Increased Parasite Burden Research Articles

Negative density-dependent parasitism in a group-living carnivore.

Animals living at high population densities commonly experience greater exposure to disease, leading to increased parasite burdens. However, social animals can benefit immunologically and hygienically from cooperation, and individuals may alter their socio-spatial behaviour in response to infection, both of which could counteract density-related increases in exposure. Consequently, the costs and benefits of sociality for disease are often uncertain. Here, we use a long-term study of a wild European badger population (Meles meles) to investigate how within-population variation in host density determines infection with multiple parasites. Four out of five parasite taxa exhibited consistent spatial hotspots of infection, which peaked among badgers living in areas of low local population density. Combined movement, survival, spatial and social network analyses revealed that parasite avoidance was the likely cause of this negative density dependence, with possible roles for localized mortality, encounter-dilution effects, and micronutrient-enhanced immunity. These findings demonstrate that animals can organize their societies in space to minimize parasite infection, with important implications for badger behavioural ecology and for the control of badger-associated diseases.

Noise pollution: acute noise exposure increases susceptibility to disease and chronic exposure reduces host survival.

Anthropogenic noise is a pervasive global pollutant that has been detected in every major habitat on the planet. Detrimental impacts of noise pollution on physiology, immunology and behaviour have been shown in terrestrial vertebrates and invertebrates. Equivalent research on aquatic organisms has until recently been stunted by the misnomer of a silent underwater world. In fish, however, noise pollution can lead to stress, hearing loss, behavioural changes and impacted immunity. But, the functional effects of this impacted immunity on disease resistance due to noise exposure have remained neglected. Parasites that cause transmissible disease are key drivers of ecosystem biodiversity and a significant factor limiting the sustainable expansion of the animal trade. Therefore, understanding how a pervasive stressor is impacting host–parasite interactions will have far-reaching implications for global animal health. Here, we investigated the impact of acute and chronic noise on vertebrate susceptibility to parasitic infections, using a model host–parasite system (guppy–Gyrodactylus turnbulli). Hosts experiencing acute noise suffered significantly increased parasite burden compared with those in no noise treatments. By contrast, fish experiencing chronic noise had the lowest parasite burden. However, these hosts died significantly earlier compared with those exposed to acute and no noise treatments. By revealing the detrimental impacts of acute and chronic noise on host–parasite interactions, we add to the growing body of evidence demonstrating a link between noise pollution and reduced animal health.

Nitric oxide debilitates the neuropathogenic schistosome Trichobilharzia regenti in mice, partly by inhibiting its vital peptidases

BackgroundAvian schistosomes, the causative agents of human cercarial dermatitis (or swimmer’s itch), die in mammals but the mechanisms responsible for parasite elimination are unknown. Here we examined the role of reactive nitrogen species, nitric oxide (NO) and peroxynitrite, in the immune response of mice experimentally infected with Trichobilharzia regenti, a model species of avian schistosomes remarkable for its neuropathogenicity.MethodsInducible NO synthase (iNOS) was localized by immunohistochemistry in the skin and the spinal cord of mice infected by T. regenti. The impact of iNOS inhibition by aminoguanidine on parasite burden and growth was then evaluated in vivo. The vulnerability of T. regenti schistosomula to NO and peroxynitrite was assessed in vitro by viability assays and electron microscopy. Additionally, the effect of NO on the activity of T. regenti peptidases was tested using a fluorogenic substrate.ResultsiNOS was detected around the parasites in the epidermis 8 h post-infection and also in the spinal cord 3 days post-infection (dpi). Inhibition of iNOS resulted in slower parasite growth 3 dpi, but the opposite effect was observed 7 dpi. At the latter time point, moderately increased parasite burden was also noticed in the spinal cord. In vitro, NO did not impair the parasites, but inhibited the activity of T. regenti cathepsins B1.1 and B2, the peptidases essential for parasite migration and digestion. Peroxynitrite severely damaged the surface tegument of the parasites and decreased their viability in vitro, but rather did not participate in parasite clearance in vivo.ConclusionsReactive nitrogen species, specifically NO, do not directly kill T. regenti in mice. NO promotes the parasite growth soon after penetration (3 dpi), but prevents it later (7 dpi) when also suspends the parasite migration in the CNS. NO-related disruption of the parasite proteolytic machinery is partly responsible for this effect.

The IL-12- and IL-23-Dependent NK Cell Response Is Essential for Protective Immunity against Secondary Toxoplasma gondii Infection.

NK cells can develop cell-intrinsic memory-like characteristics. Whether they develop these characteristics during Toxoplasma gondii infection is unknown. We addressed this question and dissected the mechanisms involved in secondary NK cell responses using a vaccine-challenge mouse model of T. gondii infection. NK cells were required for control of and survival after secondary T. gondii infection. NK cells increased in number at the reinfection site and produced IFN-γ. To test if these T. gondii experienced NK cells were intrinsically different from naive NK cells, we performed NK cell adoptive transfer into RAG2/cγ-chain-/- mice, NK cell fate mapping, and RAG1-/- mice vaccine-challenge experiments. Although NK cells contributed to immunity after reinfection, they did not develop cell-intrinsic memory-like characteristics after T. gondii vaccination. The mechanisms required for generating these secondary NK cell responses were investigated. Secondary NK cell responses were CD4+ or CD8+ T cell independent. Although IL-12 alone is required for NK cell IFN-γ production during primary T. gondii infection, in the absence of IL-12 using IL-12p35-/- mice or anti-IL-12p70, secondary NK cell responses were only partially reduced after reinfection. IL-23 depletion with anti-IL-23p19 in vivo also significantly reduced the secondary NK cell response. IL-12 and IL-23 blockade with anti-IL-12p40 treatment completely eliminated secondary NK cell responses. Importantly, blockade of IL-12, IL-23, or both significantly reduced control of parasite reinfection and increased parasite burden. Our results define a previously unknown protective role for NK cells during secondary T. gondii infection that is dependent on IL-12 and IL-23.

Deficiency of CD73 activity promotes protective cardiac immunity against Trypanosoma cruzi infection but permissive environment in visceral adipose tissue

Damaged cells release the pro-inflammatory signal ATP, which is degraded by the ectonucleotidases CD39 and CD73 to the anti-inflammatory mediator adenosine (ADO). The balance between ATP/ADO is known to determine the outcome of inflammation/infection. However, modulation of the local immune response in different tissues due to changes in the balance of purinergic metabolites has yet to be investigated. Here, we explored the contribution of CD73-derived ADO on the acute immune response against Trypanosoma cruzi parasite, which invades and proliferates within different target tissues. Deficiency of CD73 activity led to an enhanced cardiac microbicidal immune response with an augmented frequency of macrophages with inflammatory phenotype and increased CD8+ T cell effector functions. The increment of local inducible nitric oxide (NO) synthase (iNOS)+ macrophages and the consequent rise of myocardial NO production in association with reduced ADO levels induced protection against T. cruzi infection as observed by the diminished cardiac parasite burden compared to their wild-type (WT) counterpart. Unexpectedly, parasitemia was substantially raised in CD73KO mice in comparison with WT mice, suggesting the existence of tissue reservoir/s outside myocardium. Indeed, CD73KO liver and visceral adipose tissue (VAT) showed increased parasite burden associated with a reduced ATP/ADO ratio and the lack of substantial microbicidal immune response. These data reveal that the purinergic system has a tissue-dependent impact on the host immune response against T. cruzi infection.

The Paradoxical Leishmanicidal Effects of Superoxide Dismutase (SOD)-Mimetic Tempol in Leishmania braziliensis Infection in vitro.

Leishmaniasis is an infectious disease caused by protozoans of the genus Leishmania. The macrophage is the resident cell in which the parasite replicates and it is important to identify new compounds that can aid in parasite elimination since the drugs used to treat leishmaniasis are toxic and present side effects. We have previously shown that treatment of Leishmania braziliensis-infected macrophages with DETC (Diethyldithiocarbamate) induces parasite killing, in vivo. Thus, the objective of this study was to further evaluate the effect of oxidants and antioxidants in L. braziliensis-infected macrophages, following treatment with either oxidizing Hydrogen Peroxide, Menadione, DETC, or antioxidant [NAC (N-Acetyl-Cyteine), Apocynin, and Tempol] compounds. We determined the percentage of infected macrophages and number of amastigotes. Promastigote survival was also evaluated. Both DETC (SOD-inhibitor) and Tempol (SOD-mimetic) decreased the percentage of infected cells and parasite load. Hydrogen peroxide did not interfere with parasite burden, while superoxide-generator Menadione had a reducing effect. On the other hand, NAC (GSH-replenisher) and Apocynin (NADPH-oxidase inhibitor) increased parasite burden. Tempol surfaces as an interesting candidate for the chemotherapy of CL with an IC50 of 0.66 ± 0.08 mM and selectivity index of 151. While it remains obscure how a SOD-mimetic may induce leishmanicidal effects, we suggest the possibility of developing Tempol-based topical applications for the treatment of cutaneous leishmaniasis caused by L. braziliensis.

Lymphotoxin β receptor: A crucial role in Toxoplasma gondii infection

Abstract After infection with the obligate intracellular protozoan parasite Toxoplasma gondii (T. gondii) the production of cytokines (especially Interferon γ (IFNγ)) induces potent cell autonomous effector mechanisms which can control the pathogen. Lymphotoxin β receptor (LTβR) mediated signalling plays an important role in the efficient initiation of innate and adaptive host responses to a variety of pathogens. Therefore, the immune response to T. gondii infection was analyzed in vivo and in vitro in LTβR deficient (LTβR−/−) and wildtype mice (WT) mice. Compared to WT mice, LTβR−/− mice showed an increased parasite burden and a markedly increased mortality in the acute phase of T. gondii infection. FACS analysis revealed that while these mice are generally able to generate T. gondii specific CD8+ T cells this does not seem sufficient for clearing the infection. Tissue and serum of LTβR−/− mice revealed deregulated cytokine expression patterns and production, particularly regarding interferons and interleukins. Since IFNγ mediated upregulation of murine guanylate-binding proteins (mGBPs) is essential for parasite clearance, expression and localization of mGBPs was evaluated. In vivo, delayed/reduced up-regulation of mGBPs expression was observed, whereas initial in vitro experiments in LTβR−/− fibroblasts demonstrated that mGBPs can be upregulated after IFNγ treatment and are able to localize at the parasitophorous vacuole. These data suggest that defects in cytokine signalling, especially IFNγ deregulation, may contribute to the decreased survival rates of LTβR−/− mice in T. gondii infection. New insights into the pathology of T. gondii could provide new therapeutic strategies for the treatment of human toxoplasmosis.

Interferon-λ3 Promotes Epithelial Defense and Barrier Function Against Cryptosporidium parvum Infection.

Background & AimsThe epithelial response is critical for intestinal defense against Cryptosporidium, but is poorly understood. To uncover the host strategy for defense against Cryptosporidium, we examined the transcriptional response of intestinal epithelial cells (IECs) to C parvum in experimentally infected piglets by microarray. Up-regulated genes were dominated by targets of interferon (IFN) and IFN-λ3 was up-regulated significantly in infected piglet mucosa. Although IFN-λ has been described as a mediator of epithelial defense against viral pathogens, there is limited knowledge of any role against nonviral pathogens. Accordingly, the aim of the study was to determine the significance of IFN-λ3 to epithelial defense and barrier function during C parvum infection.MethodsThe significance of C parvum–induced IFN-λ3 expression was determined using an immunoneutralization approach in neonatal C57BL/6 mice. The ability of the intestinal epithelium to up-regulate IFN-λ2/3 expression in response to C parvum infection and the influence of IFN-λ2/3 on epithelial defense against C parvum invasion, intracellular development, and loss of barrier function was examined using polarized monolayers of a nontransformed porcine-derived small intestinal epithelial cell line (IPEC-J2). Specifically, changes in barrier function were quantified by measurement of transepithelial electrical resistance and transepithelial flux studies.ResultsImmunoneutralization of IFN-λ2/3 in C parvum–infected neonatal mice resulted in a significantly increased parasite burden, fecal shedding, and villus blunting with crypt hyperplasia during peak infection. In vitro, C parvum was sufficient to induce autonomous IFN-λ3 and interferon-stimulated gene 15 expression by IECs. Priming of IECs with recombinant human IFN-λ3 promoted cellular defense against C parvum infection and abrogated C parvum–induced loss of barrier function by decreasing paracellular permeability to sodium.ConclusionsThese studies identify IFN-λ3 as a key epithelial defense mechanism against C parvum infection.

Extracellular Vesicles Released by Leishmania (Leishmania) amazonensis Promote Disease Progression and Induce the Production of Different Cytokines in Macrophages and B-1 Cells.

The extracellular vesicles (EVs) released by Leishmania can contribute to the establishment of infection and host immunomodulation. In this study, we characterized the shedding of EVs from Leishmania (Leishmania) amazonensis promastigotes. This species is the causative agent of cutaneous leishmaniasis, and its role during interactions with bone marrow-derived macrophages (BMDMs) and peritoneal B-1 cells was evaluated. Leishmania amazonensis promastigotes cultivated in vitro at different times and temperatures spontaneously released EVs. EVs were purified using size-exclusion chromatography (SEC) and quantitated by nanoparticle tracking analysis (NTA). NTA revealed that the average size of the EVs was approximately 180 nm, with concentrations ranging from 1.8 × 108 to 2.4 × 109 vesicles/mL. In addition, the presence of LPG and GP63 were detected in EVs obtained at different temperatures. Naïve BMDMs stimulated with EVs exhibited increased IL-10 and IL-6 expression. However, incubating B-1 cells with parasite EVs did not stimulate IL-10 expression but led to an increase in the expression of IL-6 and TNFα. After 7 weeks post-infection, animals infected with L. amazonensis promastigotes in the presence of parasite EVs had significant higher parasite load and a polarization to Th2 response, as compared to the group infected with the parasite alone. This work demonstrated that EVs isolated from L. amazonensis promastigotes were able to stimulate macrophages and B-1 cells to express different types of cytokines. Moreover, the immunomodulatory properties of EVs probably contributed to an increase in parasite burden in mice. These findings suggest that the functionality of L. amazonensis EVs on immune system favor of parasite survival and disease progression.

STRINGS OF FURY: A CASE OF STRONGYLOIDES HYPERINFECTION SYNDROME IN A CHEMOTHERAPY-NAIVE PATIENT WITH EXTENSIVE SCLC

SESSION TITLE: Chest Infections 2 SESSION TYPE: Med Student/Res Case Report PRESENTED ON: 10/09/2018 05:00 PM - 06:00 PM INTRODUCTION: Strongyloidiasis is one of the most neglected tropical diseases. Diagnosis is difficult because of non-specific clinical features, irregular larval output and lack of specific test. This infection can be chronic and asymptomatic but a change in immune status can lead to increased parasite burden, hyperinfection syndrome, dissemination, and death if unrecognized. CASE PRESENTATION: An 80-year old Filipino male diagnosed with Small Cell Lung Cancer - extensive disease (brain and liver metastases) was admitted due to a 5-day history of watery blood-streaked stools, dry cough and decreased sensorium. Dexamethasone was started for raised intracranial pressure. The patient was started on empiric antibiotics for pneumonia (Fig2) and acute gastroenteritis. Fecalysis showed Strongyloides larvae (Fig1) and Albendazole was started. Neurologic and respiratory status worsened and necessitated ventilatory support. Endotracheal aspirate smear revealed Strongyloides rhabditiform larvae (FIg3). Blood culture revealed Klebsiella pneumoniae. Despite adequate antibiotic coverage and discontinuation of steroids, the patient continued to deteriorate and was brought home. DISCUSSION: Hyperinfection is a syndrome of accelerated autoinfection which may or may not result from alteration in immune status. Development of gastrointestinal and pulmonary symptoms is seen. The hallmark is detection of increased numbers of larvae in stool and/or sputum. Regardless of dose or route of administration, even short courses (6-17 days) of steroids in immunocompetent patients have been associated with hyperinfection syndrome and death.Hyperinfections are often complicated and, rarely, preceded by infections caused by gut flora that gain access to extraintestinal sites, presumably through ulcers induced by the filariform larvae or by virtue of being carried on the surface or in the intestinal tract of the larvae themselves. Blood cultures from patients with hyperinfection have grown Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas, Enterococcus faecalis, coagulase-negative staphylococci, Streptococcus bovis, and Streptococcus pneumoniae.Centers for Disease Control and Prevention recommend that immunosuppressive therapy should be stopped or reduced if possible. Only Ivermectin is recommended for hyperinfection however it is not available in the Philippines. Albendazole is recommended as alternative regimen for acute and chronic forms strongyloidiasis. CONCLUSIONS: As the number of immunosuppressed individuals increase, a more thorough investigation is warranted to detect situations under which S. stercoralis infection can potentially worsen. Early diagnosis is a challenge as it may mimic other diseases. Primary prevention as well as better approaches to identifying, screening, and treating those at risk will likely decrease the morbidity and mortality associated with this hyperinfection syndrome. Reference #1: Olsen A, van Lieshout L, Marti H, et al. Strongyloidiasis - the most neglected of the neglected tropical diseases? Trans R Soc Trop Med Hyg. 2009; 103:967-972. Reference #2: Mejia R, Nutman TB, Screening, prevention, and treatment for hyperinfection syndrome and disseminated infections caused by Strongyloides stercoralis. Opin Infect Dis. 2012 August ; 25(4): 458-463. Reference #3: Keiser PB, Nutman TB. Strongyloides Stercoralis In The Immunocompromised Population. Clinical Microbiology Reviews, Jan. 2004, P. 208-217 DISCLOSURES: no disclosure on file for Raquel Victoria Ecarma; No relevant relationships by Myrna Mendoza, source=Web Response No relevant relationships by Irene Rosellen Tan, source=Web Response

Leishmania donovani molecules recognized by sera of filaria infected host facilitate filarial infection.

We earlier found that F6 fraction of human filaria Brugia malayi cross-reacted with sera of Leishmania donovani infected hamsters and immunization with F6 inhibited both filarial and leishmanial infections. In the present study, we identified a 52.9-93.6 kDa fraction (Ld1) of L. donovani that cross-reacted with sera of B. malayi infected animals and investigated effect of Ld1 on filarial infection. Immunization of BALB/c mice with Ld1 facilitated B. malayi infection with remarkable increase in parasite burden. Facilitation of filarial infection was associated with downregulated cell proliferation, IL-5, IL-13, IFN-γ, TNF-α, and IL-2 levels and upregulated IL-4 and TGF-β. Ld1 exposure also suppressed MHC class-I, MHC class-II, and FcεR1 expression, and phagocytosis in naive mouse macrophages, and CD4+, CD8+, and CD19+ cell population in mouse spleen. Two-dimensional electrophoresis and matrix-assisted laser desorption ionization-time of flight-mass spectrometry revealed eight proteins in Ld1: putative heat shock protein (HSP) 70-related protein 1, HSP70 mitochondrial precursor, alanine aminotransferase, 2,3-bisphosphoglycerate-independent phosphoglycerate mutase, protein disulfide isomerase, putative ATPase beta subunit, trypanothione reductase, and a hypothetical protein. HSP70 protein mitochondrial precursor and trypanothione reductase showed homology with Trypanosoma cruzi and L. donovani, respectively, and the rest 6 proteins including hypothetical protein bear homology with L. infantum. In conclusion, the present study for the first time shows that immunization with filarial cross-reactive Ld1 fraction of L. donovani facilitates filarial infection by modulating Th1 and Th2 responses. Ld1 molecules may therefore facilitate filarial infection in filaria-leishmania co-infection.

Plant-Based Solutions to Global Livestock Anthelmintic Resistance

Anthelmintic resistance in livestock is increasing globally. Livestock intestinal parasites now develop resistance to synthetic anthelmintics within 2–10 years, collectively costing billions of dollars annually in lost revenue around the world. Over-reliance on commercial drugs and dips and changes in livestock management practices are key drivers of this trend. To date, current research has focused on identifying new anthelmintics from bacterial and fungal sources or even synthesizing new drugs that target parasite metabolism or reproduction. Plant-derived anthelmintics are a promising alternative, yet to date major research funders and scientists have overlooked this option. Until the mid-20th century, rural communities relied on plant-based methods of controlling livestock parasites. These methods include feeding livestock specific medicinal plants and trees, grazing livestock on herbal leys, and changing where livestock grazed based on ecological factors (e.g., flooding) that increased parasite burdens. Many historic texts and ethnological accounts record the ethnobotanical knowledge of rural communities and the plants they used to control livestock intestinal parasites. Some traditions persist today yet the farmers, graziers, and shepherds who hold this knowledge are rapidly disappearing and with them perhaps a potential long-term solution to anthelmintic resistance. This short perspective piece will cover recent research using ethnobotanical data as a means to identifying potential new anthelmintics; the morphological, physiological, and metabolic effect of plant secondary metabolites on parasites; and an overview of “best practices” which can reduce bias in assessments of plant bioactivity and increase reproducibility of test results. This will hopefully bring recent advances in ethnobiology, chemistry, and ecology to new audiences, and, potentially, spark new interest in using medicinal plants to improve livestock health.

Interleukin-9 promotes early mast cell-mediated expulsion of Strongyloides ratti but is dispensable for generation of protective memory

IL-9 is a cytokine with pleiotropic function that mediates allergic inflammation and immunity to intestinal helminth parasites. Accumulating evidence suggests that IL-9 acts via both, initiation and regulation of adaptive immune responses and direct activation of intestinal effector pathways. Here we use IL-9 receptor deficient mice on BALB/c and C57BL/6 genetic background to dissect effector and regulatory functions of IL-9 during infection with the parasitic nematode Strongyloides ratti. IL-9 receptor-deficient mice displayed increased intestinal parasite burden and prolonged infection irrespective of the genetic background of the mice. Increased parasite burden was correlated to a reciprocally reduced early degranulation of mucosal mast cells, reduced intestinal IL-13 expression and caused by IL-9 receptor deficiency on hematopoietic cells. We observed additional significant changes in the adaptive immune response to S. ratti infection in the absence of the IL-9 receptor that depended on the mouse strain. However, the generation of protective memory to a second infection was intact in IL-9 receptor-deficient mice, irrespective of the genetic background. In summary, our results support a central role for IL-9 as an early mast cell activating effector cytokine during intestinal helminth infection while non-redundant functions in the initiation and amplification of adaptive immune responses were not apparent.

IL-1α facilitates the entry of immune cells into the brain during chronic Toxoplasma gondii infection

Abstract Toxoplasma gondii is a parasite that causes chronic infections in the brain. Infection is asymptomatic in healthy hosts, but immunocompromised hosts experience severe disease in which fast-replicating parasites destroy brain tissue. Constant immune pressure is required to maintain control of the parasite, leading to the localized recruitment of immune cells. During chronic T. gondii infection, cell death occurs in focal areas of inflammation in the brain, suggesting the possibility of inflammatory molecule release. The alarmin IL-1α is expressed in the brain, and is upregulated by T. gondii infection. IL-1α is expressed by brain-resident microglia and infiltrating macrophages, implicating these cell types as sources of this cytokine. Mice lacking IL-1α or its receptor (IL-1R1), but not IL-1β, have defects in macrophage infiltration into the brain during chronic infection, as well as increased parasite burden in the brain. IL-1α has been the subject of less investigation than IL-1β, but may still rely on inflammatory cell death for its release. Indeed, this IL-1α-dependent immune response appears to be dependent on pyroptosis, as caspase-1/11−/− mice phenocopy IL-1R1−/− mice displaying decreased recruitment of myeloid cells into the brain and increased parasite burden. IL-1R1 is expressed on endothelial and other stromal cells in the brain vasculature, and IL-1R1−/− mice display decreased expression of the adhesion molecules ICAM-1 and VCAM-1 in the brain. These data suggest that during chronic T. gondii infection, IL-1α released from a macrophage population in the brain through pyroptosis acts on brain vasculature to modulate expression of adhesion molecules, facilitating the infiltration of monocytes to sites of infection.

Pathologic inflammation and neuronal damage during murine neurocysticercosis associates with increased expression of IL-1β

Abstract Neurocysticercosis (NCC) is the leading cause of acquired epilepsy worldwide caused by Taenia solium larvae. Disease progression involves an initial asymptomatic phase followed by a symptomatic period, in which dying organisms induce inflammation and symptoms such as seizures, intracranial hypertension, or cognitive decline. A mixed Th1/Th2 response develops in the brain, contrasting the canonical Th2 pathway associated with peripheral helminthic infections. We found that disease progression was more severe in BALB/c mice, correlating with increased parasite burdens and enhanced eosinophil and macrophage infiltration, although comparable numbers of T cells were detected. Moreover, elevated IL-1β levels were significantly elevated in BALB/c mice. Notably, Mrc1-deficient mice which exhibited a more resistant phenotype with decreased mortality and morbidity displayed low IL-1β expression. Therefore, we hypothesize that early up regulation of IL-1β in response to antigen recognition by macrophages plays a key role in damage to the nervous tissue. Comparison of glial and neuronal distribution in naïve and infected wild type C57BL6 and Balb/c mice, and also in strains with defective trafficking of eosinophils to the CNS, revealed that expression of IL-1β was detected early during infection and dramatically increased by 2 wks, colocalizing to macrophages and astrocytes. Notably, calbindin+ neurons were also significantly reduced in cerebellar regions where severe pockets of inflammatory cells are detected. Thus, our results suggest that IL-1β is a central proinflammatory mediator with neurotoxic potential during NCC infection.

Effects of host injury on susceptibility of marine reef fishes to ectoparasitic gnathiid isopods

The importance of the role that parasites play in ecological communities is becoming increasingly apparent. However much about their impact on hosts and thus populations and communities remains poorly understood. A common observation in wild populations is high variation in levels of parasite infestation among hosts. While high variation could be due to chance encounter, there is increasing evidence to suggest that such patterns are due to a combination of environmental, host, and parasite factors. In order to examine the role of host condition on parasite infection, rates of Gnathia marleyi infestation were compared between experimentally injured and uninjured fish hosts. Experimental injuries were similar to the minor wounds commonly observed in nature. The presence of the injury significantly increased the probability of infestation by gnathiids. However, the level of infestation (i.e., total number of gnathiid parasites) for individual hosts, appeared to be unaffected by the treatment. The results from this study indicate that injuries obtained by fish in nature may carry the additional cost of increased parasite burden along with the costs typically associated with physical injury. These results suggest that host condition may be an important factor in determining the likelihood of infestation by a common coral reef fish ectoparasite, G. marleyi.

Immunosenescence patterns differ between populations but not between sexes in a long-lived mammal

In animals, physiological mechanisms underlying reproductive and actuarial senescence remain poorly understood. Immunosenescence, the decline in the ability to display an efficient immune response with increasing age, is likely to influence both reproductive and actuarial senescence through increased risk of disease. Evidence for such a link has been reported from laboratory animal models but has been poorly investigated in the wild, where variation in resource acquisitions usually drives life-history trade-offs. We investigated immunosenescence patterns over 7 years in both sexes of two contrasting roe deer populations (Capreolus capreolus). We first measured twelve immune markers to obtain a thorough identification of innate and adaptive components of immunity and assessed, from the same individuals, the age-dependent variation observed in parasitic infections. Although the level of innate traits was maintained at old age, the functional innate immune traits declined with increasing age in one of two populations. In both populations, the production of inflammatory markers increased with advancing age. Finally, the adaptive response declined in late adulthood. The increasing parasite burden with age we reported suggests the effective existence of immunosenescence. Age-specific patterns differed between populations but not between sexes, which indicate that habitat quality could shape age-dependent immune phenotype in the wild.

HpARI Protein Secreted by a Helminth Parasite Suppresses Interleukin-33

SummaryInfection by helminth parasites is associated with amelioration of allergic reactivity, but mechanistic insights into this association are lacking. Products secreted by the mouse parasite Heligmosomoides polygyrus suppress type 2 (allergic) immune responses through interference in the interleukin-33 (IL-33) pathway. Here, we identified H. polygyrus Alarmin Release Inhibitor (HpARI), an IL-33-suppressive 26-kDa protein, containing three predicted complement control protein (CCP) modules. In vivo, recombinant HpARI abrogated IL-33, group 2 innate lymphoid cell (ILC2) and eosinophilic responses to Alternaria allergen administration, and diminished eosinophilic responses to Nippostrongylus brasiliensis, increasing parasite burden. HpARI bound directly to both mouse and human IL-33 (in the cytokine’s activated state) and also to nuclear DNA via its N-terminal CCP module pair (CCP1/2), tethering active IL-33 within necrotic cells, preventing its release, and forestalling initiation of type 2 allergic responses. Thus, HpARI employs a novel molecular strategy to suppress type 2 immunity in both infection and allergy.

Behavior of Neutrophil Granulocytes during Toxoplasma gondii Infection in the Central Nervous System.

Cerebral toxoplasmosis is characterized by activation of brain resident cells and recruitment of specific immune cell subsets from the periphery to the central nervous system (CNS). Our studies revealed that the rapidly invaded Ly6G+ neutrophil granulocytes are an early non-lymphoid source of interferon-gamma (IFN-γ), the cytokine known to be the major mediator of host resistance to Toxoplasma gondii (T. gondii). Upon selective depletion of Ly6G+ neutrophils, we detected reduced IFN-γ production and increased parasite burden in the CNS. Ablation of Ly6G+ cells resulted in diminished recruitment of Ly6Chi monocytes into the CNS, indicating a pronounced interplay. Additionally, we identified infiltrated Ly6G+ neutrophils to be a heterogeneous population. The Ly6G+CD62-LhiCXCR4+ subset released cathelicidin-related antimicrobial peptide (CRAMP), which can promote monocyte dynamics. On the other hand, the Ly6G+CD62-LloCXCR4+ subset produced IFN-γ to establish early inflammatory response. Collectively, our findings revealed that the recruited Ly6G+CXCR4+ neutrophil granulocytes display a heterogeneity in the CNS with a repertoire of effector functions crucial in parasite control and immune regulation upon experimental cerebral toxoplasmosis.

Causes and consequences of higher Leishmania infantum burden in patients with kala‐azar: a study of 625 patients

An infected host's Leishmania infantum load in blood is considered to be an estimate of his or her total parasite burden. Therefore, the measurement of blood parasite burden is important in the identification of factors involved in parasite control. Quantitative polymerase chain reaction was performed on blood samples from 625 patients with kala-azar consecutively admitted to a reference hospital in Teresina, Brazil. Primers were used to amplify a segment of kDNA using the TaqMan system. Non-parametric statistical tests were applied. The median blood parasite burden was 499.2 amastigote equivalents (AE)/ml. Children <1 year old (yo) had a high parasite burden, which dropped sharply after the first year of life (192.8, AE/ml at 1 < 2 yo) and remained lower until adolescence. Following adolescence, the parasite burden increased with age, peaking among elderly individuals. Men had a higher parasite burden than women. HIV-infected patients had a much higher parasite burden than non-infected patients. The parasite burden of children under 5 years with acute moderate to severe malnourishment (weight-for-age and body mass index z-scores <-2) was almost three times greater than that of better-nourished children. The parasite burden identified in deceased patients was more than twice that of surviving patients; those with a higher risk of death, sepsis, pneumonia and jaundice also had increased parasite burdens. All of these differences were statistically significant at P-values <0.05. These data indicate that the parasite burden in patients with kala-azar was associated with age- and gender-associated factors and with HIV infection status. Acute malnutrition could be either a cause or a consequence of a higher parasite burden. An individual's parasite burden influences his or her clinical profile, disease severity and mortality risk. The best explanation for the presence of a higher parasite burden in individuals with these immunoregulatory conditions and severe disease is the occurrence of acquired immunosuppression followed by heightened innate immunity.