Augmentation of innate host defenses against opportunistic fungal pathogens

Development of invasive fungal infection is the result of the complex interaction between fungal and host factors. The outcome of infection, once it has developed, depends upon appropriate use of antifungal therapy, surgical debridement as indicated, and improvement of host defenses. Thus, there have been major efforts for development of new strategies for immunomodulation and augmentation of host defenses in prevention and treatment of invasive mycoses. These modalities include granulocyte and granulocyte-macrophage colony-stimulating factors, interferon-γ, granulocyte transfusions, immunotherapy with infusion of dendritic cells and T cells, anti-heat shock protein 90 monoclonal antibodies, long pentraxin 3, mannose-binding lectin, and deferasirox. Although major strides in our understanding of augmentation of host response to invasive fungal infections are opening up novel avenues of therapy to harness patients’ innate immune systems against these frequently lethal pathogens, well-designed clinical trials are needed to demonstrate safety and efficacy of these new approaches.     

Overcoming obstacles to metastasis - defenses against host defenses: Osteopontin (OPN) as a shield against attack by cytotoxic host cells

Osteopontin (OPN) serves both a cell attachment function and a cell signalling function via the α_vβ₃ integrin, in its cell attachment capacity it can promote attachment of both osteolasts to bone hydroxyapatite and various other cell types to basement membrane/extracellular matrix. In its cell signalling capacity it initiates a signal transduction cascade that includes changes in the intracellular calcium ion levels and the tyrosine phosophorylation status of several proteins including paxillin. Effects on gene expression include suppression of the induction of nitric oxide synthase by inflammatory mediators. OPN can also reduce cell oxidant and inhibit the killing of tumor cells by activated macrophages and endothelial cells. We hepothesize that those cancer cells that produce OPN at elevated levels can suppress the oxidative burst, inhibit NO production, and thus protect themselves from killing by specific host cell types.     

Parasitism by Cuscuta pentagona attenuates host plant defenses against insect herbivores

Considerable research has examined plant responses to concurrent attack by herbivores and pathogens, but the effects of attack by parasitic plants, another important class of plant-feeding organisms, on plant defenses against other enemies has not been explored. We investigated how attack by the parasitic plant Cuscuta pentagona impacted tomato (Solanum lycopersicum) defenses against the chewing insect beet armyworm (Spodoptera exigua; BAW). In response to insect feeding, C. pentagona-infested (parasitized) tomato plants produced only one-third of the antiherbivore phytohormone jasmonic acid (JA) produced by unparasitized plants. Similarly, parasitized tomato, in contrast to unparasitized plants, failed to emit herbivore-induced volatiles after 3 d of BAW feeding. Although parasitism impaired antiherbivore defenses, BAW growth was slower on parasitized tomato leaves. Vines of C. pentagona did not translocate JA from BAW-infested plants: amounts of JA in parasite vines grown on caterpillar-fed and control plants were similar. Parasitized plants generally contained more salicylic acid (SA), which can inhibit JA in some systems. Parasitized mutant (NahG) tomato plants deficient in SA produced more JA in response to insect feeding than parasitized wild-type plants, further suggesting cross talk between the SA and JA defense signaling pathways. However, JA induction by BAW was still reduced in parasitized compared to unparasitized NahG, implying that other factors must be involved. We found that parasitized plants were capable of producing induced volatiles when experimentally treated with JA, indicating that resource depletion by the parasite does not fully explain the observed attenuation of volatile response to herbivore feeding. Collectively, these findings show that parasitic plants can have important consequences for host plant defense against herbivores.     

Toll-like receptor-2 is essential in murine defenses against Candida albicans infections

In this work, we studied the role of toll-like receptor-2 (TLR2) in murine defenses against Candida albicans. TLR2-deficient mice experimentally infected intraperitoneally (i.p.) or intravenously (i.v.) in vivo had very significant impaired survival compared with that of control mice. In vitro production of TNF-alpha and macrophage inhibitory protein-2 (MIP-2) by macrophages from TLR2-/- mice in response to yeasts and hyphae of C. albicans were significantly lower (80% and 40%, respectively; P <0.05) than production by macrophages from wild-type mice. This impaired production of TNF-alpha and MIP-2 probably contributed to the 41% decreased recruitment of neutrophils to the peritoneal cavity of i.p. infected TLR2-/- mice. In contrast, in vitro phagocytosis of yeasts and production of reactive oxygen intermediates (ROI) were not affected in macrophages from TLR2-/- animals. Our data indicate that TLR2 plays a major role in the response of macrophages to C. albicans, triggering cytokine and chemokine expression, and it is essential for in vivo protection against infection.     

Importance of spatial habitat structure on establishment of host defenses against brood parasitism

We used metapopulation dynamics to develop a mathematical simulationmodel for brood parasites and their hosts in order to investigatethe validity of the "spatial habitat structure hypothesis,"which states that a low level of parasite egg rejection in hostpopulations is due to the immigration of acceptor individualsfrom nonparasitized populations. In our model, we varied dispersalrate and the relative carrying capacity of host individualsin parasitized and unparasitized patches. When both the relativecarrying capacity in the parasite-free patch and the dispersalrate increase, the nonparasitized patch will provide more acceptorindividuals to the parasite-prone patch. As the relative carryingcapacity in the parasite-free patch increases, the equilibriumfrequency of rejecters both in the parasite-prone and in theparasite-free patch decreases toward zero for intermediate levelsof the dispersal rate. Although the rejecter strategy is moreadaptive than the acceptor strategy in the parasite-prone patch,large numbers of acceptors are produced in the parasite-freepatch dispersing to the parasitized patch. As the number ofindividuals in the parasite-free patch increases, parasitismrate can be maintained stable at a high equilibrium level inthe parasite-prone patch.     

The host type I interferon response to viral and bacterial infections

Type I interferons (IFN) are well studied cytokines with anti-viral and immune-modulating functions. Type I IFNs are produced following viral infections, but until recently, the mechanisms of viral recognition leading to IFN production were largely unknown. Toll like receptors (TLRs) have emerged as key transducers of type I IFN during viral infections by recognizing various viral components. Furthermore, much progress has been made in defining the signaling pathways downstream of TLRs for type I IFN production. TLR7 and TLR9 have become apparent as universally important in inducing type I IFN during infection with most viruses, particularly by plasmacytoid dendritic cells. New intracellular viral pattern recognition receptors leading to type I IFN production have been identified. Many bacteria can also induce the up-regulation of these cytokines. Interestingly, recent studies have found a detrimental effect on host cells if type Ⅰ IFN is produced during infection with the intracellular gram-positive bacterial pathogen, Listeria monocytogenes. This review will discuss the recent advances made in defining the signaling pathways leading to type I IFN production.     

Counterregulation of Th2 immunity by interleukin 12 reduces host defenses against Strongyloides venezuelensis infection

The aim of this study was to investigate the role of interleukin 12 (IL-12) during Strongyloides venezuelensis infection. IL-12^−/− and wild-type C57BL/6 mice were subcutaneously infected with 1500 larvae of S. venezuelensis. On days 7, 14, and 21 post-infection, we determined eosinophil and mononuclear cell numbers in the blood and broncoalveolar lavage fluid (BALF), Th2 cytokine secretion in the lung parenchyma, and serum antibody levels. The numbers of eggs in the feces and worm parasites in the duodena were also quantified. The eosinophil and mononuclear cell counts and the concentrations of IL-3, IL-5, IL-10, IL-13, and IgG1 and IgE antibodies increased significantly in infected IL-12^−/− and wild-type mice as compared with uninfected controls. However, the number of eosinophils and mononuclear cells in the blood and BALF and the Th2 cytokine levels in the lungs of infected IL-12^−/− mice were greater than in infected wild-type C57BL/6 mice. In addition, serum IgE and IgG1 levels were also significantly enhanced in the infected mice lacking IL-12. Meanwhile, parasite burden and fecal egg counts were significantly decreased in infected IL-12^−/− mice. Together, our results showed that the absence of IL-12 upregulates the Th2 immune response, which is important for control of S. venezuelensis infection.     

Plant defenses against oxidative stress

Many reactive oxygen species such as ozone, singlet oxygen, hydroxyl radical, and organic oxyradicals have been implicated in damage to plant organs and biopolymers such as chloroplasts, cell membranes, proteins, and DNA. The principal defenses against these reactive molecules and free radicals in plants include detoxifying enzymes (catalase, superoxide dismutase, etc.) and also lower molecular weight secondary products with antioxidant activity. These latter compounds include a great variety of phenolic compounds, carotenoids, nitrogenous, and sulfur-containing materials. Some of the more important mechanisms of action of the secondary compounds will be discussed, with emphasis on the use of structural and kinetic data to identify the most effective antioxidants against peroxy radical-induced damage, which is perhaps the most important of the oxidative stresses present in the usual environment of plants. © 1995 Wiley-Liss, Inc.     

Cellular defenses against excitotoxic insults

The cellular events mediating necrotic neuron death are now reasonably well understood, and involve excessive extracellular accumulation of glutamate and free cytosolic calcium. When such necrotic neurological insults occur, neurons are not passively buffeted, but instead mobilize a variety of defenses in an attempt to decrease the likelihood of neuron death, or to decrease the harm to neighboring neurons (by decreasing the likelihood of inflammation). This review considers some of these defenses, organizing them along the lines of those which decrease neuronal excitability, decrease extracellular glutamate accumulation, decrease cytosolic calcium mobilization, decrease calcium-dependent degenerative events, enhance neuronal energetics, and bias a neuron towards apoptotic, rather than necrotic, death. Although these are currently perceived as a disparate array of cellular adaptations, some experimental approaches are suggested that may help form a more unified subdiscipline of cellular defenses against neurological insults. Such an advance would help pave the way for the rational design of therapeutic interventions against necrotic insults.     

Amphibian defenses against ultraviolet-B radiation

As part of an overall decline in biodiversity, amphibian populations throughout the world are disappearing. There are a number of potential causes for these declines, including those related to environmental changes such as increasing ultraviolet-B (UV-B) radiation due to stratospheric ozone depletion. UV-B radiation can kill amphibian embryos or can cause sublethal effects that can harm amphibians in later life stages. However, amphibians have defenses against UV-B damage that can limit damage or repair it after exposure to UV-B radiation. These include behavioral, physiological, and molecular defenses. These defenses differ interspecifically, with some species more able to cope with exposure to UV-B than others. Unfortunately, the defense mechanisms of many species may not be effective against increasing persistent levels of UV-B radiation that have only been present for the past several decades due to human-induced environmental damage. Moreover, we predict that persistent UV-B-induced mortality and sublethal damage in species without adequate defenses could lead to changes in community structure. In this article we review the effects of UV-B radiation on amphibians and the defenses they use to avoid solar radiation and make some predictions regarding community structure in light of interspecific differences in UV-B tolerance.     

IL-22 mediates mucosal host defense against Gram-negative bacterial pneumonia

Emerging evidence supports the concept that T helper type 17 (T(H)17) cells, in addition to mediating autoimmunity, have key roles in mucosal immunity against extracellular pathogens. Interleukin-22 (IL-22) and IL-17A are both effector cytokines produced by the T(H)17 lineage, and both were crucial for maintaining local control of the Gram-negative pulmonary pathogen, Klebsiella pneumoniae. Although both cytokines regulated CXC chemokines and granulocyte colony-stimulating factor production in the lung, only IL-22 increased lung epithelial cell proliferation and increased transepithelial resistance to injury. These data support the concept that the T(H)17 cell lineage and its effector molecules have evolved to effect host defense against extracellular pathogens at mucosal sites.     

Role of antimicrobial peptides in host defense against mycobacterial infections

Worldwide, tuberculosis remains the most important infectious disease causing morbidity and death. Currently, at least one-third of the world's population is infected with Mycobacterium tuberculosis. In addition, the World Health Organization estimates that about 8-10 million new tuberculosis cases occur annually worldwide and this incidence is currently increasing. Moreover, multidrug-resistant tuberculosis has been increasing in incidence in many areas during the past decade. These situations underscore the importance of the development of new therapeutic agents against mycobacterial infectious diseases. In this article, it is review current progress in the understanding of antimicrobial peptides as potential candidates to develop an alternative/adjunct therapeutic strategy against tuberculosis. This immunoadjunctive therapy might be evaluated in the context of possible drug resistance. This review also summarizes the knowledge about the functions of antimicrobial peptides in the pulmonary innate host defense system and their role in mycobacterial infection, and at the same time outlines recent advances in our understanding of the combined effect of antimicrobial peptides and anti-tuberculosis drugs against intracellular mycobacteria. A concerted effort should now focus on the clinical application of antimicrobial peptides for their practical use.