The Innate Immune Response in DENV- and CHIKV-Infected Placentas and the Consequences for the Fetuses: A Minireview.

Dengue virus (DENV) and chikungunya (CHIKV) are arthropod-borne viruses belonging to the Flaviviridae and Togaviridae families, respectively. Infection by both viruses can lead to a mild indistinct fever or even lead to more severe forms of the diseases, which are characterized by a generalized inflammatory state and multiorgan involvement. Infected mothers are considered a high-risk group due to their immunosuppressed state and the possibility of vertical transmission. Thereby, infection by arboviruses during pregnancy portrays a major public health concern, especially in countries where epidemics of both diseases are regular and public health policies are left aside. Placental involvement during both infections has been already described and the presence of either DENV or CHIKV has been observed in constituent cells of the placenta. In spite of that, there is little knowledge regarding the intrinsic earlier immunological mechanisms that are developed by placental cells in response to infection by both arboviruses. Here, we approach some of the current information available in the literature about the exacerbated presence of cells involved in the innate immune defense of the placenta during DENV and CHIKV infections.

Liver immunopathogenesis in fatal cases of dengue in children: detection of viral antigen, cytokine profile and inflammatory mediators.

Introduction: Dengue virus (DENV), the etiologic agent of dengue fever illness, represents a global public health concern, mainly in tropical and subtropical areas across the globe. It is well known that this acute viral disease can progress to severe hemorrhagic stages in some individuals, however, the immunopathogenic basis of the development of more severe forms by these patients is yet to be fully understood. Objective: In this context, we investigated and characterized the histopathological features as well as the cytokine profile and cell subpopulations present in liver tissues from three fatal cases of DENV in children. Methods: Hematoxylin and Eosin, Periodic Acid Schiff and Picro Sirius Red staining were utilized for the histopathological analysis. Immunohistochemistry assay was performed to characterize the inflammatory response and cell expression patterns. Results: Vascular dysfunctions such as hemorrhage, vascular congestion and edema associated with a mononuclear infiltrate were observedin all three cases. Liver tissues exhibited increased presence of CD68+ and TCD8+ cells as well as high expression of MMP-9, TNF-a, RANTES, VEGFR-2 mediators. Viral replication was confirmed by the detection of NS3 protein. Conclusion: Taken together, these results evidenced key factors that may be involved in the development of severe alterations in liver tissues of children in response to DENV infection.

The Innate Defense in the Zika-Infected Placenta.

Zika virus (ZIKV) is an arthropod-borne virus that belongs to the Flaviviridae family, genus Flavivirus and was first isolated 1947 in Uganda, Africa, from the serum of a sentinel Rhesus monkey. Since its discovery, the virus was responsible for major outbreaks in several different countries, being linked to severe complications in pregnant women, neonatal birth defects and the congenital zika syndrome. Maternal-fetal transmission of ZIKV can occur in all trimesters of pregnancy, and the role of the placenta and its cells in these cases is yet to be fully understood. The decidua basalis and chorionic villi, maternal-fetal components of the placenta, contain a rich immunological infiltrate composed by Hofbauer cells, mastocytes, dendritic cells and macrophages, primary cells of the innate immune response that have a role that still needs to be better investigated in ZIKV infection. Recent studies have already described several histopathological features and the susceptibility and permissiveness of placenta cells to infection by the Zika virus. In this review, we address some of the current knowledge on the innate immune responses against ZIKV, especially in the placenta.

Immunopathology of Renal Tissue in Fatal Cases of Dengue in Children.

Dengue virus (DENV) infection represents a worldwide public health concern and can cause damage to multiple organs, including the kidney. In this work, we investigated the histopathological changes caused by dengue virus infection along with the detection of inflammatory mediators, cytokines, and cell expression patterns in the renal tissue of three fatal cases in children. Hematoxylin and Eosin staining was performed to analyze these histopathological changes. Immunohistochemistry allowed for the detection of immunological inflammatory markers in renal tissues that were quantified and further analyzed. Vascular congestion, edema and glomerular infiltrate were observed in the three cases, in addition to the thickening of the matrix area around the glomerular capillaries and mononuclear infiltrate associated with vascular congestion in the medullary region. The renal tissues exhibited collagen deposition and high expression of CD68+ Mø, CD8+ T, CD56+ cells and MMP-9, and the cytokine profile was mainly characterized by the expression of IFN-γ and TNF-α. Additionally, the expression of RANTES, VEGFR-2 and VCAM-1 were observed. The replication of DENV was evidenced by the detection of the NS3 protein. These results contributed to clarifying the main factors that may be involved in changes in the renal tissue of fatal cases of dengue in children.

SARS-CoV-2 Is Persistent in Placenta and Causes Macroscopic, Histopathological, and Ultrastructural Changes.

SARS-CoV-2 is a virus that belongs to the Betacoronavirus genus of the Coronaviridae family. Other coronaviruses, such as SARS-CoV and MERS-CoV, were associated with complications in pregnant women. Therefore, this study aimed to report the clinical history of five pregnant women infected with SARS-CoV-2 (four symptomatic and one asymptomatic who gave birth to a stillborn child) during the COVID-19 pandemic. They gave birth between August 2020 to January 2021, a period in which there was still no vaccination for COVID-19 in Brazil. In addition, their placental alterations were later investigated, focusing on macroscopic, histopathological, and ultrastructural aspects compared to a prepandemic sample. Three of five placentas presented SARS-CoV-2 RNA detected by RT-PCRq at least two to twenty weeks after primary pregnancy infection symptoms, and SARS-CoV-2 spike protein was detected in all placentas by immunoperoxidase assay. The macroscopic evaluation of the placentas presented congested vascular trunks, massive deposition of fibrin, areas of infarctions, and calcifications. Histopathological analysis showed fibrin deposition, inflammatory infiltrate, necrosis, and blood vessel thrombosis. Ultrastructural aspects of the infected placentas showed a similar pattern of alterations between the samples, with predominant characteristics of apoptosis and detection of virus-like particles. These findings contribute to a better understanding of the consequences of SARS-CoV-2 infection in placental tissue, vertical transmission.

Cytokines and inflammatory mediators: Markers involved in interstitial damage to the pancreas in two dengue fever cases associated with acute pancreatitis.

Dengue viral (DENV) infections can lead to acute pancreatitis and associated tissue damage. This study examined the pancreas from two fatal cases of DENV for histopathological changes as well as for the detection of cytokines, and other inflammatory mediators. Tissue sections were prepared for examination by ultrastructural and histopathological techniques. Sections from the pancreas of non-infected individuals were prepared in parallel as a control. The presence of viral replication in macrophages was detected by co-staining for the proteins NS3 and CD68 by immunofluorescence. Immunohistochemistry was used to detect cells that expressed cytokines and inflammatory mediators to characterize the inflammatory response. Edema, acinar necrosis and fibrosis areas associated with a mononuclear infiltrate were found in infected tissues. The major site of virus replication appeared to be macrophages based on their exclusive presentation of the viral protein NS3. Pancreatic tissues from the infected individuals also displayed increased levels of high mobility group box-1, caspase-3, gelatinase B and tumor necrosis factor alpha compared to controls. The presence of virus replicating macrophages in the pancreas was associated with multiple changes in tissue structure that included elevated levels of cytokines and inflammatory markers that may differentiate acute pancreatitis due to DENV infections from other causes.

Zika Induces Human Placental Damage and Inflammation.

In Brazil, an epidemic of Zika virus (ZIKV) infections was declared in 2015 that coincided with alarming reports of microcephaly in newborns associated with mother infection. Although the virus has placental tropism, changes in the tissue morphology and immunity of infected patients have not yet been elucidated. Here, we investigated the histopathological and ultrastructural changes along with the immunological profile and the BDNF expression in rare placental material. Tissues were obtained in the 2015-2016 Brazilian epidemic, of ten ZIKV-infected patients during pregnancy, five resulting in cases of fetal microcephaly and five non-microcephaly, compared to five non-infected control placentae. Viral antigens were only detected in samples from the ZIKV infected patients. Infected placentae presented histopathological severe damage, while the ultrastructural evaluation showed abnormal organelles, such as clusters of virus-like particles consistent with the ZIKV dimensions. Increased infiltration of CD68+ and TCD8+ cells, expression of MMPs, cytokines (IFN-γ and TNF-α) and other immunological mediators (RANTES/CCL5 and VEGFR-2) confirmed excessive inflammation and vascular permeability dysfunction. An evaluation of BDNF showed a decrease that could modulate neuronal damage in the developing fetus. The placental changes caused by ZIKV are not pathognomonic, however, the data provide evidence that this infection leads to severe placental injury.

Paciente com Chikungunya evoluindo com Síndrome de Angústia Respiratória do Adulto grave / Chikungunya evolving with SRDA Chikungunya patient progressing to severe Adult Respiratory Distress Syndrome

Objetivo: Demonstrar casos de Chikungunya cujos paciente evoluíram com Síndrome da Angústia Respiratória do Adulto. Métodos: Estudo descritivo e documental cuja a amostra foi composta por pacientes internados em um hospital no município de Campos dos Goytacazes, diagnosticados com sorologia IgM positiva para febre do vírus Chikungunya, que evoluíram para Síndrome da Angústia Respiratória do Adulto. Foram feitas análises de prontuários e de imagens radiológicas, além de revisão de literatura. Resultados: Foram incluídos três pacientes no estudo, sendo que um evoluiu ao óbito e os outros dois obtiveram recuperação de suas funções após o quadro agudo da doença. Conclusão: A Chikungunya é uma doença recente em território nacional, com possível evolução para quadros graves, especialmente em sua fase aguda. Por essa razão, estudos aprofundados são necessários para maior conhecimento e entendimento da patologia e de suas factíveis complicações.

Objective: To report cases of Chikungunya that progressed with Acute Respiratory Distress Syndrome. Methods: This is a descriptive and documental study, the sample of which consisted of patients who were hospitalized, in the city of Campos dos Goytacazes, diagnosed with positive IgM serology for Chikungunya fever, which progressed to Acute Respiratory Distress Syndrome. Medical records and radiological images were analyzed, and literature reviewed. Results: Three patients were included in the study, with one of them progressing to death, and the other two having their functions recovered after acute illness. Conclusion: Chikungunya is a recent disease in the national territory, with possible progression to severe conditions, especially on its acute phase. For this reason, in-depth studies are necessary for a better knowledge and understanding of the pathology and its likely complications

Renal Injury in DENV-4 Fatal Cases: Viremia, Immune Response and Cytokine Profile.

Dengue virus (DENV) infections may result in asymptomatic cases or evolve into a severe disease, which involves multiple organ failure. Renal involvement in dengue can be potentially related to an increased mortality. Aiming to better understand the role of DENV in renal injury observed in human fatal cases, post-mortem investigations were performed in four DENV-4 renal autopsies during dengue epidemics in Brazil. Tissues were submitted to histopathology, immunohistochemistry, viral quantification, and characterization of cytokines and inflammatory mediators. Probably due the high viral load, several lesions were observed in the renal tissue, such as diffuse mononuclear infiltration around the glomerulus in the cortical region and in the medullary vessels, hyalinosis arteriolar, lymphocytic infiltrate, increased capsular fibrosis, proximal convoluted tubule (PCT) damage, edema, PCT debris formation, and thickening of the basal vessel membrane. These changes were associated with DENV-4 infection, as confirmed by the presence of DENV-specific NS3 protein, indicative of viral replication. The exacerbated presence of mononuclear cells at several renal tissue sites culminated in the secretion of proinflammatory cytokines and chemokines. Moreover, it can be suggested that the renal tissue injury observed here may have been due to the combination of both high viral load and exacerbated host immune response.

Placental Histopathology and Clinical Presentation of Severe Congenital Zika Syndrome in a Human Immunodeficiency Virus-Exposed Uninfected Infant.

In the large Zika virus (ZIKV) epidemic that occurred in Brazil in 2015, the intrauterine fetal exposure to ZIKV was associated with a significant risk of developing microcephaly and neurological disorders in the infected infants. ZIKV-associated disease has since been reported in 24 countries in the Americas. At present, definitive evidence is lacking regarding the intrauterine co-exposure to ZIKV and other viral infections and whether the coinfection impacts the risk of acquiring either infection or disease severity. Here, we provide evidence of intrauterine exposure to both ZIKV and human immunodeficiency virus (HIV) infections, causing congenital Zika syndrome in an HIV-exposed uninfected infant. Clinical, imaging and laboratory examinations of the pregnant woman and the newborn were performed. Histopathology, ZIKV/HIV-specific immunoassays, and ultrastructural evaluation of the placenta were performed. The Zika-asymptomatic, HIV-positive pregnant woman underwent ultrasounds revealing fetal cerebral ventriculomegaly, microcephaly, and brain atrophy. Her baby girl was born small for gestational age and with the neurological sequelae of congenital Zika syndrome. The evaluation of the abnormally large term placenta revealed severe damage to the maternal decidua and chorionic villi, cells positive for ZIKV-specific antigens but not for HIV antigens, and intracellular membranous clusters of virus-like particles approximately 25 nm in diameter. The rapid progression and severity of the congenital Zika syndrome may be related to the uncontrolled HIV disease in the mother. The poor inflammatory response observed in the placenta may have reduced the inherent risk of mother-to-child transmission of HIV.