Genomic analyses of pneumococci from children with sickle cell disease expose host-specific bacterial adaptations and deficits in current interventions.
Sickle cell disease (SCD) patients are at high risk of contracting pneumococcal infection. To address this risk, they receive pneumococcal vaccines, and antibiotic prophylaxis and treatment. To assess the impact of SCD and these interventions on pneumococcal genetic architecture, we examined the genomes of more than 300 pneumococcal isolates from SCD patients over 20 years. Modern SCD strains retained invasive capacity but shifted away from the serotypes used in vaccines. These strains had specific genetic changes related to antibiotic resistance, capsule biosynthesis, metabolism, and metal transport. A murine SCD model coupled with Tn-seq mutagenesis identified 60 noncapsular pneumococcal genes under differential selective pressure in SCD, which correlated with aspects of SCD pathophysiology. Further, virulence determinants in the SCD context were distinct from the general population, and protective capacity of potential antigens was lost over time in SCD. This highlights the importance of understanding bacterial pathogenesis in the context of high-risk individuals.
Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105 USA.
Robert
R
Carter
Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN 38105 USA.
Joshua
J
Wolf
Tufts University School of Medicine, Department of Molecular Biology and Microbiology, 136 Harrison Avenue, Boston, MA 02111-1817 USA.
Tim
T
van Opijnen
Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN 38105 USA.
Martha
M
Muller
Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN 38105 USA.
Caroline
C
Obert
Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN 38105 USA.
Corinna
C
Burnham
Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN 38105 USA.
Beth
B
Mann
Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN 38105 USA.
Yimei
Y
Li
Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105 USA.
Randall T
RT
Hayden
Department of Experimental Hematology, St. Jude Children's Research Hospital, Memphis, TN 38105 USA.
Tamara
T
Pestina
Department of Experimental Hematology, St. Jude Children's Research Hospital, Memphis, TN 38105 USA.
Derek
D
Persons
Tufts University School of Medicine, Department of Molecular Biology and Microbiology, 136 Harrison Avenue, Boston, MA 02111-1817 USA.|Howard Hughes Medical Institute, Department of Molecular Biology and Microbiology, 136 Harrison Avenue, Boston, MA 02111-1817 USA.
Andrew
A
Camilli
Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN 38105 USA.
Patricia M
PM
Flynn
Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN 38105 USA.
Elaine I
EI
Tuomanen
Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN 38105 USA.
Jason W
JW
Rosch
D000222:Adaptation, Physiological; D000293:Adolescent; D000755:Anemia, Sickle Cell / Q000150:complications*; D001426:Bacterial Proteins / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D005260:Female; D023281:Genomics; D054884:Host-Pathogen Interactions; D006801:Humans; D007223:Infant; D008297:Male; D008969:Molecular Sequence Data; D010802:Phylogeny; D011008:Pneumococcal Infections / Q000209:etiology / Q000382:microbiology* / Q000517:prevention & control; D022242:Pneumococcal Vaccines / Q000008:administration & dosage; D011446:Prospective Studies; D013296:Streptococcus pneumoniae / Q000145:classification / Q000235:genetics* / Q000302:isolation & purification / Q000502:physiology
D001426:Bacterial Proteins; D022242:Pneumococcal Vaccines