Cellular responses in sea fan corals: granular amoebocytes react to pathogen and climate stressors

Background

Climate warming is causing environmental change making both marine and terrestrial organisms, and even humans, more susceptible to emerging diseases. Coral reefs are among the most impacted ecosystems by climate stress, and immunity of corals, the most ancient of metazoans, is poorly known. Although coral mortality due to infectious diseases and temperature-related stress is on the rise, the immune effector mechanisms that contribute to the resistance of corals to such events remain elusive. In the Caribbean sea fan corals (Anthozoa, Alcyonacea: Gorgoniidae), the cell-based immune defenses are granular acidophilic amoebocytes, which are known to be involved in wound repair and histocompatibility.

Methodology/Principal Findings

We demonstrate for the first time in corals that these cells are involved in the organismal response to pathogenic and temperature stress. In sea fans with both naturally occurring infections and experimental inoculations with the fungal pathogen Aspergillus sydowii, an inflammatory response, characterized by a massive increase of amoebocytes, was evident near infections. Melanosomes were detected in amoebocytes adjacent to protective melanin bands in infected sea fans; neither was present in uninfected fans. In naturally infected sea fans a concurrent increase in prophenoloxidase activity was detected in infected tissues with dense amoebocytes. Sea fans sampled in the field during the 2005 Caribbean Bleaching Event (a once-in-hundred-year climate event) responded to heat stress with a systemic increase in amoebocytes and amoebocyte densities were also increased by elevated temperature stress in lab experiments.

Conclusions/Significance

The observed amoebocyte responses indicate that sea fan corals use cellular defenses to combat fungal infection and temperature stress. The ability to mount an inflammatory response may be a contributing factor that allowed the survival of even infected sea fan corals during a stressful climate event.     

Protective tolerance to fungi: the role of IL-10 and tryptophan catabolism

The pro-inflammatory-anti-inflammatory signaling balance is required for successful host-fungus interactions. The occurrence and interference of regulatory T (T-reg) cells in fungal infections offers a valuable framework for events that occur at the host-fungus interface. Control of both the class and magnitude of the immune response might confer an evolutionary advantage whereby the host effectively fights infection but limits collateral immunopathology. Alternatively, fungus-induced immunosuppression could be a powerful immunoevasion strategy for the invading pathogen. Discovery of T-reg cells as a source of IL-10 might contribute to a better understanding of the opposing functions and variable levels of production of this prototypic immunoregulatory cytokine in fungal infections and inflammatory diseases. T-reg cells, however, might also represent an additional mechanistic level at which host responses are subverted by fungi.     

Exosomes and other extracellular vesicles in host–pathogen interactions

An effective immune response requires the engagement of host receptors by pathogen‐derived molecules and the stimulation of an appropriate cellular response. Therefore, a crucial factor in our ability to control an infection is the accessibility of our immune cells to the foreign material. Exosomes—which are extracellular vesicles that function in intercellular communication—may play a key role in the dissemination of pathogen‐ as well as host‐derived molecules during infection. In this review, we highlight the composition and function of exosomes and other extracellular vesicles produced during viral, parasitic, fungal and bacterial infections and describe how these vesicles could function to either promote or inhibit host immunity.     

A simple model of pathogen-immune dynamics including specific and non-specific immunity

We present and analyze a model for the dynamics of the interactions between a pathogen and its host's immune response. The model consists of two differential equations, one for pathogen load, the other one for an index of specific immunity. Differently from other simple models in the literature, this model exhibits, according to the hosts' or pathogen's parameter values, or to the initial infection size, a rich repertoire of behaviours: immediate clearing of the pathogen through aspecific immune response; or acute infection followed by clearing of the pathogen through specific immune response; or uncontrolled infections; or acute infection followed by convergence to a stable state of chronic infection; or periodic solutions with intermittent acute infections. The model can also mimic some features of immune response after vaccination. This model could be a basis on which to build epidemic models including immunological features.     

Host and pathogen ecology drive the seasonal dynamics of a fungal disease,white-nose syndrome

Seasonal patterns in pathogen transmission can influence the impact of disease on populations and the speed of spatial spread. Increases in host contact rates or births drive seasonal epidemics in some systems, but other factors may occasionally override these influences. White-nose syndrome, caused by the emerging fungal pathogen Pseudogymnoascus destructans, is spreading across North America and threatens several bat species with extinction. We examined patterns and drivers of seasonal transmission of P. destructans by measuring infection prevalence and pathogen loads in six bat species at 30 sites across the eastern United States. Bats became transiently infected in autumn, and transmission spiked in early winter when bats began hibernating. Nearly all bats in six species became infected by late winter when infection intensity peaked. In summer, despite high contact rates and a birth pulse, most bats cleared infections and prevalence dropped to zero. These data suggest the dominant driver of seasonal transmission dynamics was a change in host physiology, specifically hibernation. Our study is the first, to the best of our knowledge, to describe the seasonality of transmission in this emerging wildlife disease. The timing of infection and fungal growth resulted in maximal population impacts, but only moderate rates of spatial spread.     

Modeling Mucosal Candidiasis in Larval Zebrafish by Swimbladder Injection

Early defense against mucosal pathogens consists of both an epithelial barrier and innate immune cells. The immunocompetency of both, and their intercommunication, are paramount for the protection against infections. The interactions of epithelial and innate immune cells with a pathogen are best investigated in vivo, where complex behavior unfolds over time and space. However, existing models do not allow for easy spatio-temporal imaging of the battle with pathogens at the mucosal level.The model developed here creates a mucosal infection by direct injection of the fungal pathogen, Candida albicans, into the swimbladder of juvenile zebrafish. The resulting infection enables high-resolution imaging of epithelial and innate immune cell behavior throughout the development of mucosal disease. The versatility of this method allows for interrogation of the host to probe the detailed sequence of immune events leading to phagocyte recruitment and to examine the roles of particular cell types and molecular pathways in protection. In addition, the behavior of the pathogen as a function of immune attack can be imaged simultaneously by using fluorescent protein-expressing C. albicans. Increased spatial resolution of the host-pathogen interaction is also possible using the described rapid swimbladder dissection technique.The mucosal infection model described here is straightforward and highly reproducible, making it a valuable tool for the study of mucosal candidiasis. This system may also be broadly translatable to other mucosal pathogens such as mycobacterial, bacterial or viral microbes that normally infect through epithelial surfaces.     

Toll-Like Receptor 4 Limits Transmission of Bordetella bronchiseptica

Transmission of pathogens has been notoriously difficult to study under laboratory conditions leaving knowledge gaps regarding how bacterial factors and host immune components affect the spread of infections between hosts. We describe the development of a mouse model of transmission of a natural pathogen, Bordetella bronchiseptica, and its use to assess the impact of host immune functions. Although B. bronchiseptica transmits poorly between wild-type mice and mice lacking other immune components, it transmits efficiently between mice deficient in Toll-Like Receptor 4 (TLR4). TLR4-mutant mice were more susceptible to initial colonization, and poorly controlled pathogen growth and shedding. Heavy neutrophil infiltration distinguished TLR4-deficient responses, and neutrophil depletion did not affect respiratory CFU load, but decreased bacterial shedding. The effect of TLR4 response on transmission may explain the extensive variation in TLR4 agonist potency observed among closely related subspecies of Bordetella. This transmission model will enable mechanistic studies of how pathogens spread from one host to another, the defining feature of infectious disease.     

A simple model of pathogen–immune dynamics including specific and non-specific immunity

We present and analyze a model for the dynamics of the interactions between a pathogen and its host’s immune response. The model consists of two differential equations, one for pathogen load, the other one for an index of specific immunity. Differently from other simple models in the literature, this model exhibits, according to the hosts’ or pathogen’s parameter values, or to the initial infection size, a rich repertoire of behaviours: immediate clearing of the pathogen through aspecific immune response; or acute infection followed by clearing of the pathogen through specific immune response; or uncontrolled infections; or acute infection followed by convergence to a stable state of chronic infection; or periodic solutions with intermittent acute infections. The model can also mimic some features of immune response after vaccination. This model could be a basis on which to build epidemic models including immunological features.     

Impact of life stage specific immune priming on invertebrate disease dynamics

The immune response of a host can have important impacts on host‐pathogen interactions, but investment in immunity often changes dynamically across the life history of a host. One form of investment involves the induction of a primed immune response against previously encountered pathogens that protects the host from re‐infection. In addition to providing immediate protective effects, immune priming can also provide two types of ‘delayed’ protection against pathogens: priming across life stages (ontogenic priming) and priming across generations (trans‐generational priming). Consequently both types of immune priming have the potential to mediate life history variability in host–pathogen interactions, which could have important consequences for disease prevalence and dynamics as well as for the demographic structure of the host population. Here we develop a stage‐structured SIRS model for an invertebrate host to explore the relative and combined impact of ontogenic priming and trans‐generational priming on infection prevalence, host population size, and population age structure. Our model predicts that both types of immune priming can dramatically reduce disease prevalence at equilibrium, but their individual and combined effects on population size and age structure depend on the magnitude of tradeoffs between immune protection and reproduction as well as on the symmetry of infection parameters between life stages. This model underscores the potential importance of life‐history based immune investment patterns for disease dynamics and highlights the need for wide‐spread empirical estimation of parameters that represent the maintenance of immune priming in insects.     

Dressed to impress: impact of environmental adaptation on the Candida albicans cell wall

Candida albicans is an opportunistic fungal pathogen of humans causing superficial mucosal infections and life‐threatening systemic disease. The fungal cell wall is the first point of contact between the invading pathogen and the host innate immune system. As a result, the polysaccharides that comprise the cell wall act as pathogen associated molecular patterns, which govern the host–pathogen interaction. The cell wall is dynamic and responsive to changes in the external environment. Therefore, the host environment plays a critical role in regulating the host–pathogen interaction through modulation of the fungal cell wall. This review focuses on how environmental adaptation modulates the cell wall structure and composition, and the subsequent impact this has on the innate immune recognition of C. albicans.     

The Non-receptor Tyrosine Kinase Tec Controls Assembly and Activity of the Noncanonical Caspase-8 Inflammasome

Tec family kinases are intracellular non-receptor tyrosine kinases implicated in numerous functions, including T cell and B cell regulation. However, a role in microbial pathogenesis has not been described. Here, we identified Tec kinase as a novel key mediator of the inflammatory immune response in macrophages invaded by the human fungal pathogen C. albicans. Tec is required for both activation and assembly of the noncanonical caspase-8, but not of the caspase-1 inflammasome, during infections with fungal but not bacterial pathogens, triggering the antifungal response through IL-1β. Furthermore, we identify dectin-1 as the pathogen recognition receptor being required for Syk-dependent Tec activation. Hence, Tec is a novel innate-specific inflammatory kinase, whose genetic ablation or inhibition by small molecule drugs strongly protects mice from fungal sepsis. These data demonstrate a therapeutic potential for Tec kinase inhibition to combat invasive microbial infections by attenuating the host inflammatory response.     

Close Encounters of the Viral Kind: Cross‐Kingdom Synergies at the Host–Pathogen Interface

The synergies between viral and bacterial infections are well established. Most studies have been focused on the indirect mechanisms underlying this phenomenon, including immune modulation and alterations to the mucosal structures that promote pathogen outgrowth. A growing body of evidence implicates direct binding of virus to bacterial surfaces being an additional mechanism of synergy at the host–pathogen interface. These cross‐kingdom interactions enhance bacterial and viral adhesion and can alter tissue tropism. These bacterial–viral complexes play unique roles in pathogenesis and can alter virulence potential. The bacterial–viral complexes may also play important roles in pathogen transmission. Additionally, the complexes are recognized by the host immune system in a distinct manner, thus presenting novel routes for vaccine development. These synergies are active for multiple species in both the respiratory and gastrointestinal tract, indicating that direct interactions between bacteria and virus to modulate host interactions are used by a diverse array of species.     

Acute-phase responses vary with pathogen identity in house sparrows (Passer domesticus)

Pathogens may induce different immune responses in hosts contingent on pathogen characteristics, host characteristics, or interactions between the two. We investigated whether the broadly effective acute-phase response (APR), a whole body immune response that occurs in response to constitutive immune receptor activation and includes fever, secretion of immune peptides, and sickness behaviors such as anorexia and lethargy, varies with pathogen identity in the house sparrow (Passer domesticus). Birds were challenged with a subcutaneous injection of either a glucan at 0.7 mg/kg (to simulate fungal infection), a synthetic double-stranded RNA at 25 mg/kg (to simulate viral infection), or LPS at 1 mg/kg (to simulate a gram-negative bacterial infection), and then body mass, core body temperature changes, sickness behaviors, and secretion of an acute-phase protein, haptoglobin, were compared. Despite using what are moderate-to-high pyrogen doses for other vertebrates, only house sparrows challenged with LPS showed measurable APRs. Febrile, behavioral, and physiological responses to fungal and viral mimetics had minimal effects.     

Chlamydiales and the innate immune response: friend or foe?

Pathogenicity of Chlamydia and Chlamydia-related bacteria could be partially mediated by an enhanced activation of the innate immune response. The study of this host pathogen interaction has proved challenging due to the restricted in vitro growth of these strict intracellular bacteria and the lack of genetic tools to manipulate their genomes. Despite these difficulties, the interactions of Chlamydiales with the innate immune cells and their effectors have been studied thoroughly. This review aims to point out the role of pattern recognition receptors and signal molecules (cytokines, reactive oxygen species) of the innate immune response in the pathogenesis of chlamydial infection. Besides inducing clearance of the bacteria, some of these effectors may be used by the Chlamydia to establish chronic infections or to spread. Thus, the induced innate immune response seems to be variable depending on the species and/or the serovar, making the pattern more complex. It remains crucial to determine the common players of the innate immune response in order to help define new treatment strategies and to develop effective vaccines. The excellent growth in phagocytic cells of some Chlamydia-related organisms such as Waddlia chondrophila supports their use as model organisms to study conserved features important for interactions between the innate immunity and Chlamydia.     

Conventional dendritic cells mount a type I IFN response against Candida spp. requiring novel phagosomal TLR7-mediated IFN-β signaling

Human fungal pathogens such as the dimorphic Candida albicans or the yeast-like Candida glabrata can cause systemic candidiasis of high mortality in immunocompromised individuals. Innate immune cells such as dendritic cells and macrophages establish the first line of defense against microbial pathogens and largely determine the outcome of infections. Among other cytokines, they produce type I IFNs (IFNs-I), which are important modulators of the host immune response. Whereas an IFN-I response is a hallmark immune response to bacteria and viruses, a function in fungal pathogenesis has remained unknown. In this study, we demonstrate a novel mechanism mediating a strong IFN-β response in mouse conventional dendritic cells challenged by Candida spp., subsequently orchestrating IFN-α/β receptor 1-dependent intracellular STAT1 activation and IFN regulatory factor (IRF) 7 expression. Interestingly, the initial IFN-β release bypasses the TLR 4 and TLR2, the TLR adaptor Toll/IL-1R domain-containing adapter-inducing IFN-β and the β-glucan/phagocytic receptors dectin-1 and CD11b. Notably, Candida-induced IFN-β release is strongly impaired by Src and Syk family kinase inhibitors and strictly requires completion of phagocytosis as well as phagosomal maturation. Strikingly, TLR7, MyD88, and IRF1 are essential for IFN-β signaling. Furthermore, in a mouse model of disseminated candidiasis we show that IFN-I signaling promotes persistence of C. glabrata in the host. Our data uncover for the first time a pivotal role for endosomal TLR7 signaling in fungal pathogen recognition and highlight the importance of IFNs-I in modulating the host immune response to C. glabrata.     

烟曲霉细胞壁的组分、组装及其功能概述

环境中普遍存在的腐生丝状真菌烟曲霉Aspergillus fumigatus在免疫功能低下或缺陷的人群中可引起多种急慢性疾病,包括致死率很高的侵袭性曲霉病。细胞壁作为真菌的细胞外骨架结构不仅起维持细胞形状、保护细胞抵抗外界压力等作用,在病原真菌极性生长、入侵新的生态域、启动宿主免疫反应中也起重要作用。细胞壁组分还是真菌感染的分子诊断基础和开发抗真菌药物的理想靶标。近几十年来烟曲霉细胞壁的遗传、生物化学及免疫学方向的研究使其成为研究真菌细胞壁的模式真菌。本文主要概述烟曲霉细胞壁的组分、分子组装机制及其在真菌生存和感染中的作用,并对未来研究方向提出了展望。     

Lights,Rhythms, Infection: The Role of Light and the Circadian Clock in Determining the Outcome of Plant–Pathogen Interactions

The importance of light with respect to the outcome of plant–pathogen interactions is becoming increasingly evident: light affects both the host response and the virulence of some pathogens. The response of plants to environmental signals and stresses is modulated by the circadian clock, and it is apparent that this may include immune responses. Photo and temporal regulation of immune responses may allow plants to anticipate and react more effectively to particular pathogen infections. These aspects of regulation are sometimes overlooked when designing experiments to understand plant–pathogen interactions, complicating the interpretation of the outcomes and the direct comparisons of studies. We review recent key findings in these areas and discuss the implications for experimental design and analyses.     

Exploiting amoeboid and non-vertebrate animal model systems to study the virulence of human pathogenic fungi

Experiments with insects, protozoa, nematodes, and slime molds have recently come to the forefront in the study of host-fungal interactions. Many of the virulence factors required for pathogenicity in mammals are also important for fungal survival during interactions with non-vertebrate hosts, suggesting that fungal virulence may have evolved, and been maintained, as a countermeasure to environmental predation by amoebae and nematodes and other small non-vertebrates that feed on microorganisms. Host innate immune responses are also broadly conserved across many phyla. The study of the interaction between invertebrate model hosts and pathogenic fungi therefore provides insights into the mechanisms underlying pathogen virulence and host immunity, and complements the use of mammalian models by enabling whole-animal high throughput infection assays. This review aims to assist researchers in identifying appropriate invertebrate systems for the study of particular aspects of fungal pathogenesis.