Alterações neuroquímicas e comportamentais induzidas pela infecção por coronavírus, tanto no contexto agudo quanto nas sequelas

Abstract

COVID-19 (Coronavirus Disease-2019), initially described as a predominantly respiratory disease, has proven to be a multisystemic condition. The progression to severe forms of the disease has been attributed both to the exacerbated host immune response, resulting in the so- called "cytokine storm", and to widespread viral replication in several tissues due to the ubiquitous expression of angiotensin-converting enzyme 2 (ACE-2), used as a viral receptor. In the central nervous system (CNS), neuroinflammation stands out for its relevance in the etiopathogenesis of neuropsychiatric disorders. In this study, we used models of intranasal infection by murine betacoronaviruses (MHV-3 and MHV-A59) to investigate changes associated with acute and subacute/chronic infection, respectively. MHV-3 was able to infect and replicate in the CNS, inducing severe acute changes such as imbalance in the production of inflammatory mediators, increased glutamate release and calcium influx, mild histopathological changes, and behavioral deficits such as anhedonia, anxiety-like behavior, and motor impairment. MHV-A59, a pulmonary tropism virus that causes self-resolving disease, was used as a tool to study neuropsychiatric sequelae of long COVID. The results indicated that only females infected with MHV-A59 presented neuropsychiatric changes. These findings suggest that post-infection changes are directly related to biological sex and the influence of sex hormones. In this sense, estradiol, follicle-stimulating hormone (FSH), and testosterone were evaluated. These hormones were altered during the kinetics of infection, but we highlight that testosterone levels remained reduced throughout the study period. As demonstrated in the literature, this reduction is directly associated with the symptoms of long COVID in both sexes. Ovariectomy in infected females resulted in significant improvement in behavioral sequelae and brain histopathological score. In this context, the proof of concept consisted of treatment with the anti-inflammatory and pro-resolution peptide angiotensin (1-7), administered in the acute phase of infection, proving to be effective in preventing the neuropsychiatric sequelae previously observed. Therefore, the murine models of MHV-3 and MHV-A59 mimic fundamental aspects of severe acute COVID-19 and long COVID, respectively, providing robust preclinical platforms for pathogenesis studies and development of therapeutic interventions.