Biology subjects

Park, H.-S.

Publications and source records attributed to Park, H.-S..

11 recordsLinked to original sources

bioRxiv2025

Co-administration of intranasal parainfluenza virus vaccines expressing antigenically distinct SARS-CoV-2 S antigens elicits broad and durable immunity in hamsters

Intranasal COVID-19 vaccines with the ability to induce broad and durable mucosal and systemic immunity would be useful as stand-alone vaccines or in combination with injectable vaccines. Here, we evaluated in the hamster model the immunogenicity, breadth of immunity, and durability of protection elicited by co-administration of two live-attenuated bovine/human parainfluenza virus type 3 (B/HPIV3) vectors expressing antigenically distinct prefusion stabilized S proteins of the ancestral SARS-CoV-2 isolate (B/HPIV3/S-6P) or the Omicron/BA.5 variant (B/HPIV3/S-BA.5-2P). These vectors are being developed as bivalent pediatric vaccines against HPIV3 and SARS-CoV-2 and are based on bovine PIV3 with the fusion (F) and hemagglutinin-neuraminidase (HN) glycoproteins replaced by those of human PIV3. To broaden the S-specific antibody response, we evaluated co-administration of these B/HPIV3 S-expressing vectors. Each B/HPIV3 S-expressing vector induced robust serum anti-S IgG and IgA antibody levels to the antigen-matched S protein that were sustained for at least five months. Co-administration increased the breadth of the S-specific antibody response, spanning the antigenic breadths of the response elicited by each B/HPIV3 S-expressing vector individually. Animals that had received the mixture of vectors developed neutralizing antibodies to ancestral as well as recently circulating SARS-CoV-2 strains. Hamsters immunized intranasally were protected against Omicron/BA.5 challenge 5 months after immunization, with no weight loss, SARS-CoV-2 challenge virus replication, or increase in host inflammatory cytokines in the upper and lower airways detectable after the challenge, indicating durable protection. Thus, intranasal co-administration of live-attenuated B/HPIV3 expressing antigenically distinct S proteins induced broad and durable antibody responses and long-term protection against Omicron/BA.5 challenge. This approach warrants further development and may better protect against emerging SARS-CoV-2 variants. Author summaryCurrent SARS-CoV-2 vaccines protect against severe disease but are less efficient at blocking infection. Intranasal SARS-CoV-2 vaccines, however, have been shown to induce local immunity that better blocks infection at the nasal portal of entry and have been proposed as booster vaccines to induce better protection against SARS-CoV-2 variants. In the present study, we evaluated in hamsters an intranasal live-attenuated chimeric bovine/human parainfluenza virus type 3 (B/HPIV3) as a bivalent pediatric vaccine against PIV3 and SARS-CoV-2. Co-administration in a single intranasal dose of two B/HPIV3 vectors, one expressing the spike protein S from the antigenically distinct ancestral Wuhan-Hu-1 strain and one expressing S of Omicron/BA.5, induced broad and durable serum anti-S IgG and IgA antibody responses that remained strong for at least five months. Hamsters challenged with the Omicron/BA.5 strain five months after immunization were protected from weight loss, inflammatory responses, and challenge virus replication in the upper and lower airways after challenge. Thus, in the hamster model, intranasal immunization with live-attenuated B/HPIV3 expressing SARS-CoV-2 S can provide durable protection for several months, and combining two antigenically distinct B/HPIV3 S-expressing vectors substantially broadens the antibody response. This mucosal immunization approach may better protect against infection from emerging SARS-CoV-2 variants.

microbiology↗

bioRxiv2025

Mechanisms of sex differences in acute and long COVID sequelae in mice

Males are more likely to suffer severe outcomes during acute COVID-19 and a greater proportion of females develop post-acute sequalae of COVID-19 (PASC). To identify mechanisms of PASC, mice were infected with SARS-CoV-2 and viral, inflammatory, and neurocognitive outcomes were evaluated through 84 days post-infection. Sex differences were not observed in virus replication or persistence of viral RNA in pulmonary or extrapulmonary tissues. After infectious virus clearance, females exhibited persistent neurocognitive impairments, and greater frequencies of inflammatory myeloid cells, neuroinflammation, and dysregulated T cells, including effector memory and Tregs. Sex differences in persistent inflammation and cognitive impairments during PASC were mediated by the presence of two X chromosomes and infection-induced upregulation of the X-linked genes Xist and Tlr7, which was reversed by pharmacological inhibition of TLR7 activity during the PASC phase. Sustained X-linked TLR7-mediated inflammation underlies how the burden of PASC is greater for females and provides a therapeutic target.

immunology↗

bioRxiv2024

Intranasal parainfluenza virus-vectored vaccine expressing SARS-CoV-2 spike protein of Delta or Omicron B.1.1.529 induces mucosal and systemic immunity and protects hamsters against homologous and heterologous challenge

The continuous emergence of new SARS-CoV-2 variants requires that COVID vaccines be updated to match circulating strains. We generated B/HPIV3-vectored vaccines expressing 6P-stabilized S protein of the ancestral, B.1.617.2/Delta, or B.1.1.529/Omicron variants as pediatric vaccines for intranasal immunization against HPIV3 and SARS-CoV-2 and characterized these in hamsters. Following intranasal immunization, these B/HPIV3 vectors replicated in the upper and lower respiratory tract and induced mucosal and serum anti-S IgA and IgG. B/HPIV3 expressing ancestral or B.1.617.2/Delta-derived S-6P induced serum antibodies that effectively neutralized SARS-CoV-2 of the ancestral and B.1.617.2/Delta lineages, while the cross-neutralizing potency of B.1.1.529/Omicron S-induced antibodies was lower. Despite the lower cross-neutralizing titers induced by B/HPIV3 expressing S-6P from B.1.1.529/Omicron, a single intranasal dose of all three versions of B/HPIV3 vectors was protective against matched or heterologous WA1/2020, B.1.617.2/Delta or BA.1 (B.1.1.529.1)/Omicron challenge; hamsters were protected from challenge virus replication in the lungs, while low levels of challenge virus were detectable in the upper respiratory tract of a small number of animals. Immunization also protected against lung inflammatory response after challenge, with mild inflammatory cytokine induction associated with the slightly lower level of cross-protection of WA1/2020 and B.1.617.2/Delta variants against the BA.1/Omicron variant. Serum antibodies elicited by all vaccine candidates were broadly reactive against 20 antigenic variants, but the antigenic breadth of antibodies elicited by B/HPIV3-expressed S-6P from the ancestral or B.1.617.2/Delta variant exceeded that of the S-6P B.1.1.529/Omicron expressing vector. These results will guide development of intranasal B/HPIV3 vectors with S antigens matching circulating SARS-CoV-2 variants. Author SummaryIntranasal COVID vaccines have the potential to stimulate respiratory mucosal immunity, effectively restricting replication of SARS-CoV-2 in the respiratory tract, thereby reducing virus shedding and transmission. To develop pediatric vaccines for intranasal immunization against HPIV3 and SARS-CoV-2, we use live-attenuated bovine-human parainfluenza virus vaccine, a pediatric intranasal parainfluenza virus vaccine candidate, designed to express the stabilized SARS-CoV-2 spike protein. We compared the immunogenicity and breadth of protection of the B/HPIV3-expressed ancestral, B.1.617.2/Delta, or B.1.1.529/Omicron variants following intranasal immunization in hamsters. All three B/HPIV3 vectors replicated in the respiratory tract, induced mucosal and serum anti-S IgA and IgG, and were protective in the hamster model against matched or heterologous WA1/2020, B.1.617.2/Delta or BA.1 (B.1.1.529.1)/Omicron SARS-CoV-2 challenge. Serum antibodies elicited by all intranasal vaccine candidates were broadly reactive against 20 antigenic variants of SARS-CoV-2, but the antigenic breadth of antibodies elicited by B/HPIV3-expressed stabilized S from the ancestral or B.1.617.2/Delta variant exceeded that of the S-6P B.1.1.529/Omicron expressing vector. Thus, these intranasal vectored SARS-CoV-2 vaccine candidates induce cross-protective SARS-CoV-2 immunity with antigenic breadth similar to that of injectable SARS-CoV-2 vaccines. These results will guide development of intranasal COVID vaccines based on B/HPIV3 vectors with S antigens matching current SARS-CoV-2 variants.

microbiology↗

bioRxiv2023

Estradiol Mediates Greater Germinal Center Responses to Influenza Vaccination in Female than Male Mice

Adult females of reproductive ages develop greater antibody responses to inactivated influenza vaccine (IIV) than males. How sex, age, and sex steroid changes impact B cells and durability of IIV-induced immunity and protection over 4-months post-vaccination (mpv) was analyzed. Vaccinated adult females had greater germinal center (GC) B cell and plasmablast frequencies in lymphoid tissues, higher neutralizing antibody responses 1-4 mpv, and better protection against live H1N1 challenge than adult males. Aged mice, regardless of sex, had reduced B cell frequencies, less durable antibody responses, and inferior protection after challenge than adult mice, which correlated with diminished estradiol among aged females. To confirm that greater IIV-induced immunity was caused by sex hormones, four core genotype (FCG) mice were used, in which the testes determining gene, Sry, was deleted from ChrY and transferred to Chr3, to separate gonadal sex (i.e., ovaries or testes) from sex chromosome complement (i.e., XX or XY complement). Vaccinated, gonadal female FCG mice (XXF and XYF) had greater numbers of B cells, higher antiviral antibody titers, and reduced pulmonary virus titers following live H1N1 challenge than gonadal FCG males (XYM and XXM). To establish that lower estradiol concentrations cause diminished immunity, adult and aged females received either a placebo or estradiol replacement therapy prior to IIV. Estradiol replacement significantly increased IIV-induced antibody responses and reduced morbidity after the H1N1 challenge among aged females. These data highlight that estradiol is a targetable mechanism mediating greater humoral immunity following vaccination among adult females. ImportanceFemales of reproductive ages develop greater antibody responses to influenza vaccines than males. We hypothesized that female-biased immunity and protection against influenza was mediated by estradiol signaling in B cells. Using diverse mouse models ranging from advanced age mice to transgenic mice that separate sex steroids from sex chromosome complement, those mice with greater concentrations of estradiol consistently had greater numbers of antibody producing B cells in lymphoid tissue, higher antiviral antibody titers, and greater protection against live influenza virus challenge. Treatment of aged female mice with estradiol enhanced vaccine-induced immunity and protection against disease, suggesting that estradiol signaling in B cells is critical for improved vaccine outcomes in females.

immunology↗

bioRxiv2023

The novel spore-specific regulator SscA governs Aspergillus conidiogenesis.

A major group of fungi produces asexual spores (conidia) for propagation and infection. Despite the critical role of conidia, the underlying mechanism of spore formation, integrity, and viability is not fully elucidated. In this study, we have identified and investigated the role of the spore-specific transcription factor (TF) SscA in three representative Aspergillus species. Comparative transcriptomic analyses have revealed that 25 TF encoding genes showed higher mRNA levels in conidia than in hyphae in three species. Functional and transcriptomic analyses of the 25 genes have identified SscA as a key TF for conidial formation, maturation, germination, integrity, amino acid production, and secondary metabolism in Aspergillus nidulans conidia. Importantly, the roles of SscA are conserved in other Aspergillus species. Altogether, our study demonstrates that SscA is a novel spore-specific TF that governs production of intact and functional conidial formation in Aspergillus species. ImportanceFilamentous fungi produce myriads of asexual spores are main reproductive particles and act as infectious or allergenic agents. Although the serial of asexual sporogenesis is coordinated by various genetic regulators, there remain uncharacterized transcription factors in Aspergillus. To understand the underlying mechanism of spore formation, integrity, and viability, we have performed comparative transcriptomic analyses on three representative Aspergillus species and found a novel spore-specific transcription factor, SscA. SscA has a major role in conidial formation, maturation and dormancy, and germination in Aspergillus nidulans. Transcriptomic data indicate that SscA coordinates conidial wall integrity, amino acid production, and secondary metabolism in A. nidulans conidia. Furthermore, the roles of SscA are conserved in other Aspergillus species. Our findings that the novel SscA has broad functions in Aspergillus conidia will help to understand conidiogenesis of Aspergillus species.

microbiology↗

bioRxiv2022

Live-attenuated pediatric parainfluenza vaccine expressing 6P-stabilized SARS-CoV-2 spike protein is protective against SARS-CoV-2 variants in hamsters

The pediatric live-attenuated bovine/human parainfluenza virus type 3 (B/HPIV3)-vectored vaccine expressing the prefusion-stabilized SARS-CoV-2 spike (S) protein (B/HPIV3/S-2P) was previously evaluated in vitro and in hamsters. To improve its immunogenicity, we generated B/HPIV3/S-6P, expressing S further stabilized with 6 proline mutations (S-6P). Intranasal immunization of hamsters with B/HPIV3/S-6P reproducibly elicited significantly higher serum anti-S IgA/IgG titers than B/HPIV3/S-2P; hamster sera efficiently neutralized variants of concern (VoCs), including Omicron variants. B/HPIV3/S-2P and B/HPIV3/S-6P immunization protected hamsters against weight loss and lung inflammation following SARS-CoV-2 challenge with the vaccine-matched strain WA1/2020 or VoCs B.1.1.7/Alpha or B.1.351/Beta and induced near-sterilizing immunity. Three weeks post-challenge, B/HPIV3/S-2P- and B/HPIV3/S-6P-immunized hamsters exhibited a robust anamnestic serum antibody response with increased neutralizing potency to VoCs, including Omicron sublineages. B/HPIV3/S-6P primed for stronger anamnestic antibody responses after challenge with WA1/2020 than B/HPIV3/S-2P. B/HPIV3/S-6P will be evaluated as an intranasal vaccine to protect infants against both HPIV3 and SARS-CoV-2. AUTHOR SUMMARYSARS-CoV-2 infects and causes disease in all age groups. While injectable SARS-CoV-2 vaccines are effective against severe COVID-19, they do not fully prevent SARS-CoV-2 replication and transmission. This study describes the preclinical comparison in hamsters of B/HPIV3/S-2P and B/HPIV3/S-6P, live-attenuated pediatric vector vaccine candidates expressing the "2P" prefusion stabilized version of the SARS-CoV-2 spike protein, or the further-stabilized "6P" version. B/HPIV3/S-6P induced significantly stronger anti-S serum IgA and IgG responses than B/HPIV3/S-2P. A single intranasal immunization with B/HPIV3/S-6P elicited broad systemic antibody responses in hamsters that efficiently neutralized the vaccine-matched isolate as well as variants of concern, including Omicron. B/HPIV3/S-6P immunization induced near-complete airway protection against the vaccine-matched SARS-CoV-2 isolate as well as two variants. Furthermore, following SARS-CoV-2 challenge, immunized hamsters exhibited strong anamnestic serum antibody responses. Based on these data, B/HPIV3/S-6P will be further evaluated in a phase I study.

microbiology↗

bioRxiv2022

Greater breadth of vaccine-induced immunity in females than males is mediated by increased antibody diversity in germinal center B cells

Inactivated influenza vaccines induce greater antibody responses in females than males among both humans and mice. To test the breadth of protection, we used recombinant mouse-adapted A/California/2009 (maA/Cal/09) H1N1 viruses containing mutations at one (1M), two (2M), or three (3M) antigenic sites, in addition to a virus containing the 1M mutation and a substitution of the Ca2 antigenic site (Sub) with one derived from an H5 hemagglutinin (HA) to challenge mice of both sexes. Following maA/Cal/09 vaccination, females produced greater virus-specific class-switched IgG and IgG2c antibodies against the vaccine and all mutant viruses, and antibodies from females recognized more unique, linear HA epitopes than antibodies from males. While females had greater neutralizing antibody (nAb) titers against the vaccine virus, both sexes showed lower neutralization capacity against mutant viruses. After virus challenge, vaccinated females had lower pulmonary virus titers and reduced morbidity than males against the 1M and 2M viruses, but not the Sub virus. Females generated greater numbers of germinal center (GC) B cells containing superior somatic hypermutation frequencies than vaccinated males. Deletion of activation-induced cytidine deaminase (Aicda) eliminated female-biased immunity and protection against the 2M virus. Harnessing methods to improve GC B cell responses and frequencies of somatic hypermutations, especially in males, should be considered in the development of universal influenza vaccines. SummaryCompared with males, inactivated influenza vaccination of female mice causes greater production of class-switched, somatically-hypermutated antibodies and a more robust germinal center B cell response, leading to more diverse H1N1 antigen recognition and better protection against mutant influenza A viruses.

immunology↗

bioRxiv2022

Intranasal pediatric parainfluenza virus-vectored SARS-CoV-2 vaccine candidate is protective in macaques

Pediatric SARS-CoV-2 vaccines are needed that elicit immunity directly in the airways, as well as systemically. Building on pediatric parainfluenza virus vaccines in clinical development, we generated a live-attenuated parainfluenza virus-vectored vaccine candidate expressing SARS-CoV-2 prefusion-stabilized spike (S) protein (B/HPIV3/S-6P) and evaluated its immunogenicity and protective efficacy in rhesus macaques. A single intranasal/intratracheal dose of B/HPIV3/S-6P induced strong S-specific airway mucosal IgA and IgG responses. High levels of S-specific antibodies were also induced in serum, which efficiently neutralized SARS-CoV-2 variants of concern. Furthermore, B/HPIV3/S-6P induced robust systemic and pulmonary S-specific CD4+ and CD8+ T-cell responses, including tissue-resident memory cells in lungs. Following challenge, SARS-CoV-2 replication was undetectable in airways and lung tissues of immunized macaques. B/HPIV3/S-6P will be evaluated clinically as pediatric intranasal SARS-CoV-2/parainfluenza virus type 3 vaccine. One-Sentence SummaryIntranasal parainfluenza virus-vectored COVID-19 vaccine induces anti-S antibodies, T-cell memory and protection in macaques.

immunology↗

bioRxiv2020

Transcriptomic, protein-DNA interaction, and metabolomic studies of VosA, VelB, and WetA in Aspergillus nidulans asexual spores

In filamentous fungi, asexual development involves morphological differentiation and metabolic changes leading to the formation of asexual spores. The process of asexual spore formation in Aspergillus is precisely regulated by multiple transcription factors (TFs), including VosA, VelB, and WetA, and these three TFs are key regulators of the formation and maturation of asexual spores (conidia) in Aspergillus including the model fungus Aspergillus nidulans. To gain a mechanistic insight on the complex regulatory roles of these TFs in asexual spores, we conducted genome-wide studies on the expression, protein-DNA interactions, and primary and secondary metabolism employing A. nidulans conidia. RNA sequencing and chromatin immunoprecipitation-sequencing data have revealed that the three TFs directly or indirectly regulate the expression of genes associated with spore-wall formation/integrity, asexual development, and secondary metabolism. In addition, metabolomics analyses of wild-type and mutant conidia indicate that these three TFs regulate a diverse array of primary and secondary metabolism. In summary, WetA, VosA, and VelB play inter-dependent and distinct roles governing morphological development and primary/secondary metabolic remodeling in Aspergillus conidia. ImportanceFilamentous fungi produce a vast number of asexual spores that act as reproductive and propagator cells. These spores affect humans, due to the infectious or allergenic nature of the propagule. Aspergillus species produce asexual spores called conidia and their formation involves morphological development and metabolic changes, and the associated regulatory systems are coordinated by spore-specific transcription factors. To understand the underlying global regulatory programs and cellular outcomes associated with conidia formation, functional genomic and metabolomic analyses were performed in the model fungus Aspergillus nidulans. Our results show that the fungus specific WetA/VosA/VelB transcription factors govern the coordination of morphological and chemical developments during sporogenesis. The results of this study provide insights into the genetic regulatory networks about how morphological developments and metabolic changes are coordinated in fungi. The findings are relevant for other Aspergillus species such as the major human pathogen Aspergillus fumigatus and the aflatoxin-producer Aspergillus flavus.

microbiology↗

bioRxiv2019

ARP-T1 is a ciliary protein associated with a novel ciliopathy in inherited basal cell cancer, Bazex-Dupre-Christol Syndrome

Actin-Related Protein-Testis1 (ARP-T1)/ ACTRT1 gene mutations cause the Bazex-Dupre-Christol Syndrome (BDCS) characterized by follicular atrophoderma, hypotrichosis and basal cell cancer. Here, we report an ARP-T1 interactome (PXD016557) involved in ciliogenesis, endosomal recycling and septin ring formation. Consequently, ARP-T1 localizes to the midbody during cytokinesis and the basal body of primary cilia in G0. Tissue samples from BDCS patients show reduced ciliary length with significant correlations of ARP-T1 expression levels, confirmed by ACTRT1 knock down. We report that BDCS is a novel ciliopathy and the first case of a skin cancer ciliopathy, where ARP-T1 plays a critical role to prevent pathogenesis.

cancer biology↗

bioRxiv2019

Medroxyprogesterone reverses tolerable dose metformin-induced inhibition of invasion via matrix metallopeptidase-9 and transforming growth factor-β1 in KLE endometrial cancer cells

This study was performed to evaluate the anticancer effects of tolerable doses of metformin with or without medroxyprogesterone (MPA) in endometrial cancer cells. Cell viability, cell invasion, and levels of matrix metallopeptidase (MMP) and transforming growth factor (TGF)-{beta}1 were analyzed using three human endometrial adenocarcinoma cell lines (Ishikawa, KLE, and USPC) after treatment with different dose combinations of MPA (0, 10 M) and metformin (0, 100, 1000 M). Combining metformin (0, 100, 1000 M) and 10 M MPA induced significantly decreased cell viability in a time- and dose-dependent manner in Ishikawa cells, but not in KLE and USPC cells. There was no dose- or time-dependent cell growth inhibition, or positive western blot results for the expression of progesterone receptors and phospho-AMPKa, following treatment with any combination of metformin (0, 100, 1000 M) and 10 M MPA in KLE and USPC cells. In KLE cells, metformin treatment alone significantly inhibited cell invasion in a dose-dependent manner (1.31{+/-}0.05, 0.94{+/-}0.04, 0.83{+/-}0.05 at 0, 100 M, 1000 M, respectively; p<0.0005). The inhibitory effect of metformin was reversed to create a stimulating effect when metformin was combined with 10 M MPA (1.10{+/-}0.05, 1.42{+/-}0.18, 1.41{+/-}0.26 at 0, 100, 1000 M, respectively; p<0.005). MMP-9 and TGF-{beta}1 showed similar trends in terms of cell invasion in KLE cells. In conclusion, the anti-invasive effect of metformin in KLE cells was completely reversed to the state of no treatment by the addition of MPA; this might be mediated through MMP-9 and TGF-{beta}1. Our study suggests the possibility of these combinations doing harm, rather than good, under some conditions.

cancer biology↗