Age-dependent Immunity Research Articles

A simulation-based method to inform serosurvey design for estimating the force of infection using existing blood samples.

The extent to which dengue virus has been circulating globally and especially in Africa is largely unknown. Testing available blood samples from previous cross-sectional serological surveys offers a convenient strategy to investigate past dengue infections, as such serosurveys provide the ideal data to reconstruct the age-dependent immunity profile of the population and to estimate the average per-capita annual risk of infection: the force of infection (FOI), which is a fundamental measure of transmission intensity. In this study, we present a novel methodological approach to inform the size and age distribution of blood samples to test when samples are acquired from previous surveys. The method was used to inform SERODEN, a dengue seroprevalence survey which is currently being conducted in Ghana among other countries utilizing samples previously collected for a SARS-CoV-2 serosurvey. The method described in this paper can be employed to determine sample sizes and testing strategies for different diseases and transmission settings.

Age-dependent immunity effect in a cholera model with double transmission modes: Hopf bifurcation analysis

Age-dependent immunity effect in a cholera model with double transmission modes: Hopf bifurcation analysis

A critical role of a eubiotic microbiota in gating proper immunocompetence in Arabidopsis.

Although many studies have shown that microbes can ectopically stimulate or suppress plant immune responses, the fundamental question of whether the entire preexisting microbiota is indeed required for proper development of plant immune response remains unanswered. Using a recently developed peat-based gnotobiotic plant growth system, we found that Arabidopsis grown in the absence of a natural microbiota lacked age-dependent maturation of plant immune response and were defective in several aspects of pattern-triggered immunity. Axenic plants exhibited hypersusceptibility to infection by the bacterial pathogen Pseudomonas syringae pv. tomato DC3000 and the fungal pathogen Botrytis cinerea. Microbiota-mediated immunocompetence was suppressed by rich nutrient conditions, indicating a tripartite interaction between the host, microbiota and abiotic environment. A synthetic microbiota composed of 48 culturable bacterial strains from the leaf endosphere of healthy Arabidopsis plants was able to substantially restore immunocompetence similar to plants inoculated with a soil-derived community. In contrast, a 52-member dysbiotic synthetic leaf microbiota overstimulated the immune transcriptome. Together, these results provide evidence for a causal role of a eubiotic microbiota in gating proper immunocompetence and age-dependent immunity in plants.

Immune senescence in aged APP/PS1 mice.

To evaluate the linkage between age and deficits in innate and adaptive immunity which heralds both Alzheimer's disease (AD) onset and progression. The pathobiological events which underlie and tie these outcomes remain not fully understood. To investigate age-dependent immunity in AD, we evaluated innate and adaptive immunity in coordinate studies of regulatory T cell (Treg) function, T cell frequencies, and microglial integrity. These were assessed in blood, peripheral lymphoid tissues, and the hippocampus of transgenic (Tg) amyloid precursor protein/presenilin 1 (APP/PS1) against non-Tg mice. Additionally, immune arrays of hippocampal tissue were performed at 4, 6, 12, and 20 months of age. APP/PS1 mice showed progressive impairment of Treg immunosuppressive function with age. There was partial restoration of Treg function in 20-month-old mice. Ingenuity pathway analyses of hippocampal tissues were enriched in inflammatory, oxidative, and cellular activation pathways that paralleled advancing age and AD-pathobiology. Operative genes in those pathways included, but were not limited to triggering receptor on myeloid cells 1 (TREM1), T helper type 1 (Th1), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathways. Interleukin-17 (IL-17), nitric oxide, acute phase, and T cell receptor signaling pathways were also perturbed. Significant inflammation was observed at 6- and 12-months. However, at 20-months, age associated partial restoration of Treg function reduced inflammatory phenotype. Impaired Treg function, inflammation and oxidative stress were associated with AD pathology. Age associated partial restoration of Treg function in old mice reduced the hippocampal inflammatory phenotype. Restoring Treg suppressive function can be a therapeutic modality for AD.

Evaluating vaccine allocation strategies using simulation-assisted causal modeling

We develop a model to retrospectively evaluate age-dependent counterfactual vaccine allocation strategies against the coronavirus disease 2019 (COVID-19) pandemic. To estimate the effect of allocation on the expected severe-case incidence, we employ a simulation-assisted causal modeling approach that combines a compartmental infection-dynamics simulation, a coarse-grained causal model, and literature estimates for immunity waning. We compare Israel's strategy, implemented in 2021, with counterfactual strategies such as no prioritization, prioritization of younger age groups, or a strict risk-ranked approach; we find that Israel's implemented strategy was indeed highly effective. We also study the impact of increasing vaccine uptake for given age groups. Because of its modular structure, our model can easily be adapted to study future pandemics. We demonstrate this by simulating a pandemic with characteristics of the Spanish flu. Our approach helps evaluate vaccination strategies under the complex interplay of core epidemic factors, including age-dependent risk profiles, immunity waning, vaccine availability, and spreading rates.

1102. The Host Response to SARS-CoV-2 Infection Differs by Age

Abstract Background Infection with SARS-CoV-2 and the resulting host immune response has been primarily characterized in middle and older aged populations due to a higher incidence of symptoms in these age groups. Due to reduced severity of disease, children were poorly studied and assumed to be less frequently infected compared to older age groups. We measured the viral load and adaptive immune response across the age-spectrum to define the age-dependent viral and host responses. Methods From March 2020-March 2022, we enrolled individuals across the age spectrum who presented to U.S. military medical treatment facilities with COVID-19-like symptoms. In this longitudinal cohort study, demographic and clinical data were collected in addition to nasopharyngeal swabs and peripheral blood. Magnitude of viral RNA was measured by quantitative PCR (qPCR) from nasopharyngeal samples and SARS-CoV-2-specific IgG antibodies were measured from blood with multiplex microsphere immunoassays. Results 4,768 SARS-CoV-2 positive participants were enrolled, among whom 42, 64, 89, 380, 948 and 245 individuals were in age brackets 0-4y, 5-11y, 12-17y, 18-44, 45-64y, and >65y, respectively. Viral load as measured by qPCR was determined to be similar across age groups within the first week post symptom onset. The magnitude of the IgG antibody response against the spike protein was also compared across age groups at early and convalescent time points and was higher in those over the age of 65 years. Conclusion Early viral load during acute infection did not correlate with age in individuals who experienced COVID-19. These findings diverge from other respiratory viruses, such as respiratory syncytial virus and influenza where children tend to have higher viral loads. In contrast, the magnitude of the antibody response against the spike protein correlated with older age at acute and convalescent time points. Together our data suggest that the host response against SAR-CoV-2 differs with age and is not associated with the acute viral load. Defining age-dependent immunity against SARS-CoV-2 has the potential to identify key immunologic responses that can be used to optimize treatment and vaccine strategies. Disclosures Julia S. Rozman, n/a, Astra Zeneca: The HJF, in support of the USU IDCRP, was funded to conduct or augment unrelated Phase III Mab and vaccine trials as part of US Govt. COVID19 response Ryan C. Maves, MD, AiCuris: Grant/Research Support|Sound Pharmaceuticals: Grant/Research Support|Trauma Insights, LLC: Advisor/Consultant Mark P. Simons, PhD, AstraZeneca: The HJF, in support of the USU IDCRP, was funded to conduct or augment unrelated Phase III Mab and vaccine trials as part of US Govt. COVID19 response David Tribble, MD, DrPH, Astra Zeneca: The HJF, in support of the USU IDCRP, was funded to conduct or augment unrelated Phase III Mab and vaccine trials as part of US Govt. COVID19 response Timothy Burgess, MD, MPH, AstraZeneca: The HJF, in support of the USU IDCRP, was funded to conduct or augment unrelated Phase III Mab and vaccine trials as part of US Govt. COVID19 response Simon Pollett, MBBS, Astra Zeneca: The HJF, in support of the USU IDCRP, was funded to conduct or augment unrelated Phase III Mab and vaccine trials as part of US Govt. COVID19 response.

Modeling the protective effect of previous compulsory smallpox vaccination against human monkeypox infection: from hypothesis to a worst-case scenario

ObjectivesHuman monkeypox (MPX) cases are escalating worldwide. Smallpox vaccination, which was compulsory in Austria until 1981, was reported to confer 85% cross-protection against MPX. MethodsTo assess the impact of smallpox vaccine-induced protection, the age-dependent vaccine-induced immunity against human MPX and the probability of infection according to age in the general population of Vienna, Austria, were determined using a modified susceptible-infected-removed model. ResultsWithin the population born before 1981, the average vaccine-induced protective effect was calculated at 50.4%, whereas in the population born thereafter, protection was lacking. The overall probability of infection after exposure to an infected patient was calculated at 73.8%, which exceeds the threshold value of 46.9% for an index patient to infect at least one other person (R ≥1.0). ConclusionOur model shows that if no additional interventions are taken, the collective immunization status of the population alone will not suffice to contain human MPX. Although the majority of cases have occurred in a subpopulation, given the steadily increasing incidence, dissemination into the general population remains possible, as observed before with HIV. Our model emphasizes the need for adequate containment measures and may aid in specific risk assessment because it can easily be adapted to other populations and cohorts worldwide.

Vaccine-induced time- and age-dependent mucosal immunity to gastrointestinal parasite infection

Individuals vary broadly in their response to vaccination and subsequent challenge infection, with poor vaccine responders causing persistence of both infection and transmission in populations. Yet despite having substantial economic and societal impact, the immune mechanisms that underlie such variability, especially in infected tissues, remain poorly understood. Here, to characterise how antihelminthic immunity at the mucosal site of infection developed in vaccinated lambs, we inserted gastric cannulae into the abomasa of three-month- and six-month-old lambs and longitudinally analysed their local immune response during subsequent challenge infection. The vaccine induced broad changes in pre-challenge abomasal immune profiles and reduced parasite burden and egg output post-challenge, regardless of age. However, age affected how vaccinated lambs responded to infection across multiple immune pathways: adaptive immune pathways were typically age-dependent. Identification of age-dependent and age-independent protective immune pathways may help refine the formulation of vaccines, and indicate specificities of pathogen-specific immunity more generally.

The Impact of Age on Response to Infection in Drosophila.

This review outlines the known cellular pathways and mechanisms involved in Drosophila age-dependent immunity to pathogenic microorganisms such as bacteria and fungi. We discuss the implication of host signaling pathways such as the Toll, Immune Deficiency (IMD), Janus kinase signal transducer and activator of transcription (JAK/STAT), and Insulin/Insulin Growth Factor/Target of Rapamycin (IIS/TOR) on immune function with aging. Additionally, we review the effects that factors such as sexual dimorphism, environmental stress, and cellular physiology exert on age-dependent immunity in Drosophila. We discuss potential tradeoffs between heightened immune function and longevity in the absence of infection, and we provide detailed tables outlining the various assays and pathogens used in the cited studies, as well as the age, sex, and strains of Drosophila used. We also discuss the overlapping effects these pathways and mechanisms have on one another. We highlight the great utility of Drosophila as a model organism and the importance of a greater focus on age-dependent antiviral immunity for future studies.

Age-Dependent Pre-Vaccination Immunity Affects the Immunogenicity of Varicella Zoster Vaccination in Middle-aged Adults.

Prevention of infectious diseases is of high priority in the rapidly aging population. Unfortunately, vaccine responses in the elderly are frequently diminished. Timely vaccination of middle-aged adults might improve the immune responses to vaccines, although knowledge on pathogen-specific immune responses and factors affecting these responses, in middle-aged adults is currently limited. We thus investigated the immune responses after vaccination with Zostavax consisting of live-attenuated varicella zoster virus (VZV). Blood samples were taken pre-, 14 days, 28 days, and 1 year after a primary VZV vaccination (Zostavax) at middle age (N = 53, 50-65 years of age). VZV-specific IFNγ-producing cells were measured by ELISpot, activated T-cells by flow cytometry, antibody levels and cytokine responses by fluorescent bead-based multiplex immunoassays, and whole blood cellular kinetics by TruCOUNT analysis. Robust short-term enhancement of the VZV-specific IFNγ-producing cell numbers was observed post-vaccination in the middle-aged adults. Remarkably, long-term enhancement of VZV-specific IFNγ-producing cell numbers was induced only in participants with low numbers of VZV-specific pre-vaccination IFNγ-producing cells, who were significantly older. These participants also showed enhancement of VZV-specific activated CD4 T-cells, contrary to "exhausted" VZV-specific CD8 T-cells in participants with high numbers of VZV-specific pre-vaccination IFNγ-producing cells. Finally, a high CD4/CD8 T-cell ratio was associated with low numbers of pre-vaccination VZV-specific IFNγ-producing cells. These results suggest that adults in their early sixties, who showed a high CD4/CD8 T-cell ratio and low numbers of VZV-specific IFNγ-producing cells, benefit from VZV vaccination. This provides important knowledge on factors affecting VZV-specific immune responses in middle-aged adults as well as for strategies to strengthen immunity before reaching old age.

A mouse model with age-dependent immune response and immune-tolerance for HBV infection

BackgroundViral clearance of human HBV infection largely depends on the age of exposure. Thus, a mouse model with age-dependent immune response and immune-tolerance for HBV infection was established. MethodsHBVRag1 mice were generated by crossing Rag1−/− mice with HBV-Tg mice. Following adoptive transfer of splenocytes adult (8–9 weeks old) and young (3 weeks old) HBVRag1 mice were named as HBVRag-ReA and HBVRag-ReY mice respectively. The biochemical parameters that were associated with viral load and immune function, as well as the histological evaluation of the liver tissues between the two mouse models were detected. The immune tolerance of HBVRag-ReY mice that were reconstituted at the early stages of life was evaluated by quantitative hepatitis B core antibody assay, adoptive transfer, and modulation of gut microbiota with the addition of antibiotics. ResultsHBVRag-ReA mice indicated apparent hepatocytes damage, clearance of HBsAg and production of HBsAb and HBcAb. HBVRag-ReY mice did not develop ALT elevation, and produced HBcAb and HBsAg. A higher number of hepatic CD8+ T and B cells promoted clearance of HBsAg in HBVRag-ReA mice following 30 days of lymphocyte transfer. In contrast to HBVRag-ReA mice, HBVRag-ReY mice exhibited higher levels of Th1/Th2 cytokines. HBVRag-ReY mice exhibited significantly higher (P < .01, approximately 10-fold) serum quantitative anti-HBc levels than HBV-Tg mice, which might be similar to the phase of immune clearance and immune tolerance in human HBV infection. Furthermore, the age-related tolerance in HBVRag-ReY mice that were sensitive to antibiotic treatment was different from that noted in HBV-Tg mice. GS-9620 could inhibit the production of HBsAg, whereas HBV vaccination could induce sustained seroconversion in HBVRag-ReY mice with low levels of HBsAg. ConclusionsThe present study described a mouse model with age-dependent immunity and immune-tolerance for HBV infection in vivo, which may mimic chronic HBV infection in humans.

Global stability of an age-structured SVEIR epidemic model with waning immunity, latency and relapse

The global dynamics of an SVEIR epidemic model with age-dependent waning immunity, latency and relapse are studied. Sharp threshold properties for global asymptotic stability of both disease-free equilibrium and endemic equilibrium are given. The asymptotic smoothness, uniform persistence and the existence of interior global attractor of the semi-flow generated by a family of solutions of the system are also addressed. Furthermore, some related strategies for controlling the spread of diseases are discussed.

Influence of social contact patterns and demographic factors on influenza simulation results.

BackgroundThe demographic composition and the frequency and nature of social contacts may affect the spread of influenza virus in a population, resulting in distinct age-dependent immunity patterns. As demography and social contact rates differ strongly between European countries, this may impact infection incidence and vaccine effectiveness and thus limit the extent to which conclusions derived from observations in one country can be generalized to others. In the current study, we aimed to decipher the impact of social contact patterns and demographic factors on simulation results and, thus, to determine to what extent vaccination results can be generalized.MethodsWe simulated the transmission of four influenza strains (A(H1N1), A(H3N2), B/Victoria, B/Yamagata) in Belgium, Finland, Germany, GB, Italy, Luxembourg, Netherlands and Poland, using the simulation tool 4Flu. Individuals were connected in a dynamically evolving age-dependent contact network based on the POLYMOD study.ResultsWhen averaged over 20 years, simulation results without vaccination ranged from annually 20,984 (Germany) to 31,322 infections (Italy) per 100,000 individuals. QIV annually prevented 1758 (Poland) to 7720 infections (Germany) per 100,000. Variability of prevented cases remained high when the country-specific vaccination was replaced by unified coverage, but was reduced considerably if the same demography was used for all countries, or even more so when the same contact matrix was used.ConclusionsContact matrix and demography strongly influence the age-dependent incidence of influenza and the success of vaccination. Projecting simulation results from one country to another can, therefore, lead to erroneous results.Electronic supplementary materialThe online version of this article (doi:10.1186/s12879-016-1981-5) contains supplementary material, which is available to authorized users.

Effect of red blood cell variants on childhood malaria in Mali: a prospective cohort study

Red blood cell variants protect African children from severe falciparum malaria. However, their individual and interactive effects on mild disease and parasite density, and their modification by age-dependent immunity, are poorly understood. In this study, we address these knowledge gaps in a prospective cohort study of malaria risk and Plasmodium falciparum densities in Malian children. The Kenieroba Innate Defense Study for Malaria (KIDS-Malaria) was a 4-year prospective cohort study of children aged 6 months to 17 years undertaken in Mali between 2008 and 2011. Red blood cell variants were haemoglobin S (HbS), haemoglobin C (HbC), α thalassaemia, ABO blood groups, and glucose-6-phosphate dehydrogenase (G6PD) deficiency encoded by the X-linked A- allele. The primary outcome was malaria incidence, measured as the number of uncomplicated or severe malaria episodes over time. The secondary outcome was parasite density at the time of a malaria episode. We modelled incidence rate ratios with quasi-Poisson regression and we analysed parasite densities using generalised estimating equations. This study is registered with ClinicalTrials.gov, number NCT00669084. Between May 1, 2008, and Dec 29, 2011, we enrolled 1586 children into the study. We successfully typed all five red blood cell variants for 1543 of these children, who therefore constituted the evaluable population and in whom we diagnosed 4091 malaria episodes over 2656 child-years of follow-up. In these 1543 children, red blood cell variants were common, and occurred at the following frequencies: sickle cell trait (HbAS) 220 (14%), HbC heterozygosity (HbAC) 103 (7%), α thalassaemia 438 (28%), type O blood group 621 (40%), and G6PD deficiency 72 (9%) in 767 boys and 158 (20%) in 776 girls. The overall incidence of malaria was 1.54 episodes per child-year of follow-up, ranging from 2.78 episodes per child-year at age 3 years to 0.40 episodes per child-year at age 17 years. The malaria incidence was lower in HbAS children than in HbAA children with normal haemoglobin (adjusted incidence rate ratio [aIRR] 0.66 [95% CI 0.59-0.75], p<0.0001) and lower in G6PD A-/A- homozygous girls than in G6PD A+/A+ girls (0.51 [0.29-0.90], p=0.020), but was higher in HbAC children than in HbAA children (1.15 [1.01-1.32], p=0.039). Parasite density was lower in HbAS children (median 10,550 parasites per μL [IQR 1350-26,250]) than in HbAA children (15,150 parasites per μL [4250-31,050]; p=0.0004). The HbAS-associated reductions in malaria risk and parasite density were greatest in early childhood. The individual and interactive effects of HbAS, HbAC, and G6PD A-/A- genotypes on malaria risk and parasite density define clinical and cellular correlates of protection. Further identification of the molecular mechanisms of these protective effects might uncover new targets for intervention. Intramural Research Program, National Institute of Allergy and Infectious Diseases, National Institutes of Health.

IMPACT OF AGE-DEPENDENT RELAPSE AND IMMUNITY ON MALARIA DYNAMICS

An age-structured mathematical model for malaria is presented. The model explicitly includes the human and mosquito populations, structured by chronological age of humans. The infected human population is divided into symptomatic infectious, asymptomatic infectious and asymptomatic chronic infected individuals. The original partial differential equation (PDE) model is reduced to an ordinary differential equation (ODE) model with multiple age groups coupled by aging. The basic reproduction number [Formula: see text] is derived for the PDE model and the age group model in the case of general n age groups. We assume that infectiousness of chronic infected individuals gets triggered by bites of even susceptible mosquitoes. Our analysis points out that this assumption contributes greatly to the [Formula: see text] expression and therefore needs to be further studied and understood. Numerical simulations for n = 2 age groups and a sensitivity/uncertainty analysis are presented. Results suggest that it is important not only to consider asymptomatic infectious individuals as a hidden cause for malaria transmission, but also asymptomatic chronic infections (&gt;60%), which often get neglected due to undetectable parasite loads. These individuals represent an important reservoir for future human infectiousness. By considering age-dependent immunity types, the model helps generate insight into effective control measures, by targeting age groups in an optimal way.

A Realistic Host-Vector Transmission Model for Describing Malaria Prevalence Pattern

Malaria continues to be a major public health concern all over the world even after effective control policies have been employed, and considerable understanding of the disease biology have been attained, from both the experimental and modelling perspective. Interactions between different general and local processes, such as dependence on age and immunity of the human host, variations of temperature and rainfall in tropical and sub-tropical areas, and continued presence of asymptomatic infections, regulate the host-vector interactions, and are responsible for the continuing disease prevalence pattern.In this paper, a general mathematical model of malaria transmission is developed considering short and long-term age-dependent immunity of human host and its interaction with pathogen-infected mosquito vector. The model is studied analytically and numerically to understand the role of different parameters related to mosquitoes and humans. To validate the model with a disease prevalence pattern in a particular region, real epidemiological data from the north-eastern part of India was used, and the effect of seasonal variation in mosquito density was modelled based on local climactic data. The model developed based on general features of host-vector interactions, and modified simply incorporating local environmental factors with minimal changes, can successfully explain the disease transmission process in the region. This provides a general approach toward modelling malaria that can be adapted to control future outbreaks of malaria.

Differential Anti-Glycan Antibody Responses in Schistosoma mansoni-Infected Children and Adults Studied by Shotgun Glycan Microarray

BackgroundSchistosomiasis (bilharzia) is a chronic and potentially deadly parasitic disease that affects millions of people in (sub)tropical areas. An important partial immunity to Schistosoma infections does develop in disease endemic areas, but this takes many years of exposure and maturation of the immune system. Therefore, children are far more susceptible to re-infection after treatment than older children and adults. This age-dependent immunity or susceptibility to re-infection has been shown to be associated with specific antibody and T cell responses. Many antibodies generated during Schistosoma infection are directed against the numerous glycans expressed by Schistosoma. The nature of glycan epitopes recognized by antibodies in natural schistosomiasis infection serum is largely unknown.Methodology/Principal FindingsThe binding of serum antibodies to glycans can be analyzed efficiently and quantitatively using glycan microarray approaches. Very small amounts of a large number of glycans are presented on a solid surface allowing binding properties of various glycan binding proteins to be tested. We have generated a so-called shotgun glycan microarray containing natural N-glycan and lipid-glycan fractions derived from 4 different life stages of S. mansoni and applied this array to the analysis of IgG and IgM antibodies in sera from children and adults living in an endemic area. This resulted in the identification of differential glycan recognition profiles characteristic for the two different age groups, possibly reflecting differences in age or differences in length of exposure or infection.Conclusions/SignificanceUsing the shotgun glycan microarray approach to study antibody response profiles against schistosome-derived glycan elements, we have defined groups of infected individuals as well as glycan element clusters to which antibody responses are directed in S. mansoni infections. These findings are significant for further exploration of Schistosoma glycan antigens in relation to immunity.

Progressive cross-reactivity in IgE responses: an explanation for the slow development of human immunity to schistosomiasis?

People in regions of Schistosoma mansoni endemicity slowly acquire immunity, but why this takes years to develop is still not clear. It has been associated with increases in parasite-specific IgE, induced, some investigators propose, to antigens exposed during the death of adult worms. These antigens include members of the tegumental-allergen-like protein family (TAL1 to TAL13). Previously, in a group of S. mansoni-infected Ugandan males, we showed that IgE responses to three TALs expressed in worms (TAL1, -3, and -5) became more prevalent with age. Now, in a subcohort we examined associations of these responses with resistance to reinfection and use the data to propose a mechanism for the slow development of immunity. IgE was measured 9 weeks posttreatment and at reinfection at 2 years (n = 144). An anti-TAL5 IgE (herein referred to as TAL5 IgE) response was associated with reduced reinfection even after adjusting for age using regression analysis (geometric mean odds ratio, 0.24; P = 0.016). TAL5 IgE responders were a subset of TAL3 IgE responders, themselves a subset of TAL1 responders. TAL3 IgE and TAL5 IgE were highly cross-reactive, with TAL3 the immunizing antigen and TAL5 the cross-reactive antigen. Transcriptional and translational studies show that TAL3 is most abundant in adult worms and that TAL5 is most abundant in infectious larvae. We propose that in chronic schistosomiasis, older individuals have repeatedly experienced IgE antigens exposed when adult worms die (e.g., TAL3) and that this leads to increasing cross-reactivity with antigens of invading larvae (e.g., TAL5). Progressive accumulation of worm/larvae cross-reactivity could explain the age-dependent immunity observed in areas of endemicity.

The Schistosoma mansoni tegumental-allergen-like (TAL) protein family: influence of developmental expression on human IgE responses.

BackgroundA human IgE response to Sm22.6 (a dominant IgE target in Schistosoma mansoni) is associated with the development of partial immunity. Located inside the tegument, the molecule belongs to a family of proteins from parasitic platyhelminths, the Tegument-Allergen-Like proteins (TALs). In addition to containing dynein-light-chain domains, these TALs also contain EF-hand domains similar to those found in numerous EF-hand allergens.Methodology/Principal Findings S. mansoni genome searches revealed 13 members (SmTAL1-13) within the species. Recent microarray data demonstrated they have a wide range of life-cycle transcriptional profiles. We expressed SmTAL1 (Sm22.6), SmTAL2, 3, 4, 5 and 13 as recombinant proteins and measured IgE and IgG4 in 200 infected males (7–60 years) from a schistosomiasis endemic region in Uganda. For SmTAL1 and 3 (transcribed in schistosomula through adult-worms and adult-worms, respectively) and SmTAL5 (transcribed in cercariae through adult-worms), detectable IgE responses were rare in 7–9 year olds, but increased with age. At all ages, IgE to SmTAL2 (expressed constitutively), was rare while anti-SmTAL2 IgG4 was common. Levels of IgE and IgG4 to SmTAL4 and 13 (transcribed predominantly in the cercariae/skin stage) were all low.ConclusionsWe have not measured SmTAL protein abundance or exposure in live parasites, but the antibody data suggests to us that, in endemic areas, there is priming and boosting of IgE to adult-worm SmTALs by occasional death of long-lived worms, desensitization to egg SmTALs through continuous exposure to dying eggs and low immunogenicity of larval SmTALs due to immunosuppression in the skin by the parasite. Of these, it is the gradual increase in IgE to the worm antigens that parallels age-dependent immunity seen in endemic areas.

Age‐dependent antibody response to Plasmodium falciparum merozoite surface protein 2 (MSP‐2)

Merozoite surface protein 2 (MSP-2), a very immunogenic malaria antigen, is a highly polymorphic 45-53 kDa merozoite surface protein, which is regarded as a promising vaccine candidate. The highly polymorphic nature of MSP-2 suggests that the molecule can be involved in protective immunity against malaria. The antibody responses to MSP-2 antigen are mostly directed against polymorphic and dimorphic regions of the protein. The current study aimed at testing the reactivity of human sera from a malaria-endemic area of Gambia against MSP-2 regions 2, 3 and 4 compared to crude schizont extract in a period of 20 years. The age-dependent immunity was analysed in a manner of cross-sectional study (the data of the first visit) and also a longitudinal study design (analysing the data at four different time points from 1960 to 1980) testing the sera of 178 individuals randomly selected from the Keneba Serum Collection by using MSP-2 recombinant protein. The total IgG responses were measured by ELISA. Kolmogorov-Smirnov was used to check the normal distribution of OD, Hb and parasitaemia, and then Spearman correlation was applied to analyse the data. Most sera recognized, predominantly, the variable regions of the MSP-2, particularly the domain 3. The IgG response against all the antigens increased with age. The IgG responses against domain 3 of MSP-2 were associated with an increase in haemoglobin levels but a decrease in parasitaemia, suggesting that this immune response may be one of the most useful means for further studies on protective immunity against malaria.