Central Nervous System (CNS) infections are one of the most critical problems in public health, as frequently patients exhibit neurologic sequelae. Usually, CNS pathologies are caused by known neurotropic viruses such as measles virus (MV), herpes virus and human immunodeficiency virus (HIV), among others. However, nowadays respiratory viruses have placed themselves as relevant agents responsible for CNS pathologies. Among these neuropathological viruses are the human respiratory syncytial virus (hRSV), the influenza virus (IV), the coronavirus (CoV) and the human metapneumovirus (hMPV). These viral agents are leading causes of acute respiratory infections every year affecting mainly children under 5 years old and also the elderly. Up to date, several reports have described the association between respiratory viral infections with neurological symptoms. The most frequent clinical manifestations described in these patients are febrile or afebrile seizures, status epilepticus, encephalopathies and encephalitis. All these viruses have been found in cerebrospinal fluid (CSF), which suggests that all these pathogens, once in the lungs, can spread throughout the body and eventually reach the CNS. The current knowledge about the mechanisms and routes used by these neuro-invasive viruses remains scarce. In this review article, we describe the most recent findings associated to neurologic complications, along with data about the possible invasion routes of these viruses in humans and their various effects on the CNS, as studied in animal models.

Respiratory syncytial virus (RSV) is the major cause of respiratory illness in infants worldwide. Neurologic alterations, such as seizures and ataxia, have been associated with RSV infection. We demonstrate the presence of RSV proteins and RNA in zones of the brainsuch as the hippocampus, ventromedial hypothalamic nucleus, and brainstem-of infected mice. One month after disease resolution, rodents showed behavioral and cognitive impairment in marble burying (MB) and Morris water maze (MWM) tests. Our data indicate that the learning impairment caused by RSV is a result of a deficient induction of long-term potentiation in the hippocampus of infected animals. In addition, immunization with recombinant bacillus Calmette-Guérin (BCG) expressing RSV nucleoprotein prevented behavioral disorders, corroborating the specific effect of RSV infection over the central nervous system. Our findings provide evidence that RSV can spread from the airways to the central nervous system and cause functional alterations to the brain, both of which can be prevented by proper immunization against RSV.espiratory syncytial virus (RSV) is an enveloped virus with a negative-sensed, single-stranded RNA genome that encodes 11 proteins (1, 2). RSV is the most prevalent pathogen of the Paramyxoviridae family and is the leading cause of lower respiratory tract infection in infants worldwide. RSV infects more than 70% of children in the first year of life, and 100% of children by age 2 years (3, 4). Although most symptoms of RSV infection, such as bronchiolitis and pneumonia, are related to airway inflammation, several central nervous system (CNS) manifestations have been reported in ∼2% of patients with RSVassociated bronchiolitis (5), including seizures, central apnea, lethargy, feeding or swallowing difficulties, muscular tone or strabismus abnormalities, cerebrospinal fluid (CSF) abnormalities, and encephalopathy (6-8). Recently, there has been an increase in the number of case reports on RSV-caused encephalopathy, highlighting the importance of these symptoms (9).Previous clinical studies have suggested an association between neurological symptoms and RSV infection (6,8,10), and other studies have documented the presence of RSV and RSV-specific antibodies in the CSF of patients suffering from severe bronchiolitis (11, 12). However, the pathophysiological mechanism responsible for RSV-caused encephalopathy remains undefined.Despite evidence demonstrating the presence of RSV in the CSF of infected children and CNS alterations resulting from severe respiratory infection by this virus, several aspects of RSV biology regarding the CNS, such as the entrance mechanism, localization, and spreading of RSV in the CNS and its associated tissues, remain obscure. Here, we evaluated whether RSV was able to access the CNS and cause cognitive sequelae using BALB/c mice and Sprague-Dawley rats. Immunofluorescence and quantitative real-time RT-PCR assays revealed the presence of both RSV nucleoprotein (N) and genetic material in the brains of infected anima...

The human respiratory syncytial virus (hRSV) is by far the major cause of acute lower respiratory tract infections (ALRTIs) worldwide in infants and children younger than 2 years. The overwhelming number of hospitalizations due to hRSV-induced ALRTI each year is due, at least in part, to the lack of licensed vaccines against this virus. Thus, hRSV infection is considered a major public health problem and economic burden in most countries. The lung pathology developed in hRSV-infected individuals is characterized by an exacerbated proinflammatory and unbalanced Th2-type immune response. In addition to the adverse effects in airway tissues, hRSV infection can also cause neurologic manifestations in the host, such as seizures and encephalopathy. Although the origins of these extrapulmonary symptoms remain unclear, studies with patients suffering from neurological alterations suggest an involvement of the inflammatory response against hRSV. Furthermore, hRSV has evolved numerous mechanisms to modulate and evade the immune response in the host. Several studies have focused on elucidating the interactions between hRSV virulence factors and the host immune system, to rationally design new vaccines and therapies against this virus. Here, we discuss about the infection, pathology, and immune response triggered by hRSV in the host.

The human respiratory syncytial virus (hRSV) remains one of the leading pathogens causing acute respiratory tract infections (ARTIs) in children younger than 2 years old, worldwide. Hospitalizations during the winter season due to hRSV-induced bronchiolitis and pneumonia increase every year. Despite this, there are no available vaccines to mitigate the health and economic burden caused by hRSV infection. The pathology caused by hRSV induces significant damage to the pulmonary epithelium, due to an excessive inflammatory response at the airways. Cytokines are considered essential players for the establishment and modulation of the immune and inflammatory responses, which can either be beneficial or harmful for the host. The deleterious effect observed upon hRSV infection is mainly due to tissue damage caused by immune cells recruited to the site of infection. This cellular recruitment takes place due to an altered profile of cytokines secreted by epithelial cells. As a result of inflammatory cell recruitment, the amounts of cytokines, such as IL-1, IL-6, IL-10, and CCL5 are further increased, while IL-10 and IFN-γ are decreased. However, additional studies are required to elicit the mediators directly associated with hRSV damage entirely. In addition to the detrimental induction of inflammatory mediators in the respiratory tract caused by hRSV, reports indicating alterations in the central nervous system (CNS) have been published. Indeed, elevated levels of IL-6, IL-8 (CXCL8), CCL2, and CCL4 have been reported in cerebrospinal fluid from patients with severe bronchiolitis and hRSV-associated encephalopathy. In this review article, we provide an in-depth analysis of the role of cytokines secreted upon hRSV infection and their potentially harmful contribution to tissue damage of the respiratory tract and the CNS.

Dendritic cells (DCs) are a type of innate immune cells with major relevance in the establishment of an adaptive response, as they are responsible for the activation of lymphocytes. Since their discovery, several reports of their role during infectious diseases have been performed, highlighting their functions and their mechanisms of action. DCs can be categorized into different subsets, and each of these subsets expresses a wide arrange of receptors and molecules that aid them in the clearance of invading pathogens. Interferon (IFN) is a cytokine-a molecule of protein origin-strongly associated with antiviral immune responses. This cytokine is secreted by different cell types and is fundamental in the modulation of both innate and adaptive immune responses against viral infections. Particularly, DCs are one of the most important immune cells that produce IFN, with type I IFNs (α and β) highlighting as the most important, as they are associated with viral clearance. Type I IFN secretion can be induced via different pathways, activated by various components of the virus, such as surface proteins or genetic material. These molecules can trigger the activation of the IFN pathway trough surface receptors, including IFNAR, TLR4, or some intracellular receptors, such as TLR7, TLR9, and TLR3. Here, we discuss various types of dendritic cells found in humans and mice; their contribution to the activation of the antiviral response triggered by the secretion of IFN, through different routes of the induction for this important antiviral cytokine; and as to how DCs are involved in human infections that are considered highly frequent nowadays.

The human respiratory syncytial virus (hRSV) is the most common infectious agent that affects children before two years of age. hRSV outbreaks cause a significant increase in hospitalizations during the winter season associated with bronchiolitis and pneumonia. Recently, neurologic alterations have been associated with hRSV infection in children, which include seizures, central apnea, and encephalopathy. Also, hRSV RNA has been detected in cerebrospinal fluids (CSF) from patients with neurological symptoms after hRSV infection. Additionally, previous studies have shown that hRSV can be detected in the lungs and brains of mice exposed to the virus, yet the potential effects of hRSV infection within the central nervous system (CNS) remain unknown. Here, using a murine model for hRSV infection, we show a significant behavior alteration in these animals, up to two months after the virus exposure, as shown in marble-burying tests. hRSV infection also produced the expression of cytokines within the brain, such as IL-4, IL-10, and CCL2. We found that hRSV infection alters the permeability of the blood-brain barrier (BBB) in mice, allowing the trespassing of macromolecules and leading to increased infiltration of immune cells into the CNS together with an increased expression of pro-inflammatory cytokines in the brain. Finally, we show that hRSV infects murine astrocytes both, in vitro and in vivo . We identified the presence of hRSV in the brain cortex and colocalizes with vWF, MAP-2, Iba-1, and GFAP, which are considered markers for endothelial cells, neurons, microglia, and astrocyte, respectively. hRSV-infected murine astrocytes displayed increased production of nitric oxide (NO) and TNF-α. Our results suggest that hRSV infection alters the BBB permeability to macromolecules and immune cells and induces CNS inflammation which can contribute to the behavioral alterations observed on infected mice. A better understanding of the neuropathy caused by hRSV could help to reduce the potential detrimental effects on the CNS in hRSV-infected patients.

The mononuclear phagocyte system (MPS) comprises of monocytes, macrophages (MΦ), and dendritic cells (DCs). MPS is part of the first line of immune defense against a wide range of pathogens, including viruses, such as the human respiratory syncytial virus (hRSV). The hRSV is an enveloped virus that belongs to the Pneumoviridae family, Orthopneumovirus genus. This virus is the main etiological agent causing severe acute lower respiratory tract infection, especially in infants, children and the elderly. Human RSV can cause bronchiolitis and pneumonia and it has also been implicated in the development of recurrent wheezing and asthma. Monocytes, MΦ, and DCs significantly contribute to acute inflammation during hRSV-induced bronchiolitis and asthma exacerbation. Furthermore, these cells seem to be an important component for the association between hRSV and reactive airway disease. After hRSV infection, the first cells encountered by the virus are respiratory epithelial cells, alveolar macrophages (AMs), DCs, and monocytes in the airways. Because AMs constitute the predominant cell population at the alveolar space in healthy subjects, these cells work as major innate sentinels for the recognition of pathogens. Although adaptive immunity is crucial for viral clearance, AMs are required for the early immune response against hRSV, promoting viral clearance and controlling immunopathology. Furthermore, exposure to hRSV may affect the phagocytic and microbicidal capacity of monocytes and MΦs against other infectious agents. Finally, different studies have addressed the roles of different DC subsets during infection by hRSV. In this review article, we discuss the role of the lung MPS during hRSV infection and their involvement in the development of bronchiolitis.

No abstract