An Overview on the Field of Micro- and Nanotechnologies for Synthetic Peptide-Based Vaccines

The development of synthetic peptide-based vaccines has many advantages in comparison with vaccines based on live attenuated organisms, inactivated or killed organism, or toxins. Peptide-based vaccines cannot revert to a virulent form, allow a better conservation, and are produced more easily and safely. However, they generate a weaker immune response than other vaccines, and the inclusion of adjuvants and/or the use of vaccine delivery systems is almost always needed. Among vaccine delivery systems, micro- and nanoparticulated ones are attractive, because their particulate nature can increase cross-presentation of the peptide. In addition, they can be passively or actively targeted to antigen presenting cells. Furthermore, particulate adjuvants are able to directly activate innate immune system in vivo. Here, we summarize micro- and nanoparticulated vaccine delivery systems used in the field of synthetic peptide-based vaccines as well as strategies to increase their immunogenicity.

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A “Loss-of-Tolerance” Phenotype of the Liver Macrophage System to LPS Induces Overwhelming Systemic Inflammation and Early Death in a Knockout-Transgenic Mouse Model of Sickle Cell Disease.

Blood ◽

10.1182/blood.v106.11.2337.2337 ◽

2005 ◽

Vol 106 (11) ◽

pp. 2337-2337

Author(s):

Steffen E. Meiler ◽

Ilka Theruvath ◽

Marlene Wade ◽

C. Alvin Head

Keyword(s):

Immune Response ◽

Immune System ◽

Sickle Cell Disease ◽

Sickle Cell ◽

Innate Immune System ◽

Innate Immune ◽

Cell Disease ◽

Liver Macrophage ◽

Tnf Α

Abstract Infections and death from fulminant sepsis remain a constant threat to patients with sickle cell disease (SCD). Established explanations include an impaired ability to contain and eliminate pathogenic organisms due to defects in spleen function and adaptive immunity. To the contrary, very little is known about the “first-line” response of the innate immune system after contact with pathogen associated cell components. An escalated immune (inflammatory) response to microbial structures would provide an alternative mechanism to explain increased rates of infectious complications and septic death in sickle cell patients. To test this hypothesis, knockout-transgenic mice homozygous for the human β-sickle globin gene (SS) were treated with a low dose of the canonical infectious stimulus lipopolysaccharide (0.5 μg/g bw; i.p.; 22°C) and compared to heterozygous sickle trait (ST) and C57BL/6 animals. Phenotypically, sickle mice appeared much sicker after LPS and displayed strict seclusion behavior, cessation of food intake, and physiological signs of stress. Body core (rectal) temperature decreased precipitously and irreversibly in sickle animals (~12°C/8hrs vs. ~2°C/8hrs [ST and C57BL/6]) followed by rapid death (50%/12h; 100%/48h vs 0% [ST; C57BL/6]). Analysis of the LD50 demonstrated an ~500-fold increased sensitivity to LPS in sickle mice (0.05 μg/g vs 25 μg/g [ST]). Serum cytokines (TNF-α, IL-6) were dramatically up-regulated in SS mice compared to control (TNF-α: 16-fold/2 hr post LPS, 100-fold/3 hr post LPS). Organ-specific immunohistochemical analysis of the marker cytokine TNF-α in liver, bone marrow, spleen, lung, and kidney four hrs after LPS revealed an astonishingly super-induced expression in the liver of sickle animals compared to controls. The liver of sickle animals showed several areas of coagulative liver necrosis unrelated to LPS and consistent with ischemic injury from recurrent sickle-mediated vascular occlusion. Immunoreactivity to TNF-α was most pronounced in areas of liver injury and mostly restricted to large macrophages (F4/80 +) surrounded by a T-lymphocytic (CD3+) infiltrate. In vitro analysis of Kupffer cells to serial concentrations of LPS recapitulated the in vivo results, demonstrating up to 20-fold larger TNF-α levels in cells derived from sickle livers. To further elucidate the role of the liver macrophage in the in vivo immune response to LPS, sickle animals were challenged with LPS forty-eight hrs after Kupffer cell depletion with Gadolinium Chloride. Sickle mice treated with Gadolinium experienced enhanced survival and an ~90% reduction in serum TNF-α levels. In summary, the present study offers new insights into the responsiveness of the innate immune system in SCD to the highly conserved bacterial cell component, lipopolysaccharide. Unexpectedly, these data suggest that the liver macrophage in SCD, typically a cell type tolerant to the pro-inflammatory effects of LPS, has a cardinal role in orchestrating an excessive and harmful innate immune response to bacterial infections. Further studies will have to determine the immune response to other conserved bacterial structures and relate these findings to the human form of SCD.

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Modeling Virus-Induced Inflammation in Zebrafish: A Balance Between Infection Control and Excessive Inflammation

Frontiers in Immunology ◽

10.3389/fimmu.2021.636623 ◽

2021 ◽

Vol 12 ◽

Author(s):

Con Sullivan ◽

Brandy-Lee Soos ◽

Paul J. Millard ◽

Carol H. Kim ◽

Benjamin L. King

Keyword(s):

Immune Response ◽

Immune System ◽

Inflammatory Response ◽

Viral Infection ◽

Innate Immune Response ◽

Innate Immune System ◽

Innate Immune ◽

Zebrafish Model ◽

Infection Models

The inflammatory response to viral infection in humans is a dynamic process with complex cell interactions that are governed by the immune system and influenced by both host and viral factors. Due to this complexity, the relative contributions of the virus and host factors are best studied in vivo using animal models. In this review, we describe how the zebrafish (Danio rerio) has been used as a powerful model to study host-virus interactions and inflammation by combining robust forward and reverse genetic tools with in vivo imaging of transparent embryos and larvae. The innate immune system has an essential role in the initial inflammatory response to viral infection. Focused studies of the innate immune response to viral infection are possible using the zebrafish model as there is a 4-6 week timeframe during development where they have a functional innate immune system dominated by neutrophils and macrophages. During this timeframe, zebrafish lack a functional adaptive immune system, so it is possible to study the innate immune response in isolation. Sequencing of the zebrafish genome has revealed significant genetic conservation with the human genome, and multiple studies have revealed both functional conservation of genes, including those critical to host cell infection and host cell inflammatory response. In addition to studying several fish viruses, zebrafish infection models have been developed for several human viruses, including influenza A, noroviruses, chikungunya, Zika, dengue, herpes simplex virus type 1, Sindbis, and hepatitis C virus. The development of these diverse viral infection models, coupled with the inherent strengths of the zebrafish model, particularly as it relates to our understanding of macrophage and neutrophil biology, offers opportunities for far more intensive studies aimed at understanding conserved host responses to viral infection. In this context, we review aspects relating to the evolution of innate immunity, including the evolution of viral pattern recognition receptors, interferons and interferon receptors, and non-coding RNAs.

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Insights into Sensing of Murine Retroviruses

Viruses ◽

10.3390/v12080836 ◽

2020 ◽

Vol 12 (8) ◽

pp. 836

Author(s):

Eileen A. Moran ◽

Susan R. Ross

Keyword(s):

Immune Response ◽

Immune System ◽

Nucleic Acid ◽

Adaptive Immunity ◽

Innate Immune System ◽

Innate Immune ◽

Genetic Tool ◽

Causes Of Disease ◽

Retrovirus Infection ◽

Insight Into

Retroviruses are major causes of disease in animals and human. Better understanding of the initial host immune response to these viruses could provide insight into how to limit infection. Mouse retroviruses that are endemic in their hosts provide an important genetic tool to dissect the different arms of the innate immune system that recognize retroviruses as foreign. Here, we review what is known about the major branches of the innate immune system that respond to mouse retrovirus infection, Toll-like receptors and nucleic acid sensors, and discuss the importance of these responses in activating adaptive immunity and controlling infection.

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Phenoloxidase activity and haemolymph cytology in honeybees challenged with a virus suspension (deformed wings virus DWV) or phosphate buffered suspension (PBS)

Ciência Rural ◽

10.1590/0103-8478cr20180726 ◽

2019 ◽

Vol 49 (2) ◽

Cited By ~ 3

Author(s):

Francesca Millanta ◽

Simona Sagona ◽

Maurizio Mazzei ◽

Mario Forzan ◽

Alessandro Poli ◽

...

Keyword(s):

Immune Response ◽

Immune System ◽

Immune Responses ◽

Innate Immune System ◽

Innate Immune ◽

Additional Stress ◽

Varroa Mite ◽

Virus Suspension ◽

Phenoloxidase Activity ◽

Cell Immunity

ABSTRACT: The innate immune system of honeybees mainly consists in antimicrobial peptides, cellular immunity and melanisation. In order to investigate the immune response of honeybees to immune stressors, three stress degrees were tested. Newly emerged bees naturally DWV-infected were collected from a Varroa mite-free apiary and divided into three experimental groups: naturally DWV infected bees, PBS injected bees, and artificially DWV super infected bees. Phenoloxidase activity and haemolymph cellular subtype count were investigated. Phenoloxidase activity was highest (P<0.05) in DWV-superinfected bees, and the haemocyte population differed within the three observed groups. Although, immune responses following DWV infection have still not been completely clarified, this investigation sheds light on the relation between cell immunity and the phenoloxidase activity of DWV-naturally infected honeybees exposed to additional stress such as injury and viral superinfection.

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P53 and The Immune Response: 40 Years of Exploration—A Plan for the Future

International Journal of Molecular Sciences ◽

10.3390/ijms21020541 ◽

2020 ◽

Vol 21 (2) ◽

pp. 541 ◽

Cited By ~ 11

Author(s):

Arnold J. Levine

Keyword(s):

Immune Response ◽

Immune System ◽

Innate Immune System ◽

P53 Protein ◽

P53 Gene ◽

T Cell Response ◽

Innate Immune ◽

Transplantation Antigen ◽

Mutant Form ◽

The Future

The p53 field was born from a marriage of the techniques of cancer virus research and immunology. Over the past 40 years, it has followed the path of cancer research. Now cancer treatments are turning to immunotherapy, and there are many hints of the role of the p53 protein in both the regulation of the innate immune system and as an antigen in adaptive immune responses. The p53 gene and protein are part of the innate immune system, and play an important role in infectious diseases, senescence, aging, and the surveillance of repetitive DNA and RNAs. The mutant form of the p53 protein in cancers elicits both a B-cell antibody response (a tumor antigen) and a CD-8 killer T-cell response (a tumor-specific transplantation antigen). The future will take the p53-immune response field of research into cancer immunotherapy, autoimmunity, inflammatory responses, neuro-degeneration, aging, and life span, and the regulation of epigenetic stability and tissue regeneration. The next 40 years will bring the p53 gene and its proteins out of a cancer focus and into an organismic and environmental focus.

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Effect of Hypoglycemia on Inflammatory Responses and the Response to Low-Dose Endotoxemia in Humans

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2018-01168 ◽

2018 ◽

Vol 104 (4) ◽

pp. 1187-1199 ◽

Cited By ~ 15

Author(s):

Ahmed Iqbal ◽

Lynne R Prince ◽

Peter Novodvorsky ◽

Alan Bernjak ◽

Mark R Thomas ◽

...

Keyword(s):

Cardiovascular Risk ◽

Immune System ◽

Innate Immune System ◽

Low Dose ◽

Inflammatory Responses ◽

Platelet Reactivity ◽

Innate Immune ◽

Endotoxin Challenge ◽

Intermediate Monocytes

Abstract Context Hypoglycemia is emerging as a risk for cardiovascular events in diabetes. We hypothesized that hypoglycemia activates the innate immune system, which is known to increase cardiovascular risk. Objective To determine whether hypoglycemia modifies subsequent innate immune system responses. Design and Setting Single-blinded, prospective study of three independent parallel groups. Participants and Interventions Twenty-four healthy participants underwent either a hyperinsulinemic-hypoglycemic (2.5 mmol/L), euglycemic (6.0 mmol/L), or sham-saline clamp (n = 8 for each group). After 48 hours, all participants received low-dose (0.3 ng/kg) intravenous endotoxin. Main Outcome Measures We studied in-vivo monocyte mobilization and monocyte-platelet interactions. Results Hypoglycemia increased total leukocytes (9.98 ± 1.14 × 109/L vs euglycemia 4.38 ± 0.53 × 109/L, P < 0.001; vs sham-saline 4.76 ± 0.36 × 109/L, P < 0.001) (mean ± SEM), mobilized proinflammatory intermediate monocytes (42.20 ± 7.52/μL vs euglycemia 20.66 ± 3.43/μL, P < 0.01; vs sham-saline 26.20 ± 3.86/μL, P < 0.05), and nonclassic monocytes (36.16 ± 4.66/μL vs euglycemia 12.72 ± 2.42/μL, P < 0.001; vs sham-saline 19.05 ± 3.81/μL, P < 0.001). Following hypoglycemia vs euglycemia, platelet aggregation to agonist (area under the curve) increased (73.87 ± 7.30 vs 52.50 ± 4.04, P < 0.05) and formation of monocyte-platelet aggregates increased (96.05 ± 14.51/μL vs 49.32 ± 6.41/μL, P < 0.05). Within monocyte subsets, hypoglycemia increased aggregation of intermediate monocytes (10.51 ± 1.42/μL vs euglycemia 4.19 ± 1.08/μL, P < 0.05; vs sham-saline 3.81± 1.42/μL, P < 0.05) and nonclassic monocytes (9.53 ± 1.08/μL vs euglycemia 2.86 ± 0.72/μL, P < 0.01; vs sham-saline 3.08 ± 1.01/μL, P < 0.05), with platelets compared with controls. Hypoglycemia led to greater leukocyte mobilization in response to subsequent low-dose endotoxin challenge (10.96 ± 0.97 vs euglycemia 8.21 ± 0.85 × 109/L, P < 0.05). Conclusions Hypoglycemia mobilizes monocytes, increases platelet reactivity, promotes interaction between platelets and proinflammatory monocytes, and potentiates the subsequent immune response to endotoxin. These changes may contribute to increased cardiovascular risk observed in people with diabetes.

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Interaction of Antibiotics with Innate Host Defense Factors against Salmonella enterica Serotype Newport

mSphere ◽

10.1128/msphere.00410-17 ◽

2017 ◽

Vol 2 (6) ◽

Cited By ~ 15

Author(s):

George Sakoulas ◽

Monika Kumaraswamy ◽

Armin Kousha ◽

Victor Nizet

Keyword(s):

Innate Immunity ◽

Immune System ◽

Innate Immune System ◽

Salmonella Enterica ◽

Clinical Performance ◽

Innate Immune ◽

Content Type ◽

Antimicrobial Assay

ABSTRACT It is becoming increasingly understood that the current paradigms of in vitro antimicrobial susceptibility testing may have significant shortcomings in predicting activity in vivo. This study evaluated the activity of several antibiotics alone and in combination against clinical isolates of Salmonella enterica serotype Newport (meningitis case) utilizing both conventional and physiological media. In addition, the interactions of these antibiotics with components of the innate immune system were evaluated. Azithromycin, which has performed quite well clinically despite high MICs in conventional media, was shown to be more active in physiological media and to enhance innate immune system killing. Alternatively, chloramphenicol did not show enhanced immune system killing, paralleling its inferior clinical performance to other antibiotics that have been used to treat Salmonella meningitis. These findings are important additions to the building understanding of current in vitro antimicrobial assay limitations that hopefully will amount to future improvements in these assays to better predict clinical efficacy and activity in vivo. This study examines the pharmacodynamics of antimicrobials that are used to treat Salmonella with each other and with key components of the innate immune system. Antimicrobial synergy was assessed using time-kill and checkerboard assays. Antimicrobial interactions with innate immunity were studied by employing cathelicidin LL-37, whole-blood, and neutrophil killing assays. Ceftriaxone and ciprofloxacin were found to be synergistic in vitro against Salmonella enterica serotype Newport. Ceftriaxone, ciprofloxacin, and azithromycin each demonstrated synergy with the human cathelicidin defense peptide LL-37 in killing Salmonella. Exposure of Salmonella to sub-MICs of ceftriaxone resulted in enhanced susceptibility to LL-37, whole blood, and neutrophil killing. The activity of antibiotics in vivo against Salmonella may be underestimated in bacteriologic media lacking components of innate immunity. The pharmacodynamic interactions of antibiotics used to treat Salmonella with each other and with components of innate immunity warrant further study in light of recent findings showing in vivo selection of antimicrobial resistance by single agents in this pathogen. IMPORTANCE It is becoming increasingly understood that the current paradigms of in vitro antimicrobial susceptibility testing may have significant shortcomings in predicting activity in vivo. This study evaluated the activity of several antibiotics alone and in combination against clinical isolates of Salmonella enterica serotype Newport (meningitis case) utilizing both conventional and physiological media. In addition, the interactions of these antibiotics with components of the innate immune system were evaluated. Azithromycin, which has performed quite well clinically despite high MICs in conventional media, was shown to be more active in physiological media and to enhance innate immune system killing. Alternatively, chloramphenicol did not show enhanced immune system killing, paralleling its inferior clinical performance to other antibiotics that have been used to treat Salmonella meningitis. These findings are important additions to the building understanding of current in vitro antimicrobial assay limitations that hopefully will amount to future improvements in these assays to better predict clinical efficacy and activity in vivo.

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Mycobacterium avium Biofilm Attenuates Mononuclear Phagocyte Function by Triggering Hyperstimulation and Apoptosis during Early Infection

Infection and Immunity ◽

10.1128/iai.00820-13 ◽

2013 ◽

Vol 82 (1) ◽

pp. 405-412 ◽

Cited By ~ 25

Author(s):

Sasha J. Rose ◽

Luiz E. Bermudez

Keyword(s):

Immune System ◽

Mycobacterium Avium ◽

Innate Immune System ◽

Innate Immune ◽

Mononuclear Phagocytes ◽

Bacterial Killing ◽

Content Type ◽

Tnf Α

ABSTRACTMycobacterium aviumsubsp.hominissuisis an opportunistic human pathogen that has been shown to form biofilmin vitroandin vivo. Biofilm formationin vivoappears to be associated with infections in the respiratory tract of the host. The reasoning behind howM. aviumsubsp.hominissuisbiofilm is allowed to establish and persist without being cleared by the innate immune system is currently unknown. To identify the mechanism responsible for this, we developed anin vitromodel using THP-1 human mononuclear phagocytes cocultured with establishedM. aviumsubsp.hominissuisbiofilm and surveyed various aspects of the interaction, including phagocyte stimulation and response, bacterial killing, and apoptosis.M. aviumsubsp.hominissuisbiofilm triggered robust tumor necrosis factor alpha (TNF-α) release from THP-1 cells as well as superoxide and nitric oxide production. Surprisingly, the hyperstimulated phagocytes did not effectively eliminate the cells of the biofilm, even when prestimulated with gamma interferon (IFN-γ) or TNF-α or cocultured with natural killer cells (which have been shown to induce anti-M. aviumsubsp.hominissuisactivity when added to THP-1 cells infected with planktonicM. aviumsubsp.hominissuis). Time-lapse microscopy and the TUNEL (terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling) assay determined that contact with theM. aviumsubsp.hominissuisbiofilm led to early, widespread onset of apoptosis, which is not seen until much later in planktonicM. aviumsubsp.hominissuisinfection. Blocking TNF-α or TNF-R1 during interaction with the biofilm significantly reduced THP-1 apoptosis but did not lead to elimination ofM. aviumsubsp.hominissuis. Our data collectively indicate thatM. aviumsubsp.hominissuisbiofilm induces TNF-α-driven hyperstimulation and apoptosis of surveilling phagocytes, which prevents clearance of the biofilm by cells of the innate immune system and allows the biofilm-associated infection to persist.

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Redundant Catalases Detoxify Phagocyte Reactive Oxygen and Facilitate Histoplasma capsulatum Pathogenesis

Infection and Immunity ◽

10.1128/iai.00173-13 ◽

2013 ◽

Vol 81 (7) ◽

pp. 2334-2346 ◽

Cited By ~ 35

Author(s):

Eric D. Holbrook ◽

Katherine A. Smolnycki ◽

Brian H. Youseff ◽

Chad A. Rappleye

Keyword(s):

Immune System ◽

Innate Immune System ◽

Histoplasma Capsulatum ◽

Reactive Oxygen ◽

Innate Immune ◽

Respiratory Pathogen ◽

Human Neutrophils ◽

Content Type

ABSTRACTHistoplasma capsulatumis a respiratory pathogen that infects phagocytic cells. The mechanisms allowingHistoplasmato overcome toxic reactive oxygen molecules produced by the innate immune system are an integral part ofHistoplasma's ability to survive during infection. To probe the contribution ofHistoplasmacatalases in oxidative stress defense, we created and analyzed the virulence defects of mutants lacking CatB and CatP, which are responsible for extracellular and intracellular catalase activities, respectively. Both CatB and CatP protectedHistoplasmafrom peroxide challengein vitroand from antimicrobial reactive oxygen produced by human neutrophils and activated macrophages. Optimal protection required both catalases, as the survival of a double mutant lacking both CatB and CatP was lower than that of single-catalase-deficient cells. Although CatB contributed to reactive oxygen species defensesin vitro, CatB was dispensable for lung infection and extrapulmonary disseminationin vivo. Loss of CatB from a strain also lacking superoxide dismutase (Sod3) did not further reduce the survival ofHistoplasmayeasts. Nevertheless, some catalase function was required for pathogenesis since simultaneous loss of both CatB and CatP attenuatedHistoplasmavirulencein vivo. These results demonstrate thatHistoplasma's dual catalases comprise a system that enablesHistoplasmato efficiently overcome the reactive oxygen produced by the innate immune system.

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In Vivo Discrimination of Type 3 Secretion System-Positive and -Negative Pseudomonas aeruginosa via a Caspase-1-Dependent Pathway

Infection and Immunity ◽

10.1128/iai.00744-10 ◽

2010 ◽

Vol 78 (11) ◽

pp. 4744-4753 ◽

Cited By ~ 21

Author(s):

Tamding Wangdi ◽

Lilia A. Mijares ◽

Barbara I. Kazmierczak

Keyword(s):

Pseudomonas Aeruginosa ◽

Immune System ◽

Innate Immune System ◽

Interleukin 1 ◽

Innate Immune ◽

Secretion Systems ◽

Caspase 1 ◽

Molecular Patterns ◽

Type 3

ABSTRACT Microbe-associated molecular patterns are recognized by Toll-like receptors of the innate immune system. This recognition enables a rapid response to potential pathogens but does not clearly provide a way for the innate immune system to discriminate between virulent and avirulent microbes. We find that pulmonary infection of mice with type 3 translocation-competent Pseudomonas aeruginosa triggers a rapid inflammatory response, while infection with isogenic translocation-deficient mutants does not. Discrimination between translocon-positive and -negative bacteria requires caspase-1 activity in bone marrow-derived cells and interleukin-1 receptor signaling. Thus, the activation of caspase-1 by bacteria expressing type 3 secretion systems allows for rapid recognition of bacteria expressing conserved functions associated with virulence.

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