IMMUNE EVASION AND THE EVOLUTION OF MOLECULAR MIMICRY IN PARASITES

Parasites that are molecular mimics express proteins which resemble host proteins. This resemblance facilitates immune evasion because the immune molecules with the specificity to react with the parasite also cross‐react with the host's own proteins, and these lymphocytes are rare. Given this advantage, why are not most parasites molecular mimics? Here we explore potential factors that can select against molecular mimicry in parasites and thereby limit its occurrence. We consider two hypotheses: (1) molecular mimics are more likely to induce autoimmunity in their hosts, and hosts with autoimmunity generate fewer new infections (the “costly autoimmunity hypothesis”); and (2) molecular mimicry compromises protein functioning, lowering the within‐host replication rate and leading to fewer new infections (the “mimicry trade‐off hypothesis”). Our analysis shows that although both hypotheses may select against molecular mimicry in parasites, unique hallmarks of protein expression identify whether selection is due to the costly autoimmunity hypothesis or the mimicry trade‐off hypothesis. We show that understanding the relevant selective forces is necessary to predict how different medical interventions will affect the proportion of hosts that experience the different infection types, and that if parasite evolution is ignored, interventions aimed at reducing infection‐induced autoimmunity may ultimately fail.     

分子模拟与微生物、自身免疫交叉识别以及肿瘤免疫治疗

分子模拟是生物界广为存在的一种自然现象。细菌等病原微生物可利用蛋白质序列或结构的相似而模拟宿主细胞某些分子的功能,从而协助其入侵与存活;另一方面,微生物也可因某些蛋白质的同源或相似而致宿主交叉免疫反应,导致自身免疫参与自身免疫疾病的发生,其本质是一种交叉识别。本室及其他研究小组发现可利用不同种属某些肿瘤相关同源分子的异源性激发特异的免疫反应,并因其同源性而交叉反应于宿主分子,从而产生抗肿瘤的自身免疫,亦即通过异种同源分子的策略主动免疫治疗肿瘤。这种模拟还可以在表位肽的水平进行,相信分子模拟的深入研究将有助于揭示进化与分子识别的本质以及自身免疫的规律,从而探索分子模拟在疾病预防与治疗中的应用。     

The virtuous self‐tolerance of virtual memory T cells

“Virtual” memory CD8⁺ T cells are a subset of immune cells produced by homeostatic mechanisms involving response to self‐antigens, raising the possibility that these cells could mediate autoimmunity. New work by Drobek et al demonstrates that virtual memory T cells are indeed favored by stronger T‐cell receptor signals but exhibit minimal autoreactivity while maintaining self‐tolerance.     

Autoreactive T‐cell receptor (Vβ/D/Jβ) sequences in diabetes are homologous to insulin,glucagon, the insulin receptor,and the glucagon receptor

The hypervariable (Vβ/D/Jβ) regions of T‐cell receptors (TCR) have been sequenced in a variety of autoimmune diseases by various investigators. An analysis of some of these sequences shows that TCR from both human diabetics and NOD mice mimic insulin, glucagon, the insulin receptor, and the glucagon receptor. Such similarities are not found in the TCR produced in other human autoimmune diseases. These data may explain how insulin, glucagon, and their receptors are targets of autoimmunity in diabetes and also suggest that TCR mimicking insulin and its receptor may be targets of anti‐insulin autoantibodies. Such intra‐systemic mimicry of self‐proteins also raises complex questions about how “self” and “nonself” are regulated during TCR production, especially in light of the complementarity of insulin for its receptor and glucagon for its receptor. The data presented here suggest that some TCR may be complementary to other TCR in autoimmune diseases, a possibility that is experimentally testable. Such complementarity, if it exists, could either serve to down‐regulate the clones bearing such TCR or, alternatively, trigger an intra‐immune system civil war between them. Copyright © 2008 John Wiley & Sons, Ltd.     

Does Müllerian Mimicry Work in Nature? Experiments with Butterflies and Birds (Tyrannidae)1

The selective advantage of Müllerian mimicry in nature was investigated by releasing live mimetic and nonmimetic butterflies close to wild, aerial‐hunting tropical kingbirds (Tyrannus melancholicus) and cliff‐flycatchers (Hirundinea ferruginea) in three Amazon habitats (rain forest, a city, and “canga” vegetation). Only mimetic butterflies elicited sight‐rejections by birds, but protection conferred by mimicry was restricted to sites in which both predators and mimics co‐occurred, as in the case of six mimicry rings at a forest site and two at a city site. Most other Müllerian mimics released at city and canga vegetation were heavily attacked and consumed by birds. These results appear to reflect the birds’previous experiences with resident butterfly faunas and illustrate how birds’discriminatory behavior varied among habitats that differed in butterfly species and mimicry ring composition.     

Compositional bias and mimicry toward the nonself proteome in immunodominant T cell epitopes of self and nonself antigens.

We investigated whether and how molecular mimicry affects the shaping of the helper T cell repertoire. We implemented an algorithm that measures the probability of mimicry between epitopes of known immunogenicity and self or nonself proteomes. This algorithm yields 'similarity profiles', which represent the probability of matching between all contiguous overlapping peptides of the antigen under examination and those in the proteome(s) considered. Similarity profiles between helper T cell epitopes (of self or microbial antigens and allergens) and human or microbial SWISSPROT collections were produced. For each antigen, both collections yielded largely overlapping profiles, demonstrating that self-nonself discrimination does not rely on qualitative features that distinguish human from microbial peptides. However, epitopes whose probability of mimicry with self or nonself prevails are, respectively, tolerated or immunodominant and coexist within the same (auto-)antigen regardless of its self/nonself nature. Epitopes (on self and nonself antigens) can cross-stimulate T cells at increasing potency as their similarity with nonself augments. Mimicry, rather than complicating self-nonself discrimination, assists in the shaping of the immune repertoire and helps define the defensive or autoreactive potential of a T cell. Being a predictor of epitope immunogenicity, it bears relevance to vaccine design.     

Encapsulated fusion protein confers “sense and respond” activity to chitosan–alginate capsules to manipulate bacterial quorum sensing

We demonstrate that “nanofactory”‐loaded biopolymer capsules placed in the midst of a bacterial population can direct bacterial communication. Quorum sensing (QS) is a process by which bacteria communicate through small‐molecules, such as autoinducer‐2 (AI‐2), leading to collective behaviors such as virulence and biofilm formation. In our approach, a “nanofactory” construct is created, which comprises an antibody complexed with a fusion protein that produces AI‐2. These nanofactories are entrapped within capsules formed by electrostatic complexation of cationic (chitosan) and anionic (sodium alginate) biopolymers. The chitosan capsule shell is crosslinked by tripolyphosphate (TPP) to confer structural integrity. The capsule shell is impermeable to the encapsulated nanofactories, but freely permeable to small molecules. In turn, the capsules are able to take in substrates from the external medium via diffusion, and convert these via the nanofactories into AI‐2, which then diffuses out. The exported AI‐2 is shown to stimulate QS responses in vicinal Escherichia coli. Directing bacterial population behavior has potential applications in next‐generation antimicrobial therapy and pathogen detection. We also envision such capsules to be akin to artificial “cells” that can participate in native biological signaling and communicate in real‐time with the human microbiome. Through such interaction capabilities, these “cells” may sense the health of the microbiome, and direct its function in a desired, host‐friendly manner. Biotechnol. Bioeng. 2013; 110: 552–562. © 2012 Wiley Periodicals, Inc.     

“Making coin” and the networker: Masculine self‐making in the Australian professional managerial class

In this article I unpack the labour of “networking” to understand the changes in sociality and worker identity that have occurred in the Australian professional managerial class workforce under post‐Fordism. Drawing on fieldwork undertaken at the interface of the pubic service and private consultancy firms in Canberra, I break from dominant readings of intimacy in post‐Fordism which preference either a downwards imposition of “ways of being” from capital to worker, or a reactive self‐regulation in line with objective external structures. Networking, I argue, is as much about being recognised as patron as it is about any tangible economic benefits. The intimate relations and self‐fashioning of networking constitute attempts to embody particular classed, sexualised, gendered fantasies of the figure of “the networker” in post‐Fordist Australian business culture. This interpretation does not necessitate overlooking the tangible results of networking, and I discuss too, how masculine fantasy structures the topography of workplaces.     

Co‐ordination of Incoming and Outgoing Traffic in Antigen‐Presenting Cells by Pattern Recognition Receptors and T Cells

Dendritic cells are innate sentinels of the immune system and potent activators of naÏve T cells. Mechanisms must exist to enable these cells to achieve maximal activation of T cells specific for microbial antigens, while avoiding activation of T cells specific for self‐antigens. Here we discuss how a combination of signals from pattern recognition receptors and T cells co‐ordinates subcellular trafficking of antigen with both major histocompatibility complex class I and class II molecules and T‐cell costimulatory molecules, resulting in the preferential presentation of microbial peptides within a stimulatory context.      

Rapidly expanding knowledge on the role of the gut microbiome in health and disease

The human gut is colonized by a wide diversity of micro-organisms, which are now known to play a key role in the human host by regulating metabolic functions and immune homeostasis. Many studies have indicated that the genomes of our gut microbiota, known as the gut microbiome or our “other genome” could play an important role in immune-related, complex diseases, and growing evidence supports a causal role for gut microbiota in regulating predisposition to diseases. A comprehensive analysis of the human gut microbiome is thus important to unravel the exact mechanisms by which the gut microbiota are involved in health and disease. Recent advances in next-generation sequencing technology, along with the development of metagenomics and bioinformatics tools, have provided opportunities to characterize the microbial communities. Furthermore, studies using germ-free animals have shed light on how the gut microbiota are involved in autoimmunity. In this review we describe the different approaches used to characterize the human microbiome, review current knowledge about the gut microbiome, and discuss the role of gut microbiota in immune homeostasis and autoimmunity. Finally, we indicate how this knowledge could be used to improve human health by manipulating the gut microbiota. This article is part of a Special Issue entitled: From Genome to Function.     

Male‐mimicking females increase male‐male interactions,and decrease male survival and condition in a female‐polymorphic damselfly

Biologists are still discovering diverse and powerful ways sexual conflicts shape biodiversity. The present study examines how the proportion of females in a population that exhibit male mimicry, a mating resistance trait, influences conspecific males’ behavior, condition, and survival. Like most female‐polymorphic damselflies, Ischnura ramburii harbors both “andromorph” females, which closely resemble males, and sexually dimorphic “gynomorph” counterparts. There is evidence that male mimicry helps andromorphs evade detection and harassment, but males can also learn to target locally prevalent morph(s) via prior mate encounters. I hypothesized that the presence of male mimics could therefore predispose males to mate recognition errors, and thereby increase rates of costly male‐male interactions. Consistent with this hypothesis, male‐male interaction rates were highest in mesocosms containing more andromorph (vs. gynomorph) females. Males in andromorph‐biased mesocosms also had lower final body mass and higher mortality than males assigned to gynomorph‐majority treatments. Male survival and body mass were each negatively affected by mesocosm density, and mortality data revealed a marginally significant interaction between andromorph frequency and population density. These findings suggest that, under sufficiently crowded conditions, female mating resistance traits such as male mimicry could have pronounced indirect effects on male behavior, condition, and survival.     

Why the Outcome of Anti-Tumor Immune Responses is Heterogeneous: A Novel Idea in the Context of Immunological Heterogeneity in Cancers

The question as to why some hosts can eradicate their tumors while others succumb to tumor-progression remains unanswered. Here, a provocative concept is proposed that intrinsic differences in the T cell receptor (TCR) repertoire of individuals may influence the outcome of anti-tumor immunity by affecting the frequency and/or variety of tumor-reactive CD8 and/or CD4 tumor-infiltrating lymphocytes. This idea implicates that the TCR repertoire in a given patient might not provide sufficiently different TCR clones that can recognize tumor antigens, namely, “a hole in the TCR repertoire” might exist. This idea may provide a novel perspective to further dissect the mechanisms underlying heterogeneous anti-tumor immune responses in different hosts. Besides tumor-intrinsic heterogeneity and host microbiome, the various factors that may constantly shape the dynamic TCR repertoire are also discussed. Elucidating mechanistic differences in different individuals’ immune systems will allow to better harness immune system to design new personalized cancer immunotherapy.     

REVISING A CLASSIC BUTTERFLY MIMICRY SCENARIO: DEMONSTRATION OF MÜLLERIAN MIMICRY BETWEEN FLORIDA VICEROYS (LIMENITIS ARCHIPPUS FLORIDENSIS) AND QUEENS (DANAUS GILIPPUS BERENICE)

Batesian and Müllerian mimicry relationships differ greatly in terms of selective pressures affecting the participants; hence, accurately characterizing a mimetic interaction is a crucial prerequisite to understanding the selective milieux of model, mimic, and predator. Florida viceroy butterflies (Limenitis archippus floridensis) are conventionally characterized as palatable Batesian mimics of distasteful Florida queens (Danaus gilippus berenice). However, recent experiments indicate that both butterflies are moderately distasteful, suggesting they may be Müllerian comimics. To directly test whether the butterflies exemplify Müllerian mimicry, I performed two reciprocal experiments using red-winged blackbird predators. In Experiment 1, each of eight birds was exposed to a series of eight queens as “models,” then offered four choice trials involving a viceroy (the putative “mimic”) versus a novel alternative butterfly. If mimicry was effective, viceroys should be attacked less than alternatives. I also compared the birds' reactions to solo viceroy “mimics” offered before and after queen models, hypothesizing that attack rate on the viceroy would decrease after birds had been exposed to queen models. In Experiment 2, 12 birds were tested with viceroys as models and queens as putative mimics. The experiments revealed that (1) viceroys and queens offered as models were both moderately unpalatable (only 16% entirely eaten), (2) some birds apparently developed conditioned aversions to viceroy or queen models after only eight exposures, (3) in the subsequent choice trials, viceroy and queen “mimics” were attacked significantly less than alternatives, and (4) solo postmodel mimics were attacked significantly less than solo premodel mimics. Therefore, under these experimental conditions, sampled Florida viceroys and queens are comimics and exemplify Müllerian, not Batesian, mimicry. This compels a reassessment of selective forces affecting the butterflies and their predators, and sets the stage for a broader empirical investigation of the ecological and evolutionary dynamics of mimicry.     

Alternative prey can change model–mimic dynamics between parasitism and mutualism

Classical (conventional) Müllerian mimicry theory predicts that two (or more) defended prey sharing the same signal always benefit each other despite the fact that one species can be more toxic than the other. The quasi‐Batesian (unconventional) mimicry theory, instead, predicts that the less defended partner of the mimetic relationship may act as a parasite of the signal, causing a fitness loss to the model. Here we clarify the conditions for parasitic or mutualistic relationships between aposematic prey, and build a model to examine the hypothesis that the availability of alternative prey is crucial to Müllerian and quasi‐Batesian mimicry. Our model is based on optimal behaviour of the predator. We ask if and when it is in the interest of the predator to learn to avoid certain species as prey when there is alternative (cryptic) prey available. Our model clearly shows that the role of alternative prey must be taken into consideration when studying model–mimic dynamics. When food is scarce it pays for the predator to test the models and mimics, whereas if food is abundant predators should leave the mimics and models untouched even if the mimics are quite edible. Dynamics of the mimicry tend to be classically Müllerian if mimics are well defended, while quasi‐Batesian dynamics are more likely when they are relatively edible. However, there is significant overlap: in extreme cases mimics can be harmful to models (a quasi‐Batesian case) even if the species are equally toxic. A crucial parameter explaining this overlap is the search efficiency with which indiscriminating vs. discriminating predators find cryptic prey. Quasi‐Batesian mimicry becomes much more likely if discrimination increases the efficiency with which the specialized predator finds cryptic prey, while the opposite case tends to predict Müllerian mimicry. Our model shows that both mutualistic and parasitic relationship between model and mimic are possible and the availability of alternative prey can easily alter this relationship.     

Regulatory T cells constrain the TCR repertoire of antigen‐stimulated conventional CD4 T cells

To analyze the potential role of Tregs in controlling the TCR repertoire breadth to a non‐self‐antigen, a TCRβ transgenic mouse model (EF4.1) expressing a limited, yet polyclonal naïve T‐cell repertoire was used. The response of EF4.1 mice to an I‐Ab‐associated epitope of the F‐MuLV envelope protein is dominated by clones expressing a Vα2 gene segment, thus allowing a comprehensive analysis of the TCRα repertoire in a relatively large cohort of mice. Control and Treg‐depleted EF4.1 mice were immunized, and the extent of the Vα2‐bearing, antigen‐specific TCR repertoire was characterized by high‐throughput sequencing and spectratyping analysis. In addition to increased clonal expansion and acquisition of effector functions, Treg depletion led to the expression of a more diverse TCR repertoire comprising several private clonotypes rarely observed in control mice or in the pre‐immune repertoire. Injection of anti‐CD86 antibodies in vivo led to a strong reduction in TCR diversity, suggesting that Tregs may influence TCR repertoire diversity by modulating costimulatory molecule availability. Collectively, these studies illustrate an additional mechanism whereby Tregs control the immune response to non‐self‐antigens.     

Parasite immunology and lymphocyte population dynamics

We propose that parasites use "antigenic mimicry", the presentation of host-type antigens, not merely as a disguise, but as a means of actively diverting the immune system into an ineffective mode of response that actually protects the parasites. This suggestion is the outcome of analyzing the immune system by the principle of Darwinian selection--among lymphocyte populations differing in their relative growth capacities under particular environmental conditions. In particular, it is proposed that proliferation can be uncoupled from differentiation under certain predictable conditions; and moreover, clones that proliferate for prolonged periods of time without significant maturation into effector cells may gain a selective advantage and reach prominence. This mode of "latent proliferation" is a key to self-non-self discrimination: under physiologic conditions, those T and B cells are selected that react "proliferatively" with certain classes of self-antigens, ensuring tolerance to self. We suggest that parasites which present host-type antigens generate the same kind of dynamic selection among responding lymphocytes. The hypothesis links polyclonal activation and "immunosuppression" to "antigenic mimicry", predicts "concomitant immunity" to the same parasite and suggests a pathway leading to autoimmunity. It is also amenable to testing.     

Unlinked Mendelian inheritance of red and black pigmentation in snakes: Implications for Batesian mimicry

Identifying the genetic basis of mimetic signals is critical to understanding both the origin and dynamics of mimicry over time. For species not amenable to large laboratory breeding studies, widespread color polymorphism across natural populations offers a powerful way to assess the relative likelihood of different genetic systems given observed phenotypic frequencies. We classified color phenotype for 2175 ground snakes (Sonora semiannulata) across the continental United States to analyze morph ratios and test among competing hypotheses about the genetic architecture underlying red and black coloration in coral snake mimics. We found strong support for a two‐locus model under simple Mendelian inheritance, with red and black pigmentation being controlled by separate loci. We found no evidence of either linkage disequilibrium between loci or sex linkage. In contrast to Batesian mimicry systems such as butterflies in which all color signal components are linked into a single “supergene,” our results suggest that the mimetic signal in colubrid snakes can be disrupted through simple recombination and that color evolution is likely to involve discrete gains and losses of each signal component. Both outcomes are likely to contribute to the exponential increase in rates of color evolution seen in snake mimicry systems over insect systems.     

A Usage Scenario Independent “Air Chargeable” Flexible Zinc Ion Energy Storage Device

A rationally designed “air chargeable” energy storage device is demonstrated, which can be effectively charged by harvesting pervasive energy from the ambient environment. For an “air chargeable” zinc‐ion capacitor system, the system simply consists of a flexible bifunctional “U” shaped electrode (with the functions of energy harvesting and storage), a zinc metal electrode in middle, and two different polyelectrolytes (polyacrylamide and sodium polyacrylate) sandwiched between the zinc metal and “U” shaped electrode. When the zinc‐ion capacitor is exhausted, it can be quickly charged to 88% within 10 min by simply opening the sealing tape and allowing the air diffuse in. The capacitor exhausting‐air charging processes are repeated 60 times and the whole system works well. When the external power supplier is available, both the zinc‐ion capacitor and “air charging” component can be fully recovered. A large capacity (≈1000 mAh) “air chargeable” zinc‐vanadium battery is also demonstrated. The zinc‐vanadium battery can be fully charged by air in 1 h. This work offers a usage scenario independent reliable self‐chargeable power supply system as a promising approach to solve the intermittent and unpredictable nature of currently developed self‐chargeable devices.     

Microbiome‐Germline Interactions and Their Transgenerational Implications

It is becoming increasingly clear that most, if not all, animals and plants are associated with a diverse array of resident gut microbiota. This symbiosis is regulated by host‐microbiome interactions which influence the development, homeostasis, adaptation and evolution of the host. Recent evidence indicated that these interactions can also affect the host germline and have a potential of supporting transgenerational effects, including inheritance of acquired characteristics. Taken together, the influence of gut bacteria on the host soma and germline could potentially give rise to emergent phenotypes, which may be partially inherited by three distinguishable modes of transgenerational influence of gut bacteria: 1) “soma‐to‐soma” 2) “soma‐to‐germline” and 3) “soma‐germline‐soma”. Here, we discuss these possibilities in light of evidence supporting bacterial‐mediated modes of transgenerational inheritance.

     

Schistosoma mansoni and Biomphalaria glabrata share epitopes: antibodies to sporocysts bind host snail hemocytes

Using an independent protocol, we have confirmed that sporocysts of the human blood fluke, Schistosoma mansoni, synthesize antigens which stimulate rabbit antibody activity to epitopes on infermediate snail host hemocytes. This molecular mimicry may aid S. mansoni to escape the innate immune system of this host, Biomphalaria glabrata.