Biology subjects

Proenca-Modena, J. L.

Publications and source records attributed to Proenca-Modena, J. L..

4 recordsLinked to original sources

bioRxiv2026

Acute IFN-gamma responses drive sensory neuron injury and chronic pain after chikungunya virus infection

Chikungunya virus (CHIKV) is a mosquito-borne alphavirus that causes acute and chronic musculoskeletal disease characterized by often debilitating pain; however, the mechanisms associated with the pain remain understudied. Here, we used an experimental mouse model and patients to investigate the role of interferon-{gamma} (IFN-{gamma}) in the pain during chronic inflammation after CHIKV infection. Our data show that CHIKV induces sustained joint inflammation, cartilage catabolism, and sensory neuron injury signatures, including Atf3 upregulation, but lacks detectable viral dissemination to dorsal root ganglia. We found that IFN-{gamma} expression was higher in CHIKV-infected joints, and direct IFN-{gamma} administration recapitulates mechanical hypersensitivity and neuronal stress independently of joint degeneration. Genetic or pharmacological disruption of IFN-{gamma} signalling prevented CHIKV-induced pain and neuronal stress without altering viral burden, demonstrating that IFN-{gamma} is required for both sensory dysfunction and joint pathology. By stratifying CHIKV-infected mice based on long-term nociceptive profiles, we show that persistent-pain subgroup characterized by elevated acute-phase systemic IFN-{gamma} and chronic peripheral neuropathic features. These findings were confirmed in human patients, where acute-phase IFN-{gamma} levels distinguished those who developed chronic arthralgia from those who recovered. Overall, our findings demonstrate that persistent post-CHIKV pain is driven by an IFN-{gamma}-mediated neuroimmune mechanism.

microbiology↗

bioRxiv2021

Characterization of the interaction between SARS-CoV-2 Membrane Protein and Proliferating Cell Nuclear Antigen (PCNA) as a Potential Therapeutic Target

SARS-CoV-2 is an emerging virus from the Coronaviridae family and is responsible for the ongoing COVID-19 pandemic. In this work, we explored the previously reported SARS-CoV-2 structural membrane protein (M) interaction with human Proliferating Cell Nuclear Antigen (PCNA). The M protein is responsible for maintaining virion shape, and PCNA is a marker of DNA damage which is essential for DNA replication and repair. We validated the M PCNA interaction through immunoprecipitation, immunofluorescence co-localization, and a PLA assay. In cells infected with SARS-CoV-2 or transfected with M protein, using immunofluorescence and cell fractioning, we documented a reallocation of PCNA from the nucleus to the cytoplasm and the increase of PCNA and {gamma}H2AX (another DNA damage marker) expression. We also observed an increase of PCNA and {gamma}H2AX expression in the lung of a COVID-19 patient by immunohistochemistry. In addition, the inhibition of PCNA translocation by PCNA I1 and Verdinexor led to a reduction of plaque formation in an in vitro assay. We, therefore, propose that the transport of PCNA to the cytoplasm and its association with M could be a virus strategy to manipulate cell functions and may be considered a target for COVID-19 therapy.

molecular biology↗

bioRxiv2021

Zika Virus Infection of Murine and Human Neutrophils and their Function as Trojan Horses to the Placenta

ZIKV is a 11Kb positive stranded flavivirus transmitted by infected Aedes aegypti and by sexual intercourse. After a short period of viremia of 5-7 days, the virus is cleared, and infection resolved in 80% of individuals. However, around 27% of the fetuses from pregnant infected mothers may develop several fetal brain and ocular pathology. Here we show that murine and peripheral blood human neutrophils support ZIKV infection and replication both in vitro and in vivo, which may correlate to the facilitation of vertical transmission. ZIKV did not interfere with cell viability, neither induced ROS production nor the release of NETs by infected neutrophils. Also, ZIKV infection of neutrophils did not trigger a pro-inflammatory profile, as evidenced by qPCR and proteomic analysis. Interestingly, ZIKV-infected neutrophils were isolated from the placenta were highly infected. The transference of in vitro ZIKV-infected neutrophils to pregnant female mice favored the transference of viral particles to the fetus. Conversely, neutrophil depletion with monoclonal antibodies reduced fetal viral loads whereas the treatment with recombinant G-CSF has the opposite effect. In summary, although it has already been shown that circulating monocytes harbor ZIKV, to our knowledge, this is the first report demonstrating the role of neutrophils during ZIKV infection, and most important, that it may act as a trojan horse to placental tissue directly impacting the pathogenesis of congenital syndrome.

immunology↗

bioRxiv2021

Gas6 drives Zika virus-induced neurological complications in humans and congenital syndrome in immunocompetent mice

Zika virus (ZIKV) has the ability to cross placental and brain barriers, causing congenital malformations in neonates and neurological disorders in adults. However, the pathogenic mechanisms of ZIKV-induced neurological complications in adults and congenital malformations remain unknown. Gas6 is a soluble TAM receptor ligand able to promote flavivirus internalization and downregulation of immune responses. Here we demonstrate high Gas6 levels in the serum of patients with neurological complications which correlated with downregulation of genes associated with the type I IFN responses as consequence of Socs1 upregulation. Gas6 gamma-carboxylation is essential for ZIKV replication in monocytes, the main source of this protein. Gas6 also facilitates ZIKV replication in adult immunocompetent mice enabled susceptibility to transplacental infection and congenital malformations. Our data thus indicate that ZIKV promotes the upregulation of its ligand Gas6, which contributes to viral infectivity and drives the development of severe adverse outcomes during ZIKV infection.

microbiology↗