Ancient diversity in host-parasite interaction genes in a model parasitic nematode.

Host-parasite interactions exert strong selection pressures on the genomes of both host and parasite. These interactions can lead to negative frequency-dependent selection, a form of balancing selection that is hypothesised to explain the high levels of polymorphism seen in many host immune and parasite antigen loci. Here, we sequence the genomes of several individuals of Heligmosomoides bakeri, a model parasite of house mice, and Heligmosomoides polygyrus, a closely related parasite of wood mice. Although H. bakeri is commonly referred to as H. polygyrus in the literature, their genomes show levels of divergence that are consistent with at least a million years of independent evolution. The genomes of both species contain hyper-divergent haplotypes that are enriched for proteins that interact with the host immune response. Many of these haplotypes originated prior to the divergence between H. bakeri and H. polygyrus, suggesting that they have been maintained by long-term balancing selection. Together, our results suggest that the selection pressures exerted by the host immune response have played a key role in shaping patterns of genetic diversity in the genomes of parasitic nematodes.

Widespread sharing of pneumococcal strains in a rural African setting: proximate villages are more likely to share similar strains that are carried at multiple timepoints.

The transmission dynamics of Streptococcus pneumoniae in sub-Saharan Africa are poorly understood due to a lack of adequate epidemiological and genomic data. Here we leverage a longitudinal cohort from 21 neighbouring villages in rural Africa to study how closely related strains of S. pneumoniae are shared among infants. We analysed 1074 pneumococcal genomes isolated from 102 infants from 21 villages. Strains were designated for unique serotype and sequence-type combinations, and we arbitrarily defined strain sharing where the pairwise genetic distance between strains could be accounted for by the mean within host intra-strain diversity. We used non-parametric statistical tests to assess the role of spatial distance and prolonged carriage on strain sharing using a logistic regression model. We recorded 458 carriage episodes including 318 (69.4 %) where the carried strain was shared with at least one other infant. The odds of strain sharing varied significantly across villages (χ2=47.5, df=21, P-value <0.001). Infants in close proximity to each other were more likely to be involved in strain sharing, but we also show a considerable amount of strain sharing across longer distances. Close geographic proximity (<5 km) between shared strains was associated with a significantly lower pairwise SNP distance compared to strains shared over longer distances (P-value <0.005). Sustained carriage of a shared strain among the infants was significantly more likely to occur if they resided in villages within a 5 km radius of each other (P-value <0.005, OR 3.7). Conversely, where both infants were transiently colonized by the shared strain, they were more likely to reside in villages separated by over 15 km (P-value <0.05, OR 1.5). PCV7 serotypes were rare (13.5 %) and were significantly less likely to be shared (P-value <0.001, OR -1.07). Strain sharing was more likely to occur over short geographical distances, especially where accompanied by sustained colonization. Our results show that strain sharing is a useful proxy for studying transmission dynamics in an under-sampled population with limited genomic data. This article contains data hosted by Microreact.

Interactions between fecal gut microbiome, enteric pathogens, and energy regulating hormones among acutely malnourished rural Gambian children.

BACKGROUND: The specific roles that gut microbiota, known pathogens, and host energy-regulating hormones play in the pathogenesis of non-edematous severe acute malnutrition (marasmus SAM) and moderate acute malnutrition (MAM) during outpatient nutritional rehabilitation are yet to be explored. METHODS: We applied an ensemble of sample-specific (intra- and inter-modality) association networks to gain deeper insights into the pathogenesis of acute malnutrition and its severity among children under 5 years of age in rural Gambia, where marasmus SAM is most prevalent. FINDINGS: Children with marasmus SAM have distinct microbiome characteristics and biologically-relevant multimodal biomarkers not observed among children with moderate acute malnutrition. Marasmus SAM was characterized by lower microbial richness and biomass, significant enrichments in Enterobacteriaceae, altered interactions between specific Enterobacteriaceae and key energy regulating hormones and their receptors. INTERPRETATION: Our findings suggest that marasmus SAM is characterized by the collapse of a complex system with nested interactions and key associations between the gut microbiome, enteric pathogens, and energy regulating hormones.  Further exploration of these systems will help inform innovative preventive and therapeutic interventions. FUNDING: The work was supported by the UK Medical Research Council (MRC; MC-A760-5QX00) and the UK Department for International Development (DFID) under the MRC/DFID Concordat agreement; Bill and Melinda Gates Foundation (OPP 1066932) and the National Institute of Medical Research (NIMR), UK. This network analysis was supported by NIH U54GH009824 [CLD] and NSF OCE-1558453 [CLD].

Within-host microevolution of Streptococcus pneumoniae is rapid and adaptive during natural colonisation.

Genomic evolution, transmission and pathogenesis of Streptococcus pneumoniae, an opportunistic human-adapted pathogen, is driven principally by nasopharyngeal carriage. However, little is known about genomic changes during natural colonisation. Here, we use whole-genome sequencing to investigate within-host microevolution of naturally carried pneumococci in ninety-eight infants intensively sampled sequentially from birth until twelve months in a high-carriage African setting. We show that neutral evolution and nucleotide substitution rates up to forty-fold faster than observed over longer timescales in S. pneumoniae and other bacteria drives high within-host pneumococcal genetic diversity. Highly divergent co-existing strain variants emerge during colonisation episodes through real-time intra-host homologous recombination while the rest are co-transmitted or acquired independently during multiple colonisation episodes. Genic and intergenic parallel evolution occur particularly in antibiotic resistance, immune evasion and epithelial adhesion genes. Our findings suggest that within-host microevolution is rapid and adaptive during natural colonisation.

Carriage Dynamics of Pneumococcal Serotypes in Naturally Colonized Infants in a Rural African Setting During the First Year of Life.

Streptococcus pneumoniae (the pneumococcus) carriage precedes invasive disease and influences population-wide strain dynamics, but limited data exist on temporal carriage patterns of serotypes due to the prohibitive costs of longitudinal studies. Here, we report carriage prevalence, clearance and acquisition rates of pneumococcal serotypes sampled from newborn infants bi-weekly from weeks 1 to 27, and then bi-monthly from weeks 35 to 52 in the Gambia. We used sweep latex agglutination and whole genome sequencing to serotype the isolates. We show rapid pneumococcal acquisition with nearly 31% of the infants colonized by the end of first week after birth and quickly exceeding 95% after 2 months. Co-colonization with multiple serotypes was consistently observed in over 40% of the infants at each sampling point during the first year of life. Overall, the mean acquisition time and carriage duration regardless of serotype was 38 and 24 days, respectively, but varied considerably between serotypes comparable to observations from other regions. Our data will inform disease prevention and control measures including providing baseline data for parameterising infectious disease mathematical models including those assessing the impact of clinical interventions such as pneumococcal conjugate vaccines.

Etiology of Pediatric Bacterial Meningitis Pre- and Post-PCV13 Introduction Among Children Under 5 Years Old in Lomé, Togo.

BACKGROUND: Pediatric bacterial meningitis (PBM) causes severe morbidity and mortality within Togo. Thus, as a member of the World Health Organization coordinated Invasive Bacterial Vaccine Preventable Diseases network, Togo conducts surveillance targeting Streptococcus pneumoniae (pneumococcus), Neisseria meningitidis (meningococcus), and Haemophilus influenzae, at a sentinel hospital within the capital city, Lomé, in the southernmost Maritime region. METHODS: Cerebrospinal fluid was collected from children <5 years with suspected PBM admitted to the Sylvanus Olympio Teaching Hospital. Phenotypic detection of pneumococcus, meningococcus, and H. influenzae was confirmed through microbiological techniques. Samples were shipped to the Regional Reference Laboratory to corroborate results by species-specific polymerase chain reaction. RESULTS: Overall, 3644 suspected PBM cases were reported, and 98 cases (2.7%: 98/3644) were confirmed bacterial meningitis. Pneumococcus was responsible for most infections (67.3%: 66/98), followed by H. influenzae (23.5%: 23/98) and meningococcus (9.2%: 9/98). The number of pneumococcal meningitis cases decreased by 88.1% (52/59) postvaccine introduction with 59 cases from July 2010 to June 2014 and 7 cases from July 2014 to June 2016. However, 5 cases caused by nonvaccine serotypes were observed. Fewer PBM cases caused by vaccine serotypes were observed in infants <1 year compared to children 2-5 years. CONCLUSIONS: Routine surveillance showed that PCV13 vaccination is effective in preventing pneumococcal meningitis among children <5 years of age in the Maritime region. This complements the MenAfriVac vaccination against meningococcal serogroup A to prevent meningitis outbreaks in the northern region of Togo. Continued surveillance is vital for estimating the prevalence of PBM, determining vaccine impact, and anticipating epidemics in Togo.

Etiology of Bacterial Meningitis Among Children <5 Years Old in Côte d'Ivoire: Findings of Hospital-based Surveillance Before and After Pneumococcal Conjugate Vaccine Introduction.

BACKGROUND: Bacterial meningitis remains a major disease affecting children in Côte d'Ivoire. Thus, with support from the World Health Organization (WHO), Côte d'Ivoire has implemented pediatric bacterial meningitis (PBM) surveillance at 2 sentinel hospitals in Abidjan, targeting the main causes of PBM: Streptococcus pneumoniae (pneumococcus), Haemophilus influenzae, and Neisseria meningitidis (meningococcus). Herein we describe the epidemiological characteristics of PBM observed in Côte d'Ivoire during 2010-2016. METHODS: Cerebrospinal fluid (CSF) was collected from children aged <5 years admitted to the Abobo General Hospital or University Hospital Center Yopougon with suspected meningitis. Microbiology and polymerase chain reaction (PCR) techniques were used to detect the presence of pathogens in CSF. Where possible, serotyping/grouping was performed to determine the specific causative agents. RESULTS: Overall, 2762 cases of suspected meningitis were reported, with CSF from 39.2% (1083/2762) of patients analyzed at the WHO regional reference laboratory in The Gambia. In total, 82 (3.0% [82/2762]) CSF samples were positive for bacterial meningitis. Pneumococcus was the main pathogen responsible for PBM, accounting for 69.5% (52/82) of positive cases. Pneumococcal conjugate vaccine serotypes 5, 18C, 19F, and 6A/B were identified post-vaccine introduction. Emergence of H. influenzae nontypeable meningitis was observed after H. influenzae type b vaccine introduction. CONCLUSIONS: Despite widespread use and high coverage of conjugate vaccines, pneumococcal vaccine serotypes and H. influenzae type b remain associated with bacterial meningitis among children aged <5 years in Côte d'Ivoire. This reinforces the need for enhanced surveillance for vaccine-preventable diseases to determine the prevalence of bacterial meningitis and vaccine impact across the country.

Pediatric Bacterial Meningitis Surveillance in Nigeria From 2010 to 2016, Prior to and During the Phased Introduction of the 10-Valent Pneumococcal Conjugate Vaccine.

BACKGROUND: Historically, Nigeria has experienced large bacterial meningitis outbreaks with high mortality in children. Streptococcus pneumoniae (pneumococcus), Neisseria meningitidis (meningococcus), and Haemophilus influenzae are major causes of this invasive disease. In collaboration with the World Health Organization, we conducted longitudinal surveillance in sentinel hospitals within Nigeria to establish the burden of pediatric bacterial meningitis (PBM). METHODS: From 2010 to 2016, cerebrospinal fluid was collected from children <5 years of age, admitted to 5 sentinel hospitals in 5 Nigerian states. Microbiological and latex agglutination techniques were performed to detect the presence of pneumococcus, meningococcus, and H. influenzae. Species-specific polymerase chain reaction and serotyping/grouping were conducted to determine specific causative agents of PBM. RESULTS: A total of 5134 children with suspected meningitis were enrolled at the participating hospitals; of these 153 (2.9%) were confirmed PBM cases. The mortality rate for those infected was 15.0% (23/153). The dominant pathogen was pneumococcus (46.4%: 71/153) followed by meningococcus (34.6%: 53/153) and H. influenzae (19.0%: 29/153). Nearly half the pneumococcal meningitis cases successfully serotyped (46.4%: 13/28) were caused by serotypes that are included in the 10-valent pneumococcal conjugate vaccine. The most prevalent meningococcal and H. influenzae strains were serogroup W and serotype b, respectively. CONCLUSIONS: Vaccine-type bacterial meningitis continues to be common among children <5 years in Nigeria. Challenges with vaccine introduction and coverage may explain some of these finding. Continued surveillance is needed to determine the distribution of serotypes/groups of meningeal pathogens across Nigeria and help inform and sustain vaccination policies in the country.