Helminth parasites bias host CD4+ T helper (Th) cells toward Th2 responses, drive alternative activation of macrophages, and expand T regulatory cells. Helminth‐expressed carbohydrates play critical ...roles in driving much of this immune cell biasing. Studies on helminth glycans have focused on Lewis X, LDN, LDN‐DF, other fucosylated structures, chitin, tyvelose, and trehalose, which interact with host antigen presenting cells (APCs) minimally via C‐type lectins and/or Toll‐like receptors (TLR). Here, we review recent findings on helminth glycan activation of APCs via C‐type lectin/TLRs and introduce the concept that glycosylated helminth molecules require endocytosis to function as immune modulators. Second, we describe unpublished data showing that in vivo glycoconjugates comprising multiple copies of glycans on carriers are directly immune modulatory. Lastly, we discuss the observation that CD14 negatively regulates alternative activation of APCs during helminth infection. We close with a discussion on the use of immune modulatory glycans as vaccine adjuvants and as antiinflammatory therapeutics.
One of the limitations for clinical applications of dendritic cell (DC)-based cancer immunotherapy is the low potency in generating tumor antigen specific T cell responses. We examined the ...immunotherapeutic potential of a mitochondria-targeted nanoparticle (NP) based on a biodegradable polymer and zinc phthalocyanine (ZnPc) photosensitizer (T-ZnPc-NPs). Here, we report that tumor antigens generated from treatment of breast cancer cells with T-ZnPc-NPs upon light stimulation activate DCs to produce high levels of interferon-gamma, an important cytokine considered as a product of T and natural killer cells. The remarkable ex vivo DC stimulation ability of this tumor cell supernatant is a result of an interleukin (IL)-12/IL-18 autocrine effect. These findings contribute to the understanding of how in situ light activation amplifies the host immune responses when NPs deliver the photosensitizer to the mitochondria and open up the possibility of using mitochondria-targeted-NP-treated, light-activated cancer cell supernatants as possible vaccines.
Abstract Mass drug administration utilising a single oral dose of 40 mg/kg of praziquantel (PZQ) has been endorsed and advocated by the World Health Organisation (WHO) for the global control and ...elimination of schistosomiasis. However, this strategy is failing primarily because the drugs are not getting to the people who need them the most. The current global coverage is 20%, the drug compliance rate is less than 50%, and the drug efficacy is approximately 50%. Thus in reality, only about 5% of the reservoir human population is actually receiving intermittent chemotherapy. Despite claims that more of the drug will soon be made available the current strategy is inherently flawed and will not lead to disease elimination. We discuss the many practical issues related to this global strategy, and advocate for an integrated control strategy targeting the life cycle and the most at-risk. Moreover, we discuss how an integrated control package for schistosomiasis should fit within a larger integrated health package for rural and remote villages in the developing world. A holistic health system approach is required to achieve sustainable control and ultimately disease elimination.
Tumor growth is fueled by the use of glycolysis, which normal cells use only in the scarcity of oxygen. Glycolysis makes tumor cells resistant to normal death processes. Targeting this unique tumor ...metabolism can provide an alternative strategy to selectively destroy the tumor, leaving normal tissue unharmed. The orphan drug dichloroacetate (DCA) is a mitochondrial kinase inhibitor that has the ability to show such characteristics. However, its molecular form shows poor uptake and bioavailability and limited ability to reach its target mitochondria. Here, we describe a targeted molecular scaffold for construction of a multiple DCA loaded compound, Mito-DCA, with three orders of magnitude enhanced potency and cancer cell specificity compared to DCA. Incorporation of a lipophilic triphenylphosphonium cation through a biodegradable linker in Mito-DCA allowed for mitochondria targeting. Mito-DCA did not show any significant metabolic effects toward normal cells but tumor cells with dysfunctional mitochondria were affected by Mito-DCA, which caused a switch from glycolysis to glucose oxidation and subsequent cell death via apoptosis. Effective delivery of DCA to the mitochondria resulted in significant reduction in lactate levels and played important roles in modulating dendritic cell (DC) phenotype evidenced by secretion of interleukin-12 from DCs upon activation with tumor antigens from Mito-DCA treated cancer cells. Targeting mitochondrial metabolic inhibitors to the mitochondria could lead to induction of an efficient antitumor immune response, thus introducing the concept of combining glycolysis inhibition with immune system to destroy tumor.
Schistosomiasis is a neglected tropical disease with a very long endemic history in Asia. Great strides have been made to control the disease in China and the Philippines but the road to elimination ...is far from over, given the zoonotic nature of the schistosome parasites in both countries.
Background. In the Philippines, the current national control strategy for schistosomiasis is annual mass drug administration (MDA) with 40 mg/kg of praziquantel in all schistosomiasis-endemic ...villages with a prevalence ≥ 10%. Methods. A cross-sectional survey of schistosomiasis was conducted in 2012 on 18 221 individuals residing in 22 schistosomiasis-endemic villages in the province of Northern Samar. The prevalence of schistosomiasis, intensity of Schistosoma infection, and morbidity of disease were assessed. Results. Despite an active schistosomiasis-control program in Northern Samar for > 30 years, which included a MDA campaign in the last 5 years, the mean prevalence of schistosomiasis among 10 435 evaluated subjects was 27.1% (95% confidence interval CI, 26.3%-28.0%), and the geometric mean intensity of infection among 2832 evaluated subjects was 17.2 eggs per gram of feces (95% CI, 16.4-18.1). Ultrasonography revealed high levels of schistosomiasis-induced morbidity in the schistosomiasis-endemic communities. Left lobe liver enlargement (≥ 70 mm) was evident in 89.3% of subjects. Twenty-five percent of the study population had grade II/III liver parenchyma fibrosis, and 13.3% had splenomegaly (≥ 100 mm). Conclusions. MDA on its own was insufficient to control the prevalence of schistosomiasis, intensity of Schistosoma infection, or morbidity of the disease. Alternative control measures will be needed to complement the existing national MDA program.
Abstract
Background
Sporozoites isolated from the salivary glands of
Plasmodium
-infected mosquitoes are a prerequisite for several basic and pre-clinical applications. Although salivary glands are ...pooled to maximize sporozoite recovery, insufficient yields pose logistical and analytical hurdles; thus, predicting yields prior to isolation would be valuable. Preceding oocyst densities in the midgut is an obvious candidate. However, it is unclear whether current understanding of its relationship with sporozoite densities can be used to maximize yields, or whether it can capture the potential density-dependence in rates of sporozoite invasion of the salivary glands.
Methods
This study presents a retrospective analysis of
Anopheles stephensi
mosquitoes infected with two strains of the rodent-specific
Plasmodium berghei.
Mean oocyst densities were estimated in the midguts earlier in the infection (11–15 days post-blood meal), with sporozoites pooled from the salivary glands later in the infection (17–29 days). Generalized linear mixed effects models were used to determine if (1) mean oocyst densities can predict sporozoite yields from pooled salivary glands, (2) whether these densities can capture differences in rates of sporozoite invasion of salivary glands, and (3), if the interaction between oocyst densities and time could be leveraged to boost overall yields.
Results
The non-linear effect of mean oocyst densities confirmed the role of density-dependent constraints in limiting yields beyond certain oocyst densities. Irrespective of oocyst densities however, the continued invasion of salivary glands by the sporozoites boosted recoveries over time (17–29 days post-blood meal) for either parasite strain.
Conclusions
Sporozoite invasion of the salivary glands over time can be leveraged to maximize yields for
P. berghei
. In general, however, invasion of the salivary glands over time is a critical fitness determinant for all
Plasmodium
species (extrinsic incubation period, EIP). Thus, delaying sporozoite collection could, in principle, substantially reduce dissection effort for any parasite within the genus, with the results also alluding to the potential for changes in sporozoites densities over time to modify infectivity for the next host.
Alterations in lipid metabolism play a significant role in the pathogenesis of obesity-associated disorders, and dysregulation of the lipidome across multiple diseases has prompted research to ...identify novel lipids indicative of disease progression. To address the significant gap in knowledge regarding the effect of age and diet on the blood lipidome, we used shotgun lipidomics with electrospray ionization-mass spectrometry (ESI-MS). We analyzed blood lipid profiles of female C57BL/6 mice following high-fat diet (HFD) and low-fat diet (LFD) consumption for short (6weeks), long (22weeks), and prolonged (36weeks) periods. We examined endocannabinoid levels, plasma esterase activity, liver homeostasis, and indices of glucose tolerance and insulin sensitivity to compare lipid alterations with metabolic dysregulation. Multivariate analysis indicated differences in dietary blood lipid profiles with the most notable differences after 6weeks along with robust alterations due to age. HFD altered phospholipids, fatty acyls, and glycerolipids. Endocannabinoid levels were affected in an age-dependent manner, while HFD increased plasma esterase activity at all time points, with the most pronounced effect at 6weeks. HFD-consumption also altered liver mRNA levels of PPARα, PPARγ, and CD36. These findings indicate an interaction between dietary fat consumption and aging with widespread effects on the lipidome, which may provide a basis for identification of female-specific obesity- and age-related lipid biomarkers.
•The effect of age and diet on the female mouse blood lipidome was determined.•Short-term consumption (6weeks) of HFD had the greatest effect on the blood lipidome.•Age had a greater effect on the blood lipidome than diet.•Select lipids correlated to liver markers of metabolic regulation and inflammation.
•Schistosomiasis is a neglected tropical parasitic disease caused by the blood fluke Schistosoma.•Praziquantel is the mainstay of treatment and community-based control, but it is failing in some ...regions.•Schistosomiasis control in Asia is complicated by the zoonotic nature of the disease.•Vaccination of bovines has been proposed as a tool to assist in long-term control.•We report the results of a cluster randomized control trial using a SjCTPI-Hsp70 bovine vaccine.
Schistosomiasis is a neglected tropical parasitic disease caused by blood flukes of the genus Schistosoma. Schistosoma japonicum is zoonotic in China, the Philippines, and Indonesia, with bovines acting as major reservoirs of human infection. The primary objective of the trial was to examine the impact of a combination of human mass chemotherapy, snail control through mollusciciding, and SjCTPI bovine vaccination on the rate of human infection.
A 5-year phase IIIa cluster randomized control trial was conducted among 18 schistosomiasis-endemic villages comprising 18,221 residents in Northern Samar, The Philippines.
Overall, bovine vaccination resulted in a statistically significant decrease in human infection (relative risk RR = 0.75; 95% confidence interval CI = 0.69 to 0.82) across all trial follow-ups. The best outcome of the trial was when bovine vaccination was combined with snail mollusciciding. This combination resulted in a 31% reduction (RR = 0.69; 95% CI = 0.61 to 0.78) in human infection.
This is the first trial to demonstrate the effectiveness of a bovine vaccine for schistosomiasis in reducing human schistosome infection. The trial is registered with Australian New Zealand Clinical Trials Registry (ACTRN12619001048178).
Summary Schistosomiasis is a chronic enteropathogenic disease caused by blood flukes of the genus Schistosoma . The disease afflicts approximately 240 million individuals globally, causing ...approximately 70 million disability-adjusted life years lost. Chronic infections with morbidity and mortality occur as a result of granuloma formation in the intestine, liver, or in the case of Schistosoma haematobium , the bladder. Various methods are utilized to diagnose and evaluate liver fibrosis due to schistosomiasis. Liver biopsy is still considered the gold standard, but it is invasive. Diagnostic imaging has proven to be an invaluable method in assessing hepatic morbidity in the hospital setting, but has practical limitations in the field. The potential of non-invasive biological markers, serum antibodies, cytokines, and circulating host microRNAs to diagnose hepatic fibrosis is presently undergoing evaluation. This review provides an update on the recent advances made with respect to gastrointestinal disease associated with chronic schistosomiasis.
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