A Biosafety Level 2 Mouse Model for Studying Betacoronavirus-Induced Acute Lung Damage and Systemic Manifestations.

The emergence of life-threatening zoonotic diseases caused by betacoronaviruses, including the ongoing coronavirus disease 19 (COVID-19) pandemic, has highlighted the need for developing preclinical models mirroring respiratory and systemic pathophysiological manifestations seen in infected humans. Here, we showed that C57BL/6J wild-type mice intranasally inoculated with the murine betacoronavirus murine hepatitis coronavirus 3 (MHV-3) develop a robust inflammatory response leading to acute lung injuries, including alveolar edema, hemorrhage, and fibrin thrombi. Although such histopathological changes seemed to resolve as the infection advanced, they efficiently impaired respiratory function, as the infected mice displayed restricted lung distention and increased respiratory frequency and ventilation. Following respiratory manifestation, the MHV-3 infection became systemic, and a high virus burden could be detected in multiple organs along with morphological changes. The systemic manifestation of MHV-3 infection was also marked by a sharp drop in the number of circulating platelets and lymphocytes, besides the augmented concentration of the proinflammatory cytokines interleukin 1 beta (IL-1ß), IL-6, IL-12, gamma interferon (IFN-γ), and tumor necrosis factor (TNF), thereby mirroring some clinical features observed in moderate and severe cases of COVID-19. Importantly, both respiratory and systemic changes triggered by MHV-3 infection were greatly prevented by blocking TNF signaling, either via genetic or pharmacologic approaches. In line with this, TNF blockage also diminished the infection-mediated release of proinflammatory cytokines and virus replication of human epithelial lung cells infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Collectively, results show that MHV-3 respiratory infection leads to a large range of clinical manifestations in mice and may constitute an attractive, lower-cost, biosafety level 2 (BSL2) in vivo platform for evaluating the respiratory and multiorgan involvement of betacoronavirus infections. IMPORTANCE Mouse models have long been used as valuable in vivo platforms to investigate the pathogenesis of viral infections and effective countermeasures. The natural resistance of mice to the novel betacoronavirus SARS-CoV-2, the causative agent of COVID-19, has launched a race toward the characterization of SARS-CoV-2 infection in other animals (e.g., hamsters, cats, ferrets, bats, and monkeys), as well as adaptation of the mouse model, by modifying either the host or the virus. In the present study, we utilized a natural pathogen of mice, MHV, as a prototype to model betacoronavirus-induced acute lung injure and multiorgan involvement under biosafety level 2 conditions. We showed that C57BL/6J mice intranasally inoculated with MHV-3 develops severe disease, which includes acute lung damage and respiratory distress that precede systemic inflammation and death. Accordingly, the proposed animal model may provide a useful tool for studies regarding betacoronavirus respiratory infection and related diseases.

Implications of VIP and PACAP in Parkinson's Disease: What do we Know So Far?

BACKGROUND: Parkinson's disease is one of the most common neurodegenerative disorders and although its aetiology is not yet fully understood, neuroinflammation has been identified as a key factor in the progression of the disease. Vasoactive intestinal peptide and pituitary adenylate-cyclase activating polypeptide are two neuropeptides that exhibit anti-inflammatory and neuroprotective properties, modulating the production of cytokines and chemokines and the behaviour of immune cells. However, the role of chemokines and cytokines modulated by the endogenous receptors of the peptides varies according to the stage of the disease. METHODS: We present an overview of the relationship between some cytokines and chemokines with vasoactive intestinal peptide, pituitary adenylate cyclase activating polypeptide and their endogenous receptors in the context of Parkinson's disease neuroinflammation and oxidative stress, as well as the modulation of microglial cells by the peptides in this context. RESULTS: The two peptides exhibit neuroprotective and anti-inflammatory properties in models of Parkinson's disease, as they ameliorate cognitive functions, decrease the level of neuroinflammation and promote dopaminergic neuronal survival. The peptides have been tested in a variety of in vivo and in vitro models of Parkinson's disease, demonstrating the potential for therapeutic application. CONCLUSION: More studies are needed to establish the clinical use of vasoactive intestinal peptide and pituitary adenylate cyclase activating polypeptide as safe candidates for treating Parkinson's disease, as the use of the peptides in different stages of the disease could produce different results concerning effectiveness.