on the response to long-time ART, assessed by a change in CD4+ T-cell count in relation to viral load. The sample included 69 patients (17 females and 52 males) aged 20 to 50 with HIV-1 infection, who were undergoing ART in the Latvian Centre of Infectious Diseases. The median period of observation was 5.7 years. CD4+ T-cell count and viral load were analysed at the baseline and end of the period of observation. HLA typing was performed by polymerase chain reaction with low resolution sequence specific primers. Multiple hierarchical linear regression analysis confirmed that an increase in HIV-1 viral load was associated with a decrease in the level of CD4+ T-cell count. In addition, HLA-DRB1*04 and HLA-DQB1*06:01 alleles contributed negatively to the level of CD4+ T-cell count.


Nanoscale ◽  
2021 ◽  
Author(s):  
William Joseph McDaid ◽  
Nikolai Lissin ◽  
Ellen Pollheimer ◽  
Michelle Greene ◽  
Adam Leach ◽  
...  

For effective targeted therapy of cancer with chemotherapy-loaded nanoparticles (NPs), antigens that are selective for cancer cells should be targeted to minimise off-tumour toxicity. Human leukocyte antigens (HLAs) are an...


1985 ◽  
Vol 12 (3) ◽  
pp. 531-534 ◽  
Author(s):  
Steven T. Rosen ◽  
Ruta Radvany ◽  
Henry Roenigk ◽  
Paul I. Terasaki ◽  
Paul A. Bunn

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