Modulation of Host Immune Response during Leishmania infantum Natural Infection: A Whole-Transcriptome Analysis of the Popliteal Lymph Nodes in Dogs

Leishmania infantum, the etiological agent of canine leishmaniosis (CanL) in Europe, was responsible of the largest outbreak of human leishmaniosis in Spain. The parasite infects and survives within myeloid lineage cells, causing a potentially fatal disease if left untreated. The only treatment option relies on chemotherapy, although immunotherapy strategies are being considered as novel approaches to prevent progression of the disease. To this aim, a deeper characterization of the molecular mechanisms behind the immunopathogenesis of leishmaniosis is necessary. Thus, we evaluated, for the first time, the host immune response during L. infantum infection through transcriptome sequencing of the popliteal lymph nodes aspirates of dogs with CanL. Differential expression and weighted gene co-expression network analyses were performed, resulting in the identification of 5,461 differentially expressed genes (DEGs) and four key modules in sick dogs, compared to controls. As expected, defense response was the highest enriched biological process in the DEGs, with six genes related to immune response against pathogens (CHI3L1, SLPI, ACOD1, CCL5, MPO, BPI) included among the ten most expressed genes; and two of the key co-expression modules were associated with regulation of immune response, which also positively correlated with clinical stage and blood monocyte concentration. In particular, sick dogs displayed significant changes in the expression of Th1, Th2, Th17 and Tr1 cytokines (e. g. TNF-α, IFN-γ, IL-21, IL-17, IL-15), markers of T cell and NK cell exhaustion (e. g. LAG3, CD244, Blimp-1, JUN), and B cell, monocyte and macrophage disrupted functionality (e. g. CD40LG, MAPK4, IL-1R, NLRP3, BCMA). In addition, we found an overexpression of XBP1 and some other genes involved in endoplasmic reticulum stress and the IRE1 branch of the unfolded protein response, as well as one co-expression module associated with these processes, which could be induced by L. infantum to prevent host cell apoptosis and modulate inflammation-induced lymphangiogenesis at lymph nodes. Moreover, 21 lncRNAs were differentially expressed in sick dogs, and one key co-expression module was associated with chromatin organization, suggesting that epigenetic mechanisms could also contribute to dampening host immune response during natural L. infantum infection in the lymph nodes of dogs suffering from clinical leishmaniosis.

Strategies employed to evade the host immune response and the mechanism of drug resistance in Mycobacterium tuberculosis: In search of finding new targets

: The partial effectiveness of the host immune response to M. tuberculosis drives bacteria into a latent state, but it is difficult to eliminate the bacteria completely. Usually, this latent condition of M. tuberculosis is reversible, and reactivation of tuberculosis is the leading cause of the majority of transmission. A number of studies performed on animal models and in humans have not yet provided a detailed understanding of the mechanisms or correlates of immunity of M. tuberculosis infection or why there is a significant immunity failure to remove the pathogen. Moreover, the mechanism of resistance involved in drug-resistant M. tuberculosis leading to the emergence of strains of bacteria that show significant resistance to the majority of anti-tuberculosis drugs. We have also provided the recent findings and trends regarding the development of new drug molecules to treat drug and multidrug-resistant tuberculosis and the advancements in immunotherapy in the treatment of drug-resistant tuberculosis. This article provides an in-depth and critical analysis of various strategies employed by the drug-resistant M. tuberculosis to escape the host immune response, as a result of which this bacterium persists in the host for a longer period of time and leads to the development of tuberculosis infection. Furthermore, we also discussed the new targets for the effective treatment of drug resistant tuberculosis.

Symbiont-Mediated Protection of Acromyrmex Leaf-Cutter Ants from the Entomopathogenic Fungus Metarhizium anisopliae

In some plants and animals, beneficial microbes mediate host immune response against pathogens, including by serving as defensive symbionts that produce antimicrobial compounds. Defensive symbionts are known in several insects, including some leaf-cutter ants where antifungal-producing Actinobacteria help protect the fungal mutualist of the ants from specialized mycoparasites.

Detection of Antibody Responses Against SARS-CoV-2 in Plasma and Saliva From Vaccinated and Infected Individuals

Antibodies (Abs) are essential for the host immune response against SARS-CoV-2, and all the vaccines developed so far have been designed to induce Abs targeting the SARS-CoV-2 spike. Many studies have examined Ab responses in the blood from vaccinated and infected individuals. However, since SARS-CoV-2 is a respiratory virus, it is also critical to understand the mucosal Ab responses at the sites of initial virus exposure. Here, we examined plasma versus saliva Ab responses in vaccinated and convalescent patients. Although saliva levels were significantly lower, a strong correlation was observed between plasma and saliva total Ig levels against all SARS-CoV-2 antigens tested. Virus-specific IgG1 responses predominated in both saliva and plasma, while a lower prevalence of IgM and IgA1 Abs was observed in saliva. Antiviral activities of plasma Abs were also studied. Neutralization titers against the initial WA1 (D614G), B.1.1.7 (alpha) and B.1.617.2 (delta) strains were similar but lower against the B.1.351 (beta) strain. Spike-specific antibody-dependent cellular phagocytosis (ADCP) activities were also detected and the levels correlated with spike-binding Ig titers. Interestingly, while neutralization and ADCP potencies of vaccinated and convalescent groups were comparable, enhanced complement deposition to spike-specific Abs was noted in vaccinated versus convalescent groups and corresponded with higher levels of IgG1 plus IgG3 among the vaccinated individuals. Altogether, this study demonstrates the detection of Ab responses after vaccination or infection in plasma and saliva that correlate significantly, although Ig isotypic differences were noted. The induced plasma Abs displayed Fab-mediated and Fc-dependent functions with comparable neutralization and ADCP potencies, but a greater capacity to activate complement was elicited upon vaccination.

D-Mannose Slows Glioma Growth by Modulating Myeloperoxidase Activity

Host immune response in the tumor microenvironment plays key roles in tumorigenesis. We hypothesized that D-mannose, a simple sugar with anti-inflammatory properties, could decrease oxidative stress and slow glioma progression. Using a glioma stem cell model in immunocompetent mice, we induced gliomas in the brain and tracked MPO activity in vivo with and without D-mannose treatment. As expected, we found that D-mannose treatment decreased the number of MPO+ cells and slowed glioma progression compared to PBS-treated control animals with gliomas. Unexpectedly, instead of decreasing MPO activity, D-mannose increased MPO activity in vivo, revealing that D-mannose boosted the MPO activity per MPO+ cell. On the other hand, D-glucose had no effect on MPO activity. To better understand this effect, we examined the effect of D-mannose on bone marrow-derived myeloid cells. We found that D-mannose modulated MPO activity via two mechanisms: directly via N-glycosylation of MPO, which boosted the MPO activity of each molecule, and indirectly by increasing H2O2 production, the main substrate for MPO. This increased host immune response acted to reduce tumor size, suggesting that increasing MPO activity such as through D-mannose administration may be a potential new therapeutic direction for glioma treatment.

New insights on mucormycosis and its association with the COVID-19 pandemic

COVID-19 continues to cause significant fatality worldwide. Glucocorticoids prove to play essential roles in COVID-19 management; however, the extensive use of steroids together with the virus immune dysregulation may increase the danger of secondary infections with mucormycosis, an angioinvasive fungal infection. Unfortunately, a definite correlation between COVID-19 and elevated mucormycosis infection cases is now clear worldwide. In this review, we discuss the historical record and epidemiology of mucormycosis as well as pathogenesis and associated host immune response, risk factors, clinical presentation, diagnosis and treatment. Special emphasis is given to its association with the current COVID-19 pandemic, including latest updates on COVID-19-associated mucormycosis cases globally, with recommendations for efficacious management.

Feasibility Study Examining the Association between Gut Microbiota and Immune Response to Seasonal Influenza Vaccination in Healthy Adults

<p>Research into the effect of the gut microbiota on host immune response is continuing to shed new light on the underappreciated role of the microbiota in human health. Recent research using mice has shown that the microbiota is critical to the host immune response to influenza infection. Whilst there is great variation in the human gut microbiota, classifications called stool community types can be used to classify individuals based on the abundance of major bacterial taxa. The primary objective of this study was to investigate the feasibility of using the study protocol for a large randomised controlled trial. Healthy adult participants (n=125) aged 18 to 64 were recruited from the general population and vaccinated with the seasonal trivalent influenza vaccine. Participants were followed up over a period of six months, during which time, both stool and blood samples were collected. Blood samples were collected at Day Zero, Three, Seven, 28 and 180 to measure immune response. The immune response to vaccination was measured by HAI antibody titres at Day Zero and Day 28. Stool samples were collected at Day Zero and Day 28 to assign participants to one of the four stool community types and assess stability over time. Stool samples were assigned to stool community types using the proportions of major taxa present. The association between stool community type and either post vaccination HAI titre, seroconversion rates or seroprotection rates was also assessed. The results obtained in this study supported the feasibility of a large randomised controlled trial using the study protocol. The study demonstrated a high participant retention rate (97.6%; 95% CI = 93.1% to 99.5%), as well as high participant adherence to the study protocol and good success obtaining the required blood and stool samples.</p>