Antimicrobial Peptides Therapy: An Emerging Alternative for Treating Drug-Resistant Bacteria.

Microbial resistance to antibiotics is an ancient and dynamic issue that has brought a situation reminiscent of the pre-antibiotic era to the limelight. Currently, antibiotic resistance and the associated infections are widespread and pose significant global health and economic burden. Thus, the misuse of antibiotics, which has increased resistance, has necessitated the search for alternative therapeutic agents for combating resistant pathogens. Antimicrobial peptides (AMPs) hold promise as a viable therapeutic approach against drug-resistant pathogens. AMPs are oligopeptides with low molecular weight. They have broad-spectrum antimicrobial activities against pathogenic microorganisms. AMPs are nonspecific and target components of microbes that facilitate immune response by acting as the first-line defense mechanisms against invading pathogenic microbes. The diversity and potency of AMPs make them good candidates for alternative use. They could be used alone or in combination with several other biomaterials for improved therapeutic activity. They can also be employed in vaccine production targeting drug-resistant pathogens. This review covers the opportunities and advances in AMP discovery and development targeting antimicrobial resistance (AMR) bacteria. Briefly, it presents an overview of the global burden of the antimicrobial resistance crisis, portraying the global magnitude, challenges, and consequences. After that, it critically and comprehensively evaluates the potential roles of AMPs in addressing the AMR crisis, highlighting the major potentials and prospects.

Assessment of the pulmonary adaptive immune response to Cladosporium cladosporioides infection using an experimental mouse model.

Cladosporium cladosporioides causes asthma and superficial and deep infections, mostly in immunodeficient individuals and animals. This study aimed to investigate whether C. cladosporioides spores can enter the lungs through pulmonary circulation and influence pulmonary immune response. We intravenously injected mice with C. cladosporioides spore suspension and conducted several assays on the lungs. Pulmonary hemorrhage symptoms and congestion were most severe on days 1, 2, and 3 post-inoculation (PI). Extensive inflammatory cell infiltration occurred throughout the period of infection. More spores and hyphae colonizing the lungs were detected on days 1, 2, and 3 PI, and fewer spores and hyphae were observed within 21 d of infection. Numerous macrophages, dendritic cells, and neutrophils were observed on day 5 PI, along with upregulation of CD54, an intercellular adhesion molecule. Th1 and Th2 cells increased after infection; specifically, Th2 cells increased considerably on day 5 PI. These results suggest that days 2 and 5 PI represent the inflammatory peak in the lungs and that the Th2 and Th1 signaling pathways are potentially involved in pulmonary immune responses. In conclusion, the further adaptive immune responses played important roles in establishing effective pulmonary immunity against C. cladosporioides systemic infections based on innate immune responses.

Multigene Expression Assay for Assessment of the Immune Status of Atlantic Salmon.

We report the development of a multigene gene expression assay on the BioMark HD platform for the evaluation of immune competence (ImCom) in farmed Atlantic salmon. The first version of the assay included 92 genes selected on the basis of transcriptome analyses in 54 trials that challenged the immune system; annotations were taken into account to represent the key pathways of innate and adaptive immunity. ImCom was tested on samples collected from seven independent projects. Fish were reared from the start feeding to eight months in the sea at eight units in different parts of Norway. Several tissues were analyzed. Linear discriminant analysis (LDA) showed that no more than 10 genes were required to separate groups, and a set of 46 immune genes was sufficient for any task. The second version of the assay was tested in the gills of two groups of high-performing healthy smolts and in groups with intermediate and high mortality rates (IM and HM, respectively). A set of 645 gill samples from clinically healthy Atlantic salmon was used as a reference. The IM group showed general suppression of immunity. All HM group salmon were above the threshold by the squared deviation from the reference. This group showed marked upregulation of genes involved in acute stress and inflammation: mmp-9, mmp-13, hsp70, il-1b, lect2, and cathelicidin. Further work will clarify the boundaries of the norm and explore various cases of impaired immunity.

Immunometabolism pathways as the basis for innovative anti-viral strategies (INITIATE): A Marie Sklodowska-Curie innovative training network.

The past century has witnessed major advances in the control of many infectious diseases, yet outbreaks and epidemics caused by (re-) emerging RNA viruses continue to pose a global threat to human health. As illustrated by the global COVID19 pandemic, high healthcare costs, economic disruption and loss of productivity reinforce the unmet medical need to develop new antiviral strategies to combat not only the current pandemic but also future viral outbreaks. Pivotal for effective anti-viral defense is the innate immune system, a first line host response that senses and responds to virus infection. While molecular details of the innate immune response are well characterized, this research field is now being revolutionized with the recognition that cell metabolism has a major impact on the antiviral and inflammatory responses to virus infections. A detailed understanding of the role of metabolic regulation with respect to antiviral and inflammatory responses, together with knowledge of the strategies used by viruses to exploit immunometabolic pathways, will ultimately change our understanding and treatment of pathogenic viral diseases. INITIATE is a Marie Sklodowska-Curie Actions Innovative Training Network (MSCA-ITN), with the goal to train 15 early stage PhD researchers (ESRs) to become experts in antiviral immunometabolism (https://initiate-itn.eu/). To this end, INITIATE brings together a highly complementary international team of academic and corporate leaders from 7 European countries, with outstanding track records in the historically distinct research fields of virology, immunology and metabolism. The ESRs of INITIATE are trained in these interdisciplinary research fields through individual investigator-driven research projects, specialized scientific training events, workshops on academia-industry interactions, outreach & communication. INITIATE will deliver a new generation of creative and entrepreneurial researchers who will be able to face the inevitable future challenges in combating viral diseases.

An Assessment of the Ability of Submicron- and Micron-Size Silicone Oil Droplets in Dropped Prefillable Syringes to Invoke Early- and Late-Stage Immune Responses.

A number of biopharmaceuticals are available as lyophilized formulations along with a prefilled syringe (PFS) containing water for injection (WFI). Submicron- and micron-size droplets of lubricating silicone oil (SO) applied to the inner surface of the PFS barrel might migrate into the WFI, to which protein pharmaceuticals can adsorb, potentially inducing an immune response. In the present study, we subjected siliconized cyclo-olefin polymer PFSs filled with WFI to dropping stress to simulate actual shipping conditions as well as evaluated the risk associated with the released SO droplets. The results confirmed the undesirable effects of SO on therapeutic proteins, including adsorption to SO droplets and increased secretion of several innate cytokines from human peripheral blood mononuclear cells of a small donor panel. Assessment of immunogenicity in vivo using BALB/c mice revealed a slight increase in the plasma concentrations of antidrug antibodies over 21 days in response to SO-containing antibody samples compared to the absence of SO. These results indicate that SO droplets form complexes with pharmaceutical proteins that can potentially invoke early- and late-stage immune responses. Therefore, the use of SO-free cyclo-olefin polymer PFSs as primary containers for WFI could contribute to the enhanced safety of reconstituted biopharmaceuticals.

[Allergies as a target of interest in the era of immunotherapy]. / Las alergias como blanco de interés en la era de la inmunoterapia.

Exacerbated immune system reactions often trigger allergy pathologies, which include asthma, rhinitis, urticaria, food and drug allergies, insect bites, and may sometimes have fatal outcomes. In Mexico, more than 20% of open population, present allergic symptoms with notable increase in the last twenty years, especially in children. The Mexican Institute for Social Security (IMSS, according to its initials in Spanish) provides attention to around 7000 patients per year, mainly due to allergies deriving from therapeutic drugs and certain foods. Pharmacotherapy has been effective in reducing classical allergy symptoms, although treatment does not stop disease progression. In addition, the constant use of drugs represents a remarkable socioeconomic impact. Strategies based on the modification of immune responses in the course of allergic reactions through immunotherapy started more than 100 years ago, and some have provided cure to the disease. On the occasion of the Nobel Prize in Physiology or Medicine 2018, it was awarded to James P. Allison and Tasuku Honjo for their contributions in the regulation of the immune system against cancer, through a new generation of immunotherapy. In this review we analyzed current immunotherapeutic options, including its benefits, limitations and perspectives for the best clinical management of allergies.

Las reacciones exacerbadas del sistema inmunológico a menudo disparan patologías por cuadros alérgicos que, entre otros, incluyen asma, rinitis, urticaria, alergia a alimentos, fármacos y picaduras de insectos, y en ocasiones tienen desenlaces fatales. En México, más del 20% de la población general presenta cuadros alérgicos, con un notable incremento en los últimos veinte años, especialmente en la población pediátrica. Tan solo el Instituto Mexicano del Seguro Social (IMSS) atiende alrededor de 7000 pacientes por año, principalmente por alergias a medicamentos y algunos alimentos. La farmacoterapia ha sido muy efectiva en la disminución de los síntomas, aunque el tratamiento no detiene la progresión de la enfermedad. Además, el uso constante de fármacos representa un remarcable impacto socioeconómico. Las estrategias basadas en la modificación de respuestas inmunes en el curso de las reacciones alérgicas a través de inmunoterapia comenzaron hace más de 100 años y algunas de ellas han dado solución a este grupo de padecimientos. En ocasión de la entrega del Premio Nobel de Medicina y Fisiología 2018, este fue otorgado a los doctores James P. Allison y Tasuku Honjo por sus contribuciones en la regulación del sistema inmune contra el cáncer, por medio de una nueva generación de inmunoterapia. En esta revisión analizamos las opciones inmunoterapéuticas actuales e incluimos sus beneficios, limitantes y perspectivas para el mejor manejo clínico de las alergias.

Age-related response to an acute innate immune challenge in mice: proteomics reveals a telomere maintenance-related cost.

Ageing is characterized by the impairment of the acute innate immune response and the upregulation of low-grade inflammation, i.e. inflammaging. At the cellular level, telomeres are considered as a marker of biological ageing as their length is progressively eroded in the absence of repair mechanisms. However, the link between telomeres and inflammaging remains underexplored. We aimed to identify proteins that are differentially expressed between age classes in response to an acute inflammatory challenge. We challenged young (two months) and old (12 months) C57BL/6 mice using bacterial lipopolysaccharide (LPS) and measured telomere length and proteomic profiles in splenocytes. In total, 233 out of the 1966 proteins we quantified differed among experimental groups. A hierarchical clustering analysis revealed that nine of those 233 proteins were differently expressed among the experimental groups. Young mice responded to LPS by increasing the expression of proteins involved in the innate immune response, and interestingly, in telomere length maintenance. However, this regulation was impaired at older ages. These results are in agreement with the assumption that the strength of selection declines with age, potentially explaining the maintenance of costly, dysregulated, immune responses at old age. We suggest that the immune response is competing with the telomere maintenance process, highlighting how telomeres reflect the ageing trade-off even in a species where telomere length is not related to lifespan.

Radiation, inflammation and the immune response in cancer.

Radiation is an important component of cancer treatment with more than half of all patients receive radiotherapy during their cancer experience. While the impact of radiation on tumour morphology is routinely examined in the pre-clinical and clinical setting, the impact of radiation on the tumour microenvironment and more specifically the inflammatory/immune response is less well characterised. Inflammation is a key contributor to short- and long-term cancer eradication, with significant tumour and normal tissue consequences. Therefore, the role of radiation in modulating the inflammatory response is highly topical given the current wave of targeted and immuno-therapeutic treatments for cancer. This review provides a general overview of how radiation modulates the inflammatory and immune response-(i) how radiation induces the inflammatory/immune system, (ii) the cellular changes that take place, (iii) how radiation dose delivery affects the immune response, and (iv) a discussion on research directions to improve patient survival, reduce side effects, improve quality of life, and reduce financial costs in the immediate future. Harnessing the benefits of radiation on the immune response will enhance its maximal therapeutic benefit and reduce radiation-induced toxicity.

Lung Defense through IL-8 Carries a Cost of Chronic Lung Remodeling and Impaired Function.

IL-8-dependent inflammation is a hallmark of host lung innate immunity to bacterial pathogens, yet in many human lung diseases, including chronic obstructive pulmonary disease, bronchiectasis, and pulmonary fibrosis, there are progressive, irreversible, pathological changes associated with elevated levels of IL-8 in the lung. To better understand the duality of IL-8-dependent host immunity to bacterial infection and lung pathology, we expressed human IL-8 transgenically in murine bronchial epithelium, and investigated the impact of overexpression on lung bacterial clearance, host immunity, and lung pathology and function. Persistent IL-8 expression in bronchial epithelium resulted in neutrophilia, neutrophil maturation and activation, and chemotaxis. There was enhanced protection against challenge with Pseudomonas aeruginosa, and significant changes in baseline expression of innate and adaptive immunity transcripts for Ccl5, Tlr6, IL-2, and Tlr1. There was increased expression of Tbet and Foxp3 in response to the Pseudomonas antigen OprF, indicating a regulatory T-cell phenotype. However, this enhanced bacterial immunity came at a high price of progressive lung remodeling, with increased inflammation, mucus hypersecretion, and fibrosis. There was increased expression of Ccl3 and reduced expression of Claudin 18 and F11r, with damage to epithelial organization leading to leaky tight junctions, all of which resulted in impaired lung function with reduced compliance, increased resistance, and bronchial hyperreactivity as measured by whole-body plethysmography. These results show that IL-8 overexpression in the bronchial epithelium benefits lung immunity to bacterial infection, but specifically drives lung damage through persistent inflammation, lung remodeling, and damaged tight junctions, leading to impaired lung function.

Manipulación de la inmunosenescencia / Immunosenescence manipulation

En la actualidad existe un aumento del envejecimiento poblacional en Cuba y a nivel mundial, consecuencia del éxito de las políticas de salud pública y del desarrollo socioeconómico. Con el incremento progresivo de la edad se evidencian cambios en el sistema inmunológico que contribuyen a una susceptibilidad incrementada a las enfermedades infecciosas, condiciones patológicas relacionadas con la inflamación, enfermedades autoinmunes, el cáncer y se manifiesta una respuesta reducida ante la vacunación. La manipulación de la inmunosenescencia a través de diferentes terapéuticas se espera que contribuya al rejuvenecimiento del sistema inmune y por consiguiente a la restauración de la inmunidad en individuos inmunocomprometidos, al control del cáncer y al incremento de la eficacia de la vacunación en ancianos(AU)

There is an increase of population aging in Cuba and globally, as a result of the success of public health policies and socio-economic development. With the progressive increase in age, there are changes in the immune system that contribute to an increased susceptibility to infectious diseases, pathological conditions related to inflammation, autoimmune diseases, cancer and a reduced response to vaccination. The manipulation of immunosenescence through different therapies has been studied. It is expected to possibly contribute to the 'rejuvenation' of the immune system and consequently, to the restoration of immunity in immunocompromised individuals, the improvement of the effectiveness of vaccination in the elderly and the control of cancer(AU)

Safety and in vivo immune assessment of escalating doses of oral laquinimod in patients with RRMS.

BACKGROUND: Laquinimod is an oral immunomodulator in clinical development to treat relapsing-remitting multiple sclerosis (RRMS). Laquinimod is in clinical development for the treatment of multiple sclerosis and Huntington Disease (HD). The objective of this study is to assess the safety, tolerability, pharmacokinetics (PK) and cytoimmunologic effects following escalating doses of laquinimod in patients with RRMS. METHODS: One hundred twelve patients were randomly assigned to laquinimod/placebo in a series of separate dose-escalating cohorts starting from a daily oral dose of 0.9 mg/1.2 mg escalating to 2.7 mg, in 0.3 mg increments. RESULTS: Twenty-eight patients received placebo and 84 received laquinimod ranging from 0.9 to 2.7 mg. No deaths occurred. One serious adverse event (SAE) of perichondritis was reported, which was unrelated to laquinimod (0.9 mg). There was no increased incidence of adverse events (AEs) with escalating doses. Laquinimod-treated patients showed more abnormal laboratory levels in liver enzymes, P-amylase, C-reactive protein (CRP), and fibrinogen, but most shifts were clinically non-significant. The exposure of laquinimod was dose proportional and linear in the tested dose range. An immunological substudy showed significant dose-dependent decreases in 6-sulpho LacNAc + dendritic cell (slanDC) frequency following laquinimod compared to placebo. CONCLUSION: Laquinimod doses up to 2.7 mg were safely administered to patients with RRMS. An in vivo effect of laquinimod on the innate immune system was demonstrated. TRIAL REGISTRATION: EudraCT Number: 2009-011234-99 . Registered 23 June 2009.

[Preclinical models to establish innovative therapy strategies : Ex­vivo assessment of head and neck tumor chemo- and immune responses]. / Präklinische Modelle zur Etablierung innovativer Therapiestrategien : Ex­vivo­Testung der Chemo­ und Immunresponse von Kopf­Hals­Tumoren.

The pharmacological treatment of head and neck squamous cell carcinoma (HNSCC) is currently experiencing an expansion of the spectrum of targeting therapies. It can be expected that use of immune modulators, e.g., checkpoint-inhibitors, and their combination with chemotherapy will lead to a plethora of therapeutic options in the near future, from which the best one for the individual patient can be selected. HNSCCs are heterogeneous in their biology, and responses to chemotherapy are nonuniform and often only observable in subgroups. It would be valuable to know the chance of success of a particular treatment in advance. Evidence-based selection of the best individual treatment is difficult, since predictive biomarkers which are assessable prior to the treatment decision and reliably indicate the suitability of particular therapeutics are lacking. Pretherapeutic predictive ex-vivo chemoresponse testing of HNSCC biopsy specimens could enable identification of responders and allow a more suitable therapy regimen to be chosen for potential non-responders, without exposing them to likely ineffective therapy attempts. However, early ex-vivo assays failed regarding reliable prediction of therapeutic success, even with tolerable doses of pharmaceuticals and, in particular, their combinations. Predictive testing was hence deemed improper for the clinic. Improved methodology has now led to a reappraisal of predictive testing and its additional use in analysis of antitumor immune responses ex vivo. Here we describe recent advances and new results from ex-vivo chemoresponse testing of HNSCC and highlight their ability to facilitate establishment of innovative therapy strategies.

Comparisons of Allergenic and Metazoan Parasite Proteins: Allergy the Price of Immunity.

Allergic reactions can be considered as maladaptive IgE immune responses towards environmental antigens. Intriguingly, these mechanisms are observed to be very similar to those implicated in the acquisition of an important degree of immunity against metazoan parasites (helminths and arthropods) in mammalian hosts. Based on the hypothesis that IgE-mediated immune responses evolved in mammals to provide extra protection against metazoan parasites rather than to cause allergy, we predict that the environmental allergens will share key properties with the metazoan parasite antigens that are specifically targeted by IgE in infected human populations. We seek to test this prediction by examining if significant similarity exists between molecular features of allergens and helminth proteins that induce an IgE response in the human host. By employing various computational approaches, 2712 unique protein molecules that are known IgE antigens were searched against a dataset of proteins from helminths and parasitic arthropods, resulting in a comprehensive list of 2445 parasite proteins that show significant similarity through sequence and structure with allergenic proteins. Nearly half of these parasite proteins from 31 species fall within the 10 most abundant allergenic protein domain families (EF-hand, Tropomyosin, CAP, Profilin, Lipocalin, Trypsin-like serine protease, Cupin, BetV1, Expansin and Prolamin). We identified epitopic-like regions in 206 parasite proteins and present the first example of a plant protein (BetV1) that is the commonest allergen in pollen in a worm, and confirming it as the target of IgE in schistosomiasis infected humans. The identification of significant similarity, inclusive of the epitopic regions, between allergens and helminth proteins against which IgE is an observed marker of protective immunity explains the 'off-target' effects of the IgE-mediated immune system in allergy. All these findings can impact the discovery and design of molecules used in immunotherapy of allergic conditions.

Cost of immune priming within generations: trade-off between infection and reproduction.

Immune priming is a new paradigm in innate immunity. However, most studies have focused on the benefits of priming (enhanced survival and parasite clearance after a second challenge), while little attention has been paid to the costs. In this study, both factors were investigated in Anopheles albimanus primed against Plasmodium berghei. As previously observed in other invertebrates, compared to un-primed mosquitoes, those primed better controlled a challenge from the same parasite, and had a higher survival rate. Although there was no difference in the number of oviposited eggs between primed and control females, hatching rate was lower in primed than in control mosquitoes and it was more likely for control females to produce eggs than for primed females. Furthermore, a trade-off between parasite elimination and egg production was observed among primed mosquitoes, as primed females that successfully fought the infection were unable to produce eggs, but primed females that produced eggs were similarly infected as control un-primed ones. These results concord with recent mathematical models suggesting that reproduction affects immune priming outcomes, and may explain why in some species and under some conditions it seems that immune priming is not occurring.

Upregulation of innate antiviral restricting factor expression in the cord blood and decidual tissue of HIV-infected mothers.

Programs for the prevention of mother-to-child transmission of HIV have reduced the transmission rate of perinatal HIV infection and have thereby increased the number of HIV-exposed uninfected (HEU) infants. Natural immunity to HIV-1 infection in both mothers and newborns needs to be further explored. In this study, we compared the expression of antiviral restricting factors in HIV-infected pregnant mothers treated with antiretroviral therapy (ART) in pregnancy (n=23) and in cord blood (CB) (n=16), placental tissues (n=10-13) and colostrum (n=5-6) samples and compared them to expression in samples from uninfected (UN) pregnant mothers (n=21). Mononuclear cells (MNCs) were prepared from maternal and CB samples following deliveries by cesarean section. Maternal (decidua) and fetal (chorionic villus) placental tissues were obtained, and colostrum was collected 24 h after delivery. The mRNA and protein expression levels of antiviral factors were then evaluated. We observed a significant increase in the mRNA expression levels of antiviral factors in MNCs from HIV-infected mothers and CB, including the apolipoprotein B mRNA-editing enzyme 3G (A3G), A3F, tripartite motif family-5α (TRIM-5α), TRIM-22, myxovirus resistance protein A (MxA), stimulator of interferon (IFN) genes (STING) and IFN-ß, compared with the levels detected in uninfected (UN) mother-CB pairs. Moreover, A3G transcript and protein levels and α-defensin transcript levels were decreased in the decidua of HIV-infected mothers. Decreased TRIM-5α protein levels in the villi and increased STING mRNA expression in both placental tissues were also observed in HIV-infected mothers compared with uninfected (UN) mothers. Additionally, colostrum cells from infected mothers showed increased tetherin and IFN-ß mRNA levels and CXCL9 protein levels. The data presented here indicate that antiviral restricting factor expression can be induced in utero in HIV-infected mothers. Future studies are warranted to determine whether this upregulation of antiviral factors during the perinatal period has a protective effect against HIV-1 infection.

Quantitative assessment of human neutrophil migration across a cultured bladder epithelium.

The recruitment of immune cells from the periphery to the site of inflammation is an essential step in the innate immune response at any mucosal surface. During infection of the urinary bladder, polymorphonuclear leukocytes (PMN; neutrophils) migrate from the bloodstream and traverse the bladder epithelium. Failure to resolve infection in the absence of a neutrophilic response demonstrates the importance of PMN in bladder defense. To facilitate colonization of the bladder epithelium, uropathogenic Escherichia coli (UPEC), the causative agent of the majority of urinary tract infections (UTIs), dampen the acute inflammatory response using a variety of partially defined mechanisms. To further investigate the interplay between host and bacterial pathogen, we developed an in vitro model of this aspect of the innate immune response to UPEC. In the transuroepithelial neutrophil migration assay, a variation on the Boyden chamber, cultured bladder epithelial cells are grown to confluence on the underside of a permeable support. PMN are isolated from human venous blood and are applied to the basolateral side of the bladder epithelial cell layers. PMN migration representing the physiologically relevant basolateral-to-apical direction in response to bacterial infection or chemoattractant molecules is enumerated using a hemocytometer. This model can be used to investigate interactions between UPEC and eukaryotic cells as well as to interrogate the molecular requirements for the traversal of bladder epithelia by PMN. The transuroepithelial neutrophil migration model will further our understanding of the initial inflammatory response to UPEC in the bladder.

Herd immunity effect of the HPV vaccination program in Australia under different assumptions regarding natural immunity against re-infection.

Deterministic dynamic compartmental transmission models (DDCTMs) of human papillomavirus (HPV) transmission have been used in a number of studies to estimate the potential impact of HPV vaccination programs. In most cases, the models were built under the assumption that an individual who cleared HPV infection develops (life-long) natural immunity against re-infection with the same HPV type (this is known as SIR scenario). This assumption was also made by two Australian modelling studies evaluating the impact of the National HPV Vaccination Program to assist in the health-economic assessment of male vaccination. An alternative view denying natural immunity after clearance (SIS scenario) was only presented in one study, although neither scenario has been supported by strong evidence. Some recent findings, however, provide arguments in favour of SIS. We developed HPV transmission models implementing life-time (SIR), limited, and non-existent (SIS) natural immunity. For each model we estimated the herd immunity effect of the ongoing Australian HPV vaccination program and its extension to cover males. Given the Australian setting, we aimed to clarify the extent to which the choice of model structure would influence estimation of this effect. A statistically robust and efficient calibration methodology was applied to ensure credibility of our results. We observed that for non-SIR models the herd immunity effect measured in relative reductions in HPV prevalence in the unvaccinated population was much more pronounced than for the SIR model. For example, with vaccine efficacy of 95% for females and 90% for males, the reductions for HPV-16 were 3% in females and 28% in males for the SIR model, and at least 30% (females) and 60% (males) for non-SIR models. The magnitude of these differences implies that evaluations of the impact of vaccination programs using DDCTMs should incorporate several model structures until our understanding of natural immunity is improved.

Influence of socioeconomic status trajectories on innate immune responsiveness in children.

OBJECTIVES: Lower socioeconomic status (SES) is consistently associated with poor health, yet little is known about the biological mechanisms underlying this inequality. In children, we examined the impact of early-life SES trajectories on the intensity of global innate immune activation, recognizing that excessive activation can be a precursor to inflammation and chronic disease. METHODS: Stimulated interleukin-6 production, a measure of immune responsiveness, was analyzed ex vivo for 267 Canadian schoolchildren from a 1995 birth cohort in Manitoba, Canada. Childhood SES trajectories were determined from parent-reported housing data using a longitudinal latent-class modeling technique. Multivariate regression was conducted with adjustment for potential confounders. RESULTS: SES was inversely associated with innate immune responsiveness (p=0.003), with persistently low-SES children exhibiting responses more than twice as intense as their high-SES counterparts. Despite initially lower SES, responses from children experiencing increasing SES trajectories throughout childhood were indistinguishable from high-SES children. Low-SES effects were strongest among overweight children (p<0.01). Independent of SES trajectories, immune responsiveness was increased in First Nations children (p<0.05) and urban children with atopic asthma (p<0.01). CONCLUSIONS: These results implicate differential immune activation in the association between SES and clinical outcomes, and broadly imply that SES interventions during childhood could limit or reverse the damaging biological effects of exposure to poverty during the preschool years.

Survival cost of an early immune soliciting in nature.

If immune functions confer obvious benefits to hosts, life-history theory assumes that they also induce costs, leading to trade-offs between immunity and other fitness components. However, whether substantial fitness costs are associated with immune systems in the wild is debatable, as numerous factors may influence the costs and benefits associated with immune activation. Here, we explore the survival cost of immune deployment in postfledging birds. We injected Eurasian collared dove nestlings (Streptopelia decaocto) with antigens from Escherichia coli, and examined whether this immune challenge affected survival after fledging. To assess survival, birds were fitted with radiotags and the fate of each individual was monitored regularly. Our results show that mimicking a bacterial infection in nestlings lowered their survival prospects after fledging, in comparison to controls. The main identified cause of mortality (by examination of dead birds) was presumed to be predation. This study provides experimental evidence that immune activation may entail dramatic survival costs in a free-ranging vertebrate, and emphasizes the potential role that environmental factors such as predation may play in this interaction.