Biology subjects

Goncalves, M. R.

Publications and source records attributed to Goncalves, M. R..

3 recordsLinked to original sources

bioRxiv2026

CORONAVIRUS INFECTION ACCELERATES EXPERIMENTAL OSTEOPOROSIS THROUGH THE ACTIVATION OF OSTEOCLASTS

Coronavirus infection is increasingly associated with systemic inflammation and extrapulmonary sequelae, including bone loss. However, the impact of coronavirus infection on hosts with pre-existing osteoporosis remains poorly understood. Here, we investigated the effects of infection with the murine coronavirus MHV-A59 on bone remodeling in a mouse model of ovariectomy-induced osteoporosis. Female C57BL/6 mice underwent ovariectomy (OVX) or sham surgery and, after establishment of the osteoporotic phenotype (14 days post-surgery), were intranasally infected with MHV-A59. Clinical, inflammatory, and femur parameters were evaluated throughout acute and chronic phases of infection using histopathological, micro-computed tomography and biochemical analyses. In vitro infection assays with bone-marrow derived macrophages (BMDM) and BMDM-differentiated osteoclasts from Sham and OVX mice were also performed. MHV-A59 induced comparable lung inflammation in Sham and OVX mice. In contrast, infection accelerated bone resorption in OVX mice during the acute phase (5 dpi), whereas in non-osteoporotic animals, infection induced significant bone loss at later stages (60 dpi). These alterations were associated with increased osteoclast differentiation and activity and with elevated levels of osteometabolic and inflammatory mediators, including RANKL, CCL2, CCL3, CCL5, and TGF-{beta}1. In vitro, MHV-A59 infection enhanced the expression of osteoclast-associated markers, including Rank, Traf6, Nfac1, and cathepsin K, and inflammatory mediators by BMDM and osteoclasts. Importantly, these responses were significantly more pronounced in cells derived from OVX mice. Collectively, our findings demonstrate that coronavirus infection promotes bone resorption and accelerates early bone loss in the context of estrogen deficiency, highlighting enhanced osteoclast activity as a potential mechanism underlying this infection-induced phenotype.

cell biology↗

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↗

bioRxiv2023

Essential role of the CCL2-CCR2 axis in Mayaro virus-induced disease

Mayaro virus (MAYV) is an emerging arbovirus member of the Togaviridae family and Alphavirus genus. MAYV infection causes an acute febrile illness accompanied by persistent polyarthralgia and myalgia. Understanding the mechanisms involved in arthritis caused by alphaviruses is necessary to develop specific therapies. In this work, we investigated the role of the CCL2/CCR2 axis in the pathogenesis of MAYV-induced disease. For this, WT C57BL/6J and CCR2-/- mice were infected with MAYV subcutaneously and evaluated for disease development. MAYV infection induced an acute inflammatory disease in WT mice. The immune response profile was characterized by an increase in the production of inflammatory mediators, such as IL-6, TNF and CCL2. Higher levels of CCL2 at the local and systemic levels, was followed by significant recruitment of CCR2+ macrophages and a cellular response orchestrated by these cells. CCR2-/- mice showed an increase in CXCL-1 levels, followed by a replacement of the macrophage inflammatory infiltrate by neutrophils. Additionally, absence of the CCR2 receptor protected mice from bone loss induced by MAYV. Accordingly, the silencing of CCL2 chemokine expression in vivo and the pharmacological blockade of CCR2 promoted a partial improvement in disease. Cell culture data support the mechanism underlying MAYVs bone pathology in which: i) MAYV infection promoted a pro-osteoclastogenic microenvironment mediated by IL-6, TNF and CCL2 and ii) migration of osteoclast precursors was dependent on the CCR2/CCL2 axis. Overall, these data contribute to the understanding of the pathophysiology of MAYV infection and to the identification future of specific therapeutic targets in MAYV-induced disease. ImportanceThis work demonstrates the role of the CCL2/CCR2 axis in MAYV-induced disease. Infection of WT C57BL/6J and CCR2-/- mice was associated with high levels of CCL2, an important chemoattractant involved in the recruitment of macrophages, the main precursor of osteoclasts. In the absence of the CCR2 receptor there is a mitigation of macrophage migration to the target organs of infection and protection of these mice against bone loss induced by MAYV infection. Much evidence has shown that host immune response factors contribute significantly to the tissue damage associated to alfavirus infections. Thus, this work highlights molecular and cellular targets involved in the pathogenesis of arthritis triggered by MAYV, and identifies novel therapeutic possibilities directed to the host inflammatory response unleashed by MAYV.

cell biology↗