In vivo adaptation and persistence of Neisseria meningitidis within the nasopharyngeal mucosa.
Neisseria meningitidis (Nme) asymptomatically colonizes the human nasopharynx, yet can initiate rapidly-progressing sepsis and meningitis in rare instances. Understanding the meningococcal lifestyle within the nasopharyngeal mucosa, a phase of infection that is prerequisite for disease, has been hampered by the lack of animal models. Herein, we compare mice expressing the four different human carcinoembryonic antigen-related cell adhesion molecules (CEACAMs) that can bind the neisserial Opa protein adhesins, and find that expression of human CEACAM1 is necessary and sufficient to establish intranasal colonization. During infection, in vivo selection for phase variants expressing CEACAM1-specific Opa proteins occurs, allowing mucosal attachment and entry into the subepithelial space. Consistent with an essential role for Opa proteins in this process, Opa-deficient meningococci were unable to colonize the CEACAM1-humanized mice. While simple Opa-mediated attachment triggered an innate response regardless of meningococcal viability within the inoculum, persistence of viable Opa-expressing bacteria within the CEACAM1-humanized mice was required for a protective memory response to be achieved. Parenteral immunization with a capsule-based conjugate vaccine led to the accumulation of protective levels of Nme-specific IgG within the nasal mucus, yet the sterilizing immunity afforded by natural colonization was instead conferred by Nme-specific IgA without detectable IgG. Considered together, this study establishes that the availability of CEACAM1 helps define the exquisite host specificity of this human-restricted pathogen, displays a striking example of in vivo selection for the expression of desirable Opa variants, and provides a novel model in which to consider meningococcal infection and immunity within the nasopharyngeal mucosa.
Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
Kay O
KO
Johswich
Shannon E
SE
McCaw
Epshita
E
Islam
Anna
A
Sintsova
Angel
A
Gu
John E
JE
Shively
Scott D
SD
Gray-Owen
D000222:Adaptation, Physiological; D018829:Adhesins, Bacterial / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D001422:Bacterial Adhesion; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D004926:Escherichia coli / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D018928:Immunity, Mucosal; D008589:Meningococcal Infections / Q000276:immunology / Q000378:metabolism / Q000382:microbiology*; D051379:Mice; D008822:Mice, Transgenic; D050296:Microbial Viability; D009154:Mutation; D009305:Nasopharynx / Q000276:immunology / Q000378:metabolism / Q000382:microbiology* / Q000473:pathology; D009345:Neisseria meningitidis / Q000254:growth & development* / Q000276:immunology; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D020545:Respiratory Mucosa / Q000276:immunology / Q000378:metabolism / Q000382:microbiology* / Q000473:pathology; D012141:Respiratory Tract Infections / Q000276:immunology / Q000378:metabolism / Q000382:microbiology* / Q000473:pathology
D018829:Adhesins, Bacterial; D015703:Antigens, CD; C069847:CD66 antigens; D015815:Cell Adhesion Molecules; D020033:Protein Isoforms; D011994:Recombinant Proteins