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Department of Veterinary Medicine

Cambridge Veterinary School

Genome-wide host-pathogen analyses reveal genetic interaction points in tuberculosis disease

Wed, 01/02/2023 - 11:00

Nat Commun. 2023 Feb 1;14(1):549. doi: 10.1038/s41467-023-36282-w.


The genetics underlying tuberculosis (TB) pathophysiology are poorly understood. Human genome-wide association studies have failed so far to reveal reproducible susceptibility loci, attributed in part to the influence of the underlying Mycobacterium tuberculosis (Mtb) bacterial genotype on the outcome of the infection. Several studies have found associations of human genetic polymorphisms with Mtb phylo-lineages, but studies analysing genome-genome interactions are needed. By implementing a phylogenetic tree-based Mtb-to-human analysis for 714 TB patients from Thailand, we identify eight putative genetic interaction points (P < 5 × 10-8) including human loci DAP and RIMS3, both linked to the IFNγ cytokine and host immune system, as well as FSTL5, previously associated with susceptibility to TB. Many of the corresponding Mtb markers are lineage specific. The genome-to-genome analysis reveals a complex interactome picture, supports host-pathogen adaptation and co-evolution in TB, and has potential applications to large-scale studies across many TB endemic populations matched for host-pathogen genomic diversity.

PMID:36725857 | DOI:10.1038/s41467-023-36282-w

Fibroblast Growth Factor-23 and Risk of Cardiovascular Diseases: A Mendelian Randomization Study

Tue, 31/01/2023 - 11:00

Clin J Am Soc Nephrol. 2023 Jan 1;18(1):17-27. doi: 10.2215/CJN.05080422.


BACKGROUND: Fibroblast growth factor-23 (FGF-23) is associated with a range of cardiovascular and noncardiovascular diseases in conventional epidemiological studies, but substantial residual confounding may exist. Mendelian randomization approaches can help control for such confounding.

METHODS: SCALLOP Consortium data of 19,195 participants were used to generate an FGF-23 genetic score. Data from 337,448 UK Biobank participants were used to estimate associations between higher genetically predicted FGF-23 concentration and the odds of any atherosclerotic cardiovascular disease (n=26,266 events), nonatherosclerotic cardiovascular disease (n=12,652), and noncardiovascular diseases previously linked to FGF-23. Measurements of carotid intima-media thickness and left ventricular mass were available in a subset. Associations with cardiovascular outcomes were also tested in three large case-control consortia: CARDIOGRAMplusC4D (coronary artery disease, n=181,249 cases), MEGASTROKE (stroke, n=34,217), and HERMES (heart failure, n=47,309).

RESULTS: We identified 34 independent variants for circulating FGF-23, which formed a validated genetic score. There were no associations between genetically predicted FGF-23 and any of the cardiovascular or noncardiovascular outcomes. In UK Biobank, the odds ratio (OR) for any atherosclerotic cardiovascular disease per 1-SD higher genetically predicted logFGF-23 was 1.03 (95% confidence interval [95% CI], 0.98 to 1.08), and for any nonatherosclerotic cardiovascular disease, it was 1.01 (95% CI, 0.94 to 1.09). The ORs in the case-control consortia were 1.00 (95% CI, 0.97 to 1.03) for coronary artery disease, 1.01 (95% CI, 0.95 to 1.07) for stroke, and 1.00 (95% CI, 0.95 to 1.05) for heart failure. In those with imaging, logFGF-23 was not associated with carotid or cardiac abnormalities.

CONCLUSIONS: Genetically predicted FGF-23 levels are not associated with atherosclerotic and nonatherosclerotic cardiovascular diseases, suggesting no important causal link.

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PMID:36719157 | DOI:10.2215/CJN.05080422

Worms and gut microbes - best of frenemies

Mon, 30/01/2023 - 11:00

Parasite Immunol. 2023 Jan 29:e12974. doi: 10.1111/pim.12974. Online ahead of print.


PMID:36710383 | DOI:10.1111/pim.12974

Topical application of indigo-plant leaves extract enhances healing of skin lesion in an excision wound model in rats

Sat, 28/01/2023 - 11:00

J Appl Biomed. 2022 Dec;20(4):124-129. doi: 10.32725/jab.2022.014. Epub 2022 Nov 11.


OBJECTIVES: This study aims to evaluate the pharmacological role of indigo extract in accelerating the wound healing in a rat model.

METHODS: Female Sprague-Dawley rats were anesthetized with ketamine (30 mg/kg, i.p.) and the full thickness of the marked skin was then cut carefully and wounds were left undressed. Indigo extract (5%) in PBS was applied topically twice daily until healing was complete. A control group of rats was treated with povidone-iodide (Betadine®). Rats treated with phosphate buffer saline were used as a negative control group. The rate of wound healing was assessed daily. Histopathological examination of skin sections were qualitatively assessed by independent evaluators. The inflammatory and apoptotic markers were assessed in skin tissue homogenates using ELISA.

RESULTS: Histopathology data showed that applying indigo to skin wounds enhanced the healing process, resulting in a significant decrease in dermal inflammation in comparison to untreated rats. Topical application of indigo significantly increased antioxidant enzyme activities with reduced malondialdehyde (MDA) levels in wound tissues. The levels of matrix metalloproteases-2 and -9 were significantly lower with an accompanied increase in the level of TGF-β1 in skin tissues from rats treated with indigo compared to the control group treated with PBS.

CONCLUSIONS: The antioxidant and anti-inflammatory properties of indigo leaf extract accelerate the healing of skin injuries.

PMID:36708717 | DOI:10.32725/jab.2022.014

Questioning the fetal microbiome illustrates pitfalls of low-biomass microbial studies

Wed, 25/01/2023 - 11:00

Nature. 2023 Jan;613(7945):639-649. doi: 10.1038/s41586-022-05546-8. Epub 2023 Jan 25.


Whether the human fetus and the prenatal intrauterine environment (amniotic fluid and placenta) are stably colonized by microbial communities in a healthy pregnancy remains a subject of debate. Here we evaluate recent studies that characterized microbial populations in human fetuses from the perspectives of reproductive biology, microbial ecology, bioinformatics, immunology, clinical microbiology and gnotobiology, and assess possible mechanisms by which the fetus might interact with microorganisms. Our analysis indicates that the detected microbial signals are likely the result of contamination during the clinical procedures to obtain fetal samples or during DNA extraction and DNA sequencing. Furthermore, the existence of live and replicating microbial populations in healthy fetal tissues is not compatible with fundamental concepts of immunology, clinical microbiology and the derivation of germ-free mammals. These conclusions are important to our understanding of human immune development and illustrate common pitfalls in the microbial analyses of many other low-biomass environments. The pursuit of a fetal microbiome serves as a cautionary example of the challenges of sequence-based microbiome studies when biomass is low or absent, and emphasizes the need for a trans-disciplinary approach that goes beyond contamination controls by also incorporating biological, ecological and mechanistic concepts.

PMID:36697862 | DOI:10.1038/s41586-022-05546-8

The role of the host gut microbiome in the pathophysiology of schistosomiasis

Thu, 19/01/2023 - 11:00

Parasite Immunol. 2023 Jan 19:e12970. doi: 10.1111/pim.12970. Online ahead of print.


The pathophysiology of schistosomiasis is linked to the formation of fibrous granulomas around eggs that become trapped in host tissues, particularly the intestines and liver, during their migration to reach the lumen of the vertebrate gut. While the development of Schistosoma egg-induced granulomas is the result of finely regulated crosstalk between egg-secreted antigens and host immunity, evidence has started to emerge of the likely contribution of an additional player - the host gut microbiota - to pathological processes that culminate with the formation of these tissue lesions. Uncovering the role(s) of schistosome-mediated changes in gut microbiome composition and function in granuloma formation and, more broadly, in the pathophysiology of schistosomiasis, will shed light on the mechanisms underlying this three-way parasite-host-microbiome interplay. Such knowledge may, in turn, pave the way toward the discovery of novel therapeutic targets and control strategies. This article is protected by copyright. All rights reserved.

PMID:36655799 | DOI:10.1111/pim.12970

Evaluation of genome skimming to detect and characterise human and livestock helminths

Sat, 14/01/2023 - 11:00

Int J Parasitol. 2023 Jan 11:S0020-7519(23)00012-7. doi: 10.1016/j.ijpara.2022.12.002. Online ahead of print.


The identification of gastrointestinal helminth infections of humans and livestock almost exclusively relies on the detection of eggs or larvae in faeces, followed by manual counting and morphological characterisation to differentiate species using microscopy-based techniques. However, molecular approaches based on the detection and quantification of parasite DNA are becoming more prevalent, increasing the sensitivity, specificity and throughput of diagnostic assays. High-throughput sequencing, from single PCR targets through to the analysis of whole genomes, offers significant promise towards providing information-rich data that may add value beyond traditional and conventional molecular approaches; however, thus far, its utility has not been fully explored to detect helminths in faecal samples. In this study, low-depth whole genome sequencing, i.e. genome skimming, has been applied to detect and characterise helminth diversity in a set of helminth-infected human and livestock faecal material. The strengths and limitations of this approach are evaluated using three methods to characterise and differentiate metagenomic sequencing data based on (i) mapping to whole mitochondrial genomes, (ii) whole genome assemblies, and (iii) a comprehensive internal transcribed spacer 2 (ITS2) database, together with validation using quantitative PCR (qPCR). Our analyses suggest that genome skimming can successfully identify most single and multi-species infections reported by qPCR and can provide sufficient coverage within some samples to resolve consensus mitochondrial genomes, thus facilitating phylogenetic analyses of selected genera, e.g. Ascaris spp. Key to this approach is both the availability and integrity of helminth reference genomes, some of which are currently contaminated with bacterial and host sequences. The success of genome skimming of faecal DNA is dependent on the availability of vouchered sequences of helminths spanning both taxonomic and geographic diversity, together with methods to detect or amplify minute quantities of parasite nucleic acids in mixed samples.

PMID:36641060 | DOI:10.1016/j.ijpara.2022.12.002

Biphasic JNK signaling reveals distinct MAP3K complexes licensing inflammasome formation and pyroptosis

Mon, 09/01/2023 - 11:00

Cell Death Differ. 2023 Jan 9. doi: 10.1038/s41418-022-01106-9. Online ahead of print.


Kinase signaling in the tiered activation of inflammasomes and associated pyroptosis is a prime therapeutic target for inflammatory diseases. While MAPKs subsume pivotal roles during inflammasome priming, specifically the MAP3K7/JNK1/NLRP3 licensing axis, their involvement in successive steps of inflammasome activation is poorly defined. Using live-cell MAPK biosensors to focus on the inflammasome triggering event allowed us to identify a subsequent process of biphasic JNK activation. We find that this biphasic post-trigger JNK signaling initially facilitates the mitochondrial reactive oxygen species generation needed to support core inflammasome formation, then supports the gasdermin-mediated cell permeation required for release of active IL-1β from human macrophages. We further identify and characterize a xanthine oxidase-ROS activated MAP3K5/JNK2 substrate licensing complex as a novel regulator of the GSDMD mobilization which precedes pyroptosis. We show that inhibitors targeting this MAP3K5 cascade alleviate morbidity in mouse models of colitis and dampen both augmented IL-1β release and cell permeation in monocytes derived from patients with gain-of-function inflammasomopathies.

PMID:36624264 | DOI:10.1038/s41418-022-01106-9

Repurposing Drugs in Small Animal Oncology

Sun, 08/01/2023 - 11:00

Animals (Basel). 2022 Dec 29;13(1):139. doi: 10.3390/ani13010139.


Repurposing drugs in oncology consists of using off-label drugs that are licensed for various non-oncological medical conditions to treat cancer. Repurposing drugs has the advantage of using drugs that are already commercialized, with known mechanisms of action, proven safety profiles, and known toxicology, pharmacokinetics and pharmacodynamics, and posology. These drugs are usually cheaper than new anti-cancer drugs and thus more affordable, even in low-income countries. The interest in repurposed anti-cancer drugs has led to numerous in vivo and in vitro studies, with some promising results. Some randomized clinical trials have also been performed in humans, with certain drugs showing some degree of clinical efficacy, but the true clinical benefit for most of these drugs remains unknown. Repurposing drugs in veterinary oncology is a very new concept and only a few studies have been published so far. In this review, we summarize both the benefits and challenges of using repurposed anti-cancer drugs; we report and discuss the most relevant studies that have been previously published in small animal oncology, and we suggest potential drugs that could be clinically investigated for anti-cancer treatment in dogs and cats.

PMID:36611747 | DOI:10.3390/ani13010139

Cystic Fibrosis-Related Gut Dysbiosis: A Systematic Review

Wed, 04/01/2023 - 11:00

Dig Dis Sci. 2023 Jan 4. doi: 10.1007/s10620-022-07812-1. Online ahead of print.


BACKGROUND AND AIMS: Cystic Fibrosis (CF) is associated with gut dysbiosis, local and systemic inflammation, and impaired immune function. Gut microbiota dysbiosis results from changes in the complex gut milieu in response to CF transmembrane conductance regulator (CFTR) dysfunction, pancreatic malabsorption, diet, medications, and environmental influences. In several diseases, alteration of the gut microbiota influences local and systemic inflammation and disease outcomes. We conducted a systematic review of the gut microbiota in CF and explored factors influencing dysbiosis.

METHODS: An electronic search of three databases was conducted in January 2019, and re-run in June 2021. Human, animal, and in vitro studies were included. The primary outcome was differences in the gut microbiota between people with CF (pwCF) and healthy controls. Secondary outcomes included the relationship between the gut microbiota and other factors, including diet, medication, inflammation, and pulmonary function in pwCF.

RESULTS: Thirty-eight studies were identified. The literature confirmed the presence of CF-related gut dysbiosis, characterized by reduced diversity and several taxonomic changes. There was a relative increase of bacteria associated with a pro-inflammatory response coupled with a reduction of those considered anti-inflammatory. However, studies linking gut dysbiosis to systemic and lung inflammation were limited. Causes of gut dysbiosis were multifactorial, and findings were variable. Data on the impact of CFTR modulators on the gut microbiota were limited.

CONCLUSIONS: CF-related gut dysbiosis is evident in pwCF. Whether this influences local and systemic disease and is amenable to interventions with diet and drugs, such as CFTR modulators, requires further investigation.

PMID:36600119 | DOI:10.1007/s10620-022-07812-1

Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis

Tue, 27/12/2022 - 11:00

Genome Biol. 2022 Dec 27;23(1):268. doi: 10.1186/s13059-022-02837-1.


BACKGROUND: Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery.

RESULTS: To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3-5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism.

CONCLUSIONS: Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.

PMID:36575460 | DOI:10.1186/s13059-022-02837-1

Humoral and cellular immune responses to Lassa fever virus in Lassa fever survivors and their exposed contacts in Southern Nigeria

Sun, 25/12/2022 - 11:00

Sci Rep. 2022 Dec 25;12(1):22330. doi: 10.1038/s41598-022-26045-w.


Elucidating the adaptive immune characteristics of natural protection to Lassa fever (LF) is vital in designing and selecting optimal vaccine candidates. With rejuvenated interest in LF and a call for accelerated research on the Lassa virus (LASV) vaccine, there is a need to define the correlates of natural protective immune responses to LF. Here, we describe cellular and antibody immune responses present in survivors of LF (N = 370) and their exposed contacts (N = 170) in a LASV endemic region in Nigeria. Interestingly, our data showed comparable T cell and binding antibody responses from both survivors and their contacts, while neutralizing antibody responses were primarily seen in the LF survivors and not their contacts. Neutralizing antibody responses were found to be cross-reactive against all five lineages of LASV with a strong bias to Lineage II, the prevalent strain in southern Nigeria. We demonstrated that both T cell and antibody responses were not detectable in peripheral blood after a decade in LF survivors. Notably LF survivors maintained high levels of detectable binding antibody response for six months while their contacts did not. Lastly, as potential vaccine targets, we identified the regions of the LASV Glycoprotein (GP) and Nucleoprotein (NP) that induced the broadest peptide-specific T cell responses. Taken together this data informs immunological readouts and potential benchmarks for clinical trials evaluating LASV vaccine candidates.

PMID:36567369 | DOI:10.1038/s41598-022-26045-w

Editorial: Pattern recognition receptors at the crosstalk between innate and adaptive immune systems and implications for vaccine development

Mon, 19/12/2022 - 11:00

Front Cell Infect Microbiol. 2022 Dec 2;12:1088029. doi: 10.3389/fcimb.2022.1088029. eCollection 2022.


PMID:36530438 | PMC:PMC9755836 | DOI:10.3389/fcimb.2022.1088029

Herminthology: promoting gender equity in science and parasitology

Fri, 16/12/2022 - 11:00

Trends Parasitol. 2022 Dec 14:S1471-4922(22)00286-0. doi: 10.1016/ Online ahead of print.


PMID:36526549 | DOI:10.1016/

<em>Mycobacterium avium</em> complex (MAC) genomics and transmission in a London hospital

Wed, 14/12/2022 - 11:00

Eur Respir J. 2022 Dec 14:2201237. doi: 10.1183/13993003.01237-2022. Online ahead of print.


PMID:36517182 | DOI:10.1183/13993003.01237-2022

Dynamics of extended-spectrum cephalosporin resistance genes in Escherichia coli from Europe and North America

Mon, 12/12/2022 - 11:00

Nat Commun. 2022 Dec 12;13(1):7490. doi: 10.1038/s41467-022-34970-7.


PMID:36509735 | DOI:10.1038/s41467-022-34970-7

How to survive pig farming: Mechanism of SCC<em>mec</em> element deletion and metabolic stress adaptation in livestock-associated MRSA

Mon, 12/12/2022 - 11:00

Front Microbiol. 2022 Nov 23;13:969961. doi: 10.3389/fmicb.2022.969961. eCollection 2022.


PMID:36504815 | PMC:PMC9728531 | DOI:10.3389/fmicb.2022.969961

The Progress Test of the European Hematology Association: A New Tool for Continuous Learning

Mon, 12/12/2022 - 11:00

Hemasphere. 2022 Nov 30;6(12):e815. doi: 10.1097/HS9.0000000000000815. eCollection 2022 Dec.


PMID:36504548 | PMC:PMC9719893 | DOI:10.1097/HS9.0000000000000815

Genomic Shift in Population Dynamics of mcr-1-positive Escherichia coli in Human Carriage

Thu, 08/12/2022 - 11:00

Genomics Proteomics Bioinformatics. 2022 Dec 5:S1672-0229(22)00147-4. doi: 10.1016/j.gpb.2022.11.006. Online ahead of print.


PMID:36481457 | DOI:10.1016/j.gpb.2022.11.006

FXR inhibition may protect from SARS-CoV-2 infection by reducing ACE2

Mon, 05/12/2022 - 11:00

Nature. 2022 Dec 5. doi: 10.1038/s41586-022-05594-0. Online ahead of print.


PMID:36470304 | DOI:10.1038/s41586-022-05594-0