Publications by authors named "Alexis M Kalergis"

220 Publications

Crosstalk Between Epithelial Cells, Neurons and Immune Mediators in HSV-1 Skin Infection.

Front Immunol 2021 3;12:662234. Epub 2021 May 3.

Millennium Institute on Immunology and Immunotherapy, Pontificia Universidad Católica de Chile, Santiago, Chile.

Herpes simplex virus type 1 (HSV-1) infection is highly prevalent in humans, with approximately two-thirds of the world population living with this virus. However, only a fraction of those carrying HSV-1, which elicits lifelong infections, are symptomatic. HSV-1 mainly causes lesions in the skin and mucosae but reaches the termini of sensory neurons innervating these tissues and travels in a retrograde manner to the neuron cell body where it establishes persistent infection and remains in a latent state until reactivated by different stimuli. When productive reactivations occur, the virus travels back along axons to the primary infection site, where new rounds of replication are initiated in the skin, in recurrent or secondary infections. During this process, new neuron infections occur. Noteworthy, the mechanisms underlying viral reactivations and the exit of latency are somewhat poorly understood and may be regulated by a crosstalk between the infected neurons and components of the immune system. Here, we review and discuss the immune responses that occur at the skin during primary and recurrent infections by HSV-1, as well as at the interphase of latently-infected neurons. Moreover, we discuss the implications of neuronal signals over the priming and migration of immune cells in the context of HSV-1 infection.
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http://dx.doi.org/10.3389/fimmu.2021.662234DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8126613PMC
May 2021

Characterization of the Anti-Inflammatory Capacity of IL-10-Producing Neutrophils in Response to Infection.

Front Immunol 2021 28;12:638917. Epub 2021 Apr 28.

Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile.

Neutrophils are immune cells classically defined as pro-inflammatory effector cells. However, current accumulated evidence indicates that neutrophils have more versatile immune-modulating properties. During acute lung infection with in mice, interleukin-10 (IL-10) production is required to temper an excessive lung injury and to improve survival, yet the cellular source of IL-10 and the immunomodulatory role of neutrophils during infection remain unknown. Here we show that neutrophils are the main myeloid cells that produce IL-10 in the lungs during the first 48 h of infection. Importantly, assays with bone-marrow derived neutrophils confirmed that IL-10 can be induced by these cells by the direct recognition of pneumococcal antigens. , we identified the recruitment of two neutrophil subpopulations in the lungs following infection, which exhibited clear morphological differences and a distinctive profile of IL-10 production at 48 h post-infection. Furthermore, adoptive transfer of neutrophils from WT mice into IL-10 knockout mice ( ) fully restored IL-10 production in the lungs and reduced lung histopathology. These results suggest that IL-10 production by neutrophils induced by limits lung injury and is important to mediate an effective immune response required for host survival.
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http://dx.doi.org/10.3389/fimmu.2021.638917DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8113954PMC
April 2021

A Recombinant BCG Vaccine Is Safe and Immunogenic in Neonatal Calves and Reduces the Clinical Disease Caused by the Respiratory Syncytial Virus.

Front Immunol 2021 26;12:664212. Epub 2021 Apr 26.

Department of Veterinary Microbiology and Preventative Medicine, Iowa State University, Ames, IA, United States.

The human respiratory syncytial virus (hRSV) constitutes a major health burden, causing millions of hospitalizations in children under five years old worldwide due to acute lower respiratory tract infections. Despite decades of research, licensed vaccines to prevent hRSV are not available. Development of vaccines against hRSV targeting young infants requires ruling out potential vaccine-enhanced disease presentations. To achieve this goal, vaccine testing in proper animal models is essential. A recombinant BCG vaccine that expresses the Nucleoprotein of hRSV (rBCG-N-hRSV) protects mice against hRSV infection, eliciting humoral and cellular immune protection. Further, this vaccine was shown to be safe and immunogenic in human adult volunteers. Here, we evaluated the safety, immunogenicity, and protective efficacy of the rBCG-N-hRSV vaccine in a neonatal bovine RSV calf infection model. Newborn, colostrum-replete Holstein calves were either vaccinated with rBCG-N-hRSV, WT-BCG, or left unvaccinated, and then inoculated aerosol challenge with bRSV strain 375. Vaccination with rBCG-N-hRSV was safe and well-tolerated, with no systemic adverse effects. There was no evidence of vaccine-enhanced disease following bRSV challenge of rBCG-N-hRSV vaccinated animals, suggesting that the vaccine is safe for use in neonates. Vaccination increased virus-specific IgA and virus-neutralization activity in nasal fluid and increased the proliferation of virus- and BCG-specific CD4+ and CD8+ T cells in PBMCs and lymph nodes at 7dpi. Furthermore, rBCG-N-hRSV vaccinated calves developed reduced clinical disease as compared to unvaccinated control calves, although neither pathology nor viral burden were significantly reduced in the lungs. These results suggest that the rBCG-N-hRSV vaccine is safe in neonatal calves and induces protective humoral and cellular immunity against this respiratory virus. These data from a newborn animal model provide further support to the notion that this vaccine approach could be considered as a candidate for infant immunization against RSV.
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http://dx.doi.org/10.3389/fimmu.2021.664212DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8108697PMC
April 2021

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

Pharmaceuticals (Basel) 2021 Apr 8;14(4). Epub 2021 Apr 8.

Departamento de Genética Molecular y Microbiología, Millennium Institute on Immunology and Immunotherapy, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago 8331010, Chile.

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.
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http://dx.doi.org/10.3390/ph14040340DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8068239PMC
April 2021

Host Components That Modulate the Disease Caused by hMPV.

Viruses 2021 03 22;13(3). Epub 2021 Mar 22.

Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Millennium Institute of Immunology and Immunotherapy, Pontificia Universidad Católica de Chile, Santiago 8320000, Chile.

Human metapneumovirus (hMPV) is one of the main pathogens responsible for acute respiratory infections in children up to 5 years of age, contributing substantially to health burden. The worldwide economic and social impact of this virus is significant and must be addressed. The structural components of hMPV (either proteins or genetic material) can be detected by several receptors expressed by host cells through the engagement of pattern recognition receptors. The recognition of the structural components of hMPV can promote the signaling of the immune response to clear the infection, leading to the activation of several pathways, such as those related to the interferon response. Even so, several intrinsic factors are capable of modulating the immune response or directly inhibiting the replication of hMPV. This article will discuss the current knowledge regarding the innate and adaptive immune response during hMPV infections. Accordingly, the host intrinsic components capable of modulating the immune response and the elements capable of restricting viral replication during hMPV infections will be examined.
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http://dx.doi.org/10.3390/v13030519DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8004172PMC
March 2021

Modulation of Endosome Function, Vesicle Trafficking and Autophagy by Human Herpesviruses.

Cells 2021 Mar 4;10(3). Epub 2021 Mar 4.

Millennium Institute on Immunology and Immunotherapy, Santiago 8330025, Chile.

Human herpesviruses are a ubiquitous family of viruses that infect individuals of all ages and are present at a high prevalence worldwide. Herpesviruses are responsible for a broad spectrum of diseases, ranging from skin and mucosal lesions to blindness and life-threatening encephalitis, and some of them, such as Kaposi's sarcoma-associated herpesvirus (KSHV) and Epstein-Barr virus (EBV), are known to be oncogenic. Furthermore, recent studies suggest that some herpesviruses may be associated with developing neurodegenerative diseases. These viruses can establish lifelong infections in the host and remain in a latent state with periodic reactivations. To achieve infection and yield new infectious viral particles, these viruses require and interact with molecular host determinants for supporting their replication and spread. Important sets of cellular factors involved in the lifecycle of herpesviruses are those participating in intracellular membrane trafficking pathways, as well as autophagic-based organelle recycling processes. These cellular processes are required by these viruses for cell entry and exit steps. Here, we review and discuss recent findings related to how herpesviruses exploit vesicular trafficking and autophagy components by using both host and viral gene products to promote the import and export of infectious viral particles from and to the extracellular environment. Understanding how herpesviruses modulate autophagy, endolysosomal and secretory pathways, as well as other prominent trafficking vesicles within the cell, could enable the engineering of novel antiviral therapies to treat these viruses and counteract their negative health effects.
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http://dx.doi.org/10.3390/cells10030542DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7999576PMC
March 2021

Asymptomatic Herpes Simplex Virus Type 1 Infection Causes an Earlier Onset and More Severe Experimental Autoimmune Encephalomyelitis.

Front Immunol 2021 15;12:635257. Epub 2021 Feb 15.

Millennium Institute on Immunology and Immunotherapy, Santiago, Chile.

Multiple sclerosis (MS) is an increasingly prevalent progressive autoimmune and debilitating chronic disease that involves the detrimental recognition of central nervous system (CNS) antigens by the immune system. Although significant progress has been made in the last decades on the biology of MS and the identification of novel therapies to treat its symptoms, the etiology of this disease remains unknown. However, recent studies have suggested that viral infections may contribute to disease onset. Interestingly, a potential association between herpes simplex virus type 1 (HSV-1) infection and MS has been reported, yet a direct relationship among both has not been conclusively demonstrated. Experimental autoimmune encephalomyelitis (EAE) recapitulates several aspects of MS in humans and is widely used to study this disease. Here, we evaluated the effect of asymptomatic brain infection by HSV-1 on the onset and severity of EAE in C57BL/6 mice. We also evaluated the effect of infection with an HSV-1-mutant that is attenuated in neurovirulence and does not cause encephalitis. Importantly, we observed more severe EAE in mice previously infected either, with the wild-type (WT) or the mutant HSV-1, as compared to uninfected control mice. Also, earlier EAE onset was seen after WT virus inoculation. These findings support the notion that a previous exposure to HSV-1 can accelerate and enhance EAE, which suggests a potential contribution of asymptomatic HSV-1 to the onset and severity of MS.
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http://dx.doi.org/10.3389/fimmu.2021.635257DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7928309PMC
February 2021

Immune response during hantavirus diseases: implications for immunotherapies and vaccine design.

Immunology 2021 Jul 18;163(3):262-277. Epub 2021 Mar 18.

Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile.

Orthohantaviruses, previously named hantaviruses, cause two emerging zoonotic diseases: haemorrhagic fever with renal syndrome (HFRS) in Eurasia and hantavirus cardiopulmonary syndrome (HCPS) in the Americas. Overall, over 200 000 cases are registered every year worldwide, with a fatality rate ranging between 0·1% and 15% for HFRS and between 20% and 40% for HCPS. No specific treatment or vaccines have been approved by the U.S. Food and Drug Administration (FDA) to treat or prevent hantavirus-caused syndromes. Currently, little is known about the mechanisms at the basis of hantavirus-induced disease. However, it has been hypothesized that an excessive inflammatory response plays an essential role in the course of the disease. Furthermore, the contributions of the cellular immune response to either viral clearance or pathology have not been fully elucidated. This article discusses recent findings relative to the immune responses elicited to hantaviruses in subjects suffering HFRS or HCPS, highlighting the similarities and differences between these two clinical diseases. Also, we summarize the most recent data about the cellular immune response that could be important for designing new vaccines to prevent this global public health problem.
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http://dx.doi.org/10.1111/imm.13322DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8207335PMC
July 2021

Induction of Trained Immunity by Recombinant Vaccines.

Front Immunol 2020 7;11:611946. Epub 2021 Jan 7.

Millenium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile.

Vaccines represent an important strategy to protect humans against a wide variety of pathogens and have even led to eradicating some diseases. Although every vaccine is developed to induce specific protection for a particular pathogen, some vaccine formulations can also promote trained immunity, which is a non-specific memory-like feature developed by the innate immune system. It is thought that trained immunity can protect against a wide variety of pathogens other than those contained in the vaccine formulation. The non-specific memory of the trained immunity-based vaccines (TIbV) seems beneficial for the immunized individual, as it may represent a powerful strategy that contributes to the control of pathogen outbreaks, reducing morbidity and mortality. A wide variety of respiratory viruses, including respiratory syncytial virus (hRSV) and metapneumovirus (hMPV), cause serious illness in children under 5 years old and the elderly. To address this public health problem, we have developed recombinant BCG vaccines that have shown to be safe and immunogenic against hRSV or hMPV. Besides the induction of specific adaptive immunity against the viral antigens, these vaccines could generate trained immunity against other respiratory pathogens. Here, we discuss some of the features of trained immunity induced by BCG and put forward the notion that recombinant BCGs expressing hRSV or hMPV antigens have the capacity to simultaneously induce specific adaptive immunity and non-specific trained immunity. These recombinant BCG vaccines could be considered as TIbV capable of inducing simultaneously the development of specific protection against hRSV or hMPV, as well as non-specific trained-immunity-based protection against other pathogenic viruses.
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http://dx.doi.org/10.3389/fimmu.2020.611946DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7873984PMC
January 2021

Respiratory viral infections during pregnancy: effects of SARS-CoV-2 and other related viruses over the offspring.

J Dev Orig Health Dis 2021 Feb 2:1-6. Epub 2021 Feb 2.

Departamento de Ciencias Biológicas, Facultad de Ciencias de la Vida, Universidad Andres Bello, Santiago, Chile.

Little is known about the consequences of viral infection for pregnant woman or for the fetus. This issue became important with the appearance of the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). The infection with SARS-CoV-2 causes a respiratory syndrome known as COVID-19. The fast spreading around the world and the fact that without a treatment or vaccine humans are completely exposed, converts emerging viral diseases in a significant risk for pregnant women and their infants. At this time, during SARS-CoV-2 pandemics pregnant women are not considered as a risk population and little is known about the effects of viral infections over the offspring although the amount of emerging evidence showing detrimental effects for the mother and the fetus. This issue highlights the importance to understand the effects of viral infections during pregnancy. In this work, we analyze the effects of viral infections, like SARS-CoV-2 and other related viruses during pregnancy over the mother and the consequences for the offspring.
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http://dx.doi.org/10.1017/S2040174420001373DOI Listing
February 2021

Immune Modulation by Inhibitors of the HO System.

Int J Mol Sci 2020 Dec 30;22(1). Epub 2020 Dec 30.

Millenium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, 8331150 Santiago, Chile.

The heme oxygenase (HO) system involves three isoforms of this enzyme, HO-1, HO-2, and HO-3. The three of them display the same catalytic activity, oxidating the heme group to produce biliverdin, ferrous iron, and carbon monoxide (CO). HO-1 is the isoform most widely studied in proinflammatory diseases because treatments that overexpress this enzyme promote the generation of anti-inflammatory products. However, neonatal jaundice (hyperbilirubinemia) derived from HO overexpression led to the development of inhibitors, such as those based on metaloproto- and meso-porphyrins inhibitors with competitive activity. Further, non-competitive inhibitors have also been identified, such as synthetic and natural imidazole-dioxolane-based, small synthetic molecules, inhibitors of the enzyme regulation pathway, and genetic engineering using iRNA or CRISPR cas9. Despite most of the applications of the HO inhibitors being related to metabolic diseases, the beneficial effects of these molecules in immune-mediated diseases have also emerged. Different medical implications, including cancer, Alzheimer´s disease, and infections, are discussed in this article and as to how the selective inhibition of HO isoforms may contribute to the treatment of these ailments.
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http://dx.doi.org/10.3390/ijms22010294DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7794909PMC
December 2020

A Mineralocorticoid Receptor Deficiency in Myeloid Cells Reduces Liver Steatosis by Impairing Activation of CD8 T Cells in a Nonalcoholic Steatohepatitis Mouse Model.

Front Immunol 2020 16;11:563434. Epub 2020 Dec 16.

Departamento de Gastroenterología, Escuela de Medicina, Pontificia Universidad Catolica de Chile, Santiago, Chile.

Background And Aims: The mineralocorticoid receptor (MR) and renin-angiotensin-aldosterone system (RAAS) are implicated in non-alcoholic liver fatty disease (NALFD). However, inflammatory mechanisms linking MR and RAAS with disease pathology remain unclear. Here we aimed to evaluate the contribution of myeloid MR to the inflammatory response in an animal model of non-alcoholic steatohepatitis (NASH), induced with a methionine-choline deficient diet (MCD).

Methods: Mice with a conditional deficiency of MR in myeloid cells (MyMRKO) and their counterpart floxed control mice (FC) were fed for 18 days with MCD or chow diet, respectively. Serum levels of aminotransferases and aldosterone levels were measured and hepatic steatosis, inflammation and fibrosis scored histologically. Hepatic triglyceride content (HTC) and hepatic mRNA levels of pro-inflammatory pro-fibrotic-associated genes were also assessed. Deep flow cytometric analysis was used to dissect the immune response during NASH development.

Results: MyMRKO mice fed with an MCD diet exhibited reduced hepatic inflammation and lower HTC than controls. Absolute number and percentage of liver inflammatory infiltrate cells (except for CD8 T lymphocytes) were similar in both MyMRKO and control mice fed with an MCD diet but expression of the costimulatory molecule CD86 by dendritic cells and the CD25 activation marker in CD8 T cells were significantly reduced in MyMRKO.

Conclusions: Proinflammatory cells are functionally suppressed in the absence of MR. We hypothesized that loss of MR in myeloid cells reduces lipid accumulation in the liver, in part through modulating the adaptive immune response, which is pivotal for the development of steatosis.
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http://dx.doi.org/10.3389/fimmu.2020.563434DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7772468PMC
May 2021

SARS-CoV-2: Immune Response Elicited by Infection and Development of Vaccines and Treatments.

Front Immunol 2020 11;11:569760. Epub 2020 Dec 11.

Millennium Institute of Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile.

The World Health Organization (WHO) announced in March a pandemic caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). This new infectious disease was named Coronavirus Disease 19 (COVID-19), and at October 2020, more than 39,000,000 cases of SARS-CoV-2 have been detected worldwide leading to near 1,100,000 deaths. Clinically, COVID-19 is characterized by clinical manifestations, such as fever, dry cough, headache, and in more severe cases, respiratory distress. Moreover, neurological-, cardiac-, and renal-related symptoms have also been described. Clinical evidence suggests that migration of immune cells to the affected organs can produce an exacerbated release of proinflammatory mediators that contribute to disease and render the immune response as a major player during the development of the COVID-19 disease. Due to the current sanitary situation, the development of vaccines is imperative. Up to the date, 42 prototypes are being tested in humans in different clinical stages, with 10 vaccine candidates undergoing evaluation in phase III clinical trials. In the same way, the search for an effective treatment to approach the most severe cases is also in constant advancement. Several potential therapies have been tested since COVID-19 was described, including antivirals, antiparasitic and immune modulators. Recently, clinical trials with hydroxychloroquine-a promising drug in the beginning-were suspended. In addition, the Food and Drug Administration (FDA) approved convalescent serum administration as a treatment for SARS-CoV-2 patients. Moreover, monoclonal antibody therapy is also under development to neutralize the virus and prevent infection. In this article, we describe the clinical manifestations and the immunological information available about COVID-19 disease. Furthermore, we discuss current therapies under study and the development of vaccines to prevent this disease.
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http://dx.doi.org/10.3389/fimmu.2020.569760DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7759609PMC
January 2021

Type I Natural Killer T Cells as Key Regulators of the Immune Response to Infectious Diseases.

Clin Microbiol Rev 2021 Mar 23;34(2). Epub 2020 Dec 23.

Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile

SUMMARYThe immune system must work in an orchestrated way to achieve an optimal response upon detection of antigens. The cells comprising the immune response are traditionally divided into two major subsets, innate and adaptive, with particular characteristics for each type. Type I natural killer T (iNKT) cells are defined as innate-like T cells sharing features with both traditional adaptive and innate cells, such as the expression of an invariant T cell receptor (TCR) and several NK receptors. The invariant TCR in iNKT cells interacts with CD1d, a major histocompatibility complex class I (MHC-I)-like molecule. CD1d can bind and present antigens of lipid nature and induce the activation of iNKT cells, leading to the secretion of various cytokines, such as gamma interferon (IFN-γ) and interleukin 4 (IL-4). These cytokines will aid in the activation of other immune cells following stimulation of iNKT cells. Several molecules with the capacity to bind to CD1d have been discovered, including α-galactosylceramide. Likewise, several molecules have been synthesized that are capable of polarizing iNKT cells into different profiles, either pro- or anti-inflammatory. This versatility allows NKT cells to either aid or impair the clearance of pathogens or to even control or increase the symptoms associated with pathogenic infections. Such diverse contributions of NKT cells to infectious diseases are supported by several publications showing either a beneficial or detrimental role of these cells during diseases. In this article, we discuss current data relative to iNKT cells and their features, with an emphasis on their driving role in diseases produced by pathogenic agents in an organ-oriented fashion.
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http://dx.doi.org/10.1128/CMR.00232-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7950362PMC
March 2021

Severe respiratory disease caused by human respiratory syncytial virus impairs language learning during early infancy.

Sci Rep 2020 12 21;10(1):22356. Epub 2020 Dec 21.

Departamento de Enfermedades Infecciosas e Inmunología Pediátrica, Pontificia Universidad Católica de Chile, 8330077, Santiago, Chile.

Human respiratory syncytial virus infection is a leading cause of pediatric morbidity and mortality. A previous murine study showed that during severe acute respiratory infections the virus invades the central nervous system, and that infected animals evolve with long-lasting learning difficulties associated with long-term potentiation impairment in their hippocampus. We hypothesized here that human infants who presented a severe episode of respiratory syncytial virus infection before 6 months of age would develop long-term learning difficulties. We measured the acquisition of the native phoneme repertoire during the first year, a milestone in early human development, comprising a reduction in the sensitivity to the irrelevant nonnative phonetic information and an increase in the sensitivity to the information relevant for the native one. We found that infants with a history of severe respiratory infection by the human respiratory syncytial virus presented poor distinction of native and nonnative phonetic contrasts at 6 months of age, and remained atypically sensitive to nonnative contrasts at 12 months, which associated with weak communicative abilities. Our results uncover previously unknown long-term language learning difficulties associated with a single episode of severe respiratory infection by the human respiratory syncytial virus, which could relate to memory impairments.
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http://dx.doi.org/10.1038/s41598-020-79140-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7752900PMC
December 2020

Evaluation of the chemopreventive potentials of ezetimibe and aspirin in a novel mouse model of gallbladder preneoplasia.

Mol Oncol 2020 11 17;14(11):2834-2852. Epub 2020 Sep 17.

Departamento de Patología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.

Gallbladder stones (cholecystolithiasis) are the main risk factor for gallbladder cancer (GBC), a lethal biliary malignancy with poor survival rates worldwide. Gallbladder stones are thought to damage the gallbladder epithelium and trigger chronic inflammation. Preneoplastic lesions that arise in such an inflammatory microenvironment can eventually develop into invasive carcinoma, through mechanisms that are not fully understood. Here, we developed a novel gallbladder preneoplasia mouse model through the administration of two lithogenic diets (a low- or a high-cholesterol diet) in wild-type C57BL/6 mice over a period of 9 months. Additionally, we evaluated the chemopreventive potentials of the anti-inflammatory drug aspirin and the cholesterol absorption inhibitor ezetimibe. Both lithogenic diets induced early formation of gallbladder stones, together with extensive inflammatory changes and widespread induction of metaplasia, an epithelial adaptation to tissue injury. Dysplastic lesions were presented only in mice fed with high-cholesterol diet (62.5%) in late stages (9th month), and no invasive carcinoma was observed at any stage. The cholesterol absorption inhibitor ezetimibe inhibited gallbladder stone formation and completely prevented the onset of metaplasia and dysplasia in both lithogenic diets, whereas aspirin partially reduced metaplasia development only in the low-cholesterol diet setting. This model recapitulates several of the structural and inflammatory findings observed in human cholecystolithiasic gallbladders, making it relevant for the study of gallbladder carcinogenesis. In addition, our results suggest that the use of cholesterol absorption inhibitors and anti-inflammatory drugs can be evaluated as chemopreventive strategies to reduce the burden of GBC among high-risk populations.
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http://dx.doi.org/10.1002/1878-0261.12766DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7607176PMC
November 2020

The impact of the micronutrient iodine in health and diseases.

Crit Rev Food Sci Nutr 2020 Nov 23:1-14. Epub 2020 Nov 23.

Laboratorio de Endocrino-Inmunología, Facultad de Ciencias de la Vida, Departamento de Ciencias Biológicas, Universidad Andres Bello, Santiago, Chile.

Adequate iodine nutrition is crucial for all mammals by playing his starring role as a component of thyroid hormones, which are key regulators of cellular processes for life such as differentiation, growth, function, and metabolism. Deficiency or excess of iodine in the diet are worldwide highly frequent conditions that are responsible of health problems like hypothyroidism, hypothyroxinemia, goiter, thyroiditis, hyperthyroidism, and autoimmune thyroid diseases among others. The incorporation of iodine in salt or other nutrients resolved the consequences of severe iodine deficiency like goiter, cretinism. However, this strategy in several countries led to other ailments like Hashimoto autoimmune thyroiditis, hyperthyroidism, and hypothyroidism. The goal of this review is to analyze and discuss the different aspects of iodine nutrition for human health comprising its biological role through thyroid hormones, pathogen control, and the regulation of the intestinal microbiota.
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http://dx.doi.org/10.1080/10408398.2020.1843398DOI Listing
November 2020

Contribution of hypoxia inducible factor-1 during viral infections.

Virulence 2020 12;11(1):1482-1500

Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile , Santiago, Chile.

Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that plays critical roles during the cellular response to hypoxia. Under normoxic conditions, its function is tightly regulated by the degradation of its alpha subunit (HIF-1α), which impairs the formation of an active heterodimer in the nucleus that otherwise regulates the expression of numerous genes. Importantly, HIF-1 participates in both cancer and infectious diseases unveiling new therapeutic targets for those ailments. Here, we discuss aspects related to the activation of HIF-1, the effects of this transcription factor over immune system components, as well as the involvement of HIF-1 activity in response to viral infections in humans. Although HIF-1 is currently being assessed in numerous clinical settings as a potential therapy for different diseases, up to date, there are no clinical studies evaluating the pharmacological modulation of this transcription factor as a possible new antiviral treatment. However, based on the available evidence, clinical trials targeting this molecule are likely to occur soon. In this review we discuss the role of HIF-1 in viral immunity, the modulation of HIF-1 by different types of viruses, as well as the effects of HIF-1 over their life cycle and the potential use of HIF-1 as a new target for the treatment of viral infections.
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http://dx.doi.org/10.1080/21505594.2020.1836904DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605355PMC
December 2020

Safety and immunogenicity evaluation of recombinant BCG vaccine against respiratory syncytial virus in a randomized, double-blind, placebo-controlled phase I clinical trial.

EClinicalMedicine 2020 Oct 6;27:100517. Epub 2020 Oct 6.

Millennium Institute on Immunology and Immunotherapy, Pontificia Universidad Católica de Chile, Av. Libertador Bernardo O'Higgins No. 340, Santiago, Chile.

Background: Respiratory syncytial virus (RSV) is responsible for most respiratory tract infections and hospitalizations in infants and represents a significant economic burden for public health. The development of a safe, effective, and affordable vaccine is a priority for the WHO.

Methods: We conducted a double-blinded, escalating-dose phase 1 clinical trial in healthy males aged 18-50 years to evaluate safety, tolerability, and immunogenicity of a recombinant BCG vaccine expressing the nucleoprotein of RSV (rBCG-N-hRSV). Once inclusion criteria were met, volunteers were enrolled in three cohorts in an open and successive design. Each cohort included six volunteers vaccinated with 5 × 10, 5 × 10, or 1 × 10 CFU, as well as two volunteers vaccinated with the full dose of the standard BCG vaccine. This clinical trial (clinicaltrials.gov NCT03213405) was conducted in Santiago, Chile.

Findings: The rBCG-N-RSV vaccine was safe, well-tolerated, and no serious adverse events related to the vaccine were recorded. Serum IgG-antibodies directed against and the N-protein of RSV increased after vaccination, which were capable of neutralizing RSV . Additionally, all volunteers displayed increased cellular response consisting of IFN-γ and IL-2 production against PPD and the N-protein, starting at day 14 and 30 post-vaccination respectively.

Interpretation: The rBCG-N-hRSV vaccine had a good safety profile and induced specific cellular and humoral responses.

Funding: This work was supported by Millennium Institute on Immunology and Immunotherapy from Chile (P09/016), FONDECYT 1190830, and FONDEF D11E1098.
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http://dx.doi.org/10.1016/j.eclinm.2020.100517DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7548429PMC
October 2020

Lung pathology due to hRSV infection impairs blood-brain barrier permeability enabling astrocyte infection and a long-lasting inflammation in the CNS.

Brain Behav Immun 2021 01 24;91:159-171. Epub 2020 Sep 24.

Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Chile; Departamento de Endocrinología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Chile. Electronic address:

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 where it 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 shown by 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.
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http://dx.doi.org/10.1016/j.bbi.2020.09.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7513917PMC
January 2021

Naturally Derived Heme-Oxygenase 1 Inducers and Their Therapeutic Application to Immune-Mediated Diseases.

Front Immunol 2020 23;11:1467. Epub 2020 Jul 23.

Departamento de Genética Molecular y Microbiología, Millenium Institute on Immunology and Immunotherapy, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile.

Heme oxygenase (HO) is the primary antioxidant enzyme involved in heme group degradation. A variety of stimuli triggers the expression of the inducible HO-1 isoform, which is modulated by its substrate and cellular stressors. A major anti-inflammatory role has been assigned to the HO-1 activity. Therefore, in recent years HO-1 induction has been employed as an approach to treating several disorders displaying some immune alterations components, such as exacerbated inflammation or self-reactivity. Many natural compounds have shown to be effective inductors of HO-1 without cytotoxic effects; among them, most are chemicals present in plants used as food, flavoring, and medicine. Here we discuss some naturally derived compounds involved in HO-1 induction, their impact in the immune response modulation, and the beneficial effect in diverse autoimmune disorders. We conclude that the use of some compounds from natural sources able to induce HO-1 is an attractive lifestyle toward promoting human health. This review opens a new outlook on the investigation of naturally derived HO-1 inducers, mainly concerning autoimmunity.
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http://dx.doi.org/10.3389/fimmu.2020.01467DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7396584PMC
April 2021

Pharmacological management of human respiratory syncytial virus infection.

Expert Opin Pharmacother 2020 Dec 18;21(18):2293-2303. Epub 2020 Aug 18.

Millennium Institute on Immunology and Immunotherapy, Departamento De Genética Molecular Y Microbiología, Facultad De Ciencias Biológicas, Pontificia Universidad Católica De Chile , Santiago, Chile.

Introduction: Human respiratory syncytial virus (hRSV) is the primary viral cause of respiratory diseases, leading to bronchiolitis and pneumonia in vulnerable populations. The only current treatment against this virus is palliative, and no efficient and specific vaccine against this pathogen is available.

Areas Covered: The authors describe the disease symptoms caused by hRSV, the economic and social impact of this infection worldwide, and how this infection can be modulated using pharmacological treatments, preventing and limiting its dissemination. The authors discuss the use of antibodies as prophylactic tools -such as palivizumab- and the use of nonspecific drugs to decrease the symptoms associated with the infection -such as bronchodilators, corticoids, and antivirals. They also discuss current vaccine candidates, new prophylactic treatments, and new antivirals options, which are currently being tested.

Expert Opinion: Today, many researchers are focused on developing different strategies to modulate the symptoms induced by hRSV. However, to achieve this, understanding how current treatments are working and their shortcomings needs to be further elucidated.
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http://dx.doi.org/10.1080/14656566.2020.1806821DOI Listing
December 2020

The Role of Dendritic Cells During Infections Caused by Highly Prevalent Viruses.

Front Immunol 2020 16;11:1513. Epub 2020 Jul 16.

Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Instituto Milenio de Inmunología e Inmunoterapia, Pontificia Universidad Católica de Chile, Santiago, Chile.

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.
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http://dx.doi.org/10.3389/fimmu.2020.01513DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7378533PMC
April 2021

Current Insights in the Development of Efficacious Vaccines Against RSV.

Front Immunol 2020 17;11:1507. Epub 2020 Jul 17.

Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Instituto Milenio de Inmunología e Inmunoterapia, Pontificia Universidad Católica de Chile, Santiago, Chile.

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http://dx.doi.org/10.3389/fimmu.2020.01507DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7379152PMC
May 2021

Peripheral Blood Classical Monocytes and Plasma Interleukin 10 Are Associated to Neoadjuvant Chemotherapy Response in Breast Cancer Patients.

Front Immunol 2020 9;11:1413. Epub 2020 Jul 9.

Instituto Milenio de Inmunología e Inmunoterapia, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile.

Worldwide, breast cancer (BC) is the leading cause of cancer death among women. For many patients the most effective treatment is a resection surgery that removes the tumor. Within this subset, patients sometimes receive chemotherapy treatment (CT) prior to surgery aiming to reduce tumor size in order to preserve healthy breast tissue. This strategy is commonly called neoadjuvant chemotherapy (NAC). This approach also offers an opportunity to determine treatment sensitivity, especially in aggressive tumors. Post NAC absence of residual disease is associated to long term survival in BC patients and is used to define the need of adjuvant therapy options. Studies suggest that NAC allows the recognition of tumor antigens by immune cells potentiating the eradication of the tumor. However, the dynamic changes in patients' immune cells under NAC remain unclear. Here, we assessed changes in leucocyte and cytokine profiles in order to determine its association to NAC response in BC patients. Peripheral blood patient samples were taken prior to each NAC cycle to assess the abundance of leukocyte subsets and serum cytokines in 20 patients. These immunological features were associated with clinical outcomes including pathological response. We found a positive correlation between plasma Interleukin 10 (IL-10) and classical monocytes in HER2+ BC patients under NAC. We also observed a trend between increased IL-10 and classical monocytes levels and lower rates of pathologic complete response at the end of NAC. These data support the notion that monocyte subsets and IL-10 could be applied as a novel indicator of NAC efficacy in HER2+ BC patients. Finally, we confirm a key role of the immune system in cancer progression and CT response.
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http://dx.doi.org/10.3389/fimmu.2020.01413DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7363840PMC
April 2021

Human Norovirus Proteins: Implications in the Replicative Cycle, Pathogenesis, and the Host Immune Response.

Front Immunol 2020 16;11:961. Epub 2020 Jun 16.

Departamento de Biotecnología, Facultad de Ciencias del Mar y Recursos Biológicos, Universidad de Antofagasta, Antofagasta, Chile.

Human noroviruses (HuNoVs) are the cause of more than 95% of epidemic non-bacterial gastroenteritis worldwide, with some lethal cases. These viral agents affect people of all ages. However, young children and older adults are the highest-risk groups, being affected with the greatest rate of hospitalizations and morbidity cases. HuNoV structural proteins, especially VP1, have been studied extensively. In contrast, the functions of the non-structural proteins of the virus have been undescribed in depth. Studies on HuNoV non-structural proteins have mostly been made by expressing them individually in cultures, providing insights of their functions and the role that they play in HuNoV replication and pathogenesis. This review examines exhaustively the functions of both HuNoV structural and non-structural proteins and their possible role within the viral replicative cycle and the pathogenesis of the virus. It also highlights recent findings regarding the host's innate and adaptive immune responses against HuNoV, which are of great relevance for diagnostics and vaccine development so as to prevent infections caused by these fastidious viruses.
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http://dx.doi.org/10.3389/fimmu.2020.00961DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7308418PMC
March 2021

Could BCG Vaccination Induce Protective Trained Immunity for SARS-CoV-2?

Front Immunol 2020 8;11:970. Epub 2020 May 8.

Millenium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile.

Trained immunity is a type of non-specific memory-like immune response induced by some pathogens and vaccines, such as BCG, which can confer antigen-independent protection against a wide variety of pathogens. The BCG vaccine has been extensively used to protect against tuberculosis for almost a 100 years. Interestingly, this vaccine reduces children's mortality caused by infections unrelated to infection, a phenomenon thought to be due to the induction of trained immunity. The SARS-CoV-2 pandemic has infected, as of April 22, 2020, 2,623,231 people globally, causing a major public health problem worldwide. Currently, no vaccine or treatment is available to control this pandemic. We analyzed the number of positive cases and deaths in different countries and correlated them with the inclusion of BCG vaccination at birth in their national vaccination programs. Interestingly, those countries where BCG vaccination is given at birth have shown a lower contagion rate and fewer COVID-19-related deaths, suggesting that this vaccine may induce trained immunity that could confer some protection for SARS-CoV-2.
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http://dx.doi.org/10.3389/fimmu.2020.00970DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7227382PMC
July 2020

Innate Immune Components that Regulate the Pathogenesis and Resolution of hRSV and hMPV Infections.

Viruses 2020 06 12;12(6). Epub 2020 Jun 12.

Millennium Institute of Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago 8320000, Chile.

The human respiratory syncytial virus (hRSV) and human Metapneumovirus (hMPV) are two of the leading etiological agents of acute lower respiratory tract infections, which constitute the main cause of mortality in infants. However, there are currently approved vaccines for neither hRSV nor hMPV. Moreover, despite the similarity between the pathology caused by both viruses, the immune response elicited by the host is different in each case. In this review, we discuss how dendritic cells, alveolar macrophages, neutrophils, eosinophils, natural killer cells, innate lymphoid cells, and the complement system regulate both pathogenesis and the resolution of hRSV and hMPV infections. The roles that these cells play during infections by either of these viruses will help us to better understand the illnesses they cause. We also discuss several controversial findings, relative to some of these innate immune components. To better understand the inflammation in the lungs, the role of the respiratory epithelium in the recruitment of innate immune cells is briefly discussed. Finally, we review the main prophylactic strategies and current vaccine candidates against both hRSV and hMPV.
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http://dx.doi.org/10.3390/v12060637DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7354512PMC
June 2020

Development and analytical validation of real-time PCR for the detection of Streptococcus agalactiae in pregnant women.

BMC Pregnancy Childbirth 2020 Jun 9;20(1):352. Epub 2020 Jun 9.

Sección de Biotecnología, Instituto de Salud Pública de Chile, Santiago, Chile.

Background: Group B Streptococcus (GBS) is the leading cause of invasive neonatal infection. In this study, we aimed to evaluate the analytical validation of qualitative real-time polymerase chain reaction (qPCR) as a means to detect GBS.

Methods: Genomic DNA (gDNA) was purified from 12 ATCC bacterial strains, two belonging to GBS and the remainder acting as negative controls. Additionally, gDNA was isolated from 21 strains of GBS from various serotypes (Ia, Ib and II-VIII). All gDNA was used to evaluate the analytical validation of the qPCR method employing a specific Taqman probe. Inclusivity, exclusivity, anticipated reportable range, the limit of detection and robustness were evaluated. The methods used are described in international guidelines and other existing reports. The performance of this qPCR method for detecting GBS was compared to other microbiological methods used with vaginal-rectal samples from pregnant women.

Results: Our qPCR method for detecting GBS was analytically validated. It has a limit of detection of 0.7 GE/μL and 100% analytical specificity. It detects all strains of GBS with the same level of performance as microbiological methods.

Conclusion: Data suggest that this qPCR method performs adequately as a means to detect GBS in vaginal-rectal swabs from pregnant women.
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http://dx.doi.org/10.1186/s12884-020-03038-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7285471PMC
June 2020

Contribution of NKT cells to the immune response and pathogenesis triggered by respiratory viruses.

Virulence 2020 12;11(1):580-593

Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile , Santiago, Chile.

Human respiratory syncytial virus (hRSV) and human metapneumovirus (hMPV) cause acute respiratory tract infections in children worldwide. Natural killer T (NKT) cells are unconventional T lymphocytes, and their TCRs recognize glycolipids bound to the MHC-I-like molecule, CD1d. These cells modulate the inflammatory response in viral infections. Here, we evaluated the contribution of NKT cells in both hRSV and hMPV infections. A significant decrease in the number of neutrophils, eosinophils, and CD103DCs infiltrating to the lungs, as well as an increased production of IFN-γ, were observed upon hRSV-infection in CD1d-deficient BALB/c mice, as compared to wild-type control mice. However, this effect was not observed in the CD1d-deficient BALB/c group, upon infection with hMPV. Importantly, reduced expression of CD1d in CD11b DCs and epithelial cells was found in hRSV -but not hMPV-infected mice. Besides, a reduction in the expression of CD1d in alveolar macrophages of lungs from hRSV- and hMPV-infected mice was found. Such reduction of CD1d expression interfered with NKT cells activation, and consequently IL-2 secretion, as characterized by experiments for both hRSV and hMPV infections. Furthermore, increased numbers of NKT cells recruited to the lungs in response to hRSV- but not hMPV-infection was detected, resulting in a reduction in the expression of IFN-γ and IL-2 by these cells. In conclusion, both hRSV and hMPV might be differently impairing NKT cells function and contributing to the immune response triggered by these viruses.
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http://dx.doi.org/10.1080/21505594.2020.1770492DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7549913PMC
December 2020