Life-style metabolic diseases are steadily rising, not only in developed countries, but also in low- and middle-income countries, presenting a global health problem. Metabolic disorders like type 2 ...diabetes and cardiovascular diseases are among the ten leading causes of death defined by the WHO in 2019. Results from animal and observational human studies suggest a connection between the decline in human helminth infections and rise of life-style-associated metabolic diseases in developing regions. This trial was designed to investigate filarial infections and their impact on metabolic diseases in Cameroon. We hypothesize that the induction of regulatory immune responses during filarial infection reduces obesity-induced low-grade inflammatory immune responses and thereby improves metabolic parameters, whereas anthelmintic treatment abolishes this protective effect.
Participants infected with Mansonella perstans, Onchocerca volvulus and/or Loa loa being lean (BMI <25), overweight (BMI >25 and <30) or clinically obese (BMI ≥30) from Littoral regions of Cameroon will be evaluated for their parasitological, immunological, metabolic and biochemical profile before and after treatment of their parasitic infections. Anthropomorphic measurements and a detailed questionnaire will complement our analysis. The investigation will assess blood immune cell populations, serum adipokines and cytokines that could be influenced by the parasite infection and/or metabolic diseases. Further, parameters like blood glucose, homeostatic model assessment of insulin resistance (HOMA-IR), circulating lipids and circulating makers of liver function will be monitored. Parameters will be assessed before treatment, 12 and 18 months after treatment.
The focus of this study is to obtain a comprehensive metabolic profile of the participants in rural areas of Cameroon and to investigate the relationship between filarial immunomodulation and metabolic diseases. This study will elucidate the effect of anti-filarial treatment on the metabolic and immunological parameters that partake in the development of insulin resistance, narrowing in on a potential protective effect of filarial infections on metabolic diseases.
doi.org/10.1186/ISRCTN43845142, ISRCTN43845142 February 2020 Trial title Effects of filarial parasite infection on type 2 diabetes Issue date: 27.10.22, V.1.
Order from disorder phenomena in BaCoS2 Lenz, Benjamin; Fabrizio, Michele; Casula, Michele
Communications physics,
01/2024, Volume:
7, Issue:
1
Journal Article
Peer reviewed
Open access
Abstract
At
T
N
≃ 300K the layered insulator BaCoS
2
transitions to a columnar antiferromagnet that signals non-negligible magnetic frustration despite the relatively high
T
N
, all the more ...surprising given its quasi two-dimensional structure. Here, we show, by combining ab initio and model calculations, that the magnetic transition is an order-from-disorder phenomenon, which not only drives the columnar magnetic order, but also the inter-layer coherence responsible for the finite Néel transition temperature. This uncommon ordering mechanism, actively contributed by orbital degrees of freedom, hints at an abundance of low energy excitations above and across the Néel transition, in agreement with experimental evidence.
Eosinophilia is a hallmark of helminth infections and eosinophils are essential in the protective immune responses against helminths. Nevertheless, the distinct role of eosinophils during parasitic ...filarial infection, allergy and autoimmune disease-driven pathology is still not sufficiently understood. In this study, we established a mouse model for microfilariae-induced eosinophilic lung disease (ELD), a manifestation caused by eosinophil hyper-responsiveness within the lung.
Wild-type (WT) BALB/c mice were sensitized with dead microfilariae (MF) of the rodent filarial nematode Litomosoides sigmodontis three times at weekly intervals and subsequently challenged with viable MF to induce ELD. The resulting immune response was compared to non-sensitized WT mice as well as sensitized eosinophil-deficient dblGATA mice using flow cytometry, lung histology and ELISA. Additionally, the impact of IL-33 signaling on ELD development was investigated using the IL-33 antagonist HpARI2.
ELD-induced WT mice displayed an increased type 2 immune response in the lung with increased frequencies of eosinophils, alternatively activated macrophages and group 2 innate lymphoid cells, as well as higher peripheral blood IgE, IL-5 and IL-33 levels in comparison to mice challenged only with viable MF or PBS. ELD mice had an increased MF retention in lung tissue, which was in line with an enhanced MF clearance from peripheral blood. Using eosinophil-deficient dblGATA mice, we demonstrate that eosinophils are essentially involved in driving the type 2 immune response and retention of MF in the lung of ELD mice. Furthermore, we demonstrate that IL-33 drives eosinophil activation in vitro and inhibition of IL-33 signaling during ELD induction reduces pulmonary type 2 immune responses, eosinophil activation and alleviates lung lacunarity. In conclusion, we demonstrate that IL-33 signaling is essentially involved in MF-induced ELD development.
Our study demonstrates that repeated sensitization of BALB/c mice with L. sigmodontis MF induces pulmonary eosinophilia in an IL-33-dependent manner. The newly established model recapitulates the characteristic features known to occur during eosinophilic lung diseases (ELD) such as human tropical pulmonary eosinophilia (TPE), which includes the retention of microfilariae in the lung tissue and induction of pulmonary eosinophilia and type 2 immune responses. Our study provides compelling evidence that IL-33 drives eosinophil activation during ELD and that blocking IL-33 signaling using HpARI2 reduces eosinophil activation, eosinophil accumulation in the lung tissue, suppresses type 2 immune responses and mitigates the development of structural damage to the lung. Consequently, IL-33 is a potential therapeutic target to reduce eosinophil-mediated pulmonary pathology.
Eosinophils mediate protection against filarial nematodes. Our results demonstrate that eosinophil extracellular traps (EETosis) are induced by microfilariae and infective L3 larvae of Litomosoides ...sigmodontis. These extracellular DNA traps inhibit microfilariae motility in a DNA- and contact-dependent manner in vitro. Accordingly, microfilariae-injection triggers DNA release in an eosinophil-dependent manner in vivo and microfilariae covered with DNA traps are cleared more rapidly. Using dectin-1, we identify the required receptor for the microfilariae-induced EETosis, whereas signaling via other C-type lectin receptors, prior priming of eosinophils, and presence of antibodies are not required. The DNA released upon microfilariae-induced EETosis is mainly of mitochondrial origin, but acetylated and citrullinated histones are found within the traps. We further demonstrate that the presented DNA-dependent inhibition of microfilariae motility by eosinophils represents a conserved mechanism, as microfilariae from L. sigmodontis and the canine heartworm Dirofilaria immitis induce ETosis in murine and human eosinophils.
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•Eosinophils release extracellular DNA traps and inhibit microfilariae motility•Microfilariae-induced eosinophil extracellular DNA traps are a conserved mechanism•Microfilariae trigger DNA release by eosinophils through the dectin-1 receptor•Microfilariae coated with DNA traps are cleared more efficiently in vivo
Parasitic filariae (thread worms) cause debilitating diseases, and eosinophils are essential for protective immune responses against filariae. The mechanism by which eosinophils mediate protection is not fully understood. Ehrens et al. emphasize the importance of eosinophil extracellular DNA traps in trapping infective larval stages and the progeny of filarial worms.
Filarial nematodes can cause debilitating diseases such as lymphatic filariasis and onchocerciasis. Oxfendazole (OXF) is one promising macrofilaricidal candidate with improved oral availability ...compared to flubendazole (FBZ), and OXF is currently under preparation for phase 2 clinical trials in filariasis patients. This study aimed to investigate the immune system's role during treatment with OXF and FBZ and explore the potential to boost the treatment efficacy via stimulation of the immune system. Wild type (WT) BALB/c, eosinophil-deficient
,
, antibody-deficient μMT and B-, T-, NK-cell and ILC-deficient
mice were infected with the rodent filaria
and treated with an optimal and suboptimal regimen of OXF and FBZ for up to 5 days. In the second part, WT mice were treated for 2-3 days with a combination of OXF and IL-4, IL-5, or IL-33. Treatment of WT mice reduced the adult worm burden by up to 94% (OXF) and 100% (FBZ) compared to vehicle controls. In contrast, treatment efficacy was lower in all immunodeficient strains with a reduction of up to 90% (OXF) and 75% (FBZ) for
, 50 and 92% for
, 64 and 78% for μMT or 0% for
mice. The effect of OXF on microfilariae and embryogenesis displayed a similar pattern, while FBZ's ability to prevent microfilaremia was independent of the host's immune status. Furthermore, flow cytometric analysis revealed strain-and treatment-specific immunological changes. The efficacy of a shortened 3-day treatment of OXF (-33% adult worms vs. vehicle) could be boosted to a 91% worm burden reduction via combination with IL-5, but not IL-4 or IL-33. Our results suggest that various components of the immune system support the filaricidal effect of benzimidazoles
and present an opportunity to boost treatment efficacy.
Interleukin-4 (IL-4) is a central regulator of type 2 immunity, crucial for the defense against multicellular parasites like helminths. This study focuses on its roles and cellular sources during ...Litomosoides sigmodontis infection, a model for human filarial infections.
Utilizing an IL-4 secretion assay, investigation into the sources of IL-4 during the progression of L. sigmodontis infection was conducted. The impact of eosinophils on the Th2 response was investigated through experiments involving dblGATA mice, which lack eosinophils and, consequently, eosinophil-derived IL-4.
The absence of eosinophils notably influenced Th2 polarization, leading to impaired production of type 2 cytokines. Interestingly, despite this eosinophil deficiency, macrophage polarization, proliferation, and antibody production remained unaffected.
Our research uncovers eosinophils as a major source of IL-4, especially during the early phase of filarial infection. Consequently, these findings shed new light on IL-4 dynamics and eosinophil effector functions in filarial infections.
We present evidence for Mott quantum criticality in an anisotropic two-dimensional system of coupled Hubbard chains at half-filling. In this scenario emerging from variational cluster approximation ...and cluster dynamical mean-field theory, the interchain hopping t_{⊥} acts as a control parameter driving the second-order critical end point T_{c} of the metal-insulator transition down to zero at t_{⊥}^{c}/t≃0.2. Below t_{⊥}^{c}, the volume of the hole and electron Fermi pockets of a compensated metal vanishes continuously at the Mott transition. Above t_{⊥}^{c}, the volume reduction of the pockets is cut off by a first-order transition. We discuss the relevance of our findings to a putative quantum critical point in layered organic conductors, whose location remains elusive so far.
Group 2 innate lymphoid cells (ILC2s) are inducers of type 2 immune responses, but their role during filarial infection remains unclear. In the present study, we used the
Litomosoides sigmodontis
...rodent model of filariasis to analyze ILC2s during infection in susceptible BALB/c mice that develop a chronic infection with microfilaremia and semi-susceptible C57BL/6 mice that eliminate the filariae shortly after the molt into adult worms and thus do not develop microfilaremia. ILC2s (CD45
+
Lineage
-
TCRβ
-
CD90.2
+
Sca-1
+
IL-33R
+
GATA-3
+
) were analyzed in the pleural cavity, the site of
L. sigmodontis
infection, after the infective L3 larvae reached the pleural cavity (9 days post infection, dpi), after the molt into adult worms (30dpi) and during the peak of microfilaremia (70dpi). C57BL/6 mice had significantly increased ILC2 numbers compared to BALB/c mice at 30dpi, accompanied by substantially higher IL-5 and IL-13 levels, indicating a stronger type 2 immune response in C57BL/6 mice upon
L. sigmodontis
infection. At this time point the ILC2 numbers positively correlated with the worm burden in both mouse strains. ILC2s and GATA-3
+
CD4
+
T cells were the dominant source of IL-5 in
L. sigmodontis
-infected C57BL/6 mice with ILC2s showing a significantly higher IL-5 expression than CD4
+
T cells. To investigate the importance of ILC2s during
L. sigmodontis
infection, ILC2s were depleted with anti-CD90.2 antibodies in T and B cell-deficient
Rag2
-/-
C57BL/6 mice on 26-28dpi and the outcome of infection was compared to isotype controls.
Rag2
-/-
mice were per se susceptible to
L. sigmodontis
infection with significantly higher worm burden than C57BL/6 mice and developed microfilaremia. Depletion of ILC2s did not result in an increased worm burden in
Rag2
-/-
mice, but led to significantly higher microfilariae numbers compared to isotype controls. In conclusion, our data demonstrate that ILC2s are essentially involved in the control of microfilaremia in
Rag2
-/-
C57BL/6 mice.
We investigate the tetragonal phase of the binary transition metal
oxide CuO (t-CuO) within the context of cellular dynamical mean-field
theory. Due to its strong antiferromagnetic correlations and ...simple
structure, analysing the physics of t-CuO is of high interest as it may
pave the way towards a more complete understanding of high-temperature
superconductivity in hole-doped antiferromagnets. In this work we give a
formal justification for the weak-coupling assumption that has
previously been made for the interconnected sublattices within a single
layer of t-CuO by studying the non-local self-energies of the system. We
compute momentum-resolved spectral functions using a Matrix Product
State (MPS)-based impurity solver directly on the real axis, which does
not require any numerically ill-conditioned analytic continuation. The
agreement with photoemission spectroscopy indicates that a single-band
Hubbard model is sufficient to capture the material’s low energy
physics. We perform calculations on a range of different temperatures,
finding two magnetic regimes, for which we identify the driving
mechanism behind their respective insulating state. Finally, we show
that in the hole-doped regime the sublattice structure of t-CuO has
interesting consequences on the symmetry of the superconducting
state.
More than two-hundred-million people are infected with filariae worldwide. However, there is no vaccine available that confers long-lasting protection against filarial infections. Previous studies ...indicated that vaccination with irradiated infective L3 larvae reduces the worm load. This present study investigated whether the additional activation of cytosolic nucleic acid receptors as an adjuvant improves the efficacy of vaccination with irradiated L3 larvae of the rodent filaria
with the aim of identifying novel vaccination strategies for filarial infections. Subcutaneous injection of irradiated L3 larvae in combination with poly(I:C) or 3pRNA resulted in neutrophil recruitment to the skin, accompanied by higher IP-10/CXCL10 and IFN-β RNA levels. To investigate the impact on parasite clearance, BALB/c mice received three subcutaneous injections in 2-week intervals with irradiated L3 larvae in combination with poly(I:C) or 3pRNA prior to the challenge infection. Vaccination with irradiated L3 larvae in combination with poly(I:C) or 3pRNA led to a markedly greater reduction in adult-worm counts by 73% and 57%, respectively, compared to the immunization with irradiated L3 larvae alone (45%). In conclusion, activation of nucleic acid-sensing immune receptors boosts the protective immune response against
and nucleic acid-receptor agonists as vaccine adjuvants represent a promising novel strategy to improve the efficacy of vaccines against filariae and potentially other helminths.
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