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Title: Genome-wide identification of lineage and locus specific variation associated with pneumococcal carriage duration}
Article:
Abstract:
Streptococcus pneumoniae is a leading cause of invasive disease in infants, especially in low-income settings. Asymptomatic carriage in the nasopharynx is a prerequisite for disease, but variability in its duration is currently only understood at the serotype level. Here we developed a model to calculate the duration of carriage episodes from longitudinal swab data, and combined these results with whole genome sequence data. We estimated that pneumococcal genomic variation accounted for 63% of the phenotype variation, whereas the host traits considered here( age and previous carriage) accounted for less than 5%. We further partitioned this heritability into both lineage and locus effects, and quantified the amount attributable to the largest sources of variation in carriage duration: serotype( 17%), drug-resistance( 9%) and other significant locus effects( 7%). A pan-genome-wide association study identified prophage sequences as being associated with decreased carriage duration independent of serotype, potentially by disruption of the competence mechanism. These findings support theoretical models of pneumococcal competition and antibiotic resistance.
Introduction:
Streptococcus pneumoniae is a human pathogen that can cause diseases such as pneumonia, otitis media and meningitis. Pneumococcal disease burden is highest in children( O'Brien et al., 2009). For disease to be caused pneumococci must first transmit to the host, colonise the nasopharynx and finally cross into a normally sterile site. The pneumococcus spends most of the transmission cycle in the nasopharynx, and so understanding and predicting the amount of time spent in this niche is critical for understanding this bacterium's epidemiology, and therefore controlling transmission( Abdullahi et al., 2012a; Melegaro et al., 2007). The nasopharynx is a complex niche in which each pneumococcal genotype must tackle a wide range of factors including host immune defence( McCool et al., 2002), other bacterial species( Pericone et al., 2000), and other pneumococcal lineages( Auranen et al., 2010; Cobey and Lipsitch, 2012) in order to maintain the genotype's population. The average nasopharyngeal duration period is therefore affected by a large number of factors, which may, themselves, interact. One factor that is known to strongly associate with carriage duration is serotype: as capsular polysaccharides are important in bacterial physiology and determining host immune response, different serotypes have different clearance and acquisition rates( Abdullahi et al., 2012a; Hill et al., 2010; Högberg et al., 2007; Melegaro et al., 2004; Turner et al., 2012). Additionally, a range of other proteins have been identified as critical to the colonisation process( Kadioglu et al., 2008), some of which exhibit similar levels of diversity to the capsule polysaccharide synthesis locus( Iannelli et al., 2002; Jedrzejas et al., 2001). However, the overall and relative contributions of these sequence variations to carriage rate have not yet been characterised. In addition variation of pathogen protein sequence, accessory genes and interaction effects between genetic elements may also have as yet unknown effects on carriage duration. Changes in average carriage duration have been shown to be linked with recombination rate( Chaguza et al., 2016), which has been found to correlate with antibiotic resistance( Hanage et al., 2009) and invasive potential( Chaguza et al., 2016). The carriage duration by different serotypes is widely used in models of pneumococcal epidemiology, and consequently is important in evaluating the efficacy of the pneumococcal conjugate vaccine( PCV)( Melegaro et al., 2007; Weinberger et al., 2011). Additionally, modelling work has proposed that if alleles exist which alter carriage duration, these explain the long standing puzzle of how antibiotic-resistant and sensitive strains stably coexist in the population( Lehtinen et al., 2017). Measurement of carriage duration and the analysis of its variance beyond the resolution of serotype will have important consequences for these models. We sought to determine the overall importance of the pathogen genotype in carriage duration in a human population, and to identify and quantify the elements of the genome responsible for the variation in carriage duration. By combining epidemiological modelling of longitudinal swab data with and genome wide association study methods on the connected sequences( Figure 1), we made heritability estimates for carriage duration. We further partitioned the heritability into contributions from lineage and locus effects( Earle et al., 2016) to quantify the variation caused by each individual factor.
Discussion:
Other than serotype, the genetic determinants of pneumococcal carriage duration were previously unknown. By developing models for longitudinal swab data and combining the results with whole genome sequence data we have quantified and mapped the genetic contribution to the carriage duration of S. pneumoniae. We found that despite a range of other factors such as host age which are known to cause carriage duration to differ, sequence variation of the pneumococcal genome explains most of this variability( 63%). Common serotypes and resistance to erythromycin cause some of this effect( 19% total), as does the presence or absence of particular prophage sequence in the genome. Table 5 summarise the sources we found to be significantly associated with variation in carriage duration. We provide a quantitative estimate of how closely transmission pairs share their carriage duration, and show evidence for differences both between and within serotypes. The implication of phage as having a significant effect on carriage duration has interesting corollaries on pneumococcal genome diversification through frequent infection and loss of prophage, even during carriage episodes in this dataset. Investigating a mechanism for the prophage association, we found that having an intact comYC gene, which is frequently interrupted by prophage causing loss of function of the competence system, was associated with increased carriage duration. While the competence system is observed to remain intact over the evolutionary history of the species, these disruptive mutations spread irreversibly through the population as competent bacteria can acquire the mutation, and non-competent bacteria can no longer reverse it through recombination( Croucher et al., 2014b). Selection must therefore maintain the function at this locus over short timescales, and an increased carriage duration may be evidence of this. We therefore hypothesise that the associated prophage sequences may affect carriage duration through disruption of the competence system, without which deleterious mutations will accumulate in the population due to Muller's ratchet. The results presented here have important implications for the modelling of pneumococcal transmission and their response to perturbation of the population by vaccine. Importantly, our analysis of heritability shows that variants other than serotype affect carriage duration, consistent with recent theoretical work( Lehtinen et al., 2017). Here we have shown that these alleles do exist in a natural population, and also identified candidates for the loci which fulfil this role. Together these studies suggest that variants exist in the pneumococcal genome which alter carriage duration, which in turn is linked to antibiotic resistance. We were not able to fully explain the basis for heritability of carriage duration for a number of reasons. The close association of the phenotype with lineage limited our power to fine-map lineage associated variants other than capsule type which may affect carriage duration. Meta-analysis with more large studies with higher resolution may help to resolve these issues: we are conducting a similar study in Cape Town, South Africa which will combine sequence data with two-weekly swabs and will be compared to these results in future. Additional environmental factors that explain some of the remainder of the variance may include the variation of the host immune response and interaction with other infections or co-colonisation. In particular, co-infection with influenza A was not recorded but is known to affect population dynamics within the nasopharynx( Kono et al., 2016). This is a phenotype which would have been difficult to assay by traditional methods such as in an animal model due to the cohort size needed and the length of time experiments would need to be run for. By instead using genome-wide association study methods we have been able to quantitatively investigate a complex phenotype in a natural population. We believe that the analysis of heritability and variance explained in a phenotype of interest, as presented here, will be an important part analysis of complex bacterial traits in future studies.
Microorganisms live in most parts of our body , including the inside of our nose . Most of the microbes are harmless and can even be beneficial to our health . However , some microbes can cause diseases – although they often go unnoticed , as our immune system can remove them before we show any symptoms . For example , the bacterium Streptococcus pneumoniae can cause diseases such as pneumonia and meningitis , but generally , it lives harmlessly in the nose , and is particularly common in children and the elderly . The longer the bacteria live in the nose before being killed by the immune system , the more likely they are to be transmitted to another person . The amount of time it takes for the immune system to clear the bacteria depends on various factors , such as the age of the person or the bacterium’s defense mechanism and its genetic material . A particularly important aspect is to what subtype , also known as serotype , a bacterium belongs to , which is characterized by differences in the structure of the sugar coating that surrounds the microbe . However , until now , it was not known how much each of these factors contributes . Now , Lees et al . have developed a mathematical model to calculate how long the bacteria are carried in the nose before they are cleared away , and compared it with the genomic data of the bacteria . For this , over 14 , 000 nose swabs from almost 600 children were collected over a two-year period . In their model , Lees et al . calculated that the bacteria’s genetics explained over 60% of the variability in survival time . They also found that the serotype was the most important individual factor that influenced how long a bacterium could survive . The age of the child was less important and only accounted for 5% . In addition , Lees et al . also found that when viruses infected some S . pneumoniae , the bacteria died sooner . A next step will be to confirm the effect of a viral infection on the bacteria’s survival time in a controlled model system , and also replicate the findings in separate population study . Understanding how long people can carry bacteria and transmit them to others may help to develop new vaccination or treatment strategies to control infections . Moreover , the discovery that viruses can negatively affect how long a bacterium lives , could motivate studies to investigate these findings further .