Thy1+ NK [corrected] cells from vaccinia virus-primed mice confer protection against vaccinia virus challenge in the absence of adaptive lymphocytes

While immunological memory has long been considered the province of T- and B-lymphocytes, it has recently been reported that innate cell populations are capable of mediating memory responses. We now show that an innate memory immune response is generated in mice following infection with vaccinia virus, a poxvirus for which no cognate germline-encoded receptor has been identified. This immune response results in viral clearance in the absence of classical adaptive T and B lymphocyte populations, and is mediated by a Thy1(+) subset of natural killer (NK) cells. We demonstrate that immune protection against infection from a lethal dose of virus can be adoptively transferred with memory hepatic Thy1(+) NK cells that were primed with live virus. Our results also indicate that, like classical immunological memory, stronger innate memory responses form in response to priming with live virus than a highly attenuated vector. These results demonstrate that a defined innate memory cell population alone can provide host protection against a lethal systemic infection through viral clearance.     

Theoretical analysis of the evolution of immune memory

Background

The ability of an immune system to remember pathogens improves the chance of the host to survive a second exposure to the same pathogen. This immunological memory has evolved in response to the pathogen environment of the hosts. In vertebrates, the memory of previous infection is physiologically accomplished by the development of memory T and B cells. Many questions concerning the generation and maintenance of immunological memory are still debated. Is there a limit to how many memory cells a host can generate and maintain? If there is a limit, how should new cells be incorporated into a filled memory compartment? And how many different pathogens should the immune system remember?

Results

In this study, we examine how memory traits evolve as a response to different pathogen environments using an individual-based model. We find that even without a cost related to the maintenance of a memory pool, the positive effect of bigger memory pool sizes saturates. The optimal diversity of a limited memory pool is determined by the probability of re-infection, rather than by the prevalence of a pathogen in the environment, or the frequency of exposure.

Conclusions

Relating immune memory traits to the pathogen environment of the hosts, our population biological framework sheds light on the evolutionary determinants of immune memory.

     

Thy1+ Nk Cells from Vaccinia Virus-Primed Mice Confer Protection against Vaccinia Virus Challenge in the Absence of Adaptive Lymphocytes

While immunological memory has long been considered the province of T- and B- lymphocytes, it has recently been reported that innate cell populations are capable of mediating memory responses. We now show that an innate memory immune response is generated in mice following infection with vaccinia virus, a poxvirus for which no cognate germline-encoded receptor has been identified. This immune response results in viral clearance in the absence of classical adaptive T and B lymphocyte populations, and is mediated by a Thy1⁺ subset of natural killer (NK) cells. We demonstrate that immune protection against infection from a lethal dose of virus can be adoptively transferred with memory hepatic Thy1⁺ NK cells that were primed with live virus. Our results also indicate that, like classical immunological memory, stronger innate memory responses form in response to priming with live virus than a highly attenuated vector. These results demonstrate that a defined innate memory cell population alone can provide host protection against a lethal systemic infection through viral clearance.     

Parasites and immune responses: memory illusion?

Immunological memory responses to intracellular protozoa and extracellular helminths govern host resistance and susceptibility to reinfection. Humans and livestock living in parasitic disease endemic regions face continuous exposure from a very early age that often leads to asymptomatic chronic infection over their entire lifespan. Fundamental immunological studies suggest that the generation of T-cell memory is driven by tightly coordinated innate and adaptive cellular immune responses rapidly triggered following initial host infection. A key distinguishing feature of immune memory maintenance between the majority of parasitic diseases and most bacterial or viral diseases is long-term antigen persistence. Consequently, functional parasite immune memory is in a continuous, dynamic flux between activation and deactivation producing functional parasite killing or functional memory cell death. In this sense, T-cell immune memory can be regarded as "memory illusion." Furthermore, due to the finite capacity of memory lymphocytes to proliferate, continuous parasite antigen stimulation may exceed a threshold level at some point in the chronically infected host. This may result in suboptimal effector immune memory leading to host susceptibility to reinfection, or immune dysregulation yielding disease reactivation or immune pathology. The goal of this review is to highlight, through numerous examples, what is currently known about T-cell immune memory to parasites and to provide compelling hypotheses on the survival and maintenance of parasite "memory illusion." These novel concepts are discussed in the context of rationale parasite vaccine design strategies.     

A new theory of cytotoxic T-lymphocyte memory: implications for HIV treatment

We use simple mathematical models to examine the dynamics of primary and secondary cytotoxic T-lymphocyte (CTL) responses to viral infections. In particular, we are interested in conditions required to resolve the infection and to protect the host upon secondary challenge. While protection against reinfection is only effective in a restricted set of circumstances, we find that resolution of the primary infection requires persistence of CTL precursors (GTLp), as well as a fast rate of activation of the CTLp. Since these are commonly the defining characteristics of CTL memory, we propose that CTL memory may have evolved in order to clear the virus during primary challenge. We show experimental data from lymphocytic choriomeningitis virus infection in mice, supporting our theory on CTL memory. We adapt our models to HIV and find that immune impairment during the primary phase of the infection may result in the failure to establish CTL memory which in turn leads to viral persistence. Based on our models we suggest conceptual treatment regimes which ensure establishment of CTL memory. This would allow the immune response to control HIV in the long term in the absence of continued therapy.     

猪流行性腹泻病毒诱导的猪肠道-乳腺-sIgA轴以及免疫机制探讨

猪的“肠道-乳腺-sIgA轴”免疫通路是指侵染猪的胃肠道病原通过胃肠道免疫可以激发乳腺产生sIgA;sIgA被初生仔猪摄取可以获得针对胃肠道病原的被动免疫保护。该免疫通路的反应动力模式涉及病原侵染、抗原提呈、淋巴细胞活化、淋巴细胞的肠道和乳腺归巢以及抗体分泌等诸多环节,受到病原毒力、母猪的妊娠阶段及免疫生理状态等众多因素影响。目前,猪流行性腹泻病毒（Porcine Epidemic Diarrhea Virus,PEDV）诱发的“肠道-乳腺-sIgA轴”的理论可以解释自然感染状态下哺乳仔猪获得的被动免疫保护,但根据这一概念所设计的疫苗和免疫方案并未取得满意效果。本文综述了PEDV感染和宿主免疫各个环节的研究现状,分析了影响PEDV免疫和肠道-乳腺-sIgA轴系反应的关键病原和宿主因素,提出了在轴系理论基础上应重视PEDV灭活疫苗以及特异IgG作用的建议。     

'Small worlds' and the evolution of virulence: infection occurs locally and at a distance

Why are some discases more virulent than others? Vector-borne diseases such as malaria and water-borne diseases such as cholera are generally more virulent than diseases spread by direct contagion. One factor that characterizes both vector- and water-borne diseases is their ability to spread over long distances, thus causing infection of susceptible individuals distant from the infected individual. Here we show that this ability of the pathogen to infect distant individuals in a spatially structured host population leads to the evolution of a more virulent pathogen. We use a lattice model in which reproduction is local but infection can vary between completely local to completely global. With completely global infection the evolutionarily stable strategy (ESS) is the same as in mean-field models while a lower virulence is predicted as infection becomes more local. There is characteristically a period of relatively moderate increase in virulence followed by a more rapid rise with increasing proportions of global infection as we move beyond a ''critical connectivity''. In the light of recent work emphasizing the existence of ''small world'' networks in human populations, our results suggests that if the world is getting ''smaller''--as populations become more connected--diseases may evolve higher virulence.     

Host responses from innate to adaptive immunity after vaccination: Molecular and cellular events

The availability of effective vaccines has had the most profound positive effect on improving the quality of public health by preventing infectious diseases. Despite many successful vaccines, there are still old and new emerging pathogens against which there is no vaccine available. A better understanding of how vaccines work for providing protection will help to improve current vaccines as well as to develop effective vaccines against pathogens for which we do not have a proper means to control. Recent studies have focused on innate immunity as the first line of host defense and its role in inducing adaptive immunity; such studies have been an intense area of research, which will reveal the immunological mechanisms how vaccines work for protection. Toll-like receptors (TLRs), a family of receptors for pathogen-associated molecular patterns on cells of the innate immune system, play a critical role in detecting and responding to microbial infections. Importantly, the innate immune system modulates the quantity and quality of longterm T and B cell memory and protective immune responses to pathogens. Limited studies suggest that vaccines which mimic natural infection and/or the structure of pathogens seem to be effective in inducing long-term protective immunity. A better understanding of the similarities and differences of the molecular and cellular events in host responses to vaccination and pathogen infection would enable the rationale for design of novel preventive measures against many challenging pathogens.     

The evolutionary dynamics of timing of maternal immunity: evaluating the role of age‐specific mortality

If a female survives an infection, she can transfer antibodies against that particular pathogen to any future offspring she produces. The resulting protection of offspring for a period after their birth is termed maternal immunity. Because infection in newborns is associated with high mortality, the duration of this protection is expected to be under strong selection. Evolutionary modelling structured around a trade‐off between fertility and duration of maternal immunity has indicated selection for longer duration of maternal immunity for hosts with longer lifespans. Here, we use a new modelling framework to extend this analysis to consider characteristics of pathogens (and hosts) in further detail. Importantly, given the challenges in characterizing trade‐offs linked to immune function empirically, our model makes no assumptions about costs of longer lasting maternal immunity. Rather, a key component of this analysis is variation in mortality over age. We found that the optimal duration of maternal immunity is shaped by the shifting balance of the burden of infection between young and old individuals. As age of infection depends on characteristics of both the host and the pathogen, both affect the evolution of duration of maternal immunity. Our analysis provides additional support for selection for longer duration of maternal immunity in long‐lived hosts, even in the absence of explicit costs linked to duration of maternal immunity. Further, the scope of our results provides explanations for exceptions to the general correlation between duration of maternal immunity and lifespan, as we found that both pathogen characteristics and trans‐generational effects can lead to important shifts in fitness linked to maternal immunity. Finally, our analysis points to new directions for quantifying the trade‐offs that drive the development of the immune system.     

Dietary Bifidobacterium lactis (HN019) enhances resistance to oral Salmonella typhimurium infection in mice

The ability of a newly identified probiotic lactic acid bacterial strain, Bifidobacterium lactis (HN019), to confer protection against Salmonella typhimurium was investigated in BALB/c mice. Feeding mice with B. lactis conferred a significant degree of protection against single or multiple oral challenge with virulent S. typhimurium, in comparison to control mice that did not receive B. lactis. Protection included a ten-fold increase in survival rate, significantly higher post-challenge food intake and weight gain, and reduced pathogen translocation to visceral tissues (spleen and liver). Furthermore, the degree of pathogen translocation showed a significant inverse correlation with splenic lymphocyte proliferative responses to mitogens, blood and peritoneal cell phagocytic activity and intestinal mucosal anti-S. typhimurium antibody titers in infected mice; all of these immune parameters were enhanced in mice fed B. lactis. Together, these results suggest that dietary B. lactis can provide a significant degree of protection against Salmonella infection by enhancing various parameters of immune function that are relevant to the immunological control of salmonellosis. Thus dietary supplementation with B. lactis provides a unique opportunity for developing immune-enhancing probiotic dairy food products with proven health benefits.     

Specific Gene Expression Responses to Parasite Genotypes Reveal Redundancy of Innate Immunity in Vertebrates

Vertebrate innate immunity is the first line of defense against an invading pathogen and has long been assumed to be largely unspecific with respect to parasite/pathogen species. However, recent phenotypic evidence suggests that immunogenetic variation, i.e. allelic variability in genes associated with the immune system, results in host-parasite genotype-by-genotype interactions and thus specific innate immune responses. Immunogenetic variation is common in all vertebrate taxa and this reflects an effective immunological function in complex environments. However, the underlying variability in host gene expression patterns as response of innate immunity to within-species genetic diversity of macroparasites in vertebrates is unknown. We hypothesized that intra-specific variation among parasite genotypes must be reflected in host gene expression patterns. Here we used high-throughput RNA-sequencing to examine the effect of parasite genotypes on gene expression patterns of a vertebrate host, the three-spined stickleback (Gasterosteus aculeatus). By infecting naïve fish with distinct trematode genotypes of the species Diplostomum pseudospathaceum we show that gene activity of innate immunity in three-spined sticklebacks depended on the identity of an infecting macroparasite genotype. In addition to a suite of genes indicative for a general response against the trematode we also find parasite-strain specific gene expression, in particular in the complement system genes, despite similar infection rates of single clone treatments. The observed discrepancy between infection rates and gene expression indicates the presence of alternative pathways which execute similar functions. This suggests that the innate immune system can induce redundant responses specific to parasite genotypes.     

Predation on Multiple Trophic Levels Shapes the Evolution of Pathogen Virulence

The pathogen virulence is traditionally thought to co-evolve as a result of reciprocal selection with its host organism. In natural communities, pathogens and hosts are typically embedded within a web of interactions with other species, which could affect indirectly the pathogen virulence and host immunity through trade-offs. Here we show that selection by predation can affect both pathogen virulence and host immune defence. Exposing opportunistic bacterial pathogen Serratia marcescens to predation by protozoan Tetrahymena thermophila decreased its virulence when measured as host moth Parasemia plantaginis survival. This was probably because the bacterial anti-predatory traits were traded off with bacterial virulence factors, such as motility or resource use efficiency. However, the host survival depended also on its allocation to warning signal that is used against avian predation. When infected with most virulent ancestral bacterial strain, host larvae with a small warning signal survived better than those with an effective large signal. This suggests that larval immune defence could be traded off with effective defence against bird predators. However, the signal size had no effect on larval survival when less virulent control or evolved strains were used for infection suggesting that anti-predatory defence against avian predators, might be less constrained when the invading pathogen is rather low in virulence. Our results demonstrate that predation can be important indirect driver of the evolution of both pathogen virulence and host immunity in communities with multiple species interactions. Thus, the pathogen virulence should be viewed as a result of both past evolutionary history, and current ecological interactions.     

Trained immunity: a memory for innate host defense

Immune responses in vertebrates are classically divided into innate and adaptive, with only the latter being able to build up immunological memory. However, although lacking adaptive immune responses, plants and invertebrates are protected against reinfection with pathogens, and invertebrates even display transplant rejection. In mammals, past "forgotten" studies demonstrate cross-protection between infections independently of T and B cells, and more recently memory properties for NK cells and macrophages, prototypical cells of innate immunity, have been described. We now posit that mammalian innate immunity also exhibits an immunological memory of past insults, for which we propose the term "trained immunity." Understanding trained immunity will revolutionize our view of host defense and immunological memory, and could lead to defining a new class of vaccines and immunotherapies.     

The evolution of costly acquired immune memory

A key feature of the vertebrate adaptive immune system is acquired immune memory, whereby hosts launch a faster and heightened response when challenged by previously encountered pathogens, preventing full infection. Here, we use a mathematical model to explore the role of ecological and epidemiological processes in shaping selection for costly acquired immune memory. Applying the framework of adaptive dynamics to the classic SIR (Susceptible‐Infected‐Recovered) epidemiological model, we focus on the conditions that may lead hosts to evolve high levels of immunity. Linking our work to previous theory, we show how investment in immune memory may be greatest at long or intermediate host lifespans depending on whether immunity is long lasting. High initial costs to gain immunity are also found to be essential for a highly effective immune memory. We also find that high disease infectivity and sterility, but intermediate virulence and immune period, increase selection for immunity. Diversity in host populations through evolutionary branching is found to be possible but only for a limited range of parameter space. Our model suggests that specific ecological and epidemiological conditions have to be met for acquired immune memory to evolve.     

In Vivo Microbial Coevolution Favors Host Protection and Plastic Downregulation of Immunity

Microbiota can protect their hosts from infection. The short timescales in which microbes can evolve presents the possibility that “protective microbes” can take-over from the immune system of longer-lived hosts in the coevolutionary race against pathogens. Here, we found that coevolution between a protective bacterium (Enterococcus faecalis) and a virulent pathogen (Staphylococcus aureus) within an animal population (Caenorhabditis elegans) resulted in more disease suppression than when the protective bacterium adapted to uninfected hosts. At the same time, more protective E. faecalis populations became costlier to harbor and altered the expression of 134 host genes. Many of these genes appear to be related to the mechanism of protection, reactive oxygen species production. Crucially, more protective E. faecalis populations downregulated a key immune gene, , known to be effective against S. aureus infection. These results suggest that a microbial line of defense is favored by microbial coevolution and may cause hosts to plastically divest of their own immunity.     

Utilization of Fc receptors as a mucosal vaccine strategy against an intracellular bacterium, Francisella tularensis

Numerous studies have demonstrated that targeting Ag to Fc receptors (FcR) on APCs can enhance humoral and cellular immunity. However, studies are lacking that examine both the use of FcR-targeting in generating immune protection against infectious agents and the use of FcRs in the induction of mucosal immunity. Francisella tularensis is a category A intracellular mucosal pathogen. Thus, intense efforts are underway to develop a vaccine against this organism. We hypothesized that protection against mucosal infection with F. tularensis would be significantly enhanced by targeting inactivated F. tularensis live vaccine strain (iFt) to FcRs at mucosal sites, via intranasal immunization with mAb-iFt complexes. These studies demonstrate for the first time that: 1) FcR-targeted immunogen enhances immunogen-specific IgA production and protection against subsequent infection in an IgA-dependent manner, 2) FcgammaR and neonatal FcR are crucial to this protection, and 3) inactivated F. tularensis, when targeted to FcRs, enhances protection against the highly virulent SchuS4 strain of F. tularensis, a category A biothreat agent. In summary, these studies show for the first time the use of FcRs as a highly effective vaccination strategy against a highly virulent mucosal intracellular pathogen.     

Evolution of virulence: triggering host inflammation allows invading pathogens to exclude competitors

Virulence is generally considered to benefit parasites by enhancing resource-transfer from host to pathogen. Here, we offer an alternative framework where virulent immune-provoking behaviours and enhanced immune resistance are joint tactics of invading pathogens to eliminate resident competitors (transferring resources from resident to invading pathogen). The pathogen wins by creating a novel immunological challenge to which it is already adapted. We analyse a general ecological model of 'proactive invasion' where invaders not adapted to a local environment can succeed by changing it to one where they are better adapted than residents. However, the two-trait nature of the 'proactive' strategy (provocation of, and adaptation to environmental change) presents an evolutionary conundrum, as neither trait alone is favoured in a homogenous host population. We show that this conundrum can be resolved by allowing for host heterogeneity. We relate our model to emerging empirical findings on immunological mediation of parasite competition.     

No evidence for immune priming in ants exposed to a fungal pathogen

There is accumulating evidence that invertebrates can acquire long-term protection against pathogens through immune priming. However, the range of pathogens eliciting immune priming and the specificity of the response remain unclear. Here, we tested if the exposure to a natural fungal pathogen elicited immune priming in ants. We found no evidence for immune priming in Formica selysi workers exposed to Beauveria bassiana. The initial exposure of ants to the fungus did not alter their resistance in a subsequent challenge with the same fungus. There was no sign of priming when using homologous and heterologous combinations of fungal strains for exposure and subsequent challenges at two time intervals. Hence, within the range of conditions tested, the immune response of this social insect to the fungal pathogen appears to lack memory and strain-specificity. These results show that immune priming is not ubiquitous across pathogens, hosts and conditions, possibly because of immune evasion by the pathogen or efficient social defences by the host.     

Imperfect vaccines and the evolution of pathogens causing acute infections in vertebrates

A study by Gandon et al. (2001) considered the potential ways pathogens may evolve in response to vaccination with imperfect vaccines. In this paper, by focusing on acute infections of vertebrate hosts, we examine whether imperfect vaccines that do not completely block a pathogen's replication (antigrowth) or transmission (antitransmission) may lead to evolution of more or less virulent pathogen strains. To address this question, we use models of the within-host dynamics of the pathogen and the host's immune responses. One advantage of the use of this within-host approach is that vaccination can be easily incorporated in the models and the trade-offs between pathogen transmissibility, host recovery, and virulence that drive evolution of pathogens in these models can be easily estimated. We find that the use of either antigrowth or antitransmission vaccines leads to the evolution of pathogens with an increased within-host growth rate; infection of unvaccinated hosts with such evolved pathogens results in high host mortality and low pathogen transmission. Vaccination of only a fraction of hosts with antigrowth vaccines may prevent pathogens from evolving high virulence due to pathogen adaptation to unvaccinated hosts and thus protection of vaccinated hosts from pathogen-induced disease. In contrast, antitransmission vaccines may be beneficial only if they are effective enough to cause pathogen extinction. Our results suggest that particular mechanisms of action of vaccines and their efficacy are crucial in predicting longterm evolutionary consequences of the use of imperfect vaccines.