The tumor microenvironment (TME) is composed by cellular and non-cellular components. Examples include the following: (i) bone marrow-derived inflammatory cells, (ii) fibroblasts, (iii) blood ...vessels, (iv) immune cells, and (v) extracellular matrix components. In most cases, this combination of components may result in an inhospitable environment, in which a significant retrenchment in nutrients and oxygen considerably disturbs cell metabolism. Cancer cells are characterized by an enhanced uptake and utilization of glucose, a phenomenon described by Otto Warburg over 90 years ago. One of the main products of this reprogrammed cell metabolism is lactate. "Lactagenic" or lactate-producing cancer cells are characterized by their immunomodulatory properties, since lactate, the end product of the aerobic glycolysis, besides acting as an inducer of cellular signaling phenomena to influence cellular fate, might also play a role as an immunosuppressive metabolite. Over the last 10 years, it has been well accepted that in the TME, the lactate secreted by transformed cells is able to compromise the function and/or assembly of an effective immune response against tumors. Herein, we will discuss recent advances regarding the deleterious effect of high concentrations of lactate on the tumor-infiltrating immune cells, which might characterize an innovative way of understanding the tumor-immune privilege.
Kinetoplastida trypanosomatidae microorganisms are protozoan parasites exhibiting a developmental stage in the gut of insect vectors and tissues of vertebrate hosts. During the vertebrate infective ...stages, these parasites alter the differential expression of virulence genes, modifying their biological and antigenic properties in order to subvert the host protective immune responses and establish a persistent infection. One of the hallmarks of kinetoplastid parasites is their evasion mechanisms from host immunity, leading to disease chronification. The diseases caused by kinetoplastid parasites are neglected by the global expenditures in research and development, affecting millions of individuals in the low and middle-income countries located mainly in the tropical and subtropical regions. However, investments made by public and private initiatives have over the past decade leveraged important lines of intervention that if well-integrated to health care programs will likely accelerate disease control initiatives. This review summarizes recent advances in public health care principles, including new drug discoveries and their rational use with chemotherapeutic vaccines, and the implementation of control efforts to spatially mapping the kinetoplastid infections through monitoring of infected individuals in epidemic areas. These approaches should bring us the means to track genetic variation of parasites and drug resistance, integrating this knowledge into effective stewardship programs to prevent vector-borne kinetoplastid infections in areas at risk of disease spreading.
Humoral response in Leishmaniasis Conde, Luciana; Maciel, Gabriela; de Assis, Gustavo Meira ...
Frontiers in cellular and infection microbiology,
12/2022, Volume:
12
Journal Article
Peer reviewed
Open access
Leishmaniasis presents different types of clinical manifestations that can be divided into cutaneous leishmaniasis and visceral leishmaniasis. The host's immune system, associated with genetic and ...nutritional factors, is strongly involved in the evolution of the disease or parasite escape. Humoral immunity is characterized by the production of antibodies capable of promoting neutralization, opsonization, and activation of the complement system. In this scenario, B lymphocytes produce antibodies that play an important role in Leishmania infection although neglected for a long time. Thus, relevant aspects in the establishment of Leishmania infection will be addressed, highlighting the importance of humoral immunity during the entire process of Leishmania infection.
Chagas cardiomyopathy is the most severe clinical manifestation of chronic Chagas disease. The disease affects most of the Latin American countries, being considered one of the leading causes of ...morbidity and death in the continent. The pathogenesis of Chagas cardiomyopathy is very complex, with mechanisms involving parasite-dependent cytopathy, immune-mediated myocardial damage and neurogenic disturbances. These pathological changes eventually result in cardiac myocyte hypertrophy, arrhythmias, congestive heart failure and stroke during chronic infection phase. Herein, we show that miR-208a, a microRNA that is a key factor in promoting cardiovascular dysfunction during cardiac hypertrophy processes of heart failure, has its circulating levels increased during chronic indeterminate phase when compared to cardiac (CARD) clinical forms in patients with Chagas disease. In contrast, we have not found altered serum levels of miR-34a, a microRNA known to promote pro-apoptotic role in myocardial infarction during degenerative process of cardiac injuries thus indicating intrinsic differences in the nature of the mechanisms underlying the heart failure triggered by
infection. Our findings support that the chronic indeterminate phase is a progressive phase involved in the genesis of chagasic cardiopathy and point out the use of plasma levels of miR-208a as candidate biomarker in risk-prediction score for the clinical prognosis of Chagas disease.
The SARS-CoV-2 pandemic has had a social and economic impact worldwide, and vaccination is an efficient strategy for diminishing those damages. New adjuvant formulations are required for the high ...vaccine demands, especially adjuvant formulations that induce a Th1 phenotype. Herein we assess a vaccination strategy using a combination of Alum and polyinosinic:polycytidylic acid Poly(I:C) adjuvants plus the SARS-CoV-2 spike protein in a prefusion trimeric conformation by an intradermal (ID) route. We found high levels of IgG anti-spike antibodies in the serum by enzyme linked immunosorbent assay (ELISA) and high neutralizing titers against SARS-CoV-2
in vitro
by neutralization assay, after two or three immunizations. By evaluating the production of IgG subtypes, as expected, we found that formulations containing Poly(I:C) induced IgG2a whereas Alum did not. The combination of these two adjuvants induced high levels of both IgG1 and IgG2a. In addition, cellular immune responses of CD4
+
and CD8
+
T cells producing interferon-gamma were equivalent, demonstrating that the Alum + Poly(I:C) combination supported a Th1 profile. Based on the high neutralizing titers, we evaluated B cells in the germinal centers, which are specific for receptor-binding domain (RBD) and spike, and observed that more positive B cells were induced upon the Alum + Poly(I:C) combination. Moreover, these B cells produced antibodies against both RBD and non-RBD sites. We also studied the impact of this vaccination preparation spike protein with Alum + Poly(I:C) in the lungs of mice challenged with inactivated SARS-CoV-2 virus. We found a production of IgG, but not IgA, and a reduction in neutrophil recruitment in the bronchoalveolar lavage fluid (BALF) of mice, suggesting that our immunization scheme reduced lung inflammation. Altogether, our data suggest that Alum and Poly(I:C) together is a possible adjuvant combination for vaccines against SARS-CoV-2 by the intradermal route.
The Amazonian clearwater igapós are poorly studied floodplain ecosystems that are mainly covered by forests and are undergoing massive threats due to changes in land use and climate. Their ...hydrochemical characteristics and edaphic conditions fall between those of the eutrophic várzea floodplains on whitewater rivers and those of the oligotrophic igapós on blackwater rivers. Previous studies have indicated the management potential of timber species in the highly dynamic várzea floodplains due to the fast tree growth and high forest productivity. Timber resource management, however, is not recommended for the blackwater ecosystem because of its slow dynamics and high vulnerability to disturbances. For clearwater igapós, information on the potential for sustainable management of timber resources is lacking. In this study, we modeled the growth in diameter, height, and volume to derive species-specific minimum logging diameters (MLD) and felling cycles (FC) for eight merchantable species in the clearwater igapós of the Branco and Tapajós rivers in the northern and southern Amazon Basin, respectively. Diameter growth was modeled by analyzing the tree rings that are annually formed in the Amazonian floodplains as a consequence of the regular and predicable long-term flooding. Growth modeling followed the guidelines of the Growth-Oriented Logging (GOL) concept, with the adjustment of diameter growth improved by applying nonlinear mixed-effects regression. MLDs varied from 36 to 90 cm and FCs ranged from 6 to 21 years, which diverges from the standards of Brazilian logging regulations (MLD: 50 cm; FC: 25–35 years). This indicates the potential for timber resource management, which should be tested and introduced at small scales, integrated in protected areas to stepwise promote the sustainable management of these natural resources by traditional communities to increase their income and the conservation of this ecosystem.
•Amazonian clearwater floodplains are poorly studied and highly threatened.•Mixed-effect models improve diameter growth projections applying tree-ring data.•Tree-ring analyses of species shows varying growth rates in diameter and volume.•Estimated management criteria are compatible with Brazilian legislation standards.•Timber resource management is a bioeconomy option for traditional populations.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Antibody-based therapy depletes myeloid-biased hematopoietic stem cells (my-HSCs) to rejuvenate the immune system and improve immune responses in aged mice.
Cerebral malaria (CM) is a clinical syndrome involving irreversible and lethal signs of brain injury associated to infection by parasites of the genus
. The pathogenesis of CM derives from ...infection-induced proinflammatory cytokines associated with cytoadherence of parasitized red blood cells to brain microvasculature. Glycoconjugates are very abundant in the surface of
spp., and are critical mediators of parasite virulence in host-pathogen interactions. Herein, we show that 6-Diazo-5-oxo-L-norleucine (DON) therapeutically used for blocking hexosamine biosynthetic pathway leads to recovery in experimental murine cerebral malaria. DON-induced protection was associated with decreased parasitism, which severely reduced
transmission to mosquitoes. These findings point to a potential use of DON in combination therapies against malaria.
Cardiovascular comorbidities and immune-response dysregulation are associated with COVID-19 severity. We aimed to explore the key immune cell profile and understand its association with disease ...progression in 156 patients with hypertension that were hospitalized due to COVID-19. The primary outcome was progression to severe disease. The probability of progression to severe disease was estimated using a logistic regression model that included clinical variables and immune cell subsets associated with the primary outcome. Obesity; diabetes; oxygen saturation; lung involvement on computed tomography (CT) examination; the C-reactive protein concentration; total lymphocyte count; proportions of CD4+ and CD8+ T cells; CD4/CD8 ratio; CD8+ HLA-DR MFI; and CD8+ NKG2A MFI on admission were all associated with progression to severe COVID-19. This study demonstrated that increased CD8+ NKG2A MFI at hospital admission, in combination with some clinical variables, is associated with a high risk of COVID-19 progression in hypertensive patients. These findings reinforce the hypothesis of the functional exhaustion of T cells with the increased expression of NKG2A in patients with severe COVID-19, elucidating how severe acute respiratory syndrome coronavirus 2 infection may break down the innate antiviral immune response at an early stage of the disease, with future potential therapeutic implications.
The vast spectrum of clinical features of COVID-19 keeps challenging scientists and clinicians. Low resistance to infection might result in long-term viral persistence, but the underlying mechanisms ...remain unclear. Here, we studied the immune response of immunocompetent COVID-19 patients with prolonged SARS-CoV-2 infection by immunophenotyping, cytokine and serological analysis. Despite viral loads and symptoms comparable to regular mildly symptomatic patients, long-term carriers displayed weaker systemic IFN-I responses and fewer circulating pDCs and NK cells at disease onset. Type 1 cytokines remained low, while type-3 cytokines were in turn enhanced. Of interest, we observed no defects in antigen-specific cytotoxic T cell responses, and circulating antibodies displayed higher affinity against different variants of SARS-CoV-2 Spike protein in these patients. The identification of distinct immune responses in long-term carriers adds up to our understanding of essential host protective mechanisms to ensure tissue damage control despite prolonged viral infection.
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•Immunocompetent oligosymptomatic COVID-19 patients may have persistent infection•Long-term COVID-19 patients show low antiviral immunity, with fewer NK cells/pDCs•A systemic type 3 immune profile characterizes persistent SARS-CoV-2 infection•Long-term carriers develop anti-spike antibodies with enhanced binding capacity
Health sciences; Immunology; Virology
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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