Constitutive Immunity Research Articles

Complex of Defense Polypeptides of Wheatgrass (Elytrigia elongata) Associated with Plant Immunity to Biotic and Abiotic Stress Factors.

Plant defense polypeptides play a crucial role in providing plants with constitutive immunity against various biotic and abiotic stressors. In this study, we explored a complex of proteins from wheatgrass (Elytrigia elongata) spikelets to estimate their role in the plant's tolerance to various environmental factors. The current research shows that in vitro protein extracts from E. elongata spikelets possess antifungal activity against certain Fusarium species, which are specific cereal pathogens, at concentrations of 1-2 mg/mL. In this study, we reproduced these antifungal activities using a 4 mg/mL extract in artificial fungal infection experiments on wheat grain (Triticum aestivum) under controlled laboratory conditions. Furthermore, the tested extract demonstrated a protective effect on Saccharomyces cerevisiae exposed to hyper-salinity stress at a concentration of 2 mg/mL. A combined scheme of fractionation and structural identification was applied for the estimation of the diversity of defense polypeptides. Defensins, lipid-transfer proteins, hydrolase inhibitors (cereal bifunctional trypsin/alpha-amylase inhibitors from a Bowman-Birk trypsin inhibitor), and high-molecular-weight disease resistance proteins were isolated from the extract. Thus, wheatgrass spikelets appear to be a reservoir of defense polypeptides. Our findings contribute to a deeper understanding of plant defense proteins and peptides and their involvement in the adaptation to various stress factors, and they reveal the regulatory effect at the ecosystem level.

Constitutive Innate Immunity and Systemic Responses to Infection of the American Alligator (Alligator mississippiensis).

Uninfected alligators (Alligator mississippiensis) exhibited high constitutive levels of hepatic gene expression related to immune function, whereas the highest-expressed hepatic genes of uninfected mice were related to metabolism. Intraperitoneal challenge of mice with bacterial lipopolysaccharide results in dramatic inflammatory effects including peritoneal ascites, febrile response, dramatic alterations in electrophoretic serum profile, and mortality. In contrast, coelomic injection of alligators with 200× the murine LD50 of intraperitoneal bacterial lipopolysaccharide resulted in no changes in serum protein profiles, behavioral effects, mortality, and no coelomic ascites. However, injection of juvenile alligators with live bacteria resulted in a titer-dependent decrease in metabolic rate, as measured by oxygen consumption. These results are the opposite of those observed for mammalian and avian species. The decreased oxygen consumption was not accompanied by changes in heart or respiration rate, indicating that this phenomenon was not due to bradycardia or bradypnea. Interestingly, challenge of alligators with bacteria resulted in the complete expulsion of digestive tract contents within four hours. We interpret these activities as temporary minimization of other biological systemic activities to redirect and devote energy to immune function. The reallocation of resources within an organism to fight infection without increases in metabolic rate has not been described in other animals.

Constitutive immunity is influenced by avian influenza virus-induced modification of gut microbiota in Eurasian teal (Anas crecca)

Understanding the dynamics of migrant birds' gut microbial communities is essential for evaluating their ecological interactions, since these birds act as vectors for zoonotic viruses and their gut microbiome may have exceptional relationship with zoonotic viral infection. The Eurasian teal duck Anas crecca traverses continents during migration, combining and providing intercontinental links for avian influenza viruses (AIV) of different origins. The present study aimed to investigate how the AIV infection affects gut microbial composition and evaluate the consequent physiological stress and constitutive immunity of teal birds. Samples were collected from 2 flocks during their migratory stopover in northern Egypt. An important shift in gut microbiota of AIV-infected individuals has been detected by RT-PCR. In healthy teal, firmicutes dominated followed by proteobacteria, while the structure was reversed in infected birds. Infection with AIV significantly increased the stress hormone corticosterone, accompanied by a significant increase in both oxidative stress markers and antioxidants. Constitutive immunity, measured by plasma bactericidal effect against E. coli, the nonspecific natural antibodies, and the mediated complement activation, was reduced in AIV-infected teal birds. Constitutive immunity parameters were proportionally correlated to the firmicutes and inversely to the proteobacteria abundances, but not to the viral positivity. In conclusion, the present study provides initial evidence of the alteration of the gut microbiome in the Eurasian teal Anas crecca by AIV infection and demonstrates that the AIV-induced reduction in constitutive immunity is a consequence of the shift in microbiome composition rather than the virus infection itself or its induced stress.

Controlled expression of avian pre-migratory fattening influences indices of innate immunity.

While immunity is frequently dampened when birds engage in strenuous migratory flights, whether and how immunity changes during the rapid accumulation of energy stores in preparation for migration remains largely unknown. Here we induced pre-migratory fattening through controlled changes of daylight in common quails (Coturnix coturnix) and regularly assessed changes in three markers of constitutive innate immunity (leukocyte coping capacity or LCC, hemagglutination and hemolysis titres) and measures of body composition (lean and fat mass). All the three markers showed similar changes over the pre-migratory fattening process. LCC responses, hemagglutination titres, and hemolysis titres, were on average higher in the mid-fattening phase compared to the peak-fattening phase, when values were similar to those observed prior the start of pre-migratory fattening. At mid-fattening, we found that the birds that showed a larger accumulation of fat mass (as % of body mass) had lower LCC peak responses and hemolysis titres. Reversibly, at mid-fattening, we also found that the birds that kept a higher proportion of lean mass (as % of body mass) had the highest LCC peaks. Our results indicate that migratory birds undergo changes in immune indices (over 8 weeks) as they accumulate energy stores for migration and propose that this could be due to competing or trade-off processes between metabolic remodelling and innate immune system function.

The evolution of constitutively active humoral immune defenses in Drosophila populations under high parasite pressure.

Both constitutive and inducible immune mechanisms are employed by hosts for defense against infection. Constitutive immunity allows for a faster response, but it comes with an associated cost that is always present. This trade-off between speed and fitness costs leads to the theoretical prediction that constitutive immunity will be favored where parasite exposure is frequent. We selected populations of Drosophila melanogaster under high parasite pressure from the parasitoid wasp Leptopilina boulardi. With RNA sequencing, we found the evolution of resistance in these populations was associated with them developing constitutively active humoral immunity, mediated by the larval fat body. Furthermore, these evolved populations were also able to induce gene expression in response to infection to a greater level, which indicates an overall more activated humoral immune response to parasitization. The anti-parasitoid immune response also relies on the JAK/STAT signaling pathway being activated in muscles following infection, and this induced response was only seen in populations that had evolved under high parasite pressure. We found that the cytokine Upd3, which induces this JAK/STAT response, is being expressed by immature lamellocytes. Furthermore, these immune cells became constitutively present when populations evolved resistance, potentially explaining why they gained the ability to activate JAK/STAT signaling. Thus, under intense parasitism, populations evolved resistance by increasing both constitutive and induced immune defenses, and there is likely an interplay between these two forms of immunity.

The potential of plant antimicrobial peptides for crop protection against diseases

Antimicrobial peptides (AMPs) are the most important components of plant innate immunity to environmental stress factors and one of the most ancient tools of the defense system. Most of them are synthesized as factors of constitutive plant immunity, but there are also inducible forms belonging to “pathogenesis-related proteins” (PR-proteins from classes 12, 13 and 14). This review provides characteristics of the primary and three-dimensional structures of the main families of plant AMPs. The relationship between the types of spatial arrangement of the polypeptide chain is drawn. The functional analysis of plant AMPs is presented by data on the spectrum and quantitative level of activities against a number of economically significant fungal and bacterial phytopathogens, and related biological effects are indicated. Additionally, current information is provided on the molecular mechanisms of the antimicrobial action of plant AMPs based on defensins as the most studied structural group. In conclusion, aspects of the modes of action for plant AMPs on microorganisms are considered, on the basis of which a variant of the functional classification of these molecules is proposed. Based on these data, the prospects for their use as the basis of biopesticides for plant protection against pathogens were assessed.

Characterization of trade-offs between immunity and reproduction in the coral species Astrangia poculata.

Living organisms face ubiquitous pathogenic threats and have consequently evolved immune systems to protect against potential invaders. However, many components of the immune system are physiologically costly to maintain and engage, often drawing resources away from other organismal processes such as growth and reproduction. Evidence from a diversity of systems has demonstrated that organisms use complex resource allocation mechanisms to manage competing needs and optimize fitness. However, understanding of resource allocation patterns is limited across taxa. Cnidarians, which include ecologically important organisms like hard corals, have been historically understudied in the context of resource allocations. Improving understanding of resource allocation-associated trade-offs in cnidarians is critical for understanding future ecological dynamics in the face of rapid environmental change. Here, we characterize trade-offs between constitutive immunity and reproduction in the facultatively symbiotic coral Astrangia poculata. Male colonies underwent ex situ spawning and sperm density was quantified. We then examined the effects of variable symbiont density and energetic budget on physiological traits, including immune activity and reproductive investment. Furthermore, we tested for potential trade-offs between immune activity and reproductive investment. We found limited associations between energetic budget and immune metrics; melanin production was significantly positively associated with carbohydrate concentration. However, we failed to document any associations between immunity and reproductive output which would be indicative of trade-offs, possibly due to experimental limitations. Our results provide a preliminary framework for future studies investigating immune trade-offs in cnidarians.

Reservoir host immunology and life history shape virulence evolution in zoonotic viruses.

The management of future pandemic risk requires a better understanding of the mechanisms that determine the virulence of emerging zoonotic viruses. Meta-analyses suggest that the virulence of emerging zoonoses is correlated with but not completely predictable from reservoir host phylogeny, indicating that specific characteristics of reservoir host immunology and life history may drive the evolution of viral traits responsible for cross-species virulence. In particular, bats host viruses that cause higher case fatality rates upon spillover to humans than those derived from any other mammal, a phenomenon that cannot be explained by phylogenetic distance alone. In order to disentangle the fundamental drivers of these patterns, we develop a nested modeling framework that highlights mechanisms that underpin the evolution of viral traits in reservoir hosts that cause virulence following cross-species emergence. We apply this framework to generate virulence predictions for viral zoonoses derived from diverse mammalian reservoirs, recapturing trends in virus-induced human mortality rates reported in the literature. Notably, our work offers a mechanistic hypothesis to explain the extreme virulence of bat-borne zoonoses and, more generally, demonstrates how key differences in reservoir host longevity, viral tolerance, and constitutive immunity impact the evolution of viral traits that cause virulence following spillover to humans. Our theoretical framework offers a series of testable questions and predictions designed to stimulate future work comparing cross-species virulence evolution in zoonotic viruses derived from diverse mammalian hosts.

Arabidopsis Topless-related 1 mitigates physiological damage and growth penalties of induced immunity.

Transcriptional corepressors of the Topless (TPL) family regulate plant hormone and immunity signaling. The lack of a genome-wide profile of their chromatin associations limits understanding of the TPL family roles in transcriptional regulation. Chromatin immunoprecipitation with sequencing (ChIP-Seq) was performed on Arabidopsis thaliana lines expressing GFP-tagged Topless-related 1 (TPR1-GFP) with and without constitutive immunity via Enhanced Disease Susceptibility 1 (EDS1). RNA-Seq profiling of the TPR1-GFP lines and pathogen-infected tpl/tpr mutants, combined with measuring immunity, growth, and physiological parameters was employed to investigate TPL/TPR roles in immunity and defense homeostasis. TPR1 was enriched at promoter regions of c. 1400 genes and c. 10% of the detected binding required EDS1 immunity signaling. In a tpr1 tpl tpr4 (t3) mutant, resistance to bacteria was slightly compromised, and defense-related transcriptional reprogramming was weakly reduced or enhanced, respectively, at early (< 1 h) and late 24 h stages of bacterial infection. The t3 plants challenged with bacteria or pathogen-associated molecular pattern nlp24 displayed photosystem II dysfunctions. Also, t3 plants were hypersensitive to phytocytokine pep1 at the level of root growth inhibition. Transgenic expression of TPR1 rescued these t3 physiological defects. We propose that TPR1 and TPL family proteins function in Arabidopsis to reduce detrimental effects associated with activated transcriptional immunity.

Constitutive Innate Immunity of Migrant and Resident Long-Nosed Bats (Leptonycteris yerbabuenae) in the Drylands of Mexico

In contrast to birds, the relationship between migration and immunity has been scarcely studied in bats. We examined how the expression of the humoral portion of the constitutive immunity varied in a bat with partial, sex-biased migration: the lesser long-nosed bat (Leptonycteris yerbabuenae (Phyllostomidae)). The lesser long-nosed bat is a nectarivorous species distributed in the arid and semi-arid regions of North and Central America. We evaluated the bacteria-killing abilities (BKAs) of the plasma of male and female lesser long-nosed bats on the Pacific coast in different periods of the year. Because adult males are resident, they were used to explore the effect of reproductive activity on BKA, and we predicted higher values in mating males (i.e., individuals presenting scrotal testicles and a fresh dorsal patch). In contrast to males, most females migrate to cactus deserts in northern Mexico during pregnancy and lactation, and then return to the dry forests of west-central Mexico to mate. We predicted that the combined effect of breeding and migration would have an adverse effect on BKA; therefore, migratory pregnant and lactating females were expected to exhibit a lower BKA than mating females in west-central Mexico. We compared the BKAs of females captured in October and December in central Mexico, and we predicted that migratory females that had recently arrived in October should exhibit a lower BKA than females captured two months later. In addition, we compared the BKAs between lactating females and young in northern Mexico and predicted lower values in recently born individuals. We found that the BKAs of males were higher in reproductive individuals than in non-reproductive individuals. We found a significant difference in the BKAs between females at the two extremes of their migratory range: the values of pregnant females in Sonora and females in December were higher than those of females captured in October. Finally, we found no difference in BKAs between lactating females and young individuals. Our findings indicate that the basal levels of the innate humoral component are heightened in mating males, that this response is reduced in females that recently returned to their mating grounds, and that the constitutive immunity of young individuals matures early, probably in anticipation of the potential to encounter pathogens during their migration to west-central Mexico.

House sparrows prioritize skin repair over constitutive innate immunity during long-term chronic stress.

The reactive scope model was created to address two major unanswered questions in stress physiology: how and when does the adaptive acute stress response turn into harmful chronic stress? Previous studies suggest that immunoenhancement should occur in reactive homeostasis (acute stress) and immunosuppression should occur in homeostatic overload (chronic stress). We used this dichotomy of immune function to further elucidate the transition from acute to chronic stress by treating house sparrows (Passer domesticus) with different intensities of chronic stress and then monitoring their immune function. By varying the number of stressors given per day and the length of chronic stress bouts over a period of 6 months, we produced four treatment groups: high, medium, and low stress, and captivity-only. We tracked immunity through the bacterial killing assay and monitored healing of a 4 mm skin biopsy punch. We hypothesized that higher-stress birds would repair their skin more slowly and have lower bacterial killing capacity. The opposite was true-high-stress birds initially repaired their skin fastest. Additionally, all birds dramatically reduced bacterial killing capacity after the biopsy and increased food-derived uric acid, suggesting increased energy acquisition and a shift in immune resources to a more immediate concern (healing). Once healing finished, only the high-stress birds were unable to recover circulating immune function, suggesting that the combination of high stress and an immune challenge pushed these birds into homeostatic overload. Prioritizing healing over other immunological processes might be the best defense for a bird in its natural habitat.

Variation in symbiont density is linked to changes in constitutive immunity in the facultatively symbiotic coral, Astrangia poculata.

Scleractinian corals are essential ecosystem engineers, forming the basis of coral reef ecosystems. However, these organisms are in decline globally, in part due to rising disease prevalence. Most corals are dependent on symbiotic interactions with single-celled algae from the family Symbiodiniaceae to meet their nutritional needs, however, suppression of host immunity may be essential to this relationship. To explore immunological consequences of algal symbioses in scleractinian corals, we investigated constitutive immune activity in the facultatively symbiotic coral, Astrangia poculata. We compared immune metrics (melanin synthesis, antioxidant production and antibacterial activity) between coral colonies of varying symbiont density. Symbiont density was positively correlated to both antioxidant activity and melanin concentration, likely as a result of the dual roles of these pathways in immunity and symbiosis regulation. Our results confirm the complex nature of relationships between algal symbiosis and host immunity and highlight the need for nuanced approaches when considering these relationships.

Plasma membrane-nucleo-cytoplasmic coordination of a receptor-like cytoplasmic kinase promotes EDS1-dependent plant immunity.

Plants use cell-surface immune receptors to recognize pathogen-specific patterns to evoke basal immunity. ENHANCED DISEASE SUSCEPTIBILITY (EDS1) is known to be crucial for plant basal immunity, whereas its activation mechanism by pattern recognition remains enigmatic. Here, we show that the fungal pattern chitin induced the plasma membrane-anchored receptor-like cytoplasmic kinase PBS1-LIKE 19 (PBL19) to undergo nuclear translocation in Arabidopsis. The palmitoylation-deficient PBL19C3A variant constantly resided in the nucleus, triggering transcriptional self-amplification mainly through WRKY8 and EDS1-dependent constitutive immunity. Unexpectedly, the metacaspase-cleaved PBL19 lacking the N-terminal nuclear localization sequence specifically interacted with and phosphorylated EDS1 in the cytoplasm. Phosphodeficient EDS1 attenuated PBL19C3A-induced constitutive immunity, while phosphomimetic EDS1 complemented the loss of PBL19 for fungal resistance. Collectively, these findings reveal a compelling model wherein the plasma membrane, nuclear and cytoplasmic pools of PBL19 temporally coordinate distinct roles of immune signal receiver, amplifier and effector to boost plant antifungal immunity via EDS1.

Timing of Breeding Reveals a Trade-Off between Immune Investment and Life History in Tree Swallows.

The allocation of limited resources among life history traits creates trade-offs that constrain the range of possible phenotypes of organisms. In animals, the cost of maintaining an effective immune response may reduce the ability to invest in reproduction, resulting in altered susceptibility to disease. However, not all members of a population face identical constraints because differences in an individual's environmental context or physiological state can influence the degree to which traits are negatively associated. Here, we evaluated how variation in timing of breeding, a correlate of fitness, may result in different patterns of trait associations between immunity and reproduction. We measured constitutive immunity in breeding female tree swallows (Tachycineta bicolor) using a bacteria killing assay with blood plasma to assess the relationships between bacteria killing ability (BKA), reproductive effort, and reproductive success. We found that timing of breeding can influence the association between BKA and reproductive effort, but its effects are not homogeneous among all traits. Late-breeding tree swallows with stronger BKA laid smaller clutches, a pattern that was not apparent in early breeders. Regardless of the timing of breeding, birds with stronger BKA fed their nestlings less. Despite a negative association with reproductive effort, we found no association between immunity and reproductive success. We provide evidence that individual tree swallows do not experience some trade-offs equally, and that timing of breeding likely plays a role in how costs of immunity are weighed. To understand how investment in immunity can limit life history traits, we must consider how a variation among individuals influences the relative costs of immunity.

Differences in constitutive innate immunity between divergent Australian marsupials

Understanding immunity in wildlife populations is important from both One Health and conservation perspectives. The constitutive innate immune system is the first line of defence against pathogens, and comparisons among taxa can test the impact of evolution and life history on immune function. We investigated serum bacterial killing ability (BKA) of five marsupial species that employ varying life history strategies, demonstrated to influence immunity in other vertebrates. The brushtail possum and eastern grey kangaroo had the greatest BKA, while ringtail possums and koalas had the least. These differences were independent of social structure, captivity status and phylogeny, but were associated with diet and body size. Sex and disease status had no effect on BKA in koalas, however potential for differences between wild and captive koalas warrants further investigation. The current study has provided a foundation for future investigations into how adaptive and innate immunity interact in marsupials from an eco-evolutionary perspective.

MdBAK1 overexpression in apple enhanced resistance to replant disease as well as to the causative pathogen Fusarium oxysporum

Apple replant disease (ARD) is a complex syndrome caused by various biotic and abiotic stresses contained in replanted soil, leading to reduced plant growth and fruit yields and causing serious economic loss. Breeding disease-resistant varieties is an effective and practical method to control ARD. Effective plant defense depends in part on the plant immune responses induced by the recognition of pathogen-associated molecular patterns (PAMPs) by pattern recognition receptors (PRRs). BAK1 participates in the regulation of plant immunity as an important PRR-binding protein. In this study, MdBAK1 overexpression activated indeterminate immune responses in tissue-cultured apple plants. MdBAK1-overexpressing rooted apple plants exhibited enhanced resistance to ARD, as the inhibition of plant growth was significantly alleviated during the replanted soil treatment. In addition, MdBAK1-overexpressing apple plants showed abolished growth inhibition, wilting and root rot induced by Fusarium oxysporum, which is the main pathogen that causes ARD in China. MdBAK1 overexpression changed the microbial community structure in the rhizosphere soil, as reflected by the increase in bacterial content and the decrease in fungal content, and the root exudates of MdBAK1-overexpressing plants inhibited F. oxysporum spore germination compared with that of wild-type plants. Furthermore, the constitutive immunity and cell necrosis induced by the upregulation of MdBAK1 expression were involved in the inhibition of colonization and expansion of F. oxysporum in host plants. In short, MdBAK1 plays an important role in the regulation of apple resistance to ARD, suggesting that MdBAK1 may be a valuable gene for molecular breeding of ARD resistance.

Hemolytic parasites affect survival in migrating red-tailed hawks.

Migrating birds face a myriad of hazards, including higher exposure to parasites and numerous competing energy demands. It follows that migration may act as a selective filter and limit population growth. Understanding how individual-level physiological condition and disease status scale up to population dynamics through differential survival of individuals is necessary to identify threats and management interventions for migratory populations, many of which face increasing conservation challenges. However, linking individual physiological condition, parasite infection status and survival can be difficult. We examined the relationship among two measures of physiological condition [scaled-mass index and heterophil/leukocyte (H/L) ratio], hematozoa (i.e. hemoparasites) presence and abundance, and constitutive immunity in 353 autumn migrating red-tailed hawks (Buteo jamaicensis calurus) from 2004 to 2018. Hematazoa (i.e. Haemoproteus and Leucocytozoon) were in the blood smears from 139 red-tailed hawks (39.4%). H/L ratio decreased with scaled-mass index. Adults had a significantly higher H/L ratio than juveniles. Our two measures of immune defences, hemolytic-complement activity and bacteria-killing ability, were highly positively correlated. Our most notable finding was a negative relationship between Haemoproteus parasitemia and survival (i.e. documented individual mortality), indicating that haemosporidian parasites influence survival during a challenging life stage. The effect of haemosporidian parasites on individuals is often debated, and we provide evidence that parasitemia can affect individual survival. In contrast, we did not find evidence of trade-offs between survival and immune defences.

XAP5 CIRCADIAN TIMEKEEPER Affects Both DNA Damage Responses and Immune Signaling in Arabidopsis.

Numerous links have been reported between immune response and DNA damage repair pathways in both plants and animals but the precise nature of the relationship between these fundamental processes is not entirely clear. Here, we report that XAP5 CIRCADIAN TIMEKEEPER (XCT), a protein highly conserved across eukaryotes, acts as a negative regulator of immunity in Arabidopsis thaliana and plays a positive role in responses to DNA damaging radiation. We find xct mutants have enhanced resistance to infection by a virulent bacterial pathogen, Pseudomonas syringae pv. tomato DC3000, and are hyper-responsive to the defense-activating hormone salicylic acid (SA) when compared to wild-type. Unlike most mutants with constitutive effector-triggered immunity (ETI), xct plants do not have increased levels of SA and retain enhanced immunity at elevated temperatures. Genetic analysis indicates XCT acts independently of NONEXPRESSOR OF PATHOGENESIS RELATED GENES1 (NPR1), which encodes a known SA receptor. Since DNA damage has been reported to potentiate immune responses, we next investigated the DNA damage response in our mutants. We found xct seedlings to be hypersensitive to UV-C and γ radiation and deficient in phosphorylation of the histone variant H2A.X, one of the earliest known responses to DNA damage. These data demonstrate that loss of XCT causes a defect in an early step of the DNA damage response pathway. Together, our data suggest that alterations in DNA damage response pathways may underlie the enhanced immunity seen in xct mutants.

Immunosenescence along with direct physiological allocation trade-offs between life history and immunity in the red palm weevil Rhynchophorus ferrugineus

Recent works have generally indicated that insects exhibit two immune response strategies: external and internal immune defense. However, the immune-related trade-offs and physiological regulatory mechanisms in red palm weevil, a major invasive pest, remain unclear. Based on postinfection survivorship experiments, we initially measured baseline constitutive external immunity (antibacterial activity of external secretions) and internal immunity (phenoloxidase and antibacterial activity of hemolymph) in uninfected individuals. Then, we challenged the individual immune system and examined subsequent investment in immune function. Our data showed that multiple factors (instar, age, sex, mating status, immune treatment) interacted to affect immune components and infection outcomes, but the magnitude and nature of the impact varied in each case. Although immune senescence is a common phenomenon in which immune function decreases with age, different components of the immune system changed differentially. Notably, mating activity may impose an immunity-related cost, with some evidence of sexual dimorphism and age-associated differences. Finally, parameters related to life-history traits usually decreased temporarily because of increased immunity, suggesting that the ultimate consequences of immune function fitness may be physiologically traded off with other fitness aspects, including growth, development, mating, reproduction, and longevity. These results reveal the complex factors that impact immunity as well as the physiological regulation of individual immunity, which may determine the evolution and outcome of immune senescence and trade-offs.

TLR3 controls constitutive IFN-β antiviral immunity in human fibroblasts and cortical neurons.

Human herpes simplex virus 1 (HSV-1) encephalitis can be caused by inborn errors of the TLR3 pathway, resulting in impairment of CNS cell-intrinsic antiviral immunity. Deficiencies of the TLR3 pathway impair cell-intrinsic immunity to vesicular stomatitis virus (VSV) and HSV-1 in fibroblasts, and to HSV-1 in cortical but not trigeminal neurons. The underlying molecular mechanism is thought to involve impaired IFN-α/β induction by the TLR3 recognition of dsRNA viral intermediates or by-products. However, we show here that human TLR3 controls constitutive levels of IFNB mRNA and secreted bioactive IFN-β protein, and thereby also controls constitutive mRNA levels for IFN-stimulated genes (ISGs) in fibroblasts. Tlr3-/- mouse embryonic fibroblasts also have lower basal ISG levels. Moreover, human TLR3 controls basal levels of IFN-β secretion and ISG mRNA in induced pluripotent stem cell-derived cortical neurons. Consistently, TLR3-deficient human fibroblasts and cortical neurons are vulnerable not only to both VSV and HSV-1, but also to several other families of viruses. The mechanism by which TLR3 restricts viral growth in human fibroblasts and cortical neurons in vitro and, by inference, by which the human CNS prevents infection by HSV-1 in vivo, is therefore based on the control of early viral infection by basal IFN-β immunity.