Highlights • A novel mecA homologue, mecC , confers methicillin resistance to methicillin-resistant Staphylococcus aureus (MRSA). • mecC MRSA produce negative results with common diagnostic tools. • ...Reported from throughout Western Europe. Recent increase in Denmark. • Found in a range of host species and may pose a zoonotic risk to humans.
Vancomycin-resistant
(VREfm) is a major cause of nosocomial infection and is categorized as high priority by the World Health Organization global priority list of antibiotic-resistant bacteria. In ...the past, livestock have been proposed as a putative reservoir for drug-resistant
strains that infect humans, and isolates of the same lineage have been found in both reservoirs. We undertook cross-sectional surveys to isolate
(including VREfm) from livestock farms, retail meat, and wastewater treatment plants in the United Kingdom. More than 600 isolates from these sources were sequenced, and their relatedness and antibiotic resistance genes were compared with genomes of almost 800
isolates from patients with bloodstream infection in the United Kingdom and Ireland.
was isolated from 28/29 farms; none of these isolates were VREfm, suggesting a decrease in VREfm prevalence since the last UK livestock survey in 2003. However, VREfm was isolated from 1% to 2% of retail meat products and was ubiquitous in wastewater treatment plants. Phylogenetic comparison demonstrated that the majority of human and livestock-related isolates were genetically distinct, although pig isolates from three farms were more genetically related to human isolates from 2001 to 2004 (minimum of 50 single-nucleotide polymorphisms SNPs). Analysis of accessory (variable) genes added further evidence for distinct niche adaptation. An analysis of acquired antibiotic resistance genes and their variants revealed limited sharing between humans and livestock. Our findings indicate that the majority of
strains infecting patients are largely distinct from those from livestock in this setting, with limited sharing of strains and resistance genes.
The rise in rates of human infection caused by vancomycin-resistant
(VREfm) strains between 1988 to the 2000s in Europe was suggested to be associated with acquisition from livestock. As a result, the European Union banned the use of the glycopeptide drug avoparcin as a growth promoter in livestock feed. While some studies reported a decrease in VREfm in livestock, others reported no reduction. Here, we report the first livestock VREfm prevalence survey in the UK since 2003 and the first large-scale study using whole-genome sequencing to investigate the relationship between
strains in livestock and humans. We found a low prevalence of VREfm in retail meat and limited evidence for recent sharing of strains between livestock and humans with bloodstream infection. There was evidence for limited sharing of genes encoding antibiotic resistance between these reservoirs, a finding which requires further research.
Mobile genetic elements (MGEs) are agents of horizontal gene transfer in bacteria, but can also be vertically inherited by daughter cells. Establishing the dynamics that led to contemporary patterns ...of MGEs in bacterial genomes is central to predicting the emergence and evolution of novel and resistant pathogens. Methicillin-resistant Staphylococcus aureus (MRSA) clonal-complex (CC) 398 is the dominant MRSA in European livestock and a growing cause of human infections. Previous studies have identified three categories of MGEs whose presence or absence distinguishes livestock-associated CC398 from a closely related and less antibiotic-resistant human-associated population. Here, we fully characterise the evolutionary dynamics of these MGEs using a collection of 1180 CC398 genomes, sampled from livestock and humans, over 27 years. We find that the emergence of livestock-associated CC398 coincided with the acquisition of a Tn916 transposon carrying a tetracycline resistance gene, which has been stably inherited for 57 years. This was followed by the acquisition of a type V SCCmec that carries methicillin, tetracycline, and heavy metal resistance genes, which has been maintained for 35 years, with occasional truncations and replacements with type IV SCCmec. In contrast, a class of prophages that carry a human immune evasion gene cluster and that are largely absent from livestock-associated CC398 have been repeatedly gained and lost in both human- and livestock-associated CC398. These contrasting dynamics mean that when livestock-associated MRSA is transmitted to humans, adaptation to the human host outpaces loss of antibiotic resistance. In addition, the stable inheritance of resistance-associated MGEs suggests that the impact of ongoing reductions in antibiotic and zinc oxide use in European farms on livestock-associated MRSA will be slow to be realised.
Staphylococcus aureus is an important human bacterial pathogen that has a cosmopolitan host range, including livestock, companion and wild animal species. Genomic and epidemiological studies show ...that S. aureus has jumped between host species many times over its evolutionary history. These jumps have involved the dynamic gain and loss of host-specific adaptive genes, usually located on mobile genetic elements. The same functional elements are often consistently gained in jumps into a particular species. Further sampling of diverse animal species is likely to uncover an even broader host range and greater genetic diversity of S. aureus than is already known, and understanding S. aureus host specificity in these hosts will mitigate the risks of emergent human and livestock strains.
Based on its broad host range, S. aureus can be described as a generalist pathogen.On short evolutionary timescales, however, strains are host specialists.S. aureus is capable of rapid adaptation to a wide range of hosts, mainly through the acquisition of mobile genetic elements (MGEs).Host shifts are a dynamic and a regular feature of S. aureus evolution.A large diversity of animal strains of S. aureus remain uncharacterized.Inferring the host ecology of strains of S. aureus from their genomes will aid surveillance and diagnostics
Male C57BL/6J mice raised on high fat diet (HFD) become prediabetic and develop insulin resistance and sensory neuropathy. The same mice given low doses of streptozotocin are a model of type 2 ...diabetes (T2D), developing hyperglycemia, severe insulin resistance and diabetic peripheral neuropathy involving sensory and motor neurons. Because of suggestions that increased NAD(+) metabolism might address glycemic control and be neuroprotective, we treated prediabetic and T2D mice with nicotinamide riboside (NR) added to HFD. NR improved glucose tolerance, reduced weight gain, liver damage and the development of hepatic steatosis in prediabetic mice while protecting against sensory neuropathy. In T2D mice, NR greatly reduced non-fasting and fasting blood glucose, weight gain and hepatic steatosis while protecting against diabetic neuropathy. The neuroprotective effect of NR could not be explained by glycemic control alone. Corneal confocal microscopy was the most sensitive measure of neurodegeneration. This assay allowed detection of the protective effect of NR on small nerve structures in living mice. Quantitative metabolomics established that hepatic NADP(+) and NADPH levels were significantly degraded in prediabetes and T2D but were largely protected when mice were supplemented with NR. The data justify testing of NR in human models of obesity, T2D and associated neuropathies.
HIV-1 protease (PR), reverse transcriptase (RT), and integrase (IN) variability presents a challenge to laboratories performing genotypic resistance testing. This challenge will grow with increased ...sequencing of samples enriched for proviral DNA such as dried blood spots and increased use of next-generation sequencing (NGS) to detect low-abundance HIV-1 variants. We analyzed PR and RT sequences from >100,000 individuals and IN sequences from >10,000 individuals to characterize variation at each amino acid position, identify mutations indicating APOBEC-mediated G-to-A editing, and identify mutations resulting from selective drug pressure. Forty-seven percent of PR, 37% of RT, and 34% of IN positions had one or more amino acid variants with a prevalence of ≥1%. Seventy percent of PR, 60% of RT, and 60% of IN positions had one or more variants with a prevalence of ≥0.1%. Overall 201 PR, 636 RT, and 346 IN variants had a prevalence of ≥0.1%. The median intersubtype prevalence ratios were 2.9-, 2.1-, and 1.9-fold for these PR, RT, and IN variants, respectively. Only 5.0% of PR, 3.7% of RT, and 2.0% of IN variants had a median intersubtype prevalence ratio of ≥10-fold. Variants at lower prevalences were more likely to differ biochemically and to be part of an electrophoretic mixture compared to high-prevalence variants. There were 209 mutations indicative of APOBEC-mediated G-to-A editing and 326 mutations nonpolymorphic treatment selected. Identification of viruses with a high number of APOBEC-associated mutations will facilitate the quality control of dried blood spot sequencing. Identifying sequences with a high proportion of rare mutations will facilitate the quality control of NGS.
Most antiretroviral drugs target three HIV-1 proteins: PR, RT, and IN. These proteins are highly variable: many different amino acids can be present at the same position in viruses from different individuals. Some of the amino acid variants cause drug resistance and occur mainly in individuals receiving antiretroviral drugs. Some variants result from a human cellular defense mechanism called APOBEC-mediated hypermutation. Many variants result from naturally occurring mutation. Some variants may represent technical artifacts. We studied PR and RT sequences from >100,000 individuals and IN sequences from >10,000 individuals to quantify variation at each amino acid position in these three HIV-1 proteins. We performed analyses to determine which amino acid variants resulted from antiretroviral drug selection pressure, APOBEC-mediated editing, and naturally occurring variation. Our results provide information essential to clinical, research, and public health laboratories performing genotypic resistance testing by sequencing HIV-1 PR, RT, and IN.
Pork accounts for the largest proportion of meat consumed globally and demand is growing rapidly. Two important externalities of pig farming are land use and antimicrobial resistance (AMR) driven by ...antimicrobial use (AMU). Land use and AMU are commonly perceived to be negatively related across different production systems, so those with smaller land footprints pose greater risk to human health. However, the relationship between land use and AMU has never been systematically evaluated. We addressed this by measuring both outcomes for 74 highly diverse pig production systems. We found weak evidence of an AMU/land use tradeoff. We also found several systems characterized by low externality costs in both domains. These potentially promising systems were spread across different label and husbandry types and indeed no type was a reliable indicator of low-cost systems in both externalities. Our findings highlight the importance of using empirical evidence in decision-making, rather than relying on assumptions.
Chromothripsis is a catastrophic cellular event recently described in cancer in which chromosomes undergo massive deletion and rearrangement. Here, we report a case in which chromothripsis ...spontaneously cured a patient with WHIM syndrome, an autosomal dominant combined immunodeficiency disease caused by gain-of-function mutation of the chemokine receptor CXCR4. In this patient, deletion of the disease allele, CXCR4R334X, as well as 163 other genes from one copy of chromosome 2 occurred in a hematopoietic stem cell (HSC) that repopulated the myeloid but not the lymphoid lineage. In competitive mouse bone marrow (BM) transplantation experiments, Cxcr4 haploinsufficiency was sufficient to confer a strong long-term engraftment advantage of donor BM over BM from either wild-type or WHIM syndrome model mice, suggesting a potential mechanism for the patient’s cure. Our findings suggest that partial inactivation of CXCR4 may have general utility as a strategy to promote HSC engraftment in transplantation.
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•CXCR4 haploinsufficiency may promote HSC engraftment•Chromothriptic deletions result in functional cure of WHIM syndrome•Clinical symptoms in WHIM syndrome are dependent on myeloid deficits•Myeloid-derived cells are critical for control of HPV infection
WHIM syndrome is an inherited immunodeficiency caused by overactivity of CXCR4, a receptor controlling production and distribution of leukocytes in bone marrow and blood. We identified a WHIM patient cured by chromothripsis (chromosome shattering) that fortuitously deleted the abnormal copy of the CXCR4 gene in a single hematopoietic stem cell, which then took over the bone marrow and restored normal immune function. This experiment of nature suggests that partial CXCR4 inactivation might enhance engraftment of bone marrow in patients requiring transplantation.
The discovery of antibiotics more than 80 years ago has led to considerable improvements in human and animal health. Although antibiotic resistance in environmental bacteria is ancient, resistance in ...human pathogens is thought to be a modern phenomenon that is driven by the clinical use of antibiotics
. Here we show that particular lineages of methicillin-resistant Staphylococcus aureus-a notorious human pathogen-appeared in European hedgehogs in the pre-antibiotic era. Subsequently, these lineages spread within the local hedgehog populations and between hedgehogs and secondary hosts, including livestock and humans. We also demonstrate that the hedgehog dermatophyte Trichophyton erinacei produces two β-lactam antibiotics that provide a natural selective environment in which methicillin-resistant S. aureus isolates have an advantage over susceptible isolates. Together, these results suggest that methicillin resistance emerged in the pre-antibiotic era as a co-evolutionary adaptation of S. aureus to the colonization of dermatophyte-infected hedgehogs. The evolution of clinically relevant antibiotic-resistance genes in wild animals and the connectivity of natural, agricultural and human ecosystems demonstrate that the use of a One Health approach is critical for our understanding and management of antibiotic resistance, which is one of the biggest threats to global health, food security and development.
The redistribution of species has emerged as one of the most pervasive impacts of anthropogenic climate warming, and presents many societal challenges. Understanding how temperature regulates species ...distributions is particularly important for mobile marine fauna such as sharks given their seemingly rapid responses to warming, and the socio‐political implications of human encounters with some dangerous species. The predictability of species distributions can potentially be improved by accounting for temperature's influence on performance, an elusive relationship for most large animals. We combined multi‐decadal catch data and bio‐logging to show that coastal abundance and swimming performance of tiger sharks Galeocerdo cuvier are both highest at ~22°C, suggesting thermal constraints on performance may regulate this species' distribution. Tiger sharks are responsible for a large proportion of shark bites on humans, and a focus of controversial control measures in several countries. The combination of distribution and performance data moves towards a mechanistic understanding of tiger shark's thermal niche, and delivers a simple yet powerful indicator for predicting the location and timing of their occurrences throughout coastlines. For example, tiger sharks are mostly caught at Australia's popular New South Wales beaches (i.e. near Sydney) in the warmest months, but our data suggest similar abundances will occur in winter and summer if annual sea surface temperatures increase by a further 1–2°C.
Being able to predict how temperature regulates species distributions is particularly important for mobile marine animals such as sharks given their seemingly rapid responses to warming, and implications of human encounters with some dangerous species. We combined catch data and accelerometry tagging to show that coastal abundance and swimming activity of tiger sharks Galeocerdo cuvier are both highest at ~22°C. Our combination of distribution and performance data takes a step towards a mechanistic understanding of tiger shark's thermal niche, and delivers a simple indicator that may be useful for predicting coastal occurrences of this potentially dangerous species.
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