HORMAZABAL CASTILLO, JUAN PATRICIO

Preferred name
HORMAZABAL CASTILLO, JUAN PATRICIO
Main Affiliation
Email
jhormazabal@udd.cl
ORCID
0000-0003-0726-2778
Scopus Author ID
57225278430
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    Scopus© Citations 1  6
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    SARS-CoV-2 infectivity and antigenic evasion: spotlight on isolated Omicron sub-lineages
    (2024)
    Aldo Barrera
    ;
    Constanza Martínez-Valdebenito
    ;
    Jenniffer Angulo
    ;
    Carlos Palma
    ;
    HORMAZABAL CASTILLO, JUAN PATRICIO  
    <jats:p>Since the SARS-CoV-2 outbreak in 2019, a diversity of viral genomic variants has emerged and spread globally due to increased transmissibility, pathogenicity, and immune evasion. By the first trimester of 2023 in Chile, as in most countries, BQ and XBB were the predominant circulating sub-lineages of Omicron. The molecular and antigenic characteristics of these variants have been mainly determined using non-authentic spike pseudoviruses, which is often described as a limitation. Additionally, few comparative studies using isolates from recent Omicron sub-lineages have been conducted. In this study, we isolated SARS-CoV-2 variants from clinical samples, including the ancestral B.1.1, Delta, Omicron BA.1, and sub-lineages of BA.2 and BA.5. We assessed their infectivity through cell culture infections and their antibody evasion using neutralization assays. We observed variations in viral plaque size, cell morphology, and cytotoxicity upon infection in Vero E6-TMPRSS2 cells for each variant compared to the ancestral B.1.1 virus. BA.2-derived sub-variants, such as XBB.1.5, showed attenuated viral replication, while BA.5-derived variants, such as BQ.1.1, exhibited replication rates similar to the ancestral SARS-CoV-2 virus. Similar trends were observed in intestinal Caco-2 cells, except for Delta. Antibody neutralization experiments using sera from individuals infected during the first COVID-19 wave (FWI) showed a consistent but moderate reduction in neutralization against Omicron sub-lineages. Interestingly, despite being less prevalent, BQ.1.1 showed a 6.1-fold greater escape from neutralization than XBB.1.5. Neutralization patterns were similar when tested against sera from individuals vaccinated with 3xBNT162b2 (PPP) or Coronavac-Coronavac-BNT162b2 (CCP) schedules. However, CCP sera showed 2.3-fold higher neutralization against XBB.1.5 than FWI and PPP sera. This study provides new insights into the differences between BA.2 and BA.5-derived variants, leading to their eventual outcompetition. Our analysis offers important evidence regarding the balance between infectivity and antigenic escape that drives the evolution of second-generation SARS-CoV-2 variants in the population.</jats:p>
      5Scopus© Citations 3
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    Scopus© Citations 16  8
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    Chaperone mediated autophagy contributes to the newly synthesized histones H3 and H4 quality control
    (2022)
    HORMAZABAL CASTILLO, JUAN PATRICIO  
    ;
    Francisco Saavedra
    ;
    Claudia Espinoza-Arratia
    ;
    Nicolas W Martinez
    ;
    Tatiana Cruces
    <jats:title>Abstract</jats:title> <jats:p>Although there are several pathways to ensure that proteins are folded properly in the cell, little is known about the molecular mechanisms regulating histone folding and proteostasis. In this work, we identified that chaperone-mediated autophagy (CMA) is the main pathway involved in the degradation of newly synthesized histones H3 and H4. This degradation is finely regulated by the interplay between HSC70 and tNASP, two histone interacting proteins. tNASP stabilizes histone H3 levels by blocking the direct transport of histone H3 into lysosomes. We further demonstrate that CMA degrades unfolded histone H3. Thus, we reveal that CMA is the main degradation pathway involved in the quality control of histone biogenesis, evidencing an additional mechanism in the intricate network of histone cellular proteostasis.</jats:p>
    Scopus© Citations 8  4
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    Seroprevalence of Natural and Acquired Immunity against the SARS-CoV-2 Virus in a Population Cohort from Two Chilean Cities, 2020–2022
    (2023)
    Loreto Núñez-Franz
    ;
    Muriel Ramírez-Santana
    ;
    RUBILAR RAMIREZ, PAOLA  
    ;
    Macarena Said
    ;
    VIAL COX, MARIA CECILIA  
    <jats:p>Background: Chile has achieved the highest coverage for vaccines against the SARS-CoV-2 virus worldwide. Objective: To assess the progression of immunity (natural and acquired by vaccine) in a cohort from two Chilean cities. Methods: Individuals (n = 386) who participated in three phases of population-based serial prevalence studies were included (2020–2021 and 2022). Presence of SARS-CoV-2 antibodies was measured in serum. Data including time of vaccination and type of vaccine received were analysed with descriptive statistics. Results: Seroprevalence was 3.6% in the first round and increased to 96.9% in the second and 98.7% in the third. In the third round, 75% of individuals who had received the basal full scheme were seropositive at 180 days or more since their last dose; 98% of individuals who received one booster dose were seropositive at 180 days or more, and 100% participants who received two boosters were seropositive, regardless of time since their last dose. Participants receiving mRNA vaccines had higher seroprevalence rates over time. Conclusions: The high vaccination coverage in Chile enabled the population to maintain high levels of antibodies. Vaccination boosters are essential to maintain immunity over time, which also depends on the type of vaccine administered.</jats:p>
      1Scopus© Citations 12
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    SARS-CoV-2 Neutralizing Antibodies in Chile after a Vaccination Campaign with Five Different Schemes
    (2022)
    AGUILERA SANHUEZA, XIMENA PAZ  
    ;
    HORMAZABAL CASTILLO, JUAN PATRICIO  
    ;
    VIAL COX, MARIA CECILIA  
    ;
    CORTES SALINAS, LINA JIMENA  
    ;
    GONZALEZ WIEDMAIER, CLAUDIA MARTA  
    <jats:p>Using levels of neutralizing antibodies (nAbs), we evaluate the successful Chilean SARS-CoV-2 vaccine campaign, which combines different vaccine technologies and heterologous boosters. From a population-based study performed in November 2021, we randomly selected 120 seropositive individuals, organized into six groups of positive samples (20 subjects each) according to natural infection history and the five most frequent vaccination schemes. We conclude that the booster dose, regardless of vaccine technology or natural infection, and mRNA vaccines significantly improve nAbs response.</jats:p>
    Scopus© Citations 3  3
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    KFERQ-selective protein autophagy in Caenorhabditis elegans depends on LMP-1
    (Public Library of Science (PLoS), 2025-09-02)
    Alicia N. Minniti
    ;
    María Gallardo-Campos
    ;
    HORMAZABAL CASTILLO, JUAN PATRICIO  
    ;
    NUÑEZ VASQUEZ, GONZALO ESTEBAN  
    ;
    Carlos F. Lagos
    Mammalian cells exhibit three autophagy mechanisms: macroautophagy, microautophagy (MIA), and chaperone-mediated autophagy (CMA), each employing unique mechanisms for transporting cellular material to the lysosome for degradation. MIA involves the engulfment of proteins via lysosomes/late endosomes through membrane invagination, while CMA directly imports cytosolic proteins into lysosomes, selectively targeting those harboring the KFERQ pentapeptide motif, helped by the chaperone HSC70. Despite the identification of several genetic markers of these pathways, our understanding of the underlying mechanisms, particularly in MIA and CMA, remains limited. To study CMA in vivo we designed a photoactivatable CMA reporter consisting of a plasmid encoding the KFERQ consensus signal for CMA targeting. We generated transgenic <jats:italic><jats:italic>C. elegans</jats:italic></jats:italic> strains with diverse genetic backgrounds to analyze the role of known molecular components of CMA in mammals. Additionally, we conducted an in-silico analysis of the structural interaction between <jats:italic><jats:italic>C. elegans</jats:italic></jats:italic> LMP-1 or LMP-2 proteins with the HSP-1 chaperone. Results: Our study shows a significant alteration in the distribution pattern of the KFERQ reporter in muscle cells upon induction of selective autophagy (CMA or MIA). We found that the reporter localized into lysosomes only during starvation, which abrogated in the absence of LMP-1. This study validates CMA in <jats:italic><jats:italic>C. elegans</jats:italic></jats:italic> and provides the development of a new tool for understanding selective autophagy mechanisms and their potential implications in various organisms.
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    A Third Dose of SARS-CoV-2 mRNA Vaccine Improves Immune Response in Chronic Kidney Disease Patients
    (2023)
    POLI HARLOWE, MARIA CECILIA BERTA  
    ;
    VIAL COX, MARIA CECILIA  
    ;
    REY JURADO, EMMA  
    ;
    Natalia González
    ;
    CORTES SALINAS, LINA JIMENA  
    <jats:p>Chronic kidney disease (CKD) patients have an increased risk of morbidity and mortality following SARS-CoV-2 infection. Vaccination in these patients is prioritized, and monitoring of the immune response is paramount to define further vaccination strategies. This prospective study included a cohort of 100 adult CKD patients: 48 with kidney transplant (KT) and 52 on hemodialysis without prior COVID-19. The patients were assessed for humoral and cellular immune responses after four months of an anti-SARS-CoV-2 primary two-dose vaccination scheme (CoronaVac or BNT162b2) and one month after a booster third dose of BNT162b2 vaccine. We identified poor cellular and humoral immune responses in the CKD patients after a primary vaccination scheme, and these responses were improved by a booster. Robust polyfunctional CD4+ T cell responses were observed in the KT patients after a booster, and this could be attributed to a higher proportion of the patients having been vaccinated with homologous BNT162b2 schemes. However, even after the booster, the KT patients exhibited lower neutralizing antibodies, attributable to specific immunosuppressive treatments. Four patients suffered severe COVID-19 despite three-dose vaccination, and all had low polyfunctional T-cell responses, underscoring the importance of this functional subset in viral protection. In conclusion, a booster dose of SARS-CoV-2 mRNA vaccine in CKD patients improves the impaired humoral and cellular immune responses observed after a primary vaccination scheme.</jats:p>
      8Scopus© Citations 5