Two cases of type-a <i>Haemophilus influenzae</i> meningitis within the same week in the same hospital are phylogenetically unrelated but recently exchanged capsule genes

ABSTRACT H. influenzae causes common and sometimes severe pediatric disease including chronic obstructive respiratory disease, otitis media, and infections of the central nervous system. Serotype b strains, with a b-type capsule, have been the historical cause of invasive disease, and the introduction of a serotype b-specific vaccine has led to their decline. However, unencapsulated or non-b-type H. influenzae infections are not prevented by the vaccine and appear to be increasing in frequency. Here we report two pediatric cases of severe central nervous system H. influenzae infection presenting to the same hospital in San Diego, California during the same week in January 2016. Due to good vaccine coverage in this part of the world, H. influenzae cases are normally rare and seeing two cases in the same week was unexpected. We thus suspected a recent transmission chain, and possible local outbreak. To test this hypothesis, we isolated and sequenced whole genomes from each patient and placed them in a phylogenetic tree spanning the known diversity of H. influenzae . Surprisingly, we found that the two isolates (H1 and H2) belonged to distantly related lineages, suggesting two independent transmission events and ruling out a local outbreak. Despite being distantly related, H1 and H2 belong to two different lineages that appear to engage in frequent horizontal gene transfer (HGT), suggesting overlapping ecological niches. Together, our comparative genomic analysis supports a scenario in which an f-type ancestor of H2 arrived in North America around 2011 and acquired an a-type capsule by recombination (HGT) with a recent ancestor of H1. Therefore, as in other bacterial pathogens, capsule switching by HGT may be an important evolutionary mechanism of vaccine evasion in H. influenzae . OUTCOME Two cases of severe central nervous system H. influenzae infection occurred during the same week in the same hospital in San Diego, California – a region where such infections are usually very rare due to vaccine coverage. We thus suspected a local outbreak of an H. influenzae clone not covered by the vaccine. Using whole genome sequencing and phylogenetic analysis of two isolates (H1 and H2, one from each patient), we found that they were distantly related, rapidly ruling out a local outbreak and suggesting independent transmission events. This result highlights the potential for rapid global spread of non-vaccine H. influenzae strains. In this case, both H1 and H2 both encoded a-type capsules, whereas the vaccine targets b-type capsules. We also present comparative genomic evidence that a recent f-type ancestor of H2 acquired an a-type capsule locus from a recent ancestor of H1, and that this horizontal gene transfer (HGT) event likely happened in the past decade in North America, but probably not in the San Diego hospital. These results highlight the potential importance of HGT in the capsule locus in allowing H. influenzae to escape vaccine coverage. DATA SUMMARY H. influenzae H1 and H2 genome sequences have been deposited in NCBI under BioProject PRJNA534512. CONFLICT OF INTEREST STATEMENT The authors declare that they have no conflict of interest to report.

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