Biology subjects

Pinho, V.

Publications and source records attributed to Pinho, V..

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

Activation of bradykinin receptor B1 promotes desensitization of CXCR2 in neutrophils during severe sepsis and contributes to disease progression in mice.

Sepsis is one of the most common causes of death in intensive care units. The overproduction of proinflammatory mediators during severe sepsis leads to desensitization of CXCR2 on neutrophil, compromising their migration capacity. During early sepsis, kinins are released and bind to bradykinin 1 (BDKRB1) and bradykinin 2 (BDKRB2) receptors, however the involvement of these receptors in sepsis is not yet fully understood. This study demonstrated that the absence of BDKRB2 had no major effects compared to WT mice upon sepsis induction by CLP, suggesting that this receptor plays a minor role under these experimental conditions. In contrast, B1-/- mice showed lower mortality and bacterial recovery compared to WT-CLP mice, which was associated with an increased influx of neutrophils into the peritoneal cavity of CLP-B1-/- mice. WT-CLP mice exhibited increased expression of P110{gamma} and decreased expression of CXCR2 in neutrophils, which was partially reversed in CLP-B1-/- mice. Interestingly, local CXCL1 production was not affected by the absence of BDKRB1. In human neutrophils, LPS induced expression of BDKRB1, and antagonism of this receptor was associated with the restoration of neutrophil recruitment capacity upon stimulation with CXCL8. Furthermore, treatment with a BDKRB1 antagonist in combination with imipenem resulted in a significant improvement in mortality compared to animals treated with the antimicrobial agent alone. Our findings demonstrate that BDKRB1 plays an essential role in exacerbating the inflammatory response and CXCR2 desensitization in neutrophils during CLP-induced severe sepsis, highlighting BDKRB1 as a potential target for sepsis treatment. ImportanceSepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. Despite advances in understanding its pathophysiology, sepsis remains a leading cause of mortality in intensive care units nowadays. Here we found that B1 receptor contributes to neutrophil migration failure during severe sepsis. Inhibition of B1 improves neutrophil migration and bacterial clearance, making it a valuable therapeutic candidate for the treatment of sepsis. More importantly, treatment with a BDKRB1 antagonist in combination with imipenem resulted in a significant improvement in mortality compared to animals treated with the antimicrobial agent alone. These results highlight B1 as a potential treatment target for sepsis, offering improved modulation of the inflammatory response and synergy with antibiotics. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=120 SRC="FIGDIR/small/590213v1_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@1f0401aorg.highwire.dtl.DTLVardef@ab8eorg.highwire.dtl.DTLVardef@1ff0c26org.highwire.dtl.DTLVardef@176b5aa_HPS_FORMAT_FIGEXP M_FIG BDKRB1 activation contributes to sepsis-induced hyperinflammation: (A) BDKRB1 activation contributes to sepsis-induced hyperinflammation: (A) BDKRB1 plays an essential role in the pathogenesis of sepsis, partly by mediating impaired neutrophil migration during the disease. It exerts its effects in myeloid cells by controlling the activation of P13K{gamma} and the expression of CXCR2. (B) BDKRB1 antagonist decreases cytokine production and increases neutrophil influx into the peritoneal cavity, resulting in a reduction in bacterial recovery, highlighting DALBK as a potential adjuvant treatment for sepsis C_FIG

microbiology↗

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↗