Neurologic Alterations Due to Respiratory Virus Infections

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

Contribution of Cytokines to Tissue Damage During Human Respiratory Syncytial Virus Infection

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

Structure and Function of the Human Respiratory Syncytial Virus M2–1 Protein

Human respiratory syncytial virus (HRSV) is a non-segmented negative stranded RNA virus and is recognized as the most important viral agent of lower respiratory tract infection worldwide, responsible for up to 199,000 deaths each year. The only FDA-approved regime to prevent HRSV-mediated disease is pre-exposure administration of a humanized HRSV-specific monoclonal antibody, which although being effective, is not in widespread usage due to its cost. No HRSV vaccine exists and so there remains a strong need for alternative and complementary anti-HRSV therapies. The HRSV M2–1 protein is a transcription factor and represents an attractive target for the development of antiviral compounds, based on its essential role in the viral replication cycle. To this end, a detailed analysis of M2–1 structure and functions will aid in identifying rational targets for structure-based antiviral drug design that can be developed in future translational research. Here we present an overview of the current understanding of the structure and function of HRSV M2–1, drawing on additional information derived from its structural homologues from other related viruses

Análisis de la expresión de CXCR3 y su ligando CXCL10 en cáncer papilar de tiroides

Tesis (Bioquímico, Magíster en Bioquímica)Esta tesis se realizó en el laboratorio de Biología Celular y Farmacología de la Universidad Andrés Bello y fue financiada por el proyecto CONSORCIO TECNÓLOGICO EN BIOMEDICINA CTU06 ÁREA 2El cáncer de tiroides es la patología más común del sistema endocrino y el cáncer papilar de tiroides (CPT) es la manifestación más frecuente, dentro del cáncer tiroideo, con una incidencia entre el 75 al 80%. Si bien el CPT presenta un crecimiento lento y los pacientes que lo padecen tienen una alta sobrevida, éste presenta una alta frecuencia de metástasis a los nódulos linfáticos cervicales, característica que lo sitúa en un tipo de cáncer agresivo. Los factores moleculares involucrados en los procesos que conllevan a la metástasis del CPT a los nódulos linfáticos, se desconocen. Se ha propuesto que existen moléculas con capacidad quimioatractante, que estarían involucradas en conferir la capacidad proliferativa, migratoria e invasiva de las células tumorales hacia los nódulos linfáticos. Existen evidencias que sugieren a las quimioquinas y sus receptores, como aquellas señales específicas en el proceso de metástasis. Entre estas moléculas se encuentran el receptor CXCR3 y su quimioquina CXCL10. Se ha demostrado que CXCR3 y CXCL10 participarían en metástasis a los nódulos linfáticos en cáncer de colon y de mama. Estudios recientes muestran que tanto CXCR3 y CXCL10 se encuentran presentes en el infiltrado linfocitario en enfermedades inflamatorias de la tiroides. Con estos antecedentes planteo la siguiente hipótesis: "El receptor de quimioquinas CXCR3 y su quimioquina CXCL10, se encuentran sobreexpresados en el CPT. Éste aumento en la expresión se correlacionaría con factores clínicos de agresividad tumoral ". Para evaluar esta hipótesis se analizó, mediante PCR en tiempo real, el contenido de ARNrn de CXCR3 en muestras de CPT y tejido control correspondiente a la zona contralateral al tumor .Mediante inmunohistoquírnica se analizó el contenido y localización de las proteínas CXCR3 y CXCL10 en muestras control y con CPT. Se realizó un estudio de correlación entre los parámetros clínicos de agresividad y el contenido de CXCR3. Finalmente se evaluó, en una línea celular de CPT llamada TPC-1, el rol de CXCR3 y CXCL10 en la proliferación tumoral. Los resultados de esta tesis, apoyan parte de nuestra hipótesis, debido a que indican que el ARNm de CXCR3 aumenta 1 ,5 veces en CPT en comparación al tejido control. Este resultado se correlacionó con el aumento del 20% del contenido de CXCR3 y CXCL10 en muestras con CPT en comparación al tejido control. Los parámetros clínicos de agresividad no mostraron relación con respecto al contenido de CXCR3. CXCL10 no estimuló la proliferación de las células TPC-1 a las 24 hrs. de incubación en forma significativa. Basado en estos hallazgos, podemos concluir que en el CPT hay un aumento en la expresión de CXCR3 y su ligando CXCL10. La expresión aumentada de CXCL10 muestra una tendencia a conferir a las células de CPT una mayor capacidad de proliferación, proceso que es de gran importancia en la progresión tumoral.Thyroid cancer is the most common pathology of the endocrine system and the papillary thyroid cancer (PTC) it's the most frequent type of Cancer with an incidence of 75 to 80%. Even though, that PTC has a low growth and the patients that suffer PTC have high survival this type of PTC has a high tendency to develop cervical lymph node metastases. This features makes this type of cancer an aggressive one. The molecular players involved in the processes that lead to metastasis of PTC to the lymph nodes are unknown. It has been proposed that molecules with chemoattractant capacity, could confer to tumor cells the proliferative, migratory and invasive capacity to make metastasis to the lymph nodes. There are evidences in the literature that support that chemokines and their receptors could play this role in metastasis. It has been shown that in colon and breast cancer the receptor CXCR3 and its ligand CXCL10 participate in the metastasis to the lymph nodes. Recent studies have shown that both CXCR3 and CXCL10 are present in the infiltrating lymphocytes in inflammatory diseases of the thyroid gland. Base on this evidences I propose the following hypothesis: "The chemokine receptor CXCR3 and its chemokine CXCL10, are overexpressed in PTC. This overexpression would correlate with clinical factors of tumor aggressiveness ". To test this hypothesis we analyzed by real time PCR the content of CXCR3 mRNA in PTC and control samples that are from the contralateral of side of the tumor tissue from patients with PTC. Immunohistochemistry analysis was done control and PTC samples to study the localization and content of CXCR3 and CXCL10. A correlation analysis was done among the content of CXCR3 in PTC and clinical parameters of aggressiveness. Finally, the role of CXCR3 and CXCL10 in tumor proliferation was evaluted in vitro in the PTC cell line named TPC-I. An increase of 1.5 times CXCR3 mRNA in samples with PTC compared with control tissue. This result correlates with the 20% higher expression of CXCR3 and CXCL10 proteins in PTC compared with control samples. This results support our hypothesis. The clinical parameters of aggressiveness did not correlate with CXCR3 content in PTC. CXCL10 did not increased the proliferation of TPC-I cells at 24 hrs of incubation significantly. Based on these findings, we conclude that exist an increase in the expression of CXCR3 and its ligand CXCL10 in CPT . The increased expression of CXCL10 in CPT has a tendency to confer to CPT the capacity of proliferate, a process that is of great importance in tumor progression

Contribution of Pro-Inflammatory Molecules Induced by Respiratory Virus Infections to Neurological Disorders

Neurobehavioral alterations and cognitive impairment are common phenomena that represent neuropsychiatric disorders and can be triggered by an exacerbated immune response against pathogens, brain injury, or autoimmune diseases. Pro-inflammatory molecules, such as cytokines and chemokines, are produced in the brain by resident cells, mainly by microglia and astrocytes. Brain infiltrating immune cells constitutes another source of these molecules, contributing to an impaired neurological synapse function, affecting typical neurobehavioral and cognitive performance. Currently, there is increasing evidence supporting the notion that behavioral alterations and cognitive impairment can be associated with respiratory viral infections, such as human respiratory syncytial virus, influenza, and SARS-COV-2, which are responsible for endemic, epidemic, or pandemic outbreak mainly in the winter season. This article will review the brain′s pro-inflammatory response due to infection by three highly contagious respiratory viruses that are the leading cause of acute respiratory illness, morbidity, and mobility in infants, immunocompromised and elderly population. How these respiratory viral pathogens induce increased secretion of pro-inflammatory molecules and their relationship with the alterations at a behavioral and cognitive level will be discussed

Potential Neurocognitive Symptoms Due to Respiratory Syncytial Virus Infection

Respiratory infections are among the major public health burdens, especially during winter. Along these lines, the human respiratory syncytial virus (hRSV) is the principal viral agent causing acute lower respiratory tract infections leading to hospitalization. The pulmonary manifestations due to hRSV infection are bronchiolitis and pneumonia, where the population most affected are infants and the elderly. However, recent evidence suggests that hRSV infection can impact the mother and fetus during pregnancy. Studies have indicated that hRSV can infect different cell types from the placenta and even cross the placenta barrier and infect the fetus. In addition, it is known that infections during the gestational period can lead to severe consequences for the development of the fetus due not only to a direct viral infection but also because of maternal immune activation (MIA). Furthermore, it has been described that the development of the central nervous system (CNS) of the fetus can be affected by the inflammatory environment of the uterus caused by viral infections. Increasing evidence supports the notion that hRSV could invade the CNS and infect nervous cells, such as microglia, neurons, and astrocytes, promoting neuroinflammation. Moreover, it has been described that the hRSV infection can provoke neurological manifestations, including cognitive impairment and behavioral alterations. Here, we will review the potential effect of hRSV in brain development and the potential long-term neurological sequelae

Pathophysiological, immunological, and inflammatory features of long COVID

The COVID-19 pandemic continues to cause severe global disruption, resulting in significant excess mortality, overwhelming healthcare systems, and imposing substantial social and economic burdens on nations. While most of the attention and therapeutic efforts have concentrated on the acute phase of the disease, a notable proportion of survivors experience persistent symptoms post-infection clearance. This diverse set of symptoms, loosely categorized as long COVID, presents a potential additional public health crisis. It is estimated that 1 in 5 COVID-19 survivors exhibit clinical manifestations consistent with long COVID. Despite this prevalence, the mechanisms and pathophysiology of long COVID remain poorly understood. Alarmingly, evidence suggests that a significant proportion of cases within this clinical condition develop debilitating or disabling symptoms. Hence, urgent priority should be given to further studies on this condition to equip global public health systems for its management. This review provides an overview of available information on this emerging clinical condition, focusing on the affected individuals’ epidemiology, pathophysiological mechanisms, and immunological and inflammatory profiles

TCR Repertoire Characterization for T Cells Expanded in Response to hRSV Infection in Mice Immunized with a Recombinant BCG Vaccine

T cells play an essential role in the immune response against the human respiratory syncytial virus (hRSV). It has been described that both CD4+ and CD8+ T cells can contribute to the clearance of the virus during an infection. However, for some individuals, such an immune response can lead to an exacerbated and detrimental inflammatory response with high recruitment of neutrophils to the lungs. The receptor of most T cells is a heterodimer consisting of α and β chains (αβTCR) that upon antigen engagement induces the activation of these cells. The αβTCR molecule displays a broad sequence diversity that defines the T cell repertoire of an individual. In our laboratory, a recombinant Bacille Calmette–Guérin (BCG) vaccine expressing the nucleoprotein (N) of hRSV (rBCG-N-hRSV) was developed. Such a vaccine induces T cells with a Th1 polarized phenotype that promote the clearance of hRSV infection without causing inflammatory lung damage. Importantly, as part of this work, the T cell receptor (TCR) repertoire of T cells expanded after hRSV infection in naïve and rBCG-N-hRSV-immunized mice was characterized. A more diverse TCR repertoire was observed in the lungs from rBCG-N-hRSV-immunized as compared to unimmunized hRSV-infected mice, suggesting that vaccination with the recombinant rBCG-N-hRSV vaccine triggers the expansion of T cell populations that recognize more viral epitopes. Furthermore, differential expansion of certain TCRVβ chains was found for hRSV infection (TCRVβ+8.3 and TCRVβ+5.1,5.2) as compared to rBCG-N-hRSV vaccination (TCRVβ+11 and TCRVβ+12). Our findings contribute to better understanding the T cell response during hRSV infection, as well as the functioning of a vaccine that induces a protective T cell immunity against this virus

Respiratory Syncytial Virus: Pathology, therapeutic drugs and prophylaxis

International audienceHuman Respiratory Syncytial Virus (hRSV) is the leading cause of lower respiratory tract diseases, affecting particularly newborns and young children. This virus is able to modulate the immune response, generating a pro-inflammatory environment in the airways that causes obstruction and pulmonary alterations in the infected host. To date, no vaccines are available for human use and the first vaccine that reached clinical trials produced an enhanced hRSV-associated pathology 50 years ago, resulting in the death of two children. Currently, only two therapeutic approaches have been used to treat hRSV infection in high risk children: 1. Palivizumab, a humanized antibody against the F glycoprotein that reduces to half the number of hospitalized cases and 2. Ribavirin, which fails to have a significant therapeutic effect. A major caveat for these approaches is their high economical cost, which highlights the need of new and affordable therapeutic or prophylactic tools to treat or prevents hRSV infection. Accordingly, several efforts are in progress to understand the hRSV-associated pathology and to characterize the immune response elicited by this virus. Currently, preclinical and clinical trials are being conducted to evaluate safety and efficacy of several drugs and vaccines, which have shown promising results. In this article, we discuss the most important advances in the development of drugs and vaccines, which could eventually lead to better strategies to treat or prevent the detrimental inflammation triggered by hRSV infection

Inflammatory damage on respiratory and nervous systems due to hRSV infection

International audienceThe exacerbated inflammatory response elicited by human Respiratory Syncytial Virus (hRSV) in the lungs of infected patients causes a major health burden in the pediatric and elderly population. Since the discovery of hRSV, the exacerbated host immune-inflammatory response triggered by this virus has been extensively studied. In this article, we review the effects on the airways caused by immune cells and cytokines/chemokines secreted during hRSV infection. While molecules such as interferons contribute at controlling viral infection, IL-17 and others produce damage to the hRSV-infected lung. In addition to affecting the airways, hRSV infection can cause significant neurologic abnormalities in the host, such as seizures and encephalopathy. Although the origin of these symptoms remains unclear, studies from patients suffering neurological alteration suggest an involvement of the inflammatory response against hRSV