Biology subjects

Oliva, J.

Publications and source records attributed to Oliva, J..

6 recordsLinked to original sources

bioRxiv2026

Identification of UCB-9721 as a potent inhibitor of MyoA, the essential class XIV myosin motor of apicomplexan parasites

The virulence of Toxoplasma gondii and other apicomplexan parasites relies on a unique form of cellular motility driven by MyoA, an unconventional class XIV myosin motor protein. To identify new chemical probes for investigating the molecular mechanisms of parasite motility, we screened over 50,000 small molecules for inhibitors of T. gondii MyoA (TgMyoA). The top hit from the screen, UCB-9721, is almost 40-fold more potent as an inhibitor of TgMyoA actin-activated ATPase activity than the previously described TgMyoA inhibitor, KNX-002, and 45-fold more potent at inhibiting parasite motility, with no detectable toxicity towards mammalian cells. UCB-9721 also inhibited the motility and/or growth of the related apicomplexan parasites Plasmodium falciparum, Cryptosporidium parvum, and Babesia duncani, suggesting that this compound will be a useful new chemical probe for studying motility and MyoA function in apicomplexan parasites more broadly. While UCB-9721 and KNX-002 were identified independently, they share a similar chemical scaffold. To determine why UCB-9721 is so much more potent than KNX-002 and to inform future development of this inhibitor class, we undertook comparative molecular docking analyses, targeted TgMyoA mutagenesis, and a directed structure-activity relationship analysis. The results identified the sulfonamide group of UCB-9721 and its hydrogen bond interactions with R249, E275 and a stabilized water network within the TgMyoA binding pocket as key to the compounds increased potency. Further development of UCB-9721, informed by the results presented here, may transform this promising new chemical class into actionable drug development leads against this important group of human and animal pathogens.

microbiology↗

bioRxiv2026

Inhibition of KDM5A/B promotes antitumor innate immune responses in HHV-8/KSHV2 positive B-cell lymphomas

Summary/AbstractHistone methylation is a dynamic and reversible epigenetic modification that critically controls the progression of human diseases, including infections and cancers. Here we reported that histone lysine demethylases (KDMs) in the KDM5 family KDM5A/B play profound roles in suppressing lytic reactivation of oncogenic human herpesvirus 8 (HHV-8), i.e., Kaposis sarcoma-associated herpesvirus (KSHV), as well as antiviral/antitumor innate immune responses in KSHV-infected B-cell lymphomas. We showed that KSHV lytic replication decreases KDM5A/B protein stability by enhancing their K-48 linked polyubiquitination while KDM5A/B depletion facilitates KSHV lytic reactivation. Mechanistic studies illustrated that KDM5A/B associate with KSHV LANA protein and dampen its chromatin association at both KSHV viral lytic promoter and promoters of antitumor immune-responsive genes (IRGs). In comparisons to normal B cells, KDM5A/B expression significantly increased in B-cell lymphoma cells, including KSHV-positive primary effusion lymphoma (PEL). We demonstrated that KDM5A/B inhibition remarkably induces both KSHV lytic reactivation and innate immune responses in PEL cells, resulting in a strong viral oncolytic effect, both in vitro in cell cultures and in vivo using a PEL xenograft mouse model. Overall, our studies identified the novel functions of KDM5A/B to silence KSHV lytic replication and antiviral/antitumor innate immune responses, which can be blocked to benefit the treatment of KSHV-associated B-cell lymphomas that are usually aggressive and difficult to treat.

microbiology↗

bioRxiv2026

Serological investigation of influenza D virus in cats and dogs in Europe

A multicentric European study investigated the seroprevalence of influenza D virus (IDV) in domestic cats and dogs. Serum samples from Italy, France and Ukraine (2015-2018, 2020, 2023-2024) showed no IDV positivity in Italy or in France. In Ukraine, 2.46% of dogs and 0.85% of cats tested positive in 2024.

immunology↗

bioRxiv2024

Developmental regulators drive DUX4 expression in facioscapulohumeral muscular dystrophy

Facioscapulohumeral muscular dystrophy (FSHD) is a progressive muscle wasting disease caused by misexpression of the Double Homeobox 4 (DUX4) transcription factor in skeletal muscle. While epigenetic derepression of D4Z4 macrosatellite repeats is recognized to cause DUX4 misexpression in FSHD, the factors promoting DUX4 transcription are unknown. Here, we show that SIX (sine oculis) transcription factors, critical during embryonic development, muscle differentiation, regeneration and homeostasis, are key regulators of DUX4 expression in FSHD muscle cells. In this study, we demonstrate SIX1, SIX2, and SIX4 to be necessary for induction of DUX4 transcription in differentiating FSHD myotubes in vitro, with SIX1 and SIX2 being the most critical in driving DUX4 expression. Interestingly, DUX4 downregulates SIX RNA levels, suggesting negative feedback regulation. Our findings highlight the involvement of SIX transcription factors in driving the pathogenesis of FSHD by promoting DUX4 and DUX4 target gene expression. TeaserWe identified a family of developmental regulators that promote aberrant DUX4 expression in FSHD differentiating muscle cells.

molecular biology↗

bioRxiv2020

A Newcastle disease virus (NDV) expressing membrane-anchored spike as a cost-effective inactivated SARS-CoV-2 vaccine

A successful SARS-CoV-2 vaccine must be not only safe and protective but must also meet the demand on a global scale at low cost. Using the current influenza virus vaccine production capacity to manufacture an egg-based inactivated Newcastle disease virus (NDV)/SARS-CoV-2 vaccine would meet that challenge. Here, we report pre-clinical evaluations of an inactivated NDV chimera stably expressing the membrane-anchored form of the spike (NDV-S) as a potent COVID-19 vaccine in mice and hamsters. The inactivated NDV-S vaccine was immunogenic, inducing strong binding and/or neutralizing antibodies in both animal models. More importantly, the inactivated NDV-S vaccine protected animals from SARS-CoV-2 infections or significantly attenuated SARS-CoV-2 induced disease. In the presence of an adjuvant, antigen-sparing could be achieved, which would further reduce the cost while maintaining the protective efficacy of the vaccine.

microbiology↗

bioRxiv2020

Newcastle disease virus (NDV) expressing the spike protein of SARS-CoV-2 as vaccine candidate

Due to the lack of protective immunity of humans towards the newly emerged SARS-CoV-2, this virus has caused a massive pandemic across the world resulting in hundreds of thousands of deaths. Thus, a vaccine is urgently needed to contain the spread of the virus. Here, we describe Newcastle disease virus (NDV) vector vaccines expressing the spike protein of SARS-CoV-2 in its wild type or a pre-fusion membrane anchored format. All described NDV vector vaccines grow to high titers in embryonated chicken eggs. In a proof of principle mouse study, we report that the NDV vector vaccines elicit high levels of antibodies that are neutralizing when the vaccine is given intramuscularly. Importantly, these COVID-19 vaccine candidates protect mice from a mouse-adapted SARS-CoV-2 challenge with no detectable viral titer and viral antigen in the lungs. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSThe spike (S) protein of the SARS-CoV-2 is the major antigen that notably induces neutralizing antibodies to block viral entry. Many COVID-19 vaccines are under development, among them viral vectors expressing the S protein of SARS-CoV-2 exhibit many benefits. Viral vector vaccines have the potential of being used as both live or inactivated vaccines and they can induce Th1 and Th2-based immune responses following different immunization regimens. Additionally, viral vector vaccines can be handled under BSL-2 conditions and they grow to high titers in cell cultures or other species restricted-hosts. For a SARS-CoV-2 vaccine, several viral vectors are being tested, such as adenovirus, measles virus and Modified vaccinia Ankara. Added value of this studyThe NDV vector vaccine against SARS-CoV-2 described in this study has advantages similar to those of other viral vector vaccines. But the NDV vector can be amplified in embryonated chicken eggs, which allows for high yields and low costs per dose. Also, the NDV vector is not a human pathogen, therefore the delivery of the foreign antigen would not be compromised by any pre-existing immunity in humans. Finally, NDV has a very good safety record in humans, as it has been used in many oncolytic virus trials. This study provides an important option for a cost-effective SARS-CoV-2 vaccine. Implications of all the available evidenceThis study informs of the value of a viral vector vaccine against SARS-CoV-2. Specifically, for this NDV based SARS-CoV-2 vaccine, the existing egg-based influenza virus vaccine manufactures in the U.S. and worldwide would have the capacity to rapidly produce hundreds of millions of doses to mitigate the consequences of the ongoing COVID-19 pandemic.

microbiology↗