bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mosaic HIV-1 vaccination induces anti-viral CD8
+
T cell functionality in the phase 1/2a clinical trial APPROACH
Authors: van Duijn Janine , Stieh Daniel , Fernandez Natalia , King Deborah , Gilmour Jill , Tolboom Jeroen , Callewaert Katleen , Willems Wouter , Pau Maria G. , De Rosa Stephen C. , McElrath M. Juliana , Barouch Dan H. , Hayes Peter 
Published: October 2023

ABSTRACT

The ability of vaccine-induced T cells to inhibit viral replication may contribute to protect against human immunodeficiency virus (HIV) acquisition. Here, we tested
ex vivo
viral inhibitory activity of T cell responses induced by a multivalent HIV vaccine based on the replication-incompetent recombinant adenovirus serotype 26 vector with a mosaic immunogen strategy (Ad26.Mos.HIV), designed for broad immune coverage of diverse HIV-1 strains. Using clinical trial samples with a diverse range of T cell responses measured by IFN-γ ELISpot, anti-viral function of vaccine-induced CD8+ T cells was assessed by inhibition of HIV-1 replication in autologous CD4+ T cells to a panel of HIV-1 isolates.
Ex vivo
expanded CD8+ T cells were able to inhibit replication of HIV in autologous CD4+ T cells, with 94% of vaccinees inhibiting at least one out of eight HIV isolates, and a median of 5 isolates inhibited at peak immunogenicity. Correlations between viral inhibition and ICS as well as ELISpot responses were explored, demonstrating positive correlations. Broad ELISpot responsiveness to different regions of the Env, Gag, and Pol proteins was associated with breadth of viral inhibitory responses. Moreover, polyfunctionality of CD8+ T cells correlated well with viral inhibition. These findings indicate that functional immunological breadth as well as antigenic breadth is important to induce antiviral activity. This study advances the understanding of vaccine-induced T cell functionality and demonstrates for the first time that Ad26.Mos.HIV vaccination in combination with adjuvanted gp140 can induce broad viral inhibitory activity toward a panel of diverse HIV-1 clades.

IMPORTANCE

The functionality of CD8+ T cells against human immunodeficiency virus-1 (HIV-1) antigens is indicative of HIV-progression in both animal models and people living with HIV. It is, therefore, of interest to assess CD8+ T cell responses in a prophylactic vaccination setting, as this may be an important component of the immune system that inhibits HIV-1 replication. T cell responses induced by the adenovirus serotype 26 (Ad26) mosaic vaccine regimen were assessed previously by IFN-γ ELISpot and flow cytometric assays, yet these assays only measure cytokine production but not the capacity of CD8+ T cells to inhibit replication of HIV-1. In this study, we demonstrate direct anti-viral function of the clinical Ad26 mosaic vaccine regimen through
ex vivo
inhibition of replication of diverse clades of HIV-1 isolates in the participant’s own CD4+ T cells.
Whole genome structural predictions reveal hidden diversity in putative oxidative enzymes of the lignocellulose-degrading ascomycete
Parascedosporium putredinis
NO1
Authors: Scott Conor J. R. , Leadbeater Daniel R. , Oates Nicola C. , James Sally R. , Newling Katherine , Li Yi , McGregor Nicholas G. S. , Bird Susannah , Bruce Neil C. 
Published: October 2023

ABSTRACT

Economic valorization of lignocellulose is paramount to realizing a true circular bioeconomy; however, this requires the development of systems and processes to expand the repertoire of bioproducts beyond current renewable fuels, chemicals, and sustainable materials.
Parascedosporium putredinis
NO1 is an ascomycete that thrived at the later stages of a wheat-straw composting community culture, indicating a propensity to degrade recalcitrant lignin-enriched biomass, but exists within an underrepresented and underexplored fungal lineage. This strain has been proven to be an exciting candidate for the identification of new enzymes targeting recalcitrant components of lignocellulose following the recent discovery of a new lignin β-ether linkage cleaving enzyme. The first genome for the genus
Parascedosporium
for
P. putredinis
NO1 genome was sequenced, assembled, and annotated. The genome is 39 Mb in size, consisting of 21 contigs annotated to contain 9.998 protein-coding sequences. The carbohydrate-active enzyme (CAZyme) repertoire was compared to 2570 ascomycete genomes and in detail with
Trichoderma reesei
,
Fusarium oxysporum
, and sister taxa
Scedosporium boydii
. Significant expansion in the oxidative auxiliary activity class of CAZymes was observed in the
P. putredinis
NO1 genome, resulting from increased sequences encoding putative lytic polysaccharide monooxygenases (LPMOs), oxidative enzymes acting within LPMO redox systems, and lignin-degrading laccases.
P. putredinis
NO1 scored above the 95th percentile for AA gene density across the ascomycete phylum, suggesting a primarily oxidative strategy for lignocellulose breakdown. Novel structure-based searching approaches were employed, revealing 17 new sequences with structural similarity to LPMO, laccase, and peroxidase sequences and which are potentially new lignocellulose-degrading enzymes.

IMPORTANCE

An annotated reference genome has revealed
P. putredinis
NO1 as a useful resource for the identification of new lignocellulose-degrading enzymes for biorefining of woody plant biomass. Utilizing a “structure-omics”-based searching strategy, we identified new potentially lignocellulose-active sequences that would have been missed by traditional sequence searching methods. These new identifications, alongside the discovery of novel enzymatic functions from this underexplored lineage with the recent discovery of a new phenol oxidase that cleaves the main structural β-O-4 linkage in lignin from
P. putredinis
NO1, highlight the underexplored and poorly represented family Microascaceae as a particularly interesting candidate worthy of further exploration toward the valorization of high value biorenewable products.
The interaction of human immunodeficiency virus-1 and human endogenous retroviruses in patients (primary cell cultures) and cell line models
Authors: Mantovani Federica , Kitsou Konstantina , Paraskevis Dimitrios , Lagiou Pagona , Magiorkinis Gkikas 
Published: October 2023

ABSTRACT

Human endogenous retroviruses (HERVs) integrated into the human genome millions of years ago, and their expression has been described both in healthy tissues and in pathology. In the present study, we study the differential expression of multiple HERV families in the presence of human immunodeficiency virus (HIV) infection in the peripheral blood mononuclear cells (PBMCs) of HIV-positive individuals, in HIV-infected cell lines, and
in vitro
HIV-infected macrophages/monocytes of healthy donors, utilizing publicly available data sets for secondary analysis using a pipeline appropriate for HERV transcription detection and comparison. We recognized significantly decreased expression of HERV-H in treatment-naïve HIV patients with viremia and increased expression of multiple HERV families in the PBMCs of HIV-infected individuals under combination antiretroviral therapy compared to healthy donors, in
in vitro
HIV-infected Stanford University pediatric T (SUP-T1) cells at 24 hours after HIV infection compared to non-infected SUP-T1 cells, and in
in vitro
HIV-infected MT4 T cells at 3 days after HIV infection compared to non-infected MT4 T cells. We recognized significantly increased expression of HERV-W, after HIV infection in monocyte-derived macrophage cell culture; no difference was found in HERV expression after HIV infection of monocyte cultures. We found a significantly decreased expression of HERV-K (HML-6) in donor-derived macrophage cultures at 36 hours after HIV infection, which does not persist at 6 days after infection. HIV infection modifies the expression of multiple HERV families in the PBMCs of HIV patients and in T cell-derived cultures, while the effect of HIV infection on HERV expression appears to be more restricted in cells of monocytic origin.

IMPORTANCE

In this work, we demonstrated that human immunodeficiency virus (HIV) infection leads to the modification of the human endogenous retrovirus (HERV) expression. Differential expression of multiple HERVs was found in peripheral blood mononuclear cells derived from HIV-infected patients compared to healthy donors and HIV-infected T cell cultures compared to non-infected. The effect of HIV presence on HERV expression appears to be more restricted in cells of monocytic origin, as only deregulation of HERV-W and HERV-K (HML-6) was found in these cell cultures after their infection with HIV. Multiple factors contribute to this aberrant HERV expression, and its levels appear to be modified in a time-dependent manner. Further studies and the development of optimized
in vitro
protocols are warranted to elucidate the interactions between HIV and HERVs in detail.
Wolbachia
interferes with Zika virus replication by hijacking cholesterol metabolism in mosquito cells
Authors: Edwards Brent , Ghedin Elodie , Voronin Denis 
Published: October 2023

ABSTRACT

Zika virus is a member of the arbovirus
Flaviviridae
family transmitted by
Aedes
mosquitos and it is associated with microcephaly in infants born to infected mothers.
Wolbachia
is an intracellular gram-negative alpha-proteobacteria that infects many species of arthropods, including mosquitos. The presence of
Wolbachia
in mosquitos has been shown to control the vector population and suppress arbovirus transmission. One mechanism of
Wolbachia
-mediated interference with virus replication is competition over host resources between
Wolbachia
and the virus. We hypothesize that cholesterol metabolism is involved in
Wolbachia
-mediated virus suppression due to its important role in Zika virus replication. In this study, we determined that
Wolbachia
impacted virus replication by altering cholesterol biosynthesis in
Aedes albopictus
C6/36 cells, diverting resources from the host cell mevalonate (MVA) pathway to fulfill the needs of the bacteria. This resulted in a decrease of total cholesterol, increased
Wolbachia
loads, and decreased viral titers. Inhibition of the MVA pathway using fluvastatin decreased total cholesterol and viral titers, mimicking the effects of
Wolbachia
on the virus in
Wolbachia-
free cells. We also found that
Wolbachia-
infected cells had depleted lipid droplets, the main component of which is cholesterol esters. We confirmed that cholesterol esterases were upregulated in response to virus infection in C6/36 cells. Functional analysis showed that alteration of cholesterol metabolism simulated
Wolbachia
-mediated inhibition of virus infection in C6/36 cells. Our study provides a mechanism behind
Wolbachia
-induced interference of arbovirus replication and could help advance strategies to control arbovirus pathogens in insect vectors and human infections.

IMPORTANCE

Arthropod-borne viruses are emerging pathogens that are spread widely by mosquitos. Zika virus is an arbovirus that can infect humans and be transmitted from an infected mother to the fetus, potentially leading to microcephaly in infants. One promising strategy to prevent disease caused by arboviruses is to target the insect vector population. Recent field studies have shown that mosquito populations infected with
Wolbachia
bacteria suppress arbovirus replication and transmission. Here, we describe how intracellular bacteria redirect resources within their host cells and suppress Zika virus replication at the cellular level. Understanding the mechanism behind
Wolbachia
-induced interference of arbovirus replication could help advance strategies to control arbovirus pathogens in insect vectors and human populations.
Hundred-fold increase in SARS-CoV-2 spike antibody levels over three years in a hospital clinical laboratory
Authors: Caturegli Patrizio , Laeyendecker Oliver , Tobian Aaron A. R. , Sullivan David J. 
Published: October 2023

ABSTRACT

Natural infection with the SARS-CoV-2 virus and vaccination increase the serum spike antibody levels. These levels, which differ among the various commercial assays, are used by the FDA to qualify individuals as potential COVID-19 convalescent plasma (CCP) donors. Over a 3-year period (April 2020–February 2023), we performed a retrospective analysis of spike IgG antibodies measured by a tertiary hospital clinical immunology laboratory using the Euroimmun SARS-CoV-2 IgG ELISA. The 3-year interval was classified into five periods based on the SARS-CoV-2 strain variant epidemiology. A total of 15,820 sera, derived from 11,022 individuals (6,362 females and 4,660 males) ranging from severe immunocompromised state to routine health visits, were tested. Spike IgG levels rose significantly over time, from a median ELISA 0.13 Arbitrary Units (AU) in the first period to 48.7 in the last period (
P
< 0.0001). The 80th percentile of the spike IgG distribution was 0.55, 8.1, 9.6, 64.9, and 151 AU in the five periods. Using 3.5 AU, the FDA threshold for qualifying CCP donors with this Euroimmun assay, the percentage of subjects eligible for CCP donation would have been 11%, 44%, 61%, 81%, and 91% in the five time periods. Overall, spike antibody levels have risen more than 100-fold during the pandemic, while SARS-CoV-2 variants have become resistant to monoclonal antibodies. Since CCP containing high titers of spike antibodies is known to be most effective against variants, restricting CCP donors to those with antibody values in the upper two deciles may allow greater therapeutic transfusion protection.

IMPORTANCE
Despite the evolution of SARS-CoV-2 variants of concern and ongoing transmission, COVID-19 hospitalization and mortality rates continue to decline. Both the percent seropositive and antibody levels have risen over the past 3 years. Here, we observe more than 90% seropositivity as well as more than a hundred-fold increase in spike IgG levels in a tertiary hospital clinical immunology laboratory setting. Antibody effector functions (such as neutralization, opsonization, and complement activation) and cell-mediated immunity all contribute to protection from COVID-19 progression to hospitalization, and all correlate to the total SARS-CoV-2 antibody levels. We recommend therapeutic COVID-19 convalescent plasma be restricted to the top 20% of potential donors to maintain activity against ongoing SARS-CoV-2 variant evolution.
Differential skin immune responses in mice intradermally infected with
Candida auris
and
Candida albicans
Authors: Datta Abhishek , Das Diprasom , Nett Jeniel E. , Vyas Jatin M. , Lionakis Michail S. , Thangamani Shankar 
Published: October 2023

ABSTRACT

Candida auris
, an emerging multi-drug-resistant fungal pathogen, uniquely colonizes the human skin long term, leading to subsequent development of life-threatening invasive infections in humans. The factors regulating skin colonization of
C. auris
are not well understood. In this study, we established an intradermal mouse model of
C. auris
infection to define the innate and adaptive immune response to this emerging pathogen and compare it to
Candida albicans
. Our results indicate that compared to
C. albicans
-infected mice,
C. auris
-infected mouse skin tissue had significantly higher fungal load after 3 and 14 days post-infection.
C. auris
infection was associated with a significantly decreased accumulation of CD11b+ Ly6G+ neutrophils and increased numbers of CD11b+ Ly6 C
hi
inflammatory monocytes and CD11b+ CD207+ Langerhans cells at the site of infection. Furthermore, a significant decrease in the absolute numbers of type 3 innate lymphoid cells and Th17 cells was observed in
C. auris
-infected skin tissue. Taken together, our findings indicate that the skin immune responses are different between
C. auris
- and
C. albicans
-infected mice. The increased fungal load observed in
C. auris
-infected mouse skin tissue is associated with less potent innate and adaptive immune responses induced by this emerging pathogen relative to
C. albicans
.

IMPORTANCE

Candida auris
is a globally emerging fungal pathogen that transmits among individuals in hospitals and nursing home residents. Unlike other
Candida
species,
C. auris
predominantly colonizes and persists in skin tissue, resulting in outbreaks of nosocomial infections. Understanding the factors that regulate
C. auris
skin colonization is critical to develop novel preventive and therapeutic approaches against this emerging pathogen. We established a model of intradermal
C. auris
inoculation in mice and found that mice infected with
C. auris
elicit less potent innate and adaptive immune responses in the infected skin compared to
C. albicans
. These findings help explain the clinical observation of persistent
C. auris
colonization in skin tissue.
The
Alternaria alternata
StuA transcription factor interacting with the pH-responsive regulator PacC for the biosynthesis of host-selective toxin and virulence in citrus
Authors: Chen Yanan , Cao Yingzi , Jiao Chen , Sun Xuepeng , Gai Yunpeng , Zhu Zengrong , Li Hongye 
Published: October 2023

ABSTRACT

The tangerine pathotype of
Alternaria alternata
produces a host-selective toxin termed
Alternaria citri
toxin (ACT). The molecular mechanisms underlying the global regulation and biosynthesis of ACT remain unknown. In the present study, the function of an APSES transcription factor StuA was investigated. StuA was shown to be required for ACT biosynthesis and fungal virulence. StuA was found, for the first time, to physically interact with a pH-responsive transcription regulator PacC using yeast two-hybrid, bimolecular fluorescence complementation, and GST pull-down assays. Functional analyses revealed that StuA and PacC regulate the expression of genes involved in toxin biosynthesis and virulence. Mutation of
stuA
via targeted gene deletion or silencing
pacC
yielded fungal strains that decreased the expression of seven toxin biosynthetic genes (
ACCT
) and toxin production. EMSA analyses revealed that PacC could bind to the promoters of
ACTT6
encoding an enoyl-CoA hydratase and
ACTTR
encoding an ACT pathway-specific transcription factor. Site-directed mutagenesis of five potential protein kinase A (PKA) phosphorylation sites in StuA revealed that none of the sites was involved in ACT production, indicating that the function of StuA in the regulation of
ACT
gene expression is not dependent on phosphorylation. Overall, our results confirmed that PacC is one of the key regulators interacting with StuA for the biosynthesis of ACT. Environmental pH may play a decisive role during
A. alternata
pathogenesis. Our results also revealed a previously unrecognized (StuA-PacC)→ACTTR module for the biosynthesis of ACT in
A. alternata
.

IMPORTANCE

In this study, we used
Alternaria alternata
as a biological model to report the role of StuA in phytopathogenic fungi. Our findings indicated that StuA is required for
Alternaria citri
toxin (ACT) biosynthesis and fungal virulence. In addition, StuA physically interacts with PacC. Disruption of
stuA
or
pacC
led to decreased expression of seven toxin biosynthetic genes (ACCT) and toxin production. PacC could recognize and bind to the promoter regions of
ACTT6
and
ACTTR
. Our results revealed a previously unrecognized (StuA-PacC)→ACTTR module for the biosynthesis of ACT in
A. alternata
, which also provides a framework for the study of StuA in other fungi.
Perceptions of key stakeholders on taxes on tobacco and alcohol products in Nepal
Authors: Acharya Yubraj , Karmacharya Vipassana , Paudel Uttam , Joshi Supriya , Ghimire Ramesh , Adhikari Shiva Raj 
Published: October 2023

BackgroundNon-communicable diseases (NCDs) are on the rise in Nepal. Consumption of alcohol and tobacco products remains high. Taxes on these products are significantly below the rate recommended by the WHO. In an effort to understand the reasons behind the slow progress towards the adoption of higher health taxes to curb NCDs, we documented the perceptions of key stakeholders on health taxes, including perceived barriers and facilitators to adopting higher health taxes.MethodsWe conducted 45 in-depth interviews with individuals comprising government officials; producers, wholesale distributors and sellers of alcohol and tobacco products; and consumers and representatives from civil society organisations. We conducted a thematic analysis of the resulting data.ResultsRespondents from alcohol and tobacco industries are not supportive of higher health taxes. They argued that higher taxes can increase illicit trade and worsen inequality. Strikingly, several government officials shared the industries’ concerns, arguing that health taxes have limited potential to reduce consumption of alcohol and tobacco products to help curb NCDs. In terms of barriers to adoption of higher health taxes, several local government representatives opined that close ties between industries and politicians at the federal level is a major hindrance.ConclusionsIn order to adopt higher health taxes, the government will need to counter the false narrative pushed by alcohol and tobacco industries on the negative economic effects of such taxes. Health taxes earmarked for NCDs need to reflect the amount of revenue raised, reoriented towards prevention efforts and communicated clearly to the public.
Policy networks and competing interests in the development of the Mexican sugar-sweetened beverages tax
Authors: Carriedo Angela , Cairney Paul , Barquera Simón , Hawkins Benjamin 
Published: October 2023

IntroductionSugar taxes threaten the business models and profits of the food and beverage industry (F&BI), which has sought to avert, delay or influence the content of health taxes globally. Mexico introduced a sugar-sweetened beverage (SSB) tax in 2014 and other regulatory measures to improve population diets. This paper examines how policy networks emerged within and affected the development and implementation of the Mexican SSB tax.MethodsThis qualitative study analyses 31 interviews conducted with key stakeholders involved in the soda tax policy process and 145 documents, including grey literature and peer-reviewed literature. The policy network approach was used to map contacts, interconnections, relationships and links between the state, civil society and commercial actors involved in the SSB tax. These findings were used to examine the responsiveness, participation and accountability of the soda tax policy formulation.ResultsComplex interconnections were identified between state and non-state actors. These included advisory relationships, financial collaborations and personal connections between those in high-level positions. Relationships between the government and the F&BI were not always disclosed. International organisations and academics were identified as key financial or technical supporters of the tax. Key governance principles of participation, responsiveness and accountability were undermined by some of these relationships, including the participation of non-state actors in policy development and the powerful role of the F&BI in evaluation and monitoring.ConclusionThis case study exemplifies the importance of links and networks between actors in health policymaking. The F&BI influence endangers the primary aim of the SSB tax to protect health. The identified links highlight the normalisation of connections among actors with competing aims and interests toward health, thereby jeopardising attempts to tackle obesity rates.