Acquired Host Defense Research Articles

IgE Effector Mechanisms, in Concert with Mast Cells, Contribute to Acquired Host Defense against Staphylococcusaureus

Allergies are considered to represent mal-directed type 2 immune responses against mostly innocuous exogenous compounds. Immunoglobulin E (IgE) antibodies are a characteristic feature of allergies and mediate hypersensitivity against allergens through activation of effector cells, particularly mast cells (MCs). Although the physiological functions of this dangerous branch of immunity have remained enigmatic, recent evidence shows that allergic immune reactions can help to protect against the toxicity of venoms. Because bacteria are a potent alternative source of toxins, we assessed the possible role of allergy-like type 2 immunity in antibacterial host defense. We discovered that the adaptive immune response against Staphylococcus aureus (SA) skin infection substantially improved systemic host defense against secondary SA infections in mice. Moreover, this acquired protection depended on IgE effector mechanisms and MCs. Importantly, our results reveal a previously unknown physiological function of allergic immune responses, IgE antibodies, and MCs in host defense against a pathogenic bacterium.

IgE antibodies, FcεRIα, and IgE-mediated local anaphylaxis can limit snake venom toxicity

Type 2 cytokine-related immune responses associated with development of antigen-specific IgE antibodies can contribute to pathology in patients with allergic diseases and to fatal anaphylaxis. However, recent findings in mice indicate that IgE also can enhance defense against honeybee venom. We tested whether IgE antibodies, IgE-dependent effector mechanisms, and a local anaphylactic reaction to an unrelated antigen can enhance defense against Russell viper venom (RVV) and determined whether such responses can be influenced by immunization protocol or mouse strain. We compared the resistance of RVV-immunized wild-type, IgE-deficient, and Fcer1a-deficient mice after injection of a potentially lethal dose of RVV. A single prior exposure to RVV enhanced the ability of wild-type mice, but not mice lacking IgE or functional FcεRI, to survive challenge with a potentially lethal amount of RVV. Moreover, IgE-dependent local passive cutaneous anaphylaxis in response to challenge with an antigen not naturally present in RVV significantly enhanced resistance to the venom. Finally, we observed different effects on resistance to RVV or honeybee venom in BALB/c versus C57BL/6 mice that had received a second exposure to that venom before challenge with a high dose of that venom. These observations illustrate the potential benefit of IgE-dependent effector mechanisms in acquired host defense against venoms. The extent to which type 2 immune responses against venoms can decrease pathology associated with envenomation seems to be influenced by the type of venom, the frequency of venom exposure, and the genetic background of the host.

Vitamin D Every Day to Keep the Infection Away?

Within the last decade, vitamin D has emerged as a central regulator of host defense against infections. In this regard, vitamin D triggers effective antimicrobial pathways against bacterial, fungal and viral pathogens in cells of the human innate immune system. However, vitamin D also mediates potent tolerogenic effects: it is generally believed that vitamin D attenuates inflammation and acquired immunity, and thus potentially limits collateral tissue damage. Nevertheless, several studies indicate that vitamin D promotes aspects of acquired host defense. Clinically, vitamin D deficiency has been associated with an increased risk for various infectious diseases in epidemiological studies; yet, robust data from controlled trials investigating the use of vitamin D as a preventive or therapeutic agent are missing. In this review, we summarize the current knowledge regarding the effect of vitamin D on innate and acquired host defense, and speculate on the difficulties to translate the available molecular medicine data into practical therapeutic or preventive recommendations.

Identification of 15 new psoriasis susceptibility loci highlights the role of innate immunity.

SummaryTo gain further insight into the genetic architecture of psoriasis, we conducted a meta-analysis of three genome-wide association studies (GWAS) and two independent datasets genotyped on the Immunochip, involving 10,588 cases and 22,806 controls in total. We identified 15 new disease susceptibility regions, increasing the number of psoriasis-associated loci to 36 for Caucasians. Conditional analyses identified five independent signals within previously known loci. The newly identified shared disease regions encompassed a number of genes whose products regulate T-cell function (e.g. RUNX3, TAGAP and STAT3). The new psoriasis-specific regions were notable for candidate genes whose products are involved in innate host defense, encoding proteins with roles in interferon-mediated antiviral responses (DDX58), macrophage activation (ZC3H12C), and NF-κB signaling (CARD14 and CARM1). These results portend a better understanding of shared and distinctive genetic determinants of immune-mediated inflammatory disorders and emphasize the importance of the skin in innate and acquired host defense.

Pathogenesis and treatment concepts of orthopaedic biofilm infections

Implant-associated infection is caused by surface-adhering bacteria persisting as biofilm. Periprosthetic joint infection is difficult to diagnose and treat. The high susceptibility of implanted devices to infection is because of a locally acquired host defense defect, and persistence is mainly because of the rapid formation of a biofilm resistant to host defense and antimicrobial agents. Successful treatment of periprosthetic joint infection requires the optimal surgical procedure combined with long-term antimicrobial therapy directed against surface-adhering microorganisms. Surgical treatment according to an algorithm has been validated in several observational studies. The role of rifampin against device-associated staphylococcal infection has been evaluated in an animal model, in observational studies and in a controlled trial. Given the limited efficacy of traditional antibiotics in implant-associated infections, novel strategies such as coating of the device, vaccination against biofilms, and quorum-sensing inhibitors are promising future options for prevention and treatment.

Mechanism of Immunity to Tick infestation in Livestock

Immunological interaction at the tick host interface involves both innate and acquired host defenses against infestation and Immunomodulatory countermeasures by thetick. Acquired resistance to tick infestation involves humoral and cellular immlmoregulatory effector pathways. Tick-borne disease-causing agentspr exploit tick suppression of host defenses during transmission and initiation of infection. Because of the public health importance of ticks and tick- borne diseases, it is crucial that we understand these interactions and exploit them in novel immunological control. The tick-host-pathogen interface is characterized * Disease-causing agents transmitted by blood- by complex immunological interactions. Immuno- feeding arthropods are significant public health logical interaction at the tick host interface involve concerns. In addition to the emergence of new both innate and acquired host defenses against diseases, many well-recognised vector-borne diseases infestation and Immunomodulatory countermeasures are occurring more frequently and are increasing the by the tick. The cellular and molecular immunological range over which they occur. Many factors contribute bases of these host-parasite relationships are being to the emergence and re-emergence of arthropod- defined. Acquired resistance to tick infestation borne diseases: insecticide/acaricide resistance; drug involves humoral and cellular immlmoregulatory resistance; economic and social factors; environ- effector pathways. It impairs tick engorgement, ova mental change; and genetic changes in the vector- production, and viability Ticks responds by borne pathogens. suppressing antibody production, complement and * On a global basis, ticks are second only to cytokine elaboration by both antigen-presenting cells mosquitoes as vectors of disease-causing agents to and specific T cell subset . Tick countermeasures to humans, and they are the most important arthropod host defenses reduce T-lymphocyte proliferation, transmitting pathogens to other animal species.The elaboration of the Th1 cytokines interleukin-2 and public health importance of ticks is not diminishing. interferon-y, production of macrophage cytokines Furthermore, new tick-borne disease causing agents interleukin-1 and tumor necrosis factor, and antibody are being discovered. Lyme borreliosis, caused by responses. Tick-borne disease-causing agentspr Borrelia burgdorferi, occurs in regions with temperate exploit tick suppression of host defenses during climates, and it is the most frequently reported vector- transmission and initiation of infection. Because of the borne disease in the United States. In the United public health importance of ticks and tick-borne States, the vectors of B. burgdorferi are Ixodes diseases, it is crucial that we understand these scapularis in the east and midwest and Ixodes interactions and exploit them in novel immunological pacificus in the west. In addition to B. burgdorferi, I. control.The dynamic balance between acquired scapularis is a vector of the human pathogens: resistance and tick modulation of host immunity Babesia microti; the causative agent of human affects engorgement and pathogen transmission. So a granulocytic ehrlichiosis and a recently described thorough understanding of mechanism of host encephalitis-like virus, In addition, Ehrlichia immunity to ticks is essential for rational devlopement chaffeensis, transmitted by Amblyomma americanum, of antitick vaccine.

EnteroaggregativeEscherichia coli(EAEC) Impairs Growth while Malnutrition Worsens EAEC Infection: A Novel Murine Model of the Infection Malnutrition Cycle

Enteroaggregative Escherichia coli is emerging as an increasingly recognized cause of persistent, mildly inflammatory diarrhea in the United States, especially among patients with AIDS, as well as among children, for whom it is accompanied by growth shortfalls. We describe a novel model of disease induced in neonatal and weaned C57BL/6 mice by pathogenic strains of enteroaggregative E. coli 042 and JM221. Enteroaggregative E. coli caused growth impairment (up to 47%), persistent stool shedding (for >3 weeks), and a substantial tissue burden of organisms (150,000 organisms per milligram of tissue), as well as histopathological changes in the colonic epithelium (days 4 and 6 of infection) using the model. Undernutrition in neonatal mice, as well as in weaned mice, intensified infection by 1-4 logs, as assessed by quantitative polymerase chain reaction for fecal shedding of organisms. Growth impairment was dependent on both microorganism burden and challenge dose. Both neonatal and weaned mice provide models for a vicious cycle of enteroaggregative E. coli infection that causes growth shortfalls and undernutrition, thus worsening infection. Hence, these neonatal and weaned mice provide the opportunity to dissect mechanisms of this cycle in childhood malnutrition, as well as to define the role played by innate and acquired host defenses in this important infection.

Targeted Immunotherapy for Staphylococcal Infections

Staphylococcal infections represent an enormous burden to the public health system in the US and worldwide. While traditionally restricted to the hospital setting, highly virulent strains have recently emerged that may cause severe, even fatal, disease in healthy adults outside healthcare settings. This situation, together with the increasing resistance to many antibacterials in a wide variety of staphylococcal strains, requires that vaccine development for staphylococcal diseases be re-evaluated. Finding a vaccine for staphylococci is not trivial, as protective immunity to staphylococcal infections does not appear to exist at a significant degree, which may be partly due to the fact that our immune system is in constant contact with staphylococcal antigens and many strains are commensal organisms on human epithelia. Furthermore, the most virulent species, Staphylococcus aureus, produces protein A, a powerful means to evade acquired host defense. While two high-profile vaccine preparations have failed clinical trials within the last few years, promising results from novel approaches based on the combination of systematically selected antigens have been reported. These combinatory vaccines target microbial surface components recognizing adhesive matrix molecules (MSCRAMMs), a family of bacterial proteins that bind to human extracellular matrix components. In addition, polysaccharide and other nonprotein antigens may represent suitable vaccine targets on the staphylococcal cell surface.

“In Vivo” Depletion of Macrophages by Liposome-Mediated “Suicide”

Publisher Summary Macrophages are multifunctional cell and play a key role in natural and acquired host defense reactions, in homeostasis, and in the regulation of numerous biological processes. The main tools used are phagocytosis followed by intracellular digestion and production and release of soluble mediators, such as cytokines, chemokines, and nitric oxide (NO). Macrophages can be found as resident cells in all organs of the body, and they can be recruited to sites of inflammation. The depletion of macrophages followed by functional studies in such macrophage-depleted animals forms a generally accepted approach to establish their role in any particular biomedical phenomenon. The methods for depletion of macrophages are based on the liposome-mediated intracellular delivery of the bisphosphonate clodronate. Liposomes are used as a Trojan horse to get the small clodronate molecules into the macrophage. Once ingested by macrophages, the phospholipid bilayers of liposomes are disrupted under the influence of lysosomal phospholipases. The strongly hydrophilic clodronate molecules intracellularly released do not escape from the cell. As a result, the intracellular clodronate concentration increases as more liposomes are ingested and digested. At a certain clodronate concentration, irreversible damage causes the macrophage to be killed by apoptosis. Free clodronate molecules show an extremely short half-life in circulation and body fluids. They are removed by the renal system. Clodronate in its free form is used widely as a drug for the treatment of malignant hypercalcemia and painful bone metastasis caused by hormone-refractory prostate cancer, emphasizing its nontoxic nature.

Intrinsic and innate defenses in the lung: intersection of pathways regulating lung morphogenesis, host defense, and repair.

This Perspective series seeks to summarize the present concepts regarding the biological processes that mediate intrinsic and innate host defense against microbial invasion of the lung. From an evolutionary standpoint, the requirements for an extensive gas exchange region that comes in direct contact with inhaled particles and pathogens present a formidable challenge that has been countered by the layering and intersection of several intrinsic defense systems. These systems, detailed in the accompanying articles, maintain pulmonary form and function required for ventilation by means of structural, mechanical, chemical, and cellular strategies, as well as innate and acquired host defenses. The epithelial barrier itself represents a first line of defense against pathogens, and its effectiveness is greatly enhanced by fluid homeostasis and mucociliary clearance. As discussed by Knowles and Boucher in this series, these mechanisms protect the epithelium and physically remove inhaled pathogens from the lung. Additional protection comes from polypeptide mediators of the innate host defense, such as the defensins and other antibiotic peptides reviewed by Ganz in this series, and the collectin family, considered by McCormack and Whitsett. Professional phagocytes also play their part in host defense in this tissue, in part by responding to molecules found on the surface of common pathogenic microbes. Finally, the cytokine and chemokine pathways that cooperate with host defense polypeptides to mediate initial host defenses by phagocytes also orchestrate tissue repair and subsequent acquired immune responses following infection, as discussed by Strieter et al. The interplay of these various mechanisms is depicted in Figure ​Figure11. Figure 1 The sterility of the respiratory tract is maintained by the concerted actions of the epithelial barrier, innate defense molecules, and responses of both the epithelium and professional phagocytes that remove pathogens and their products from the lung. ... The concerted effects of mechanical, innate, and acquired host defense systems serve to recognize, localize, kill, and remove pathogens to maintain sterility of pulmonary tissues and the host. In general, pathogens are cleared from the lung without persistent or robust inflammation, thus protecting its inherent structure and maintaining its function following exposure to microbes. It is the failure of various arms of the host defense systems that allows local or systemic infection and destruction of lung tissue that are frequently the basis of morbidity and mortality from common lung diseases, whether related to genetic or environmental disease processes. Deficient or uncontrolled host defenses and inflammation underlie some of the most common pulmonary disorders — chronic obstructive pulmonary disease, cystic fibrosis, acute and chronic pneumonia, asthma, emphysema, and bronchopulmonary dysplasia.

Evolution and diversity of the complement system of poikilothermic vertebrates.

In mammals the complement system plays an important role in innate and acquired host defense mechanisms against infection and in various immunoregulatory processes. The complement system is an ancient defense mechanism that is already present in the invertebrate deuterostomes. In these species as well as in agnathans (the most primitive vertebrate species), both the alternative and lectin pathway of complement activation are already present, and the complement system appears to be involved mainly in opsonization of foreign material. With the emergence of immunoglobulins in cartilaginous fish, the classical and lytic pathways first appear. The rest of the poikilothermic species, from teleosts to reptilians, appear to contain a well-developed complement system resembling that of homeothermic vertebrates. However, important differences remain. Unlike homeotherms, several species of poikilotherms have recently been shown to possess multiple forms of complement components (C3 and factor B) that are structurally and functionally more diverse than those of higher vertebrates. It is noteworthy that the multiple forms of C3 that have been characterized in several teleost fish are able to bind with varying efficiencies to various complement-activating surfaces. We hypothesize that this diversity has allowed these animals to expand their innate capacity for immune recognition.

Immune response to fungal infection.

In general, fungi are saprophytes that are well adapted to grow in nature supported by diverse nutritional substrates. For fungi, in contrast to many other microorganisms that infect humans, parasitism is an accidental phenomenon rather than an obligatory requirement for survival. Thus, with progressive improvement in our capabilities to prolong survival of patients with global defects in host defense mechanisms, clinical experience suggests that human tissues may support growth of numerous species of saprophytic fungi that share the capacity to grow at 37 degrees C. Normally, however, a broad array of natural and acquired host defense mechanisms make the occurrence of progressive, systemic, life-threatening mycoses extremely rare events. When one or another of these host defense mechanisms is compromised, one of a variety of significant fungal infections may then progress. Mycoses may be broadly categorized into those controlled largely by natural cellular defenses vs. acquired cell-mediated immunity. Notwithstanding data that permit such general classification of host factors controlling one or another invasive mycosis, the diverse structural and antigenic properties of individual fungi create unique patterns of infections in individual, characteristic host settings. Thus, while some broad generalizations are possible, definition of predisposing factors for specific individual mycoses (and, ultimately, prospects for corrective immunotherapy) requires careful characterization of diverse features of fungal forms mediating divergent immune responses.

Differential inhibition of macrophage microbicidal activity by liposomes.

In vitro culture of murine resident peritoneal macrophages with lymphokine (LK)-rich leukocyte culture fluids induces enhanced microbicidal activity against amastigotes of the protozoan parasite Leishmania tropica. Macrophages infected with Leishmania and treated with LKs after infection acquire the capacity to kill the intracellular parasite within 72 h. When compared with control macrophage cultures treated with medium lacking LKs, 80 to 90% fewer macrophages treated with LKs contained amastigotes. In experiments designed to test liposome delivery of LKs to infected macrophages, addition of multilamellar liposomes composed of phosphatidylcholine and phosphatidylserine (molar ratio, 7:3) completely abrogated LK-induced microbicidal activity. Liposomes containing only phosphatidylcholine were not inhibitory. Inhibition of LK activity by the liposomes occurred regardless of whether the liposomes contained LKs. Liposomal inhibition of activated macrophage effector activity was limited to intracellular killing; LK-induced macrophage extracellular cytolysis (i.e., tumor cytotoxicity) was not affected by liposome treatment. These data indicate that elucidation of the effects of liposome composition on acquired host defense mechanisms may be useful for the design of drug delivery systems that allow expression or augmentation of immunologically induced mechanisms for the intracellular destruction of infectious agents.

Effects of antithymocyte and antimacrophage sera on the survival of mice infected with Listeria monocytogenes.

Antisera prepared in rabbits against purified mouse thymocytes (antithymocyte serum; ATS) and peritoneal macrophages (antimacrophage serum; AMS) were injected intraperitoneally into Balb/c mice infected with the bacterium Listeria monocytogenes. When administered near the initiation of infection, the ATS significantly decreased the survival time of the animals and increased the mortality rate. When ATS was administered 6 days after a sublethal dose of L. monocytogenes had been inoculated, an overt disease did not evolve. ATS that significantly potentiated primary listeriosis also had high cytotoxicity titers for thymocytes and lymphoid cells from the peritoneal cavity. Although cytotoxic activity against peritoneal macrophages could be demonstrated in lower dilutions of the ATS, this activity did not appear to correlate with the effects of the sera on listeriosis. The injection of AMS did not enhance the infectious process. In some trials more deaths occurred among mice receiving normal rabbit serum than those receiving AMS. All of the AMS had cytotoxic titers against peritoneal macrophages, and the sera were usually inactive against thymocytes and peritoneal lymphoid cells. Listeria was isolated from fatally infected mice with nearly equal success in all of the serum-treated groups, and the serum treatments did not appear to alter the pattern of gross lesions. The afferent limb of the immune response was markedly affected by the presence of antibodies to lymphocytes. However, antibodies reacting with macrophages did not demonstrably enhance the Listeria process, which depends upon cellular immunity as the principal means of acquired host defense.