Biology subjects

Fonseca, T.

Publications and source records attributed to Fonseca, T..

3 recordsLinked to original sources

bioRxiv2025

Annexin A1 as a key modulator of lung inflammation during coronavirus infections

Exacerbated inflammation is a major contributor to tissue damage and mortality in infectious diseases, including SARS-CoV-2. The resolution phase of inflammation is critical for restoring tissue homeostasis following an injury. Annexin A1 (AnxA1) is a ubiquitous protein that plays a fundamental role in the resolution of inflammation, including in preclinical models of infectious disease. Here, we investigated the role of AnxA1 in coronavirus infection and its potential as a host-targeted therapeutic strategy against SARS-CoV-2. Wild-type (WT) and AnxA1 knockout (AnxA1KO) mice were intranasally infected with the murine betacoronavirus MHV-3 to study the endogenous role of AnxA1. Immunohistochemistry and Western blot analyses in the lungs of MHV-3-infected mice revealed increased AnxA1 expression and its cleavage, which was associated with neutrophilic infiltration (Ly6G+ cells) mainly in peribronchiolar and perivascular regions. AnxA1-deficient mice exhibited higher neutrophilic infiltration and lung damage, alongside increased CXCL1 production in the lungs, when compared to WT-infected mice. In a murine model of SARS-CoV-2 infection in K18-hACE2 mice, we found increased AnxA1 cleavage associated with lung inflammation. Treatment of SARS-CoV-2-infected K18-hACE2 mice with the AnxA1-mimetic peptide, Ac2-26, reduced lung damage and lethality, without altering the host ability to deal with viral replication. Notably, Ac2-26-treated mice exhibited similar levels of protection to that afforded by the nucleotide analogue Remdesivir, following SARS-CoV-2 infection. Our findings highlight the protective role of the endogenous AnxA1 in mitigating coronavirus-induced lung inflammation and underscore the therapeutic potential of AnxA1 mimetic Ac2-26 as a host-targeted therapy against SARS-CoV-2.

immunology↗

bioRxiv2024

Neuropsychiatric sequelae in an experimental model of post-COVID syndrome in mice

The global impact of the COVID-19 pandemic has been unprecedented, and presently, the world is facing a new challenge known as Post-COVID syndrome (PCS). Current estimates suggest that more than 65 million people are grappling with PCS, encompassing several manifestations, including pulmonary, musculoskeletal, metabolic, and neuropsychiatric sequelae (cognitive and behavioral). The mechanisms underlying PCS remain unclear. The present study aimed to: (i) comprehensively characterize the acute effects of pulmonary inoculation of the betacoronavirus MHV-A59 in immunocompetent mice at clinical, cellular, and molecular levels; (ii) examine potential acute and long-term pulmonary, musculoskeletal, and neuropsychiatric sequelae induced by the betacoronavirus MHV-A59; and to (iii) assess sex-specific differences. Male and female C57Bl/6 mice were initially inoculated with varying viral titers (3x103 to 3x105 PFU/30 L) of the betacoronavirus MHV-A59 via the intranasal route to define the highest inoculum capable of inducing disease without causing mortality. Further experiments were conducted with the 3x104 PFU inoculum. Mice exhibited an altered neutrophil/lymphocyte ratio in the blood in the 2nd and 5th day post-infection (dpi). Marked lung lesions were characterized by hyperplasia of the alveolar walls, infiltration of polymorphonuclear leukocytes (PMN) and mononuclear leukocytes, hemorrhage, increased concentrations of CCL2, CCL3, CCL5, and CXCL1 chemokines, as well as high viral titers until the 5th dpi. While these lung inflammatory signs resolved, other manifestations were observed up to the 60 dpi, including mild brain lesions with gliosis and hyperemic blood vessels, neuromuscular dysfunctions, anhedonic-like behavior, deficits in spatial working memory, and short-term aversive memory. These musculoskeletal and neuropsychiatric complications were exclusive to female mice and were prevented after ovariectomy. In summary, our study describes for the first time a novel sex-dependent model of PCS focused on neuropsychiatric and musculoskeletal disorders. This model provides a unique platform for future investigations regarding the effects of acute therapeutic interventions on the long-term sequelae unleashed by betacoronavirus infection.

neuroscience↗

bioRxiv2018

Photodynamic therapy effect on the ultrastructure of Trichomonas vaginalis trophozoites and their effectiveness in experimentally infected animals.

BackgroundTrichomonas vaginalis is an amitochondrial parasitic that causes human trichomoniasis, the most common non-viral sexually transmitted infection in the world. The therapy of choice is metronidazole (MTZ). Despite MTZ effectiveness, resistant cases are becoming more frequent. Another point to emphasize are the side effects that may result in treatment discontinuation, leading to further spread of infection and emergence of resistant strains. This scenario reveals the need to develop new therapeutic options. Photodynamic therapy (PDT) is an experimental treatment that involves the activation of photosensitive substances and the generation of cytotoxic oxygen species and free radicals to promote the selective destruction of target tissues. A previous study, from our group, identified an excellent in vitro PDT activity using methylene blue and light emitting diode against MTZ sensitive and resistant strains of T. vaginalis. The aim of this study was to evaluate the efficacy of PDT in vivo and clarify its high trichomonicidal potential by evaluating its action upon T. vaginalis trophozoites through transmission electron microscopy (TEM).\n\nMethodologySeven-week-old female Balb/c mice were infected intravaginally with T. vaginalis trophozoites. On the third day of infection, methylene blue was introduced into the vaginal canal of the animals, which then received 68.1 J / cm2 of radiation for 35.6 sec. Control groups without infection and infected, treated with metronidazole were also included for comparison. Twenty-four hours after treatment the vaginal canal of the animals was scraped and the samples processed by the immunocytochemistry technique. After in vitro photodynamic treatment, T. vaginalis trophozoites were processed for TEM. Ultrathin sections were collected in 400-mesh copper grids, contrasted with 5% uranyl acetate and 3% lead citrate, in aqueous solutions for 20 and 5 min., respectively and observed in a Jeol JEM 230 transmission electron microscope.\n\nResultsTEM showed morphological changes such as centripetal displacement of organelles, cannibalism, hydrogenosomal damage, intense cytoplasmic vacuolization, dilated endoplasmic reticulum cisternae and membrane discontinuity, in both resistant and sensitive strains, suggesting that trichomonicidal activity is mainly due to necrosis.\n\nPDT significantly reduced infection in animals treated with a single therapy session, compared to control groups, being statistically as efficient as MTZ.\n\nConclusionsOur results demonstrated high trichomonicidal activity of PDT with morphological alterations compatible with necrosis. Therefore these results indicate that PDT represents not only an alternative therapy for refractory trichomoniasis, but also routinely for this important neglected parasitic disease.

pharmacology and toxicology↗