Behavioral alterations in long-term Toxoplasma gondii infection of C57BL/6 mice are associated with neuroinflammation and disruption of the blood brain barrier.

The Apicomplexa protozoan Toxoplasma gondii is a mandatory intracellular parasite and the causative agent of toxoplasmosis. This illness is of medical importance due to its high prevalence worldwide and may cause neurological alterations in immunocompromised persons. In chronically infected immunocompetent individuals, this parasite forms tissue cysts mainly in the brain. In addition, T. gondii infection has been related to mental illnesses such as schizophrenia, bipolar disorder, depression, obsessive-compulsive disorder, as well as mood, personality, and other behavioral changes. In the present study, we evaluated the kinetics of behavioral alterations in a model of chronic infection, assessing anxiety, depression and exploratory behavior, and their relationship with neuroinflammation and parasite cysts in brain tissue areas, blood-brain-barrier (BBB) integrity, and cytokine status in the brain and serum. Adult female C57BL/6 mice were infected by gavage with 5 cysts of the ME-49 type II T. gondii strain, and analyzed as independent groups at 30, 60 and 90 days postinfection (dpi). Anxiety, depressive-like behavior, and hyperactivity were detected in the early (30 dpi) and long-term (60 and 90 dpi) chronic T. gondii infection, in a direct association with the presence of parasite cysts and neuroinflammation, independently of the brain tissue areas, and linked to BBB disruption. These behavioral alterations paralleled the upregulation of expression of tumor necrosis factor (TNF) and CC-chemokines (CCL2/MCP-1, CCL3/MIP-1α, CCL4/MIP-1ß and CCL5/RANTES) in the brain tissue. In addition, increased levels of interferon-gamma (IFNγ), TNF and CCL2/MCP-1 were detected in the peripheral blood, at 30 and 60 dpi. Our data suggest that the persistence of parasite cysts induces sustained neuroinflammation, and BBB disruption, thus allowing leakage of cytokines of circulating plasma into the brain tissue. Therefore, all these factors may contribute to behavioral changes (anxiety, depressive-like behavior, and hyperactivity) in chronic T. gondii infection.

CCR5 Antagonist Maraviroc Inhibits Acute Exacerbation of Lung Inflammation Triggered by Influenza Virus in Cigarette Smoke-Exposed Mice.

Influenza A virus (IAV) infection is a common cause of acute exacerbations of chronic obstructive pulmonary disease (AECOPD). Since macrophage inflammatory protein 1 α, a chemokine that acts through CC-chemokine receptor (CCR)-5, appears elevated in COPD patients' airways, we evaluated whether CCR5 antagonist Maraviroc could inhibit the exacerbated lung inflammatory response noted after IAV H1N1 infection in mice exposed to cigarette smoke (Cs). C57BL/6 mice, subjected or not to Cs inhalation for 11 days, were infected with H1N1 at day 7. Maraviroc (10 mg/kg) or dexamethasone (1 mg/kg) were given in a therapeutic schedule, followed by the analyses of lung function, survival rate, and inflammatory changes. As compared to mice subjected to Cs or H1N1 alone, the insult combination significantly worsened airway obstruction, neutrophil infiltration in the airways, and the survival rate. All changes were sensitive to Maraviroc but not dexamethasone. Maraviroc also reduced the accumulation of neutrophils and macrophages as well as CXCL1 production in the lung tissue, and serum levels of IL-6, whereas comparable viral titers in the lungs were noted in all infected groups. Collectively, these findings suggest that Maraviroc oral treatment could be an effective therapy for controlling acute exacerbations of respiratory diseases such as COPD.