Characterization of the Human Plasma Biofilm Model (hpBIOM) to Identify Potential Therapeutic Targets for Wound Management of Chronic Infections.

The treatment of chronic wounds still represents a major challenge in wound management. Recent estimates suggest that 60-80% of chronic wounds are colonized by pathogenic microorganisms, which are strongly considered to have a major inhibiting influence on the healing process. By means of an innovative biofilm model based on human plasma, the time-dependent behavior of various bacterial strains under wound-milieu-like conditions were investigated, and the growth habits of different cocci species were compared. Undescribed fusion events between colonies of MRSA as well as of Staphylococcus epidermidis were detected, which were associated with the remodeling and reorganization of the glycocalyx of the wound tissue. After reaching a maximum colony size, the spreading of individual bacteria was observed. Interestingly, the combination of different cocci species with Pseudomonas aeruginosa in the human plasma biofilm revealed partial synergistic effects in these multispecies organizations. RT-qPCR analyses gave a first impression of the relevant proteins involved in the formation and maturation of biofilms, especially the role of fibrinogen-binding proteins. Knowledge of the maturation and growth behavior of persistent biofilms investigated in a translational human biofilm model reflects a starting point for the development of novel tools for the treatment of chronic wounds.

Lactobacilli in COVID-19: A Systematic Review Based on Next-Generation Sequencing Studies.

The global pandemic was caused by the SARS-CoV-2 virus, known as COVID-19, which primarily affects the respiratory and intestinal systems and impacts the microbial communities of patients. This systematic review involved a comprehensive search across the major literature databases to explore the relationship between lactobacilli and COVID-19. Our emphasis was on investigations employing NGS technologies to explore this connection. Our analysis of nine selected studies revealed that lactobacilli have a reduced abundance in the disease and an association with disease severity. The protective mechanisms of lactobacilli in COVID-19 and other viral infections are likely to be multifaceted, involving complex interactions between the microbiota, the host immune system, and the virus itself. Moreover, upon closely examining the NGS methodologies and associated statistical analyses in each research study, we have noted concerns regarding the approach used to delineate the varying abundance of lactobacilli, which involves potential biases and the exclusion of pertinent data elements. These findings provide new insight into the relationship between COVID-19 and lactobacilli, highlighting the potential for microbiota modulation in COVID-19 treatment.

Roles and functions of IAV proteins in host immune evasion.

Influenza A viruses (IAVs) evade the immune system of the host by several regulatory mechanisms. Their genomes consist of eight single-stranded segments, including nonstructural proteins (NS), basic polymerase 1 (PB1), basic polymerase 2 (PB2), hemagglutinin (HA), acidic polymerase (PA), matrix (M), neuraminidase (NA), and nucleoprotein (NP). Some of these proteins are known to suppress host immune responses. In this review, we discuss the roles, functions and underlying strategies adopted by IAV proteins to escape the host immune system by targeting different proteins in the interferon (IFN) signaling pathway, such as tripartite motif containing 25 (TRIM25), inhibitor of nuclear factor κB kinase (IKK), mitochondrial antiviral signaling protein (MAVS), Janus kinase 1 (JAK1), type I interferon receptor (IFNAR1), interferon regulatory factor 3 (IRF3), IRF7, and nuclear factor-κB (NF-κB). To date, the IAV proteins NS1, NS2, PB1, PB1-F2, PB2, HA, and PA have been well studied in terms of their roles in evading the host immune system. However, the detailed mechanisms of NS3, PB1-N40, PA-N155, PA-N182, PA-X, M42, NA, and NP have not been well studied with respect to their roles in immune evasion. Moreover, we also highlight the future perspectives of research on IAV proteins.

Subversion strategies of lysosomal killing by intracellular pathogens.

Many pathogenic organisms need to reach either an intracellular compartment or the cytoplasm of a target cell for their survival, replication or immune system evasion. Intracellular pathogens frequently penetrate into the cell through the endocytic and phagocytic pathways (clathrin-mediated endocytosis, phagocytosis and macropinocytosis) that culminates in fusion with lysosomes. However, several mechanisms are triggered by pathogenic microorganisms - protozoan, bacteria, virus and fungus - to avoid destruction by lysosome fusion, such as rupture of the phagosome and thereby release into the cytoplasm, avoidance of autophagy, delaying in both phagolysosome biogenesis and phagosomal maturation and survival/replication inside the phagolysosome. Here we reviewed the main data dealing with phagosome maturation and evasion from lysosomal killing by different bacteria, protozoa, fungi and virus.

Avenues within the gut-liver-brain axis linking chronic liver disease and symptoms.

Symptoms of fatigue, social withdrawal and mood disturbances are commonly encountered in patients with chronic liver disease and have a detrimental effect on patient quality of life. Treatment options for these symptoms are limited and a current area of unmet medical need. In this review, we will evaluate the potential mechanistic avenues within the gut-liver-brain axis that may be altered in the setting of chronic liver disease that drive the development of these symptoms. Both clinical and pre-clinical studies will be highlighted as we discuss how perturbations in host immune response, microbiome, neural responses, and metabolites composition can affect the central nervous system.

Cellular Attributes of Candida albicans Biofilm-Associated in Resistance Against Multidrug and Host Immune System.

One of the ubiquitous hospital-acquired infections is associated with Candida albicans fungus. Usually, this commensal fungus causes no harm to its human host, as it lives mutually with mucosal/epithelial tissue surface cells. Nevertheless, due to the activity of various immune weakening factors, this commensal starts reinforcing its virulence attributes with filamentation/hyphal growth and building an absolute microcolony composed of yeast, hyphal, and pseudohyphal cells, which is suspended in an extracellular gel-like polymeric substance (EPS) called biofilms. This polymeric substance is the mixture of the secreted compounds from C. albicans as well as several host cell proteins. Indeed, the presence of these host factors makes their identification and differentiation process difficult by host immune components. The gel-like texture of the EPS makes it sticky, which adsorbs most of the extracolonial compounds traversing through it that aid in penetration hindrance. All these factors further contribute to the multidrug resistance phenotype of C. albicans biofilm that is spotlighted in this article. The mechanisms it employs to escape the host immune system are also addressed effectively. The article focuses on cellular and molecular determinants involved in the resistance of C. albicans biofilm against multidrug and the host immune system.

Antibiotic resistance and host immune system-induced metal bactericidal control are key factors for microbial persistence in the developing human preterm infant gut microbiome.

The human gut microbiome, which develops and stabilizes during the early stages of infant life, plays an essential role in host health through the production of metabolic resources and the stimulation and training of the immune system. To study colonization and community functional dynamics of the microbiota based on responses to host immune processes during the normal and dysbiotic establishment of the gut, metaproteomics was conducted on 91 fecal samples collected over the first 90 days of life from 17 hospitalized premature infants. Microbial responses to antibiotic administration and host-imposed metal bactericidal control correlated with community assembly and resiliency of microbes in the developing preterm gut. Specifically, proteins related to antibiotic resistance and metal homeostasis mechanisms were predominant in persisting members in the infant gut environment over the first several weeks of life. Overall, this metaproteomics study provides a unique approach to examine the temporal expansion and resilience of microbial colonization, as it allows simultaneous examination of both host and microbial metabolic activities. Understanding the interplay between host and microbes may elucidate the microbiome's potential immunomodulatory roles relevant to necrotizing enterocolitis and other dysbiotic conditions in preterm infants.

Can Radiotherapy Empower the Host Immune System to Counterattack Neoplastic Cells? A Systematic Review on Tumor Microenvironment Radiomodulation.

Despite the rising evidence in favor of immunotherapy (IT), the treatment of oncological patients affected by so-called "cold tumors" still represents an open issue. Cold tumors are characterized by an immunosuppressive (so-called cold) tumor microenvironment (TME), which favors host immune system suppression, cancer immune-escape, and a worse response to IT. However, the TME is not a static element, but dynamically mutates and can be changed. Radiotherapy (RT) can modulate a cold microenvironment, rendering it better at tumor killing by priming the quiescent host immune system, with a consequent increase in immunotherapy response. The combination of TME radiomodulation and IT could therefore be a strategy for those patients affected by cold tumors, with limited or no response to IT. Thus, this review aims to provide an easy, rapid, and practical overview of how RT could convert the cold TME and why cold tumor radiomodulation could represent an interesting strategy in combination with IT.

Aging and Microbiome in the Modulation of Vaccine Efficacy.

From infancy through to old age, the microbiome plays an important role in modulating the host-immune system. As we age, our immune system and our gut microbiota change significantly in composition and function, which is linked to an increased vulnerability to infectious diseases and a decrease in vaccine responses. Our microbiome remains largely stable throughout adulthood; however, aging causes a major shift in the composition and function of the gut microbiome, as well as a decrease in diversity. Considering the critical role of the gut microbiome in the host-immune system, it is important to address, prevent, and ameliorate age-related dysbiosis, which could be an effective strategy for preventing/restoring functional deficits in immune responses as we grow older. Several factors, such as the host's genetics and nutritional state, along with the gut microbiome, can influence vaccine efficacy or reaction. Emerging evidence suggests that the microbiome could be a significant determinant of vaccine immunity. Physiological mechanisms such as senescence, or the steady loss of cellular functions, which affect the aging process and vaccination responses, have yet to be comprehended. Recent studies on several COVID-19 vaccines worldwide have provided a considerable amount of data to support the hypothesis that aging plays a crucial role in modulating COVID-19 vaccination efficacy across different populations.

Probiotics as a biotherapeutics for the management and prevention of respiratory tract diseases.

Respiratory diseases are responsible for a greater mortality rate around the world. Viral or bacterial infections in the respiratory tract have been identified as major causative agents for death and disability among the population. Respiratory tract infections (RTIs) cause severe respiratory ailments starting from coldlike symptoms, eventually affecting the lungs and other viscera, and are mainly categorized into two types depending on the affected area: upper RTIs and lower RTIs. Respiratory viruses belong to several viral families such as influenza virus, enterovirus, adenovirus, respiratory syncytial virus, and recently severe acute respiratory syndrome coronavirus 2. Studies have indicated that people with good immune functions are less prone to respiratory infections and also their recovery rate is quicker. Innate and acquired immune systems actively participate in the recognition and elimination of the pathogenic agents. In the present context, the potential of probiotics is recognized as viable microorganisms that support the balance of the beneficial microbial population in the gastrointestinal tract and promote host immunity. The probiotics have long been known to regulate bodily immune functions and have been used against general RTIs such as cough, pharyngitis, laryngitis, pneumonia, and asthma. In addition, intervention with probiotics could directly affect the composition of the gut microbiota that have been shown to palliate respiratory diseases by modulating pulmonary immune activities through the gut-lung axis, and therefore, probiotics could become an alternative therapeutic approach for RTIs.

Establishing Imaging Biomarkers of Host Immune System Efficacy during Glioblastoma Therapy Response: Challenges, Obstacles and Future Perspectives.

This hypothesis proposal addresses three major questions: (1) Why do we need imaging biomarkers for assessing the efficacy of immune system participation in glioblastoma therapy response? (2) Why are they not available yet? and (3) How can we produce them? We summarize the literature data supporting the claim that the immune system is behind the efficacy of most successful glioblastoma therapies but, unfortunately, there are no current short-term imaging biomarkers of its activity. We also discuss how using an immunocompetent murine model of glioblastoma, allowing the cure of mice and the generation of immune memory, provides a suitable framework for glioblastoma therapy response biomarker studies. Both magnetic resonance imaging and magnetic resonance-based metabolomic data (i.e., magnetic resonance spectroscopic imaging) can provide non-invasive assessments of such a system. A predictor based in nosological images, generated from magnetic resonance spectroscopic imaging analyses and their oscillatory patterns, should be translational to clinics. We also review hurdles that may explain why such an oscillatory biomarker was not reported in previous imaging glioblastoma work. Single shot explorations that neglect short-term oscillatory behavior derived from immune system attack on tumors may mislead actual response extent detection. Finally, we consider improvements required to properly predict immune system-mediated early response (1-2 weeks) to therapy. The sensible use of improved biomarkers may enable translatable evidence-based therapeutic protocols, with the possibility of extending preclinical results to human patients.

Corrigendum: An Evolutionary Arms Race Between Burkholderia pseudomallei and Host Immune System: What Do We Know?

[This corrects the article DOI: 10.3389/fmicb.2020.612568.].

Host Protease Activity on Bacterial Pathogens Promotes Complement and Antibiotic-Directed Killing.

Our understanding of how the host immune system thwarts bacterial evasive mechanisms remains incomplete. Here, we show that host protease neutrophil elastase acts on Acinetobacter baumannii and Pseudomonas aeruginosa to destroy factors that prevent serum-associated, complement-directed killing. The protease activity also enhances bacterial susceptibility to antibiotics in sera. These findings implicate a new paradigm where host protease activity on bacteria acts combinatorially with the host complement system and antibiotics to defeat bacterial pathogens.

Insights into the molecular determinants involved in Mycobacterium tuberculosis persistence and their therapeutic implications.

The establishment of persistent infections and the reactivation of persistent bacteria to active bacilli are the two hurdles in effective tuberculosis treatment. Mycobacterium tuberculosis, an etiologic tuberculosis agent, adapts to numerous antibiotics and resists the host immune system causing a disease of public health concern. Extensive research has been employed to combat this disease due to its sheer ability to persist in the host system, undetected, waiting for the opportunity to declare itself. Persisters are a bacterial subpopulation that possesses transient tolerance to high doses of antibiotics. There are certain inherent mechanisms that facilitate the persister cell formation in Mycobacterium tuberculosis, some of those had been characterized in the past namely, stringent response, transcriptional regulators, energy production pathways, lipid metabolism, cell wall remodeling enzymes, phosphate metabolism, and proteasome protein degradation. This article reviews the recent advancements made in various in vitro persistence models that assist to unravel the mechanisms involved in the persister cell formation and to hunt for the possible preventive or treatment measures. To tackle the persister population the immunodominant proteins that express specifically at the latent phase of infection can be used for diagnosis to distinguish between the active and latent tuberculosis, as well as to select potential drug or vaccine candidates. In addition, we discuss the genes engaged in the persistence to get more insights into resuscitation and persister cell formation. The in-depth understanding of persistent cells of mycobacteria can certainly unravel novel ways to target the pathogen and tackle its persistence.

Significance of Endogenous Antimicrobial Peptides on the Health of Food Animals.

Acquired resistance to in-feed antibiotic growth promoters continues to be an imperative problem in the livestock industries, thereby necessitating continuous pursuit for alternatives. Antimicrobial peptides (AMPs) represent a critical part of the host's innate immune system and have been documented to have immunomodulatory activity. Increasing research evidence suggests that in contrast to antibiotics, AMPs exert broad-spectrum antibacterial activity in a manner that reduces bacterial acquisition of resistance genes. This review summarizes current knowledge on the protective effects of endogenous (natural) AMPs in the gastrointestinal tract of food animals. Factors limiting the efficacy of these AMPs were also discussed and mitigating strategies were proposed.

Transcriptome profiling analysis of caeca in chicks challenged with Salmonella Typhimurium reveals differential expression of genes involved in host mucosal immune response.

Temporal regulation of global gene expression in the caeca of chickens infected with Salmonella Typhimurium has not been investigated previously. In this study, we performed the transcriptome analysis of the caeca of Salmonella Typhimurium challenged chicks to understand the regulation of the mucosal immune system in a temporal manner. The Salmonella infection resulted in the activation of the caecal immune system by the upregulation of the differentially expressed genes (DEGs; false discovery rate (FDR) < 0.05; log2 fold change > 1) involved in biological pathways such as Toll-like receptor signaling pathway, Salmonella infection, cytokine-cytokine receptor interaction, phagosome, apoptosis and intestinal immune network for IgA production. The activation of biological pathways such as RIG-I-like receptor signaling pathway, ErbB signaling pathway and cellular senescence showed a time-dependent response of the host immune system. A 49% increase in the DEGs on day 7 compared with day 3 post-infection (p.i.) suggested a time-dependent role of multiple genes such as AvBD1, AvBD2, AvBD7, IL2, IL10, IL21, SIVA1, CD5, CD14 and GPR142 in the regulation of the immune system. Nested network analysis of the individual biological pathways showed that IL6 played a significant role in the immune system regulation by activating the pathways, including Toll-like receptor signaling pathway, Salmonella infection, intestinal immune network for IgA production and C-type lectin receptor signaling pathway. The downregulated DEGs (FDR < 0.05; log2 fold change < -1) showed that Salmonella challenge affected the functions of pathways, such as tryptophan metabolism, retinol metabolism, folate biosynthesis and pentose and glucoronate interconversions, suggesting the disruption of cellular mechanisms involved in nutrient synthesis, absorption and metabolism. Overall, the immune response was temporally regulated through the activation of Toll-like signaling receptor pathway, cytokine-cytokine interactions and Salmonella infection, where IL6 played a significant role in the modulation of caecal immune system against Salmonella Typhimurium. KEY POINTS: • The immune response to Salmonella Typhimurium challenge was temporally regulated in the caeca of chickens. • Many newly identified genes have been shown to be involved in the activation of the immune system. • Toll-like receptors and interleukins played a key role in immune system regulation.

Hepatobiliary surgeons meet immunologists: the case of colorectal liver metastases patients.

The burgeoning field of cancer immunology demands a change in the paradigm of cancer patient management. The understanding of the course of a given malignant disease should also include the host immune system as one of the key factors in determining the patient's prognosis. Surgical and medical oncologists need to understand the basic and advanced applications of immunotherapies, which are rapidly evolving, and are nowadays an integral part of the armamentarium for the treatment of cancer patients. In the present work, we review the current knowledge concerning the immune landscape of colorectal cancer (CRC) patients with liver metastases, as recently discovered.

The Shifting Paradigm of Prognostic Factors of Colorectal Liver Metastases: From Tumor-Centered to Host Immune-Centered Factors.

The determinants of prognosis in patients with colorectal liver metastases (CLM) have been traditionally searched among the tumoral factors, either of the primary colorectal tumor or of the CLM. While many different scoring systems have been developed based on those clinic-pathological factors with disparate results, there has been the introduction of genetic biological markers that added a theranostic perspective. More recently, other important elements, such as those factors related to the host immune system, have been proposed as determinants of prognosis of CLM patients. In the present work, we review the current prognostic factors of CLM patients as well as the burgeoning shifting paradigm of prognostication that relies on the host immune system.

Immunosuppressive mechanism of Hypoderma lineatum secreted serine esterase, a potential modulatory method used to inhibit transplant rejection

Background: Although immunosuppressive therapies have made organ transplantation a common medical procedure worldwide, chronic toxicity has a major issue for long-term treatment. One method to improve therapies and methods is the application of immunomodulatory agents from parasites such as Hypoderma lineatum. Hypodermin A (HA) is a serine esterase secreted by the larvae of Hypoderma lineatum, several studies demonstrated its immunosuppressive mechanism in vitro, and recently we discovered that HA inhibits the expression of interferon (IFN)-γ and interleukin (IL)-2 and activates IL-10 expression. Therefore, we hypothesized that it might be a potential agent used to block allograft rejections. However, most studies of the immunosuppressive mechanisms associated with HA were undertaken at the cellular level. In order to augment these studies, we evaluated the immunosuppressive effects of HA in vivo using an HA transgenic mouse model. Result: Our results revealed similar findings to those reported by in vitro studies, specifically that HA induced prostaglandin E2 expression, downregulated IFN-γ and IL-2 expression, and promoted IL-10 secretion via E-type prostanoid receptor 4. Additionally, we observed that HA overexpression inhibited lipopolysaccharide-induced TLR4 activation. These findings provide insight into a new potential agent capable of blocking graft rejection. Conclusion: Our founding suggested that HA-related treatment could be a promising option to improve the viability of grafts in human.