Streptococcus Pneumoniae: Molecular Mechanisms of Host-Pathogen Interactions

458 Pages·2015·27.768 MB·English

by  Jeremy Brown MA MB BS MRCP MD, Sven Hammerschmidt, Carlos Orihuela

STREPTOCOCCUS PNEUMONIAE
STREPTOCOCCUS
PNEUMONIAE
Molecular Mechanisms of
(cid:1)
Host pathogen Interactions
Editedby
Jeremy Brown
CentreforInflammationandTissueRepair,DepartmentofMedicine,
UniversityCollegeMedicalSchool,London,UnitedKingdom
Sven Hammerschmidt
DepartmentGeneticsofMicroorganisms,InterfacultyInstituteforGeneticsandFunctionalGenomics,
Ernst-Moritz-ArndtUniversita¨tGreifswald,Greifswald,Germany
Carlos Orihuela
DepartmentofMicrobiologyandImmunology,TheUniversityofTexasHealthScienceCenter
atSanAntonio,SanAntonio,TXUSA
AMSTERDAM(cid:129)BOSTON(cid:129)HEIDELBERG(cid:129)LONDON
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SANFRANCISCO(cid:129)SINGAPORE(cid:129)SYDNEY(cid:129)TOKYO
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List of Contributors
Vaibhav Agarwal Medical Protein Chemistry, David H. Dockrell The Florey Institute for Host-
Department of Laboratory Medicine, Lund Pathogen Interactions, University of Sheffield
University, Malmo¨ , Sweden; German Research School of Medicine, Royal Hallamshire Hospital,
Foundation-DFGOfficeIndia,NewDelhi,India Sheffield,UK
Simone Bergmann Institute of Microbiology, Claire Durmort Univ. Grenoble Alpes, IBS,
Technische Universita¨t Braunschweig, Grenoble, France; CNRS, IBS, Grenoble, France;
Braunschweig,Germany CEA,DSV,IBS,Grenoble,France
Hester J. Bootsma Laboratory of Pediatric Daniela M. Ferreira Department of Clinical
Infectious Diseases, Department of Pediatrics, Sciences, Liverpool School of Tropical Medicine,
Radboud University Medical Centre, Nijmegen, Liverpool,UK
The Netherlands; Centre for Infectious Diseases Adam Finn Bristol Childrens Vaccine Centre,
Research, Diagnostics and Screening, National UniversityofBristol,UK
Institute for Public Health and the Environment
John P. Fobiwe Center for Infectious Diseases and
(RIVM),Bilthoven,TheNetherlands
Infection Control and Center for Sepsis Care and
Jeremy S. Brown Centre for Inflammation and Control,JenaUniversityHospital,Jena,Germany
Tissue Repair, University College London,
Sergio Gala´n-Bartual Department of
London,UK
CrystallographyandStructuralBiology,Instituto
Joa´oA.Carric¸o InstitutodeMicrobiologia,Instituto de Qu´ımica-F´ısica Rocasolano, CSIC, Madrid,
de Medicina Molecular, Faculdade de Medicina, Spain
UniversidadedeLisboa,Lisboa,Portugal
Gustavo Ga´mez Basic and Applied Microbiology
Scott Chancey Division of Infectious Diseases, Research Group (MICROBA), School of
Department of Medicine, Emory University Microbiology and Universidad de Antioquia,
School of Medicine, and Laboratories of Medell´ın, Colombia; Genetics, Regeneration and
Microbial Pathogenesis, Department of Veterans Cancer Research Group, University Research
AffairsMedicalCenter,Atlanta,GA,USA Centre (SIU), Universidad de Antioquia,
Dalia Denapaite Department of Microbiology, Medell´ın,Colombia
University of Kaiserslautern, Kaiserslautern, Pedro Garcı´a Departamento de Microbiolog´ıa
Germany Molecular y Biolog´ıa de las Infecciones, Centro
Hector D. de Paz Pediatric Infectious Diseases de Investigaciones Biolo´gicas, CSIC, Madrid,
Research Group, Sant Joan de Deu Foundation, Spain; CIBER de Enfermedades Respiratorias
HospitalSantJoandeDeu,Barcelona,Spain (CIBERES),Madrid,Spain
Dimitri A. Diavatopoulos Laboratory of Pediatric NicolasGisch DivisionofBioanalyticalChemistry,
Infectious Diseases, Department of Pediatrics, Priority Area Infections, Research Center Borstel,
Leibniz-Center for Medicine and Biosciences,
Radboud University Medical Center, Nijmegen,
Borstel,Germany
The Netherlands; Laboratory of Medical
Immunology, Department of Laboratory Stephen B. Gordon Department of Clinical
Medicine, Radboud University Medical Center, Sciences, Liverpool School of Tropical Medicine,
Nijmegen,TheNetherlands Liverpool,UK
ix
x
LISTOFCONTRIBUTORS
Nina Gratz Department of Infectious Diseases, St. Sylvia Kohler Department Genetics of
Jude Children’s Research Hospital, Memphis, Microorganisms,InterfacultyInstituteforGenetics
TN,USA and Functional Genomics, Ernst-Moritz-Arndt
AndersP.Hakansson DepartmentofMicrobiology UniversityGreifswald,Greifswald,Germany
and Immunology, University at Buffalo, State LipNamLoh DepartmentofInfectiousDiseases,St.
University of New York, Buffalo, NY, USA; The JudeChildren’sResearch Hospital, Memphis,TN,
Witebsky Center for Microbial Pathogenesis and USA
Immunology, University at Buffalo, State Rick Malley Kenneth McIntosh Chair in Pediatric
University of New York, Buffalo, NY, USA; New Infectious Diseases, Boston Children’s Hospital,
York State Center of Excellence in Bioinformatics HarvardMedicalSchool,Boston,MA,USA
andLifeSciences,Buffalo,NY,USA
Laura R. Marks Pediatric Infectious Diseases
Regine Hakenbeck Department of Microbiology, Research Group, Sant Joan de Deu Foundation,
University of Kaiserslautern, Kaiserslautern, HospitalSantJoandeDeu,Barcelona,Spain
Germany
Jonathan A. McCullers Department of Pediatrics,
Sven Hammerschmidt Department Genetics of The University of Tennessee Health Science
Microorganisms, Interfaculty Institute for Center,Memphis,TN,USA
Geneticsand Functional Genomics, Ernst-Moritz-
Lesley McGee Respiratory Diseases Branch,
Arndt University Greifswald, Greifswald,
Centers for Disease Control and Prevention,
Germany
Atlanta,GA,USA
Peter W.M. Hermans Laboratory of Pediatric
Jose´ Melo-Cristino Instituto de Microbiologia,
Infectious Diseases, Department of Pediatrics,
Instituto de Medicina Molecular, Faculdade de
Radboud University Medical Centre, Nijmegen,
Medicina,UniversidadedeLisboa,Lisboa,Portugal
The Netherlands; Centre for Molecular and
Biomolecular Informatics, Nijmegen Centre for Timothy J. Mitchell School of Immunity and
Molecular Life Sciences, Radboud University Infection,CollegeofMedicalandDentalSciences,
MedicalCentre,Nijmegen,TheNetherlands UniversityofBirmingham,Birmingham,UK
Juan A. Hermoso Department of Crystallography Renato Morona Research Centre for Infectious
and Structural Biology, Instituto de Qu´ımica- Diseases, Department of Molecular and Cellular
F´ısicaRocasolano,CSIC,Madrid,Spain Biology, School of Biological Sciences, University
ofAdelaide,Adelaide,SA,Australia
Markus Hilleringmann Department of Applied
Carmen Mun˜oz-Almagro 1Pediatric Infectious
SciencesandMechatronics,MunichUniversityof
Diseases Research Group, Sant Joan de Deu
AppliedSciences,Munich,Germany
Foundation, Hospital Sant Joan de Deu,
Anthony J. Infante Department of Pediatrics, The Barcelona, Spain; Molecular Microbiology
University of Texas Health Science Center at San Department, University Hospital Sant Joan de
Antonio,SanAntonio,TX,USA Deu,Barcelona,Spain
Aras Kadioglu Department of Clinical Infection, Daniel R. Neill Department of Clinical Infection,
Microbiology & Immunology, Institute of Microbiology & Immunology, Institute of
Infection & Global Health, University of Infection & Global Health, University of
Liverpool,Liverpool,UK Liverpool,Liverpool,UK
Colin C. Kietzman Department of Infectious Marco R. Oggioni Department of Genetics,
Diseases, St. Jude Children’s Research Hospital, UniversityofLeicester,Leicester,UK
Memphis,TN,USA
Abiodun D. Ogunniyi Research Centre for
Keith P. Klugman Hubert Department of Global Infectious Diseases, School of Molecular and
Health, Rollins School of Public Health, Emory Biomedical Science, University of Adelaide,
University,Atlanta,GA,USA Adelaide,SA,Australia
xi
LISTOFCONTRIBUTORS
Melissa B. Oliver Department of Microbiology Kirsty R. Short Department of Viroscience,
and Immunology, Wake Forest School of Erasmus Medical Center, Rotterdam, The
Medicine,Winston-Salem,NC,USA Netherlands; School of Biomedical Sciences,
CarlosJ.Orihuela DepartmentofMicrobiology,The UniversityofQueensland,Brisbane,Australia
UniversityofAlabamaatBirmingham,AL,USA Alistair J. Standish Research Centre for Infectious
James C. Paton Research Centre for Infectious Diseases, Department of Molecular and Cellular
Diseases, School of Molecular and Biomedical Biology, School of Biological Sciences, University
Science, University of Adelaide, Adelaide, SA, ofAdelaide,Adelaide,SA,Australia
Australia
W. Edward Swords Department of Microbiology
Inmaculada Pe´rez-Dorado Department of Crystal- and Immunology, Wake Forest School of
lographyandStructuralBiology,InstitutodeQu´ı- Medicine,Winston-Salem,NC,USA
mica-F´ısica Rocasolano, CSIC, Madrid, Spain;
Herve´ Tettelin Department of Microbiology and
DepartmentofLifeSciences,CentreforStructural
Immunology, Institute for Genome Sciences,
Biology, Imperial College London, South Ken-
University of Maryland School of Medicine,
sington,London,UK
Baltimore,MD,USA
Katharina Peters The Centre for Bacterial Cell
Claudia Trappetti School of Molecular and
Biology, Institute for Cell and Molecular
Biosciences, Newcastle University, Newcastle Biomedical Science, University of Adelaide,
Adelaide,Australia
uponTyne,UK
MathiasW.Pletz CenterforInfectiousDiseasesand Elaine Tuomanen Department of Infectious
Infection Control and Center for Sepsis Care and Diseases, St. Jude Children’s Research Hospital,
Control,JenaUniversityHospital,Jena,Germany Memphis,TN,USA
Ma´rioRamirez InstitutodeMicrobiologia,Instituto Mark van der Linden National Reference Center
de Medicina Molecular, Faculdade de Medicina, for Streptococci, Department of Medical
UniversidadedeLisboa,Lisboa,Portugal Microbiology, University Hospital (RWTH),
Martin Rieger Department of Microbiology, Aachen,Germany
University of Kaiserslautern, Kaiserslautern, Waldemar Vollmer The Centre for Bacterial Cell
Germany Biology, Institute for Cell and Molecular
Hazeline Roche-Hakansson Department of Biosciences, Newcastle University, Newcastle
Microbiology and Immunology, University at uponTyne,UK
Buffalo, State University of New York, Buffalo,
Ulrich Za¨hringer Division of Bioanalytical
NY,USA
Chemistry, Priority Area Infections, Research
Jason W. Rosch Department of Infectious Center Borstel, Leibniz-Center for Medicine and
Diseases, St. Jude Children’s Research Hospital, Biosciences,Borstel,Germany
Memphis,TN,USA
Aldert Zomer Laboratory of Pediatric Infectious
Yvonne Scha¨hle Department of Microbiology,
Diseases, Department of Pediatrics, Radboud
University of Kaiserslautern, Kaiserslautern,
University Medical Centre, Nijmegen, The
Germany Netherlands; Centre for Molecular and
Laura Selva Department of Microbiology and Biomolecular Informatics, Nijmegen Centre for
Immunology, University at Buffalo, State Molecular Life Sciences, Radboud University
UniversityofNewYork,Buffalo,NY,USA MedicalCentre,Nijmegen,TheNetherlands
Preface
Streptococcuspneumoniae(thepneumococcus) morbidity and socioeconomic cost associated
has been and continues to be among the with nonlethal pneumococcal infections is also
chief causes of human misery and death. It very large. For these reasons, research on basic
is capable of a broad swath of disease mani- pneumococcal biology, disease pathogenesis,
festations, including otitis media, the more and interactions with the host continues to be
serious community-acquired pneumonia, and vital for human health, and is probably under-
devastating illnesses such as septicemia and supported given the global burden of pneumo-
meningitis. As a commensal colonizer of the coccaldiseaseinbothdevelopingandindustrial
nasopharynx, the pneumococcus is the pro- countries.
totypical opportunistic pathogen, but it is The human effort to prevent pneumococcal
also capable of causing disease in previ- disease has also directly and indirectly led to
ously seemingly healthy individuals. While the some of our greatest biological discoveries.
overall attack rate for the pneumococcus is Pneumococci were used to obtain evidence of
low, so many individuals are colonized that geneticrecombinationbyGriffithin1928;iden-
the global burden of disease is enormous. tification of DNA as the transforming principle
Primarily affected are infants whose immune byAvery,Macleod,andMcCarthyin1944;and
system has not yet developed the capacity to the discovery of antibody-mediated opsoniza-
ward off infection, the elderly whose immune tion by Neufeld (1902, 1904, and 1910), the lat-
system is waning, and those who are immuno- terbeing the basis of many of today’s vaccines.
compromised. Most often age and immuno- The pneumococcus remains the subject of
suppression overlap, with malnourished and continued intense research, with considerable
smoke-exposed children and the elderly with progress having been made in our understand-
multiple underlying medical conditions being ing of the molecular basis of pneumococcal
at greatest risk. Epidemiological studies sug- biology. It is probably one of the most studied
gest that the number of children who succumb singlebacterial pathogens,andrightlysogiven
topneumococcaldiseaseexceeds650,000annu- its importance for human disease. Important
ally worldwide. For the elderly, the case- discoveries that are relevant not just for the
fatality rate for pneumococcal pneumonia is pneumococcus, but more broadly for bacterial
10(cid:1)15%, climbing approximately 10% with pathogens, continue today despite more than
every decade of life after 65 years. As a result, 120 years of research on the pneumococcus.
and despite effective antibiotics, the mortality For example, recent studies suggest that the
rate for an 85-year-old with pneumococcal pneumococcus uses epigenetics to regulate the
pneumonia is 30(cid:1)45%, reinforcing Sir William expression of its virulence genes, the first
Osler’s early-twentieth-century observation that descriptionofthisforabacterium,andthatthe
the pneumococcus is the “old man’s friend” pneumococcusmaycausecardiac damage dur-
and that this pathogen is still highly relevant in ing pneumonia.In addition,thepneumococcus
the twenty-first century. Importantly, the has been at the forefront of the bacterial
xiii
xiv
PREFACE
genome sequencing revolution, with sequences about what might be the important questions
now available for thousands of strains, as well to address in order to better understand how
as in investigating the cell biology of bacterial and why the pneumococcus is such a success-
infection and defining the role of cellular ful pathogen. We have summarized some of
immuneresponsesinpreventingmucosalinfec- these questions in Table 1. These are very
tionsbyextracellularpathogens. muchourpersonalviewsofareasthatcouldbe
In this textbook we present what we believe important for future research, and are not
is an exciting, up-to-date description of the meant to be exhaustive; other questions we
epidemiology, evolution, microbiology, patho- have not included or considered will be
genesis, immunology, and cell biology of the equally important. Many of these questions are
pneumococcus. We have strived to do so with probably self-evident to researchers in the
afocusonthemolecularmechanisms responsi- field, but others may be less so. We hope that
ble. The chapters are written by recognized you as a reader will find them stimulating and
experts in their respective areas, and we are perhaps the basis of potential future research
extremely thankful for their willingness to par- projects. Below, we have discussed in more
ticipate. The sheer number of important new detail important aspects of pneumococcal biol-
revelations in recent years about the biology of ogy underpinning why we feel some of these
pneumococcus and the pathogenesis of pneu- potentialresearchquestionsareimportant.
mococcal infection have made the need for a Much attention has been paid to the role of
new textbook obvious. By presenting up-to- the polysaccharide capsule for pneumococcal
date reviews of a wide range of different areas, biology, and deservedly so, as the capsule is
this book allows the reader a thorough over- both the principal virulence determinant of the
view of the biology of this important pathogen pneumococcus and the target antigen for cur-
and its capacity to modulate the host immune rently licensed vaccines. The capsule protects
response. The textbook is most obviously of the bacteria from entrapment in mucus during
importance for researchers working on the colonization, opsonophagocytosis by neutro-
pneumococcus,butitisalsoofinterestforany- phils and macrophages, and by killing by
oneworkinginthefieldofbacterialpathogene- neutrophil-extracellulartraps.Althoughantibo-
sis or involved in caring for patients with dies against the capsule are highly protective,
pneumococcal infection. We hope that readers the pneumococcus has more than 90 biochemi-
will obtain a greater appreciation of the tre- cally and immunologically distinct capsule
mendous accomplishments made in under- types, providing a considerable amount of sur-
standing how the pneumococcus causes face antigenic variation. Importantly, extensive
disease,howitadaptstothehostenvironment, epidemiological and experimental evidence
howweasthehostprotectourselvesagainstit, indicates that different capsule types have dis-
and the challenges that face current and future tinct propensities to cause invasive disease.
generations of investigators as we strive to Serotypeswithlowernumbers,thatis,1,2,3,4,
fully understand the biology of the complex were those first isolated from patients as they
interactions between the pneumococcus and are (or used to be) frequent causes of invasive
ourselves. infections.Capsular serotypesdivide into three
As editors, it has been our privilege to read groups: those where colonization events are
eachchapterandthereforeobtainabroadover- more frequentlyassociated with invasive infec-
view of what we know and, perhaps more tion (e.g., serotypes 1, 5, 7F, and 14); those that
importantly, what we don’t know about the are less likely to cause invasive infection per
pneumococcus. This has allowed us to think colonization event but are common causes of
xv
PREFACE
TABLE1 ImportantQuestionsAboutStreptococcuspneumoniaeBiologyandPotentialAreasforFutureResearch
Howdoescapsularserotypeaffectdifferentaspectsofpneumococcalbiology?Whatarethemolecularbasisforand
relationshipsbetweencapsulestructure,underlyingproteinvirulencefactors,andfunctionalinteractionswiththehost?
Whydoesthepneumococcushaveapolysaccharidecapsulewhenothernasopharyngealbacterialcommensalsseemto
copeperfectlywellwithoutone?
Whataretheeffectsoftherespiratorytractmicrobiomeondevelopmentofpneumococcalcolonizationanddisease?
Dorespiratoryvirusesotherthaninfluenzaincreasepneumococcalvirulence?Ifso,bywhatmechanisms?
Howcan“wetbiology”catchupwiththeexplosionofgenomesequencedata?Canwedevisemuchbettermethodsof
rapidlyascertaininggenefunction?
Whydoesthepneumococcushavesuchvariationingenomecontentandsuchalargeaccessorygenome?Whatarethe
effectsofthisonpneumococcalbiology?
Whatistheminimumgenomerequirementforabacteriumtobephenotypicallyapneumococcus?
Whyisthepneumococcusafrequentcauseoffataldisease,whereasS.mitis(itsclosestgeneticrelation)isonlyarare
causeofinfections?
Whydoesthepneumococcushavesomanysurfaceadhesins?Isthisduetoredundancyortheneedforpneumococcito
sequentiallyinteractwithhostcells?
Whatisthefunctionalsignificanceofthelargedifferencesingenefunctionbetweenstrainsforsomegenes?Isthisa
biologicallyimportanteffect,andifsohowcanweovercomeitsroleinconfoundingdataobtainedwithmutants?
Howispneumococcalvirulenceregulated?Istherea“masterregulator”ofvirulence?Whatenvironmentalsignals
stimulateaninvasivephenotype?
Whatistheroleofredundancyofnutrientacquisition—forexample,carbohydratesandcations?
Whydomanypneumococcalproteinvirulencefactorshavemultiplefunctions?Whichfunctionsareactuallyrelevant
duringcolonizationanddisease?
Howcanweexplainserotype-andstrain-dependentcolonization/virulencephenotypes?Whatisitaboutthe
pneumococcalnasopharyngealcolonizationstrategythatdrivesdevelopmentofinvasivedisease?
Mostmurineinfectiondatahavebeenusedinaninnateimmunesetting;whataretheeffectsofanadaptiveimmune
responseonpneumococcalandhostdeterminantsofsuccessfulinfection?
Whatarethemajorhostfactorscausingthemarkedbipolaragedistributionofpneumococcalinfection,withmostdisease
affectinginfantsortheelderly?
Whyispneumococcalinfectionmoreprevalentinpatientswithsomechronicdiseases?
Whatarethemainantigentargetsandmechanismsofnaturallyacquiredadaptiveimmunitytothepneumococcus?
Howdoepigeneticdifferencesinhumansinfluencetheirsusceptibilitytopneumococcalinfections,andwhicharethehost
geneticdeterminantsfavoringinvasiveinfections?
Whatarethemolecularmechanismsusedbypneumococcitobreachtherespiratoryepithelialbarrier,andwhichrouteis
exploitedbythisextracellularpathogenduringactualdisease?
Howdothephysiologyandgeneexpressionprofileofthepneumococcuschangeinthevariousenvironmentalconditions
(i.e.,atdifferentanatomicalsites)thebacteriaencountersduringactualinfection?
xvi
PREFACE
infections as they are highly prevalent as naso- to evade complement-mediated immunity by
pharyngealcommensals(e.g.,6Aand19F);and expressing sufficient levels of proteins such as
finally, those serotypes that are rare both as PspC (CbpA) or PspA, which bind the comple-
commensals andascauses ofinfection (e.g.,88, ment inhibitor factor H or prevent bacterial
89,and90).Thesedatasuggestthatthephysio- recognition by C-reactive protein, respectively.
logical properties of different capsular sero- Likewise, astrain with a capsularserotype that
typeshaveconsiderableinfluenceonarangeof inhibits epithelial cell adhesion could express
pneumococcal interactions with the host, greater levels of compensatory protein adhe-
including those necessary for colonization or sins, often involved in recruiting host extracel-
forbacterial survival during moreinvasivedis- lular matrix or serum proteins, to overcome
ease. We have only really just begun to assess this deficit. This would explain why switching
the molecular basis for how capsular serotype capsule types does not always result in a viru-
affectsmultipleareasofpneumococcalbiology, lent strain, as the required complement of pro-
and this remains an important area for future teins for that specific capsular serotype may
research. not be encoded in the genome of the recipient
However, capsular serotype alone does not strain. The compensatory properties addres-
fully explain virulence, as evidenced by multi- sing the restrictions imposed by capsular type
plestudiesdemonstratingthatisogeniccapsule may not always be dependent on a single pro-
switching only sometimes confers virulence to tein, but instead could be characterized by the
a previously nonvirulent strain, and in some necessity to reach a certain activity threshold.
instances may even reduce virulence. A strik- For example, for a strain from a capsular sero-
ing observation from genome sequencing data typethattendstopreventadhesion,highlevels
is the sheer amount of genetic variation among of expression of a single powerful adhesin or
pneumococcal strains, with a core genome the collective effects of lower levels of expres-
that is estimated to be only about 50% of the sion of multiple adhesins could both overcome
genome of a specific strain. Hence there are the limitations imposed by the capsule. With
considerable differences in the protein content evolutionary pressure to minimize bacterial
between strains that will contribute toward expression of superfluous products, a reason-
capsular serotype-independent effects on able presumption is that pathogenic pneumo-
pneumococcal biology; moreover, we do not cocci carry the minimal compensatory factors
yet understand why there are such large varia- necessary to adequately complement their spe-
tions in genetic content between pneumococci cific capsule type. As such, loss of any one pro-
or how this may influence disease pathogene- tein virulence factor could be sufficient to drop
sisandpneumococcalecology. thebacteriabelowtherequiredthresholdforvir-
Multiple core and noncore protein virulence ulence and would lead to an attenuated mutant
determinants such as the pore-forming toxin that is unable to cause severe disease during
pneumolysin and adhesins like the pili, respec- infection. This model potentially explains why
tively, have been investigated and shown to experimentaldeletionofanyoneofthemultiple
have major roles during infection. We can sur- knownadhesinsorproteinsthatinhibitcomple-
mise that the physiological properties and lim- ment activity tend to have a strong attenuated
itations imposed on the pneumococcus by its phenotype in the laboratory. Overall, the exist-
particular capsular serotype could be comple- ing data suggest that a complex interplay
mented or overcome by protein determinants. between capsular type and the panoply of pro-
For example, a strain expressing a capsular tein virulence determinants expressed by each
serotypethatisrelativelyinefficientatblocking strain will combine to influence each strain’s
complement deposition could boost its ability ability to cause invasive disease. Further effort