Pathogenesis Of Infectious Diseases Research Articles

Racial Health Disparity and COVID-19.

The infection by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and resultant coronavirus diseases-19 (COVID-19) disproportionally affects minorities, especially African Americans (AA) compared to the Caucasian population. The AA population is disproportionally affected by COVID-19, in part, because they have high prevalence of underlying conditions such as obesity, diabetes, and hypertension, which are known to exacerbate not only kidney diseases, but also COVID-19. Further, a decreased adherence to COVID-19 guidelines among tobacco smokers could result in increased infection, inflammation, reduced immune response, and lungs damage, leading to more severe form of COVID-19. As a result of high prevalence of underlying conditions that cause kidney diseases in the AA population coupled with tobacco smoking make the AA population vulnerable to severe form of both COVID-19 and kidney diseases. In this review, we describe how tobacco smoking interact with SARS-CoV-2 and exacerbates SARS-CoV-2-induced kidney diseases including renal failure, especially in the AA population. We also explore the role of extracellular vesicles (EVs) in COVID-19 patients who smoke tobacco. EVs, which play important role in tobacco-mediated pathogenesis in infectious diseases, have also shown to be important in COVID-19 pathogenesis and organ injuries including kidney. Further, we explore the potential role of EVs in biomarker discovery and therapeutics, which may help to develop early diagnosis and treatment of tobacco-induced renal injury in COVID-19 patients, respectively.Graphical

Clinical relevance of T follicular helper cells in systemic lupus erythematosus

ABSTRACT Introduction T helper cells regulate a variety of immune responses and are involved in the pathogenesis of infection, allergy and autoimmune diseases. T follicular helper (Tfh) cells, which induce B cell maturation, play an important role in the production of the extremely diverse autoantibodies found in systemic lupus erythematosus (SLE). Area covered We provide an overview of the plasticity and diversity of Tfh cells in humans and their involvement in the pathology and pathogenesis of SLE. Our review outlines the potential of Tfh cells as a therapeutic target for SLE. Expert opinion Tfh cells are involved in the pathogenesis of SLE based on their plasticity and diversity. Tfh cell differentiation and function are variably regulated by cytokines (IL-12, interferons, IL-2, etc), co-stimulatory molecules (ICOS, CD40L, OX40, etc), and intracellular signals (JAK-STAT, etc). Elucidation of the mechanisms underlying Tfh cell differentiation and function may lead to the development of new therapies for SLE.

Understanding the pathogenesis of infectious diseases by single-cell RNA sequencing.

Infections are highly orchestrated and dynamic processes, which involve both pathogen and host. Transcriptional profiling at the single-cell level enables the analysis of cell diversity, heterogeneity of the immune response, and detailed molecular mechanisms underlying infectious diseases caused by bacteria, viruses, fungi, and parasites. Herein, we highlight recent remarkable advances in single-cell RNA sequencing (scRNA-seq) technologies and their applications in the investigation of host-pathogen interactions, current challenges and potential prospects for disease treatment are discussed as well. We propose that with the aid of scRNA-seq, the mechanism of infectious diseases will be further revealed thus inspiring the development of novel interventions and therapies.

Overview of Pathogenesis, Diagnostics, and Therapeutics of Infectious Diseases: Dengue and Zika.

The emergence of more virulent SARS virus has made scientists look back at other so-called neglected diseases such as dengue, Zika, and chikungunya, etc. Until recently these neglected diseases have not received much attention for their control or elimination from society. Over the past decade several attempts to investigate the pathogenicity, diagnostic, and therapeutic strategies for flavivirus caused diseases have been made. Herein we have reviewed the progress made toward the detection and treatment of two diseases—dengue and Zika. The above flavivirus related pathogenesis is concerned with the host immune system and known to be mediated through various receptors along with antibody-mediated disease enhancement. Moreover, researchers have been progressing toward discovering new drugs and therapeutic methods that target various stages of the flavivirus life cycle to minimize the above caused mortality and morbidity. The available diagnostics are based on serological, small molecule detection systems and point-of-care sensing devices. In this work, we have reviewed the advancements made toward understanding the pathogenesis, diagnostics, and therapeutics of the viral diseases caused by dengue and Zika.

Modern and Classical Aspects on Infectious Diseases and their Management w.s.r. to Current Pandemic Situation: A Review

The ancient term Sankramaka Roga resembles communicable diseases as per modern science. These diseases mainly arise due to the influence of microbial invasion inside the body. The transmissions of such disease from one person to another take places via various means including Gatra Sansparsha, Prasnaga, sleeping and eating together; sharing objects and sexual contact, etc. The microbial toxin induces pathogenesis of infectious diseases after invasion of microorganism inside the body. Sankramaka Roga turned to Janapadodhwamsa if large numbers of people get affected, this condition can be correlated with resembles situation as per modern science. The modern science described uses of antibiotics and immune-therapy for the management of these diseases. Similarly Ayurveda rely on natural drugs, classical formulations, Panchakarma and Rasayana Chikitsa, etc. to treat Sankramaka Roga. Ayurveda concept of Ahara-Vihara, Dinacharya, Ratricharya, Ritucharya and Sadvritta improves immune system thus helps to prevent pathogenesis of Sankramaka Roga. Present article explores modern and classical aspects on infectious diseases and their management w.s.r. to current pandemic situation.

Diarrheal pathogens trigger rapid evolution of the guanylate cyclase-C signaling axis in bats

The pathogenesis of infectious diarrheal diseases is largely attributed to enterotoxins that cause dehydration by disrupting intestinal water absorption. We investigated patterns of genetic variation in mammalian guanylate cyclase-C (GC-C), an intestinal receptor targeted by bacterially encoded heat-stable enterotoxins (STa), to determine how host species adapt in response to diarrheal infections. Our phylogenetic and functional analysis of GC-C supports long-standing evolutionary conflict with diarrheal bacteria in primates and bats, with highly variable susceptibility to STa across species. In bats, we further show that GC-C diversification has sparked compensatory mutations in the endogenous uroguanylin ligand, suggesting an unusual scenario of pathogen-driven evolution of an entire signaling axis. Together, these findings suggest that conflicts with diarrheal pathogens have had far-reaching impacts on the evolution of mammalian gut physiology.

Free radical damage: role in varicella zoster virus infection

Study of the role of lipid peroxidation and antioxidant system in patients with infectious diseases is of great interest to researchers. Numerous studies have led to a common understanding of their contribution to the pathogenesis of infectious diseases, as well as to the complications development. However, the state of lipid peroxidation and antioxidant protection in patients with chickenpox (varicella) has not been sufficiently studied which is important for the development of new targeted treatments.
 The aim of the research - to assess the state of lipid peroxidation (LPO) and the antioxidant system (AOS) in the dynamics in patients with chickenpox, depending on the severity of the disease.
 Materials and methods. We selected for participating in the study 240 chickenpox patients (142 women and 98 men) aged 18-40 years. Chickenpox was diagnosed using clinical, serological, and molecular genetic methods. The state assessment of LPO in chickenpox patients was based on the determination of serum diene conjugates (DC), malondialdehyde (MDA) levels and the total oxidative activity (TOA) of blood plasma.
 Results. Study showed that the process of lipid peroxidation increases and the activity of the antioxidant system decreases in patients with chickenpox during the acute period of the disease. The extent of these processes becomes greater as the severity of chickenpox increases. A decrease in the activity of antioxidant enzymes and a disruption in the functioning of the glutathione system in patients with moderate to severe hypertension leads to disruption of protective mechanisms and, as a result, to an increase in the free radical chain reactions, the uncontrolled growth of which causes irreversible damage to the membranes of various cells, which underlies visceropathy in chickenpox patients.
 Conclusions. Antioxidant system is activated in the acute period in patients with mild chickenpox. It is evidenced by an increase in the overall antioxidant activity of blood plasma (p=0.045) and red blood cells (p=0.00087), in the activity of catalase (p=0.001), superoxide dismutase (p=0.0093), glutathione peroxidase (p=0.036), glutathione reductase of plasma and red blood cells, and an increase in the concentration of oxidized and reduced glutathione in blood. Lipid peroxidation is hyperactivated in the acute period in patients with a moderate and severe course of the disease and an excess amount of primary and secondary hydroperoxides of fatty acids accumulates in the blood. This is accompanied by indicates a developing imbalance between the oxidative and antioxidant systems in group of patients with moderate and severe chickenpox. Our findings confirm the usefulness of antioxidants in the treatment of chickenpox.

Dendritic cell migration in inflammation and immunity.

Dendritic cells (DCs) are the key link between innate immunity and adaptive immunity and play crucial roles in both the promotion of immune defense and the maintenance of immune tolerance. The trafficking of distinct DC subsets across lymphoid and nonlymphoid tissues is essential for DC-dependent activation and regulation of inflammation and immunity. DC chemotaxis and migration are triggered by interactions between chemokines and their receptors and regulated by multiple intracellular mechanisms, such as protein modification, epigenetic reprogramming, metabolic remodeling, and cytoskeletal rearrangement, in a tissue-specific manner. Dysregulation of DC migration may lead to abnormal positioning or activation of DCs, resulting in an imbalance of immune responses and even immune pathologies, including autoimmune responses, infectious diseases, allergic diseases and tumors. New strategies targeting the migration of distinct DC subsets are being explored for the treatment of inflammatory and infectious diseases and the development of novel DC-based vaccines. In this review, we will discuss the migratory routes and immunological consequences of distinct DC subsets, the molecular basis and regulatory mechanisms of migratory signaling in DCs, and the association of DC migration with the pathogenesis of autoimmune and infectious diseases.

Dynamics of the host chromatin three-dimensional response to influenza virus infection.

The spatial organization of chromatin is known to be highly dynamic in response to environmental stress. However, it remains unknown how chromatin dynamics contributes to or modulates the pathogenesis of immune and infectious diseases. Influenza virus is a single-stranded RNA virus, and transcription and replication of the virus genome occur in the nucleus. Since viral infection is generally associated with virus-driven hijack of the host cellular machineries, influenza virus may utilize and/or affect the nuclear system. In this review article, we focus on recent studies showing that the three-dimensional structure of chromatin changes with influenza virus infection, which affects the pathology of infection. Also, we discuss studies showing the roles of epigenetics in influenza virus infection. Understanding how this affects immune responses may lead to novel strategies to combat immune and infectious diseases.

Luteolin prevents THP-1 macrophage pyroptosis by suppressing ROS production via Nrf2 activation

Pyroptosis plays an important role in the pathogenesis of numerous infectious, autoimmune, and inflammatory diseases, which makes it a promising target for intervention. In this study, the effect of luteolin on pyroptosis and the underlying mechanism were investigated using the canonical NLRP3 inflammasome in THP-1 macrophages induced by LPS/ATP. The results showed that luteolin exhibited a potent preventive effect on THP-1 macrophage pyroptosis, as evidenced by the increase in cell viability and the decrease in LDH release. Moreover, luteolin was found to significantly reduce the expression of NLRP3, pro-CASP-1 and CASP-1, which are the key components of NLRP3 inflammasome, as well as the expression of N-GSDMD and IL-1β, and we proved that the inhibition of luteolin on NLRP3 inflammasome activation is ROS-dependent. Furthermore, it was demonstrated that luteolin promoted Nrf2 nuclear translocation, thereby increasing the expression of HO-1 that reduces ROS production, while the anti-pyroptotic effect of luteolin was reversed by a specific Nrf2 inhibitor. Additionally, luteolin inhibited NF-κB p65 phosphorylation and nuclear translocation. In summary, we conclude that luteolin prevents THP-1 macrophage pyroptosis by suppressing ROS production via Nrf2 activation as well as NF-κB inactivation. These results support luteolin as a potential bioactive chemical against pyroptosis-related inflammatory diseases.

ЗНАЧЕНИЕ СОДЕРЖАНИЯ ВЕЩЕСТВ НИЗКОЙ И СРЕДНЕЙ МОЛЕКУЛЯРНОЙ МАССЫ И ОЛИГОПЕПТИДОВ В ПАТОГЕНЕЗЕ ВЕТРЯНОЙ ОСПЫ

Endogenous intoxication syndrome is an important link in the pathogenesis of many infectious diseases. The role of low and medium molecular weight substances and oligopeptides acting as indicators of endogenous intoxication syndrome in the pathogenesis of varicella was studied, depending on the period of the disease, the severity of the course and the presence of complications. Based on this goal, 125 patients with varicella aged 18 to 49 years were examined. Determination of the content of substances of low and medium molecular weight in biological body fluids (blood plasma, red blood cells and urine) was carried out by the method of M. Ya.Malakhova (1995) on a spectrophotometer SF-46. The Lowru (1951) method was used to determine the level of oligopeptides in body fluids. The maximum level of substances of low and medium molecular weight was observed in patients with a complicated course of varicella during the height of the disease, as well as in patients with a severe course of the disease during the height. When determining the oligopeptides, the highest values were also obtained at the height of the disease in the severe course, as well as in the complicated course at admission. During the examination, the dependence of the studied indicators on the period of the disease, the severity, as well as the presence of complications was revealed. Thus, the most pronounced changes in the level of low and medium molecular weight substances and oligopeptides were observed in severe, and the least – in the mild course of varicella in all the studied media. In patients with developed complications, the disease was more severe, while the changes in the studied parameters were more pronounced.

The Use of High Resolution Melting (HRM) Method to Detect rs1800629 of Tumor Necrosis Factor-alpha (TNF-alpha) Gene among Tuberculosis Patients

The rs1800629 polymorphism plays a crucial role in the pathogenesis of infectious and autoimmune diseases. Meanwhile, tuberculosis (TB) remains a health primary infectious disease in Indonesia. The purpose of this study is to evaluate the HRM method in detecting the rs1800629 genotype, in the TNF-α gene’s promoter region, within TB patients. The benefit of this study is to accelerate the detection of rs1800629 with a simple, rapid, and cost-effective method for genotyping and mutation screening that does not include the use of a fluorescent probe. In this experimental study, the rs1800629 genotyped in a total of 25 tuberculosis patients using KAPA HRM kit in MyGo Mini PCR, and all amplified PCR products subsequently dispatched for direct DNA sequencing to Macrogen Inc, South Korea. Based on the results, a 100% concordance find in the genotyping of rs1800629 between HRM and sequencing. The authors provided evidence to use HRM in detecting rs1800629 within the TNF-α promotor region. This application as a genotyping assay in tuberculosis patients is a low-cost, rapid, and accurate detection. However, further studies using the HRM method in case-control samples of tuberculosis are required to evaluate the method’s effectiveness and to obtain more information regarding the genotype’s susceptibility to tuberculosis and its adverse effect treatment, including anti-tuberculosis drug, induced liver injury (AT-DILI), and multidrug-resistant TB (MDR-TB), within the Indonesian population.

Oxidative Stress and Inflammation in SARS-CoV-2- and Chlamydia pneumoniae-Associated Cardiovascular Diseases.

Throughout the years, a growing number of studies have provided evidence that oxidative stress and inflammation may be involved in the pathogenesis of infectious agent-related cardiovascular diseases. Amongst the numerous respiratory pathogens, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel coronavirus responsible for the global ongoing pandemic, and Chlamydia pneumoniae, a widely known intracellular obligate bacteria, seem to have an essential role in promoting reactive oxygen species and cytokine production. The present review highlights the common oxidative and inflammatory molecular pathways underlying the cardiovascular diseases associated with SARS-CoV-2 or C. pneumoniae infections. The main therapeutic and preventive approaches using natural antioxidant compounds will be also discussed.

MSphere of Influence: Forgotten Questions.

ABSTRACTLaura-Isobel McCall studies the relationship between location and disease pathogenesis, with a focus on infectious diseases and neglected diseases of poverty. In this mSphere of Influence article, she reflects on how three papers, “Opposing effects of fasting metabolism on tissue tolerance in bacterial and viral inflammation” (A. Wang, S. C. Huen, H. H. Luan, S. Yu, et al., Cell 166:1512−1525.e12, 2016, https://doi.org/10.1016/j.cell.2016.07.026), “Three-dimensional microbiome and metabolome cartography of a diseased human lung” (N. Garg, M. Wang, E. Hyde, R. R. da Silva, et al., Cell Host Microbe 22:705−716.e4, 2017, https://doi.org/10.1016/j.chom.2017.10.001), and “‘It’s like a phantom disease’: patient perspectives on access to treatment for Chagas disease in the United States” (C. J. Forsyth, S. Hernandez, C. A. Flores, M. F. Roman, et al., Am J Trop Med Hyg 98:735−741, 2018, https://doi.org/10.4269/ajtmh.17-0691), shaped her spatial approach to infectious disease pathogenesis and helped her broaden her perspective from a pathogen-centric focus to a holistic view that include diseases tolerance mechanisms and barriers to health care access.

Mesenchymal Stem Cells: A Novel Therapeutic Approach to Enhance Protective Immunomodulation and Erythropoietic Recovery in Malaria.

Mesenchymal stem cells (MSCs) are self-renewing, multi-potent heterogeneous stem cells that display strong tissue protective and restorative properties by differentiating into cells of the mesodermal lineages. In addition to multi-lineage differentiation capacity, MSCs play important roles in regulating immune responses, inflammation, and tissue regeneration. MSCs play a role in the outcome of the pathogenesis of several infectious diseases. A unique subset of MSCs accumulates in secondary lymphoid organs during malaria disease progression. These MSCs counteract the capacity of malaria parasites to subvert activating co-stimulatory molecules and to regulate expression of negative co-stimulatory molecules on T lymphocytes. Consequently, MSCs have the capacity to restore the functions of CD34+ haematopoietic cells and CD4+ and CD8+ T cells during malaria infection. These observations suggest that cell-based therapeutics for intervention in malaria may be useful in achieving sterile clearance and preventing disease reactivation. In addition, MSCs provide host protection against malaria by reprogramming erythropoiesis through accelerated formation of colony-forming-units-erythroid (CFU-E) cells in the bone marrow. These findings suggest that MSCs are positive regulators of erythropoiesis, making them attractive targets for treatment of malarial anemia. MSC-based therapies, unlike anti-malarial drugs, display therapeutic effects by targeting a large variety of cellular processes rather than a single pathway. In the present review we focus on these recent research findings and discuss clinical applications of MSC-based therapies for malaria.Graphical

OMIP 075: A 22-color panel for the measurement of antigen-specific T-cell responses in human and nonhuman primates.

OMIP 075: A 22-color panel for the measurement of antigen-specific T-cell responses in human and nonhuman primates.

The effect of estrogen in coronavirus disease 2019.

The outcomes of coronavirus disease 2019 (COVID-19) vary between men and women. Some statistical reports have shown that men have a higher risk of developing COVID-19 and suffer from worse outcomes than females. Although there are many factors that can explain the high prevalence of COVID-19 in men, such as lifestyle habits and the different profile of comorbidities among sexes, the distinctions between male and female immune systems cannot be ignored. It has been sufficiently shown that sex differences have a critical influence on the shaping of immune response, which then leads to different pathogenesis in infectious diseases. Compared with males, females typically have a more effective innate and adaptive immune response to viral infections in COVID-19. What’s more, there is a growing body of evidence showing that estrogen exerts an effect on the regulation of immune response. This article examines the effect and mechanism of estrogen on COVID-19.

Dysregulation of piwi‐interacting RNA expression in primary human cardiac myocytes during early phase of Trypanosoma cruzi infection

Trypanosoma cruzi, the causative agent of Chagas Disease, is an obligate intracellular parasite that has caused severe mortality and morbidity historically in Central and South America. Due to international travel, globalization, and migration, this neglected tropical disease is now present in most industrialized countries. About 30% of those who develop chronic T. cruzi infection will exhibit various pathologies, including cardiomyopathies, neurological and/or gastrointestinal diseases. We and others have implicated gene dysregulation as necessary in facilitating T. cruzi infection. However, the role of small noncoding RNAs during infection is still being investigated. Hence, the molecular mechanisms that contribute to chronic chagas cardiomyopathies remains to be elucidated. In this study, we aim to delineate dysregulation of a class of small non-coding RNAs, piwi-interacting RNAs (piRNAs), during the early phase of T. cruzi infection in primary human cardiomyocytes (PHCM). We hypothesize that dysregulated piRNAs target genes that may play important roles in infection. After parasite challenge, we extracted PHCM RNA for subsequent RNA sequencing. We then utilized bioinformatic tools in order to analyze differential expression of piRNAs, to predict mRNA targeting, and to map piRNAs to biological pathways. We found an average of 21,595,866 of clean reads (88.4%) mapped to the human reference genome. During the course of infection, T. cruzi induced differential expression of 217 unique piRNAs. In silico analysis predicted that both dysregulated known and novel piRNAs could target several genes of interest, including NFATC2, FOS, and TGF-b1, and related genes known to interact with these targets. These novel findings are the first to implicate that Trypanosoma cruzi induces differential expression of piRNAs in PHCM, which advances our knowledge of piRNAs in infectious disease pathogenesis.

Suppression of T-cell Immune responses by Neutrophils in a direct contact manner

Abstract Neutrophils are protective against early Mycobacterium tuberculosis (Mtb) infection, but overactive neutrophil response is often associated with chronic lung inflammation, tissue damage and compromised T-cell immunity, implying potential immunosuppression by neutrophils in Mtb infection. To test this, we examined the effect of peripheral blood neutrophils on the immune responses of T-cells from the peripheral blood mononuclear cells (PBMC) of persons with latent tuberculosis infection. Co-cultures of PBMC with autologous neutrophils at different ratios inhibited Mtb-stimulated T-cell proliferation and cytokines IFN-γ, IL-17 and IL-10 production dose dependently without affecting cell viability as determined by resazurin assay for cell metabolism and annexin V/PI staining for cell death. Neutralization of IL-10 and TGF-β failed to rescue neutrophil suppression of T-cell IFN-γ production. Neutrophils suppressed IFN-γ mRNA expression as determined by qPCR. Neutrophils inhibited purified T-cells stimulated with immobilized anti-CD3 and anti-CD28 mAbs, suggesting direct effect on T-cells without the involvement of antigen presenting cells. Trans-well study showed that cell-cell contact is required for this suppression. Further assessment of granulocyte derived suppressor cell phenotype and blocking the interaction between immune checkpoint molecules, PD-1 and PD-L1, refuted their roles in suppression of T-cells responses in Mtb infection. Together, these data suggest that neutrophils suppress T-cell immune responses by direct cell-cell contact mechanism and identification of molecular details of such suppression will shed new insights into the pathogenesis of tuberculosis and other infectious diseases.

Comparison of young-versus-old cytokine expression profiles in response to TLR agonists in murine and human whole blood.

Abstract Aging is met with multifaceted shifts in the makeup and function of immune cell populations, collectively known as “immunosenescence”, which render elderly populations more susceptible to pathogenesis of infectious disease and negatively impact responsiveness to vaccines. Highly efficacious vaccines to protect the elderly remain an unmet medical need. However, it has been demonstrated in recent years that robust vaccine responses can be generated in elderly populations through the use of adjuvants. While the positive impact of adjuvant inclusion in elderly vaccines is evident, a deeper understanding of the adjuvant-related, pathway-specific modulations necessary to overcome immunosenescence is needed. We hypothesize that by evaluating functional and phenotypic data from high-density immunoassays using aged murine and human samples we will identify mechanisms contributing to vaccine non-responsiveness in the elderly. To interrogate deficiencies in aged murine and human cytokine responses to immune pathway modulators, we utilized multiplex cytokine assays to compare young-versus-old in vitro cytokine expression of whole blood stimulated with TLR agonists. The results of these experiments will be discussed and could provide key insights for the rational use of adjuvants in vaccine development that may overcome age-related vaccine non-responsiveness and will also help bridge the gap in translatability of immune dysfunction-related findings between aged preclinical animal species and humans.