Toll-like receptor 9 and 4 gene polymorphisms in susceptibility and severity of malaria: a meta-analysis of genetic association studies.

BACKGROUND: Malaria is still a major public health problem in sub-Saharan Africa and South-east Asia. The clinical presentations of malaria infection vary from a mild febrile illness to life-threatening severe malaria. Toll like receptors (TLRs) are postulated to be involved in the innate immune responses to malaria. Individual studies showed inconclusive findings. This study aimed to assess the role of TLR4 (D299G, T399I) and TLR9 (T1237C, T1486C) in severity or susceptibility of malaria by meta-analysis of data from eligible studies. METHODS: Relevant case-control studies that assessed the association between TLR 4/9 and malaria either in susceptibility or progression were searched in health-related electronic databases. Quality of included studies was evaluated with Newcastle-Ottawa scale. Pooled analyses for specific genetic polymorphisms were done under five genetic models. Stratified analysis was done by age and geographical region (Asian countries vs non-Asian countries). RESULTS: Eleven studies (2716 cases and 2376 controls) from nine endemic countries were identified. Five studies (45.4%) obtained high score in quality assessment. Overall, a significant association between TLR9 (T1486C) and severity of malaria is observed in allele model (OR: 1.26, 95% CI: 1.08-1.48, I2 = 0%) or homozygous model (OR: 1.55, 95% CI: 1.08-2.28, I2 = 0%). For TLR9 (T1237C), a significant association with severity of malaria is observed in in heterozygous model (OR:1.89, 95% CI: 1.11-3.22, I2 = 75%). On stratifications, TLR9 (T1486C) is only significantly associated with a subgroup of children of non-Asian countries under allele model (OR: 1.25, 95% CI: 1.02-1.38), while 1237 is with a subgroup of adults from Asian countries under heterozygous model (OR: 2.0, 95% CI: 1.09-3.64, I2 = 39%). Regarding the susceptibility to malaria, TLR9 (T1237C) is significantly associated only with the children group under recessive model (OR: 2.21, 95% CI: 1.06-4.57, I2=85%) and homozygous model (OR: 1.49, 95% CI: 1.09-2.0, I2 = 0%). For TLR4 (D299G, T399I), none is significantly associated with either severity of malaria or susceptibility to malaria under any genetic models. CONCLUSIONS: The findings suggest that TLR 9 (T1486C and T1237C) seems to influence the progression of malaria, under certain genetic models and in specific age group of people from specific geographical region. TLR 9 (T1237C) also plays a role in susceptibility to malaria under certain genetic models and only with children of non-Asian countries. To substantiate these, future well designed studies with larger samples across endemic countries are needed.

Systems analysis and controlled malaria infection in Europeans and Africans elucidate naturally acquired immunity.

Controlled human infections provide opportunities to study the interaction between the immune system and malaria parasites, which is essential for vaccine development. Here, we compared immune signatures of malaria-naive Europeans and of Africans with lifelong malaria exposure using mass cytometry, RNA sequencing and data integration, before and 5 and 11 days after venous inoculation with Plasmodium falciparum sporozoites. We observed differences in immune cell populations, antigen-specific responses and gene expression profiles between Europeans and Africans and among Africans with differing degrees of immunity. Before inoculation, an activated/differentiated state of both innate and adaptive cells, including elevated CD161+CD4+ T cells and interferon-γ production, predicted Africans capable of controlling parasitemia. After inoculation, the rapidity of the transcriptional response and clusters of CD4+ T cells, plasmacytoid dendritic cells and innate T cells were among the features distinguishing Africans capable of controlling parasitemia from susceptible individuals. These findings can guide the development of a vaccine effective in malaria-endemic regions.

Haemonchus contortus infection induces a variable immune response in resistant and susceptible Pelibuey sheep.

The immune response and phenotypic characteristics of Pelibuey lambs were analysed after the induction of a Haemonchus contortus trickle infection. Male lambs (n = 29; 20 kg live weight) were infected with 100 H. contortus infective larvae per kg of live weight on day 3, 5 and 7 of the experiment. The number of eggs per gram (epg), seven haematological parameters and the immunoglobulin A (IgA) level were analysed for 56 experimental days. In addition, histopathological samples from the fundic abomasal region and the relative expression of 10 immune-related genes from 15 infected and three non-infected lambs were analysed at day 0 and 49 of the experiment. The epg count and some haematological parameters (leucocytes, red blood cells, haemoglobin and total protein) with statistically significant differences (P < 0.01) were used to identify nine resistant and 20 susceptible lambs (1166 ±â€¯1071 and 3171 ±â€¯1463 epg, respectively). Moreover, acute infiltration of immune cells and parasitic granuloma formation were observed in susceptible lambs; the resistant group had moderate inflammatory cell infiltration. With respect to relative gene expression, resistant lambs showed upregulation (P < 0.001) of 10 genes, from 2.2 to 15.99 fold. Moreover, there was a strong indirect correlation (P < 0.05) between the epg count and interleukin 5 (IL5) gene expression. By contrast, there was an average 0.34 fold downregulation in nine of the immune-related genes (P ≤ 0.05) in susceptible lambs (the only exception was Fc fragment of IgE receptor Ia [FCER1A] upregulation). In addition, there was a direct correlation (P ≤ 0.05) between the epg count and the expression of IL8, which encodes an inflammatory chemokine. In conclusion, this study showed differential IL5 and IL8 gene expression during haemonchosis in resistant and susceptible Pelibuey lambs, respectively, together with a variable immune response based on histopathological and haematological parameters.

Immune response dynamics and Lutzomyia longipalpis exposure characterize a biosignature of visceral leishmaniasis susceptibility in a canine cohort.

BACKGROUND: Reports have shown correlations between the immune response to vector saliva and Leishmaniasis outcome. We followed dogs in an endemic area for two years characterizing resistance or susceptibility to canine visceral leishmaniasis (CVL) according to Leishmania infantum diagnosis and clinical development criteria. Then, we aimed to identify a biosignature based on parasite load, serum biological mediators' interactions, and vector exposure intensity associated with CVL resistance and susceptibility. METHODOLOGY/PRINCIPAL FINDINGS: A prospective two-year study was conducted in an area endemic for CVL. Dogs were evaluated at 6-month intervals to determine infection, clinical manifestations, immune profile, and sandfly exposure. CVL resistance or susceptibility was determined upon the conclusion of the study. After two years, 78% of the dogs were infected with L. infantum (53% susceptible and 47% resistant to CVL). Susceptible dogs presented higher splenic parasite load as well as persistence of the parasite during the follow-up, compared to resistant ones. Susceptible dogs also displayed a higher number of correlations among the investigated biological mediators, before and after infection diagnosis. At baseline, anti-saliva antibodies, indicative of exposure to the vector, were detected in 62% of the dogs, reaching 100% in one year. Higher sandfly exposure increased the risk of susceptibility to CVL by 1.6 times (CI: 1.11-2.41). We identified a discriminatory biosignature between the resistant and susceptible dogs assessing splenic parasite load, interaction of biological mediators, PGE2 serum levels and intensity of exposure to sandfly. All these parameters were elevated in susceptible dogs compared to resistant animals. CONCLUSIONS/SIGNIFICANCE: The biosignature identified in our study reinforces the idea that CVL is a complex multifactorial disease that is affected by a set of factors which are correlated and, for a better understanding of CVL, should not be evaluated in an isolated way.

Distinct hepatic myeloid and lymphoid cell repertoires are associated with susceptibility and resistance to Ascaris infection.

The soil-transmitted helminth Ascaris lumbricoides infects ~800 million people worldwide. Some people are heavily infected, harbouring many worms, whereas others are only lightly infected. The mechanisms behind this difference are unknown. We used a mouse model of hepatic resistance to Ascaris, with C57BL/6J mice as a model for heavy infection and CBA/Ca mice as a model for light infection. The mice were infected with the porcine ascarid, Ascaris suum or the human ascarid, A. lumbricoides and immune cells in their livers and spleens were enumerated using flow cytometry. Compared to uninfected C57BL/6J mice, uninfected CBA/Ca mice had higher splenic CD4+ and γδ T cell counts and lower hepatic eosinophil, Kupffer cell and B cell counts. Infection with A. suum led to expansions of eosinophils, Kupffer cells, monocytes and dendritic cells in the livers of both mouse strains and depletions of hepatic natural killer (NK) cells in CBA/Ca mice only. Infection with A. lumbricoides led to expansions of hepatic eosinophils, monocytes and dendritic cells and depletions of CD8+, αß, NK and NK T cells in CBA/Ca mice, but not in C57BL/6J mice where only monocytes expanded. Thus, susceptibility and resistance to Ascaris infection are governed, in part, by the hepatic immune system.

Comparison between Trichinella patagoniensis and Trichinella spiralis infection in BALB/c mice.

In Argentina, trichinellosis is an endemic disease acquired mainly through consumption of raw pork infected with nematodes larvae from the Trichinella genus. For years, the only species involved in outbreaks in humans and pig foci in Argentina was Trichinella spiralis. In 2008 the presence of a new Trichinella taxon from a cougar (Puma concolor) was detected and recorded in the province of Rio Negro, Argentina, and the finding was established as a new species in 2012: Trichinella patagoniensis. To the best of our knowledge, there is no information available on the intestinal phase and antibody response in a susceptible host during T. patagoniensis infection. Therefore, our research has been designed to study experimental infection with T. patagoniensis compared to infection with T. spiralis in BALB/c mice. One hundred and twenty eight BALB/c mice were divided into two groups and individuals in each group were infected per os with 500 larvae of T. patagoniensis or 500 larvae of T. spiralis, respectively. After that, they were euthanized on different days. Adult worm recovery from small intestines and artificial digestion of each carcass was performed. Histopathology of small intestines was performed using hematoxylin-eosin staining. Systemic cytokines and antibody kinetics were evaluated. Intestinal adult worm recovery of T. patagoniensis and T. spiralis took place until day 17 and 25, respectively. Systemic IFN-γ, IL-10, and TNF showed significant variations in T. patagoniensis infected mice. Seroconversion was detected in animals as from 15 days post-infection (pi) for both T. patagoniensis and T. spiralis, reaching the highest OD value at 42 days pi. Similar microscopic lesions were observed in the small intestine from mice infected with the same dose of T. spiralis and T. patagoniensis. Our findings contribute new information regarding the intestinal phase and the antibody kinetics of T. patagoniensis in BALB/c mice.

Susceptibility of patients receiving chemotherapy for haematological malignancies to scabies.

BACKGROUND: Scabies is a contagious dermatosis. The risk factors for its transmission remain unclear. A scabies outbreak, involving patients who were receiving chemotherapy for haematological malignancies, occurred at our hospital. METHODS: The outbreak population was analysed to determine whether the incidence of scabies was higher among contact patients receiving chemotherapy for haematological malignancies. RESULTS: A patient with crusted scabies was the index case, and 18 of 78 contact healthcare workers (HCWs) and 22 of 135 contact patients were diagnosed with classical scabies. Ten of 17 contact patients with haematological malignancies and 12 of 118 contact patients with other diseases were infected with scabies. The incidence rate was significantly higher among the patients with haematological malignancies (P<0.001). The patients with haematological malignancies had a significantly lower mean minimum neutrophil count than those with other diseases (1159/µL vs 3761/µL, P=0.0012). Most haematological patients did not require special nursing assistance, suggesting that the higher incidence of scabies among these patients resulted from their immunodeficiency rather than greater skin-to-skin contact with infected HCWs. CONCLUSION: Our study suggests that patients receiving chemotherapy for haematological malignancies are more susceptible to scabies than patients with other diseases, and require stricter protection.

House finches with high coccidia burdens experience more severe experimental Mycoplasma gallisepticum infections.

Parasites co-infecting hosts can interact directly and indirectly to affect parasite growth and disease manifestation. We examined potential interactions between two common parasites of house finches: the bacterium Mycoplasma gallisepticum that causes conjunctivitis and the intestinal coccidian parasite Isospora sp. We quantified coccidia burdens prior to and following experimental infection with M. gallisepticum, exploiting the birds' range of natural coccidia burdens. Birds with greater baseline coccidia burdens developed higher M. gallisepticum loads and longer lasting conjunctivitis following inoculation. However, experimental inoculation with M. gallisepticum did not appear to alter coccidia shedding. Our study suggests that differences in immunocompetence or condition may predispose some finches to more severe infections with both pathogens.

Horses are susceptible to natural, but resistant to experimental, infection with the liver fluke, Fasciola hepatica.

Fasciola hepatica is a common parasite of livestock in Ireland, causing significant economic losses and affecting animal welfare. A previous abattoir study of 200 horses led to an estimated 9.5 % prevalence of infection in horses slaughtered in Ireland. However, the epidemiology and pathogenic significance of this infection in this species is not well-described. The objectives of this study were to determine the susceptibility of horses to oral challenge infection with F. hepatica metacercariae, and to document the course of the infection along with serological and biochemical response. We attempted an experimental infection of horses (n = 10; 9 geldings and 1 mare) with F. hepatica. Four were given 1000 metacercariae, four 500 metacercariae and two were sham-infected. Blood and faecal samples were taken at intervals up to 18 weeks post-infection (wpi). ELISA assays were used to assess sero-conversion in the experimental horses and also in a panel of sera from horses of known fluke status. No flukes were recovered from any of the livers, and neither were any lesions that could be attributed to F. hepatica infection observed. Coproantigen ELISA was negative throughout for all horses. Three antibody detection ELISAs, useful in diagnosing fasciolosis in other species, had limitations as diagnostic aids as determined using a panel of sera from horses of known F. hepatica infection status. This study is limited by the relatively small number of animals included, and the relatively short duration of the study period. Failure to establish infection after oral challenge raises fundamental questions on the pathophysiology and epidemiology of equine fasciolosis.

Characterising interactions between co-infecting parasites using age-intensity profiles.

Interactions between co-infecting parasite species can impact transmission. Whether co-infection is beneficial or detrimental to a target parasite, and whether the mechanism involves changes in host susceptibility or parasite clearance, can be difficult to assess. We demonstrate the potential for host age-parasite intensity curves to allow assessment of these factors. A model is developed to generate predictions and test these predictions using helminth parasites of white-tailed deer (Odocoileus virginianus). We identify three beneficial interactions involving five helminth species, including susceptibility and clearance-based mechanisms. Our results suggest that analysis of age-intensity data represents a new tool for assessing the nature and strength of co-infecting parasite interactions.

The experimental study on susceptibility of common European songbirds to Plasmodium elongatum (lineage pGRW6), a widespread avian malaria parasite.

BACKGROUND: Plasmodium elongatum (cytochrome b lineage pGRW6) is a widespread avian malaria parasite, often causing severe disease in non-adapted hosts. This parasite lineage is of global distribution however, its virulence remains insufficiently understood, particularly in wild birds. Surprisingly, this infection has never been reported in Common starlings Sturnus vulgaris and Common crossbills Loxia curvirostra, common European songbirds which were extensively sampled across Europe. A hypothesis was proposed that these birds might be resistant to the pGRW6 infection. The aim of this study was to test this hypothesis. METHODS: Lineage pGRW6 was isolated from a naturally infected Eurasian reed warbler, multiplied in vivo and inoculated in Common starlings and Common crossbills. Experimental and control groups (8 birds in each) were maintained in controlled conditions and examined microscopically every 4 days. Haematocrit value and body mass were monitored in parallel. At the end of the experiment (44 days post exposure), samples of internal organs were collected and examined using histological methods for possible presence of phanerozoites. RESULTS: All control birds remained uninfected. Experimental starlings were resistant. All exposed crossbills were susceptible and survived until the end of this study. Prepatent period was 12-16 days post exposure. Light parasitaemia (< 0.7%) developed in all birds, and only few phanerozoites were seen in bone marrow cells of 5 of 8 experimentally infected crossbills. Significant changes were reported only in haematocrit value but not body mass in the exposed crossbills compared to controls. CONCLUSION: Plasmodium elongatum (pGRW6) is of low virulence in Common crossbills and is unable to develop in Common starlings, indicating innate resistance of the later bird species. Low virulence in Common crossbills is likely due to the inability or low ability of this parasite lineage to develop phanerozoites resulting in light (if at all) damage of stem bone marrow cells. This study suggests that susceptibility of different bird species to the lineage pGRW6 is markedly variable. The global distribution of this parasite might be due to low virulence in wild adapted avian hosts, which survive this infection and serve as reservoirs host for non-adapted birds in whom this infection is often lethal.

Depletion of Host Cell Focal Adhesion Kinase Increases the Susceptibility to Invasion by Trypanosoma cruzi Metacyclic Forms.

Focal adhesion kinase (FAK), a cytoplasmic protein tyrosine kinase (PTK), is implicated in diverse cellular processes, including the regulation of F-actin dynamics. Host cell F-actin rearrangement is critical for invasion of Trypanosoma cruzi, the protozoan parasite that causes Chagas disease. It is unknown whether FAK is involved in the internalization process of metacyclic trypomastigote (MT), the parasite form that is important for vectorial transmission. MT can enter the mammalian host through the ocular mucosa, lesion in the skin, or by the oral route. Oral infection by MT is currently a mode of transmission responsible for outbreaks of acute Chagas disease. Here we addressed the question by generating HeLa cell lines deficient in FAK. Host cell invasion assays showed that, as compared to control wild type (WT) cells, FAK-deficient cells were significantly more susceptible to parasite invasion. Lysosome spreading and a disarranged actin cytoskeleton, two features associated with susceptibility to MT invasion, were detected in FAK-deficient cells, as opposed to WT cells that exhibited a more organized F-actin arrangement, and lysosomes concentrated in the perinuclear area. As compared to WT cells, the capacity of FAK-deficient cells to bind a recombinant protein based on gp82, the MT surface molecule that mediates invasion, was higher. On the other hand, when treated with FAK-specific inhibitor PF573228, WT cells exhibited a dense meshwork of actin filaments, lysosome accumulation around the nucleus, and had increased resistance to MT invasion. In cells treated with PF573228, the phosphorylation levels of FAK were reduced and, as a consequence of FAK inactivation, diminished phosphorylation of extracellular signal-regulated protein kinases (ERK1/2) was observed. Fibronectin, known to impair MT invasion, induced the formation of thick bundles of F-actin and ERK1/2 dephosphorylation.

Distinctive site preference of the fish parasite Myxobolus cerebralis (Cnidaria, Myxozoa) during host invasion.

Here, we experimentally studied the site preference of Myxobolus cerebralis, one of the most pathogenic myxozoan (Cnidaria, Myxozoa) fish parasites, which causes whirling disease in salmonids. Parasite invasion was examined in three fish species with various susceptibility levels: the type host brown trout, the highly susceptible rainbow trout, and the non-susceptible gibel carp, in which parasite spores do not develop. We investigated the first two hours of fish invasion, and measured the site preference of triactinomyxons (TAMs) during attachment and penetration of fish in three body parts (gills, fins, skin). Infection prevalence and intensity were estimated using a species-specific nested PCR, optimised in the present study. The highest infection prevalence was detected in the most susceptible fish species, rainbow trout. Interestingly, higher prevalence was observed in gibel carp than in the type host, brown trout (95.2% vs. 85.7%). Considering body locations, remarkable differences were detected in infection intensities. The highest intensity was observed in fins, whereas skin was the least infected body part in every fish species examined. Infection prevalence and intensity did not differ significantly among fish species. Thus, we confirmed that M. cerebralis TAMs cannot discern fish species. Furthermore, we proved experimentally that fish fin is significantly more attractive to fish-invading parasite TAMs than gills or skin.

Transcriptome variation in response to gastrointestinal nematode infection in goats.

Gastrointestinal nematodes (GIN) are a major constraint for small ruminant production. Due to the rise of anthelmintic resistance throughout the world, alternative control strategies are needed. The development of GIN resistance breeding programs is a promising strategy. However, a better understanding of the mechanisms underlying genetic resistance might lead to more effective breeding programmes. In this study, we compare transcriptome profiling of abomasal mucosa and lymph node tissues from non-infected, resistant and susceptible infected Creole goats using RNA-sequencing. A total of 24 kids, 12 susceptible and 12 GIN resistant based on the estimated breeding value, were infected twice with 10,000 L3 Haemonchus contortus. Physiological and parasitological parameters were monitored during infection. Seven weeks after the second infection, extreme kids (n = 6 resistant and 6 susceptible), chosen on the basis of the fecal egg counts (FEC), and 3 uninfected control animals were slaughtered. Susceptible kids had significantly higher FEC compared with resistant kids during the second infection with no differences in worm burden, male and female worm count or establishment rate. A higher number of differentially expressed genes (DEG) were identified in infected compared with non-infected animals in both abomasal mucosa (792 DEG) and lymph nodes (1726 DEG). There were fewer DEG in resistant versus susceptible groups (342 and 450 DEG, in abomasal mucosa and lymph nodes respectively). 'Cell cycle' and 'cell death and survival' were the main identified networks in mucosal tissue when comparing infected versus non-infected kids. Antigen processing and presentation of peptide antigen via major histocompatibility complex class I were in the top biological functions for the DEG identified in lymph nodes. The TGFß1 gene was one of the top 5 upstream DEG in mucosal tissue. Our results are one of the fist investigating differences in the expression profile induced by GIN infection in goats.

Haematobia irritans parasitism of F1 yak × beef cattle (Bos grunniens × Bos taurus) hybrids.

The horn fly Haematobia irritans (Diptera: Muscidae) is a blood obligate ectoparasite of bovids that causes annual losses to the U.S. beef cattle industry of over US$1.75 billion. Climate warming, the anthropogenic dispersion of bovids and the cross-breeding of beef cattle with other bovid species may facilitate novel horn fly-host interactions. In particular, hybridizing yaks [Bos grunniens (Artiodactyla: Bovidae)] with beef cows (Bos taurus) for heterosis and carcass improvements may increase the exposure of yak × beef hybrids to horn flies. The present paper reports on the collection of digital images of commingled beef heifers (n = 12) and F1 yak × beef hybrid bovids (heifers, n = 7; steers, n = 5) near Laramie, Wyoming (∼ 2200 m a.s.l.) in 2018. The total numbers of horn flies on beef heifers and F1 yak × beef heifers [mean ± standard error (SE): 88 ± 13 and 70 ± 17, respectively] did not differ significantly; however, F1 yak × beef steers had greater total horn fly abundance (mean ± SE: 159 ± 39) than female bovids. The present report of this experiment is the first such report in the literature and suggests that F1 yak × beef bovids are as susceptible as cattle to horn fly parasitism. Therefore, similar monitoring and treatment practices should be adopted by veterinarians, entomologists and producers.

Sand crickets (Gryllus firmus) have low susceptibility to entomopathogenic nematodes and their pathogenic bacteria.

The entomopathogenic nematode, Steinernema scapterisci, a specialist parasite of crickets, has been successfully used to combat the southern mole cricket, Neoscapteriscus borellii, which is an invasive pest of turf grass. As an entomopathogenic nematode, S. scapterisci causes rapid death of the insects it infects and uses bacteria to facilitate its parasitism. However, our understanding of the relative contributions of the nematode, S. scapterisci, and its bacterial symbiont, Xenorhabdus innexi, to parasitism remains limited. Here we utilized the sand cricket, Gryllus firmus, as a model host to evaluate the contributions of the EPNs S. scapterisci and S. carpocapsae, as well as their symbiotic bacteria, X. innexi and X. nematophila, respectively, to the virulence of the nematode-bacterial complex. We found that G. firmus has reduced susceptibility to infection from both S. scapterisci and the closely related generalist parasite S. carpocapsae, but that S. scapterisci is much more virulent than S. carpocapsae. Further, we found that N. borellii has reduced susceptibility to X. nematophila, and that G. firmus has reduced susceptibility to X. nematophila, X. innexi, and Serratia marcescens, much more so than other insects that have been studied. We found that the reduced susceptibility of G. firmus to bacterial infection is dependent on development, with adults being less susceptible to infection than nymphs. Our data provide evidence that unlike other EPNs, the virulence of S. scapterisci to crickets is dependent on the nematode rather than the bacterial symbiont that it carries and we speculate that S. scapterisci may be evolving independence from X. innexi.

Establishment of Cooperia oncophora in calves.

The establishment rate of Cooperia oncophora related to host age and previous infection was investigated in young calves. Calves of similar age were kept on a feed pad and allocated into multiple groups, based on their age and weight. Two groups (each n = 16) received trickle infections with an ivermectin-susceptible C. oncophora isolate of 2000 or 10,000 infective stage larvae per week while another group (n = 16) was kept as an uninfected control. At intervals over a period of 11 months, two animals from each group were challenged with 15,000 infective stage larvae of an ivermectin-resistant isolate, 25 days later orally treated with ivermectin and 5 days after that slaughtered for worm counts. On three occasions additional calves (n = 2), subjected to the high trickle infection rate, received an ivermectin treatment to remove the existing worm burden, prior to challenge as above. Further calves (n = 4) of similar age were introduced at the beginning and the end of the experiment to determine the effect of larval age on establishment rate. The establishment in the two trickle infection groups declined to <10% within the first three months, which was significantly different from the control group. In the animals receiving the high trickle infection, but an anthelmintic treatment before challenge the establishment rate was not significantly different from the controls. Over the duration of the experiment establishment in the control group declined from 53% to <20%, which was similar to the decrease recorded at the beginning and the end of the experiment in the animals to determine the effect of larval age. The findings indicate that an existing C. oncophora burden had a strong effect on the establishment of incoming larvae in the trickle infected groups, but this was not observed if the existing burden was removed before the final challenge. The decline in establishment rate in the control group was attributed to the age of the larvae and not the age of the calves per se.

Correlation of malaria parasitaemia with peripheral blood monocyte to lymphocyte ratio as indicator of susceptibility to severe malaria in Ghanaian children.

BACKGROUND: Even though malaria is generally on the decline due extensive control and elimination efforts, it still remains a public health problem for over 40% of the world's population. During the course of malaria infection, parasites and red blood cells come under oxidative stress and there is host immune response in an attempt to protect the red blood cells. The frequency of monocytes and lymphocytes in peripheral blood might, therefore, be expected to reflect the state of an individual's immune response to the infection. Circulating monocytes and lymphocytes could therefore serve as an index in relation to malaria parasitaemia. The purpose of this study was to determine whether the relative count of monocytes to lymphocytes in peripheral blood (M:L ratio) can predict parasitaemia and, therefore, the severity of malaria infection. METHODS: Two millilitre of venous blood sample were taken from participants by venisection into anticoagulant tubes. Thick and thin blood films were made and stained with Giemsa and examined for malaria parasites. Whole blood specimen were analysed for full blood count using ABX Pentra 60 C+ automated haematological analyzer. Data was entered into Microsoft Word and analysed using Statistical Package for Social Sciences (SPSS, Version 20.0) and Graphpad prism. Spearman's correlation was used to determine correlation between occurrences of clinical malaria and the monocytes and lymphocytes ratio. Statistical significance was taken as p ≤ 0.05 with 95% confidence interval. RESULTS: The study comprised of 1629 (m = 896; f = 733) children up to 5 years presenting with clinical malaria as cases and 445 (m = 257; f = 188) apparently healthy children as controls. The results indicated that there was a significant positive correlation between the monocytes to lymphocytes ratio and the presence of parasites (p = 0.04) and the level of parasitaemia within the age group of 0-3 years (p = 0.02) and 4-5 years (p = 0.03). CONCLUSIONS: The monocyte to lymphocyte ratio obtained correlated positively with the presence of malaria as well as the level of parasitaemia. The outcome of this work implies that monocyte to lymphocyte ratio can be used to predict the level of parasitaemia and together with other factors, the development of severe malaria.

Host-Parasite Interactions Promote Disease Tolerance to Intestinal Helminth Infection.

Parasitic helminths are among the most pervasive pathogens of the animal kingdom. To complete their life cycle, these intestinal worms migrate through host tissues causing significant damage in their wake. As a result, infection can lead to malnutrition, anemia and increased susceptibility to co-infection. Despite repeated deworming treatment, individuals living in endemic regions remain highly susceptible to re-infection by helminths, but rarely succumb to excessive tissue damage. The chronicity of infection and inability to resist numerous species of parasitic helminths that have co-evolved with their hosts over millenia suggests that mammals have developed mechanisms to tolerate this infectious disease. Distinct from resistance where the goal is to destroy and eliminate the pathogen, disease tolerance is an active process whereby immune and structural cells restrict tissue damage to maintain host fitness without directly affecting pathogen burden. Although disease tolerance is evolutionary conserved and has been well-described in plant systems, only recently has this mode of host defense, in its strictest sense, begun to be explored in mammals. In this review, we will examine the inter- and intracellular networks that support disease tolerance during enteric stages of parasitic helminth infection and why this alternative host defense strategy may have evolved to endure the presence of non-replicating pathogens and maintain the essential functions of the intestine.

Deletion of Interleukin-4 Receptor Alpha-Responsive Keratinocytes in BALB/c Mice Does Not Alter Susceptibility to Cutaneous Leishmaniasis.

The skin microenvironment at the site of infection plays a role in the early events that determine protective T helper 1/type 1 immune responses during cutaneous leishmaniasis (CL) infection. During CL in nonhealing BALB/c mice, early interleukin-4 (IL-4) can instruct dendritic cells for protective Th1 immunity. Additionally, keratinocytes, which are the principal cell type in the skin epidermis, have been shown to secrete IL-4 early after Leishmania major infection. Here, we investigated whether IL-4/IL-13 signaling via the common IL-4 receptor alpha chain (IL-4Rα) on keratinocytes contributes to susceptibility during experimental CL. To address this, keratinocyte-specific IL-4Rα-deficient (KRT14cre IL-4Rα-/lox) mice on a BALB/c genetic background were generated by gene targeting and site-specific recombination (Cre/loxP) under the control of the keratinocyte-specific krt14 locus. Following high-dose infection with L. major IL-81 and LV39 promastigotes subcutaneously in the footpad, footpad swelling, parasite burden, IFN-γ/IL-4/IL-13 cytokine production, and type 1 and type 2 antibody responses were similar between KRT14cre IL-4Rα-/lox and littermate control IL-4Rα-/lox BALB/c mice. An intradermal infection with low-dose L. major IL-81 and LV39 promastigotes in the ear showed results in infected KRT14cre IL-4Rα-/lox BALB/c mice similar to those of littermate control IL-4Rα-/lox BALB/c mice, with the exception of a significant decrease observed in parasite burden only at the site of LV39 infection in the ear. Collectively, our results show that autocrine and paracrine signaling of IL-4/IL-13 through the IL-4Rα chain on keratinocytes does not influence the establishment of a nonhealing Th2 immune response in BALB/c mice during L. major infection.