Immunodominant T-Cell Epitopes in the VP1 Capsid Protein of Rhinovirus Species A and C

Abstract

Rhinovirus (RV) species A and C are the most frequent cause of respiratory viral illness worldwide, and RV-C has been linked to more severe exacerbations of asthma in young children. Little is known about the immune responses to the different RV species, although studies comparing IgG1 antibody titers found impaired antibody responses to RV-C. Therefore, the aim of this study was to assess whether T-cell immunity to RV-C is similarly impaired. We measured T-cell proliferation to overlapping synthetic peptides covering the entire VP1 capsid protein of an RV-A and RV-C genotype for 20 healthy adult donors. Human leukocyte antigen (HLA) was typed in all the donors in order to investigate possible associations between the HLA type and RV peptide recognition. Total and specific IgG1 antibody titers to the VP1 proteins of both RV-A and RV-C were also measured to examine associations between the antibody and T-cell responses. We identified T-cell epitopes that are specific to and representative of each RV-A and RV-C species. These epitopes stimulated CD4 ؉ -specific T-cell proliferation, with similar magnitudes of response for both RV species. All the donors, independent of their HLA-DR or -DQ type, were able to recognize the immunodominant RV-A and -C regions of VP1. Furthermore, the presence or absence of specific antibody titers was not related to changes in T-cell recognition. Our results indicate a dissociation between the antibody and T-cell responses to rhinoviruses. The species-representative T-cell epitopes identified in this study are valuable tools for future studies investigating T-cell responses to the different RV species. IMPORTANCERhinoviruses (RVs) are mostly associated with the common cold and asthma exacerbations, although their contributions to most upper and lower respiratory tract diseases have increasingly been reported. Species C (RV-C) has been associated with more frequent and severe asthma exacerbations in young children and, along with RV-A, is the most clinically relevant species. Little is known about how our immune system responds to rhinoviruses, and there are limited tools to study specific adaptive immunity against each rhinovirus species. In this study, we identified immunodominant T-cell epitopes of the VP1 proteins of RV-A and RV-C, which are representative of each species. The study found that T-cell responses to RV-A and RV-C were of similar magnitudes, in contrast with previous findings showing RV-C-specific antibody responses were low. These findings will provide the basis for future studies on the immune response to rhinoviruses and can help elucidate the mechanisms of severity of rhinovirus-induced infections.

T‐cell responses against rhinovirus species A and C in asthmatic and healthy children

“…Immunodominant peptides of the VP1 capsid protein of rhinoviruses A and C, recently identified as specific for and representative of each RV‐A and RV‐C species by an epitope‐mapping study , were combined into pools representing each species (Table ). From a measure that considered the size of the stimulations of individual subjects and the frequency of stimulation in the sample (reactivity score) these peptides accounted for almost 50% of the reactivity score achieved with all the peptides for both RV‐A and RV‐C.…”

“…The current study describes T‐cell responses to RV‐A and RV‐C in a pediatric clinical cohort of asthma‐diagnosed children. The responses measured are induced by pools of peptides containing epitopes of the RV‐A and RV‐C VP1 proteins that are both species‐specific and representative of memory T‐cell responses made to each species . We aimed to characterize and compare T‐cell responses between RV‐A and RV‐C and to test the hypothesis that T‐cell responses would differ between asthmatic children and healthy controls.…”

Overview of human rhinovirus immunogenic epitopes for rational vaccine design

“…In a study on donor blood, human CD4 + T-cell epitopes were identified in VP1 capsid protein of group A and group C rhinoviruses. Interestingly, the location of the immunodominant T-cell epitopes was different for group A and group C RVs [3]. Immunodominant areas for VP1 of group A rhinoviruses were homologous with group B RVs and other enteroviruses, but not with group C RVs.…”

“…About 90% of the serotyped RV strains use intercellular adhesion molecule-1 (ICAM-1) (so-called 'major group' of RVs), whereas strains belonging to the 'minor group' use a low-density lipoprotein receptor [2]. In addition, a cadherin-related family member 3 molecule (CDHR3) has been identified as a receptor for the RV-C group [3]. In the 1960s and 1970s, several studies of whole-virion formalin-inactivated RV vaccines administered to humans found that strong, longlasting, strain-specific protective immunity was established.…”

“…For the study [5], H-like highlight indicates two parts of NIm-IB peptide. For some studies, the location of immunogenic epitopes deposited in the Immune Epitope Database (IEDB) is indicated with colored frames: red frames indicate neutralizing epitopes; black frames for the study by Eldmayr et al [13] show separate viral peptides tested; for the study by Niespodziana et al [15] blue frame indicates the peptide shown to be the major target for natural humoral immune responses in RV-infected humans; for the study by Sam Narean et al [8] blue frames indicate peptides identified as targets for binding IgG antibody induced in VP0-immunized mice purple frames (study [17]) indicate confirmed epitopes restricted by different HLA alleles (human donor blood); orange frames indicate immunodominant epitopes for group C rhinoviruses; green frames indicate immunodominant epitopes for group A rhinoviruses [3]. * Epitopes located in this region of RV A2 were evaluated in multiple studies ( [5][6][7] and others).…”