Population subdivision and the detection of recombination in non-typable Haemophilus influenzae

Abstract

The disparity in diversity between unencapsulated (non-typable; NT) and encapsulated, serotypable Haemophilus influenzae (Hi) has been recognized for some time. It has previously been suggested that the wider diversity evidenced within NTHi compared with typable lineages may be due to different rates of recombination within the encapsulated and NT populations. To examine whether there is evidence for different levels of recombination within typable and NT lineages of Hi, we performed a statistical genetic analysis of 819 distinct genotypes of Hi to explore the congruence of serotype with population genetic clustering, and to identify patterns of recombination within the Hi population. We find that a significantly larger proportion of NT isolates show evidence of recombination, compared with typable isolates, and also that when admixture is present, the total amount of recombination per strain is greater within NT isolates, compared with the typable population. Furthermore, we demonstrate significant heterogeneity in the number of admixed individuals between NT lineages themselves, while such variation was not observed in typable lineages. This variability suggests that factors other than the presence of capsule are important determinants of recombination rate in the Hi population. INTRODUCTIONHaemophilus influenzae (Hi) is a Gram-negative bacterium commonly isolated from episodes of asymptomatic nasopharyngeal carriage. While the vast majority of Hi exists in carriage rather than disease states, it remains a globally significant pathogen, capable of causing both localized mucosal infections, such as otitis media, and invasive infections, such as meningitis and septicaemia (Turk, 1984). Hi is thought to cause at least three million cases of serious illness every year, mostly in young children (WHO, 2005). To date, six distinct serotypes (designated a-f) of Hi are distinguishable (Pittman, 1930), while a substantial proportion of the population is unencapsulated and so remains non-typable (NT). Of the encapsulated population, serotype b has historically been the most significant pathogen, and is responsible for approximately 95 % of all invasive Hi disease in unvaccinated children (Falla et al., 1993;Peltola, 2000). An effective vaccine against H. influenzae serotype b (Hib) disease has been available since the early 1980s (Anderson, 1983;Chu et al., 1983), and its introduction into childhood immunization programs in the developed world has all but eliminated Hib disease in western countries (for example, see Bisgard et al., 1998;Booy et al., 1997). However, vaccination is rare in many developing countries, where Hib remains a significant cause of mortality, causing an estimated 380 000 deaths each year (WHO, 2005).While Hib disease is controlled by vaccination in the developed world, Hi possessing the other serotypes, as well as NTHi, are also reported to be capable of causing invasive disease (St Geme, 1993;Tsang et al., 2007; WaggonerFountain et al., 1995). NTHi is also a leading cause of economically signific...

Classification, Identification, and Clinical Significance of Haemophilus and Aggregatibacter Species with Host Specificity for Humans

“…The clusters obtained by Bayesian analysis correlate well with the classical subdivisions of the H. influenzae population but show limited concordance with the clades of Erwin et al (70). Compared with encapsulated isolates, a significantly larger proportion of unencapsulated isolates showed evidence of recombination, and when admixture was present, the total amount of recombination per strain was greater for unencapsulated strains (67 barrier to transformation, and factors other than the capsule may constitute decisive determinants of the recombination rate in the H. influenzae population.…”

“…Clade 2 corresponds closely to phylogenetic group II, and the major modifications are the dissection of phylogenetic group I into the remaining 12 clades and STs outside clades. Most recently, a statistical (Bayesian) genetic analysis of 819 distinct H. influenzae MLST genotypes was performed (67). The clusters obtained by Bayesian analysis correlate well with the classical subdivisions of the H. influenzae population but show limited concordance with the clades of Erwin et al (70).…”

Pneumococcal vaccine impacts on the population genomics of non-typeable Haemophilus influenzae

“…We have shown the existence of a discrete lineage structure that is stable over time and which did not measurably shift in response to PCV13. The clonality of the population was concordant with previous examinations of population structure based on MLST 21 and whole genomes of geographically diverse isolates collections 17 . The hierarchical analysis we used gave greater phylogenetic clarity and revealed hitherto unrecognized resolution of the lineages of NTHi.…”

Hierarchical and Spatially Explicit Clustering of DNA Sequences with BAPS Software

“…Hence, phylogenetic tools, such as BEAST (Drummond and Rambaut 2007), need to be complemented with population genetic analysis that allows for an admixture within and between lineages. We have recently successfully identified significant variation in the extent of recombination and its association with several ecological and genetic factors using the population genetic software package, BAPS (Corander and Marttinen 2006; Corander and Tang 2007; Corander et al 2008a; Corander et al 2008b; Tang et al 2009; Cheng et al 2011), on large collections of DNA sequence data from pathogen populations (Hanage et al 2009; Castillo-Ramírez et al 2012; Connor et al 2012; Corander et al 2012; Willems et al 2012). For instance, we have showed that hospital-adapted virulent and resistant strains of the major source of nosocomial infections, Enterococcus faecium , display a marked reduction in their amount of recombination compared with commensal strains.…”