Staphylococci are the most common cause of orthopaedic device-related infections (ODRIs), with Staphylococcus aureus responsible for a third or more of cases. This prospective clinical and laboratory study investigated the association of genomic and phenotypic variation with treatment outcomes in ODRI isolates. Eighty-six invasive S. aureus isolates were collected from patients with ODRI, and clinical outcome was assessed after a follow-up examination of 24 months. Each patient was then considered to have been "cured" or "not cured" based on predefined clinical criteria. Whole genome sequencing and molecular characterisation identified isolates belonging to globally circulating community- and hospital-acquired lineages. Most isolates were phenotypically susceptible to methicillin and lacked the SCCmec cassette (MSSA; 94%), but contained several virulence genes, including toxins and biofilm genes. While recognising the role of the host immune response, we identified genetic variance which could be associated with the infection severity or clinical outcome. While this and several other studies reinforce the role antibiotic resistance (e.g., MRSA infection) has on treatment failure, it is important not to overlook MSSA that can cause equally destructive infections and lead to poor patient outcomes.

Recombination of short DNA fragments via horizontal gene transfer (HGT) can introduce beneficial alleles, create genomic disharmony through negative epistasis, and create adaptive gene combinations through positive epistasis. For non-core (accessory) genes, the negative epistatic cost is likely to be minimal because the incoming genes have not co-evolved with the recipient genome and are frequently observed as tightly linked cassettes with major effects. By contrast, interspecific recombination in the core genome is expected to be rare because disruptive allelic replacement is likely to introduce negative epistasis. Why then is homologous recombination common in the core of bacterial genomes? To understand this enigma, we take advantage of an exceptional model system, the common enteric pathogens Campylobacter jejuni and C. coli, that are known for very high magnitude interspecies gene flow in the core genome. As expected, HGT does indeed disrupt co-adapted allele pairings, indirect evidence of negative epistasis. However, multiple HGT events enable recovery of the genome’s co-adaption between introgressing alleles, even in core metabolism genes (e.g., formate dehydrogenase). These findings demonstrate that, even for complex traits, genetic coalitions can be decoupled, transferred, and independently reinstated in a new genetic background – —facilitating transition between fitness peaks. In this example, the two-step recombinational process is associated with C. coli that are adapted to the agricultural niche.

Background Combined pathogen genomic surveillance with advanced bioinformatics analyses has the potential to inform public health risk and targeted interventions. In this study, we analyse the two most common pathogenic Campylobacter species in human gastrointestinal infection. These enteric bacteria are ubiquitous in the gut of birds and mammals, which can commonly infect humans via consumption of contaminated food. Rising incidence and antimicrobial resistance (AMR) are a major global concern and there is an urgent need to quantify the main routes to human infection. We test the utility of machine learning methods for probabilistic assignment of genome sequenced campylobacteriosis isolates to possible sources in the United States between 2009 and 2019.Methods As part of routine US national surveillance (2009 through 2019), 8,856 Campylobacter isolate genomes were sequenced from human infections and 16,703 from possible sources. Targeting genetic variation associated with host adaptation, we used machine learning and probabilistic models to attribute the source of human infections and estimate the relative importance of different disease reservoirs.Findings Probabilistic attribution identified poultry as the primary infection source of human clinical isolates, responsible for an estimated 68% of cases. Most of the remaining clinical isolates were attributed to cattle (28%), with only a small contribution from wild bird (3%) and pork sources (1%). An increase in fluoroquinolone and aminoglycoside resistant isolates underpinned increased multidrug resistance in human infection cases, that could be attributed to chicken sources.Interpretation National-scale surveillance and quantification of the relative contribution of infection sources can guide policy. Our study suggests that the greatest reductions in human campylobacteriosis in the US will come from interventions that focus on poultry, which may also reduce the spread of AMR.

Recombination of short DNA fragments via horizontal gene transfer (HGT) can introduce beneficial alleles, create genomic disharmony through negative epistasis, and create adaptive gene combinations through positive epistasis. For non-core (accessory) genes, the negative epistatic cost is likely to be minimal because the incoming genes have not co-evolved with the recipient genome and are frequently observed as tightly linked cassettes with major effects. By contrast, interspecific recombination in the core genome is expected to be rare because disruptive allelic replacement is likely to introduce negative epistasis. Why then is homologous recombination common in the core of bacterial genomes? To understand this enigma, we take advantage of an exceptional model system, the common enteric pathogens Campylobacter jejuni and C. coli, that are known for very high magnitude interspecies gene flow in the core genome. As expected, HGT does indeed disrupt co-adapted allele pairings, indirect evidence of negative epistasis. However, multiple HGT events enable recovery of the genome’s co-adaption between introgressing alleles, even in core metabolism genes (e.g., formate dehydrogenase). These findings demonstrate that, even for complex traits, genetic coalitions can be decoupled, transferred, and independently reinstated in a new genetic background – —facilitating transition between fitness peaks. In this example, the two-step recombinational process is associated with C. coli that are adapted to the agricultural niche.

Background Combined pathogen genomic surveillance with advanced bioinformatics analyses has the potential to inform public health risk and targeted interventions. In this study, we analyse the two most common pathogenic Campylobacter species in human gastrointestinal infection. These enteric bacteria are ubiquitous in the gut of birds and mammals, which can commonly infect humans via consumption of contaminated food. Rising incidence and antimicrobial resistance (AMR) are a major global concern and there is an urgent need to quantify the main routes to human infection. We test the utility of machine learning methods for probabilistic assignment of genome sequenced campylobacteriosis isolates to possible sources in the United States between 2009 and 2019.Methods As part of routine US national surveillance (2009 through 2019), 8,856 Campylobacter isolate genomes were sequenced from human infections and 16,703 from possible sources. Targeting genetic variation associated with host adaptation, we used machine learning and probabilistic models to attribute the source of human infections and estimate the relative importance of different disease reservoirs.Findings Probabilistic attribution identified poultry as the primary infection source of human clinical isolates, responsible for an estimated 68% of cases. Most of the remaining clinical isolates were attributed to cattle (28%), with only a small contribution from wild bird (3%) and pork sources (1%). An increase in fluoroquinolone and aminoglycoside resistant isolates underpinned increased multidrug resistance in human infection cases, that could be attributed to chicken sources.Interpretation National-scale surveillance and quantification of the relative contribution of infection sources can guide policy. Our study suggests that the greatest reductions in human campylobacteriosis in the US will come from interventions that focus on poultry, which may also reduce the spread of AMR.

Staphylococci are the most common cause of orthopaedic device-related infections (ODRIs), with Staphylococcus aureus responsible for a third or more of cases. This prospective clinical and laboratory study investigated the association of genomic and phenotypic variation with treatment outcomes in ODRI isolates. Eighty-six invasive S. aureus isolates were collected from patients with ODRI, and clinical outcome was assessed after a follow-up examination of 24 months. Each patient was then considered to have been "cured" or "not cured" based on predefined clinical criteria. Whole genome sequencing and molecular characterisation identified isolates belonging to globally circulating community- and hospital-acquired lineages. Most isolates were phenotypically susceptible to methicillin and lacked the SCCmec cassette (MSSA; 94%), but contained several virulence genes, including toxins and biofilm genes. While recognising the role of the host immune response, we identified genetic variance which could be associated with the infection severity or clinical outcome. While this and several other studies reinforce the role antibiotic resistance (e.g., MRSA infection) has on treatment failure, it is important not to overlook MSSA that can cause equally destructive infections and lead to poor patient outcomes.

Campylobacter is a leading cause of food-borne gastroenteritis worldwide, linked to the consumption of contaminated poultry meat. Targeting this pathogen at source, chicken vaccines can give short term reductions in Campylobacter in chicken guts. However, this has not reduced Campylobacter in the food chain or human infection. This is because vaccines typically target only a subset of strains and rapid evolution diminishes efficacy over time. To address this, we developed an autogenous vaccine against strains harbouring genes linked to survival outside of the host, whilst remaining selectively neutral against other strains in the chicken gut. This altered the chicken microbiome in favour of strains that were less likely to persist through poultry production to infect humans. Monitoring flocks revealed a near-complete shift in the post-vaccination Campylobacter population with a ~50% reduction in strains harbouring extra-gut survival genes. Based on these findings, a logistic regression model predicted vaccine efficacy could target a large proportion of clinically relevant strains. Reshaping livestock microbiomes towards less harmful commensal pathogen strains, has major potential for reducing pathogens in the food production chain.

Campylobacter is a leading cause of food-borne gastroenteritis worldwide, linked to the consumption of contaminated poultry meat. Targeting this pathogen at source, chicken vaccines can give short term reductions in Campylobacter in chicken guts. However, this has not reduced Campylobacter in the food chain or human infection. This is because vaccines typically target only a subset of strains and rapid evolution diminishes efficacy over time. To address this, we developed an autogenous vaccine against strains harbouring genes linked to survival outside of the host, whilst remaining selectively neutral against other strains in the chicken gut. This altered the chicken microbiome in favour of strains that were less likely to persist through poultry production to infect humans. Monitoring flocks revealed a near-complete shift in the post-vaccination Campylobacter population with a ~50% reduction in strains harbouring extra-gut survival genes. Based on these findings, a logistic regression model predicted vaccine efficacy could target a large proportion of clinically relevant strains. Reshaping livestock microbiomes towards less harmful commensal pathogen strains, has major potential for reducing pathogens in the food production chain.

Background Combined pathogen genomic surveillance with advanced bioinformatics analyses has the potential to inform public health risk and targeted interventions. In this study, we analyse the two most common pathogenic Campylobacter species in human gastrointestinal infection. These enteric bacteria are ubiquitous in the gut of birds and mammals, which can commonly infect humans via consumption of contaminated food. Rising incidence and antimicrobial resistance (AMR) are a major global concern and there is an urgent need to quantify the main routes to human infection. We test the utility of machine learning methods for probabilistic assignment of genome sequenced campylobacteriosis isolates to possible sources in the United States between 2009 and 2019.Methods As part of routine US national surveillance (2009 through 2019), 8,856 Campylobacter isolate genomes were sequenced from human infections and 16,703 from possible sources. Targeting genetic variation associated with host adaptation, we used machine learning and probabilistic models to attribute the source of human infections and estimate the relative importance of different disease reservoirs.Findings Probabilistic attribution identified poultry as the primary infection source of human clinical isolates, responsible for an estimated 68% of cases. Most of the remaining clinical isolates were attributed to cattle (28%), with only a small contribution from wild bird (3%) and pork sources (1%). An increase in fluoroquinolone and aminoglycoside resistant isolates underpinned increased multidrug resistance in human infection cases, that could be attributed to chicken sources.Interpretation National-scale surveillance and quantification of the relative contribution of infection sources can guide policy. Our study suggests that the greatest reductions in human campylobacteriosis in the US will come from interventions that focus on poultry, which may also reduce the spread of AMR.

Listeria monocytogenes is a dangerous bacterium found in food that can cause severe illness and even death in humans. It has different types, some of which are more likely to infect people. Biofilms, crucial for survival and infection, hold the key to understanding transmission. To unravel the genetic basis of biofilm formation, we undertook a study employing genome-wide association studies and gene transcription profiling. We identified 273 genes associated with robust biofilm formation through GWAS and discovered differential expression in 220 genes through RNAseq. Statistical analysis revealed fewer overlapping genes than expected by chance, supporting an evolutionary scenario where initial adaptation relies on gene expression variation, followed by slower adaptation through genetic changes within the core genome.