RESUMEN
BACKGROUND: Around 30% of the HCV infected patients can spontaneously clear the virus. Cumulative evidence suggests the role of neutralizing antibodies in such spontaneous resolution. Understanding the epitope specificity of such antibodies will inform the rational vaccine design as such information is limited to date. In addition to conformational epitope targeted antibodies, linear epitope specific antibodies have been identified that are broadly cross reactive against diverse HCV strains. In this study, we have characterized the potential role of three conserved linear epitopes in the spontaneous clearance of HCV. METHODS: We tested the reactivity of sera from chronic patients (CP) and spontaneous resolvers (SR) with linear peptides corresponding to three conserved regions of HCV envelope protein E2 spanning amino acids 412-423, 523-532 and 432-443 using ELISA. Subsequently, we characterized the dependency of HCV neutralization by the reactive serum samples on the antibodies specific for these epitopes using pseudoparticle-based neutralization assay. In ELISA most of the CP sera showed reactivity to multiple peptides while most of the SR samples were reactive to a single peptide suggesting presence of more specific antibodies in the SR sera. In most of the HCVpp neutralizing sera of particular peptide reactivity the neutralization was significantly affected by the presence of respective peptide. HCV neutralization by CP sera was affected by multiple peptides while 75% of the HCVpp neutralizing SR sera were competed by the 432 epitope. CONCLUSIONS: These findings suggest that individuals who spontaneously resolve HCV infection at the acute phase, can produce antibodies specific for conserved linear epitopes, and those antibodies can potentially play a role in the spontaneous viral clearance. The epitope present in the 432-443 region of E2 was identified as the primary neutralizing epitope with potential role in spontaneous viral clearance and this epitope potentiates for the design of immunogen for prophylactic vaccine.
Asunto(s)
Anticuerpos Neutralizantes/inmunología , Epítopos/inmunología , Anticuerpos contra la Hepatitis C/inmunología , Hepatitis C/prevención & control , Vacunas contra Hepatitis Viral/inmunología , Anticuerpos Monoclonales/genética , Anticuerpos Monoclonales/inmunología , Anticuerpos Neutralizantes/genética , Reacciones Cruzadas/genética , Reacciones Cruzadas/inmunología , Epítopos/genética , Genotipo , Hepacivirus/genética , Hepacivirus/inmunología , Hepacivirus/patogenicidad , Hepatitis C/genética , Hepatitis C/inmunología , Hepatitis C/virología , Anticuerpos contra la Hepatitis C/genética , Humanos , Pruebas de Neutralización , Proteínas del Envoltorio Viral/genética , Proteínas del Envoltorio Viral/inmunología , Vacunas contra Hepatitis Viral/genéticaRESUMEN
The emergence of multidrug-resistant pathogens presents a global challenge for treating and preventing disease spread through zoonotic transmission. The water and foodborne Enterohaemorrhagic Escherichia coli (EHEC) are capable of causing intestinal and systemic diseases. The root cause of the emergence of these strains is their metabolic adaptation to environmental stressors, especially acidic pH. Acid treatment is desired to kill pathogens, but the protective mechanisms employed by EHECs cross-protect against antimicrobial peptides and thus facilitate opportunities for survival and pathogenesis. In this review, we have discussed the correlation between acid tolerance and antibiotic resistance, highlighting the identification of novel targets for potential production of antimicrobial therapeutics. We have also summarized the molecular mechanisms used by acid-adapted EHECs, such as the two-component response systems mediating structural modifications, competitive inhibition, and efflux activation that facilitate cross-protection against antimicrobial compounds. Moving beyond the descriptive studies, this review highlights low pH stress as an emerging player in the development of cross-protection against antimicrobial agents. We have also described potential gene targets for innovative therapeutic approaches to overcome the risk of multidrug-resistant diseases in healthcare and industry.
RESUMEN
B cell activation is regulated by the stimulatory or inhibitory co-receptors of B cell receptors (BCRs). Here, we investigated the signaling mechanism of Fc receptor-like 1 (FcRL1), a newly identified BCR co-receptor. FcRL1 was passively recruited into B cell immunological synapses upon BCR engagement in the absence of FcRL1 cross-linking, suggesting that FcRL1 may intrinsically regulate B cell activation and function. BCR cross-linking alone led to the phosphorylation of the intracellular Y281ENV motif of FcRL1 to provide a docking site for c-Abl, an SH2 domain-containing kinase. The FcRL1 and c-Abl signaling module, in turn, potently augmented B cell activation and proliferation. FcRL1-deficient mice exhibited markedly impaired formation of extrafollicular plasmablasts and germinal centers, along with decreased antibody production upon antigen stimulation. These findings reveal a critical BCR signal-enhancing function of FcRL1 through its intrinsic recruitment to B cell immunological synapses and subsequent recruitment of c-Abl upon BCR cross-linking.
Asunto(s)
Linfocitos B/inmunología , Linfocitos B/metabolismo , Activación de Linfocitos/genética , Activación de Linfocitos/inmunología , Proteínas de la Membrana/metabolismo , Proteínas Proto-Oncogénicas c-abl/metabolismo , Animales , Formación de Anticuerpos/genética , Formación de Anticuerpos/inmunología , Eliminación de Gen , Proteínas de la Membrana/química , Proteínas de la Membrana/genética , Ratones , Mutación , Unión Proteica , Dominios y Motivos de Interacción de Proteínas , Receptores de Antígenos de Linfocitos B/química , Receptores de Antígenos de Linfocitos B/metabolismo , Transducción de Señal , Dominios Homologos srcRESUMEN
BACKGROUND: Hepatitis C virus (HCV) infections are amongst the leading public health concerns in Pakistan with a high disease burden. Despite the availability of effective antiviral treatments in the country the disease burden in general population has not lowered. This could be attributed to the asymptomatic nature of this infection that results in lack of diagnosis until the late symptomatic stage. To better estimate and map HCV infections in the country a population-based analysis is necessary for an effective control of the infection. METHODS: Serologic samples of ~66,000 participants from all major cities of the Punjab province were tested for anti-HCV antibodies. The antibody-based seroprevalence was associated with socio-demographic variables including geographical region, age, gender and sex, and occupation. RESULTS: Overall serological response to HCV surface antigens was observed in over 17% of the population. Two of the districts were identified with significantly high prevalence in general population. Analysis by occupation showed significantly high prevalence in farmers (over 40%) followed by jobless and retired individuals, laborers and transporters. A significant difference in seroprevalence was observed in different age groups amongst sex and genders (male, female and transgender) with highest response in individuals of over 40 years of age. Moreover, most of the tested IDUs showed positive response for anti-HCV antibody. CONCLUSION: This study represents a retrospective analysis of HCV infections in general population of the most populated province of Pakistan to identify socio-demographic groups at higher risk. Two geographical regions, Faisalabad and Okara districts, and an occupational group, farmers, were identified with significantly high HCV seroprevalence. These socio-demographic groups are the potential focused groups for follow-up studies on factors contributing to the high HCV prevalence in these groups towards orchestrating effective prevention, control and treatment.