Sterilizing Immunity Elicited by Neisseria meningitidis Carriage Shows Broader Protection than Predicted by Serum Antibody Cross-Reactivity in CEACAM1 -Humanized Mice

Abstract

bNeisseria meningitidis asymptomatically colonizes the human upper respiratory tract but is also the cause of meningitis and severe septicemia. Carriage or disease evokes an immune response against the infecting strain. Hitherto, we have known little about the breadth of immunity induced by natural carriage of a single strain or its implications for subsequent infectious challenge. In this study, we establish that transgenic mice expressing human CEACAM1 support nasal colonization by a variety of strains of different capsular types. Next, we nasally challenged these mice with either of the N. meningitidis strains H44/76 (serogroup B, ST-32) and 90/18311 (serogroup C, ST-11), while following the induction of strain-specific immunoglobulin. When these antisera were tested for reactivity with a diverse panel of N. meningitidis strains, very low levels of antibody were detected against all meningococcal strains, yet a mutually exclusive "fingerprint" of high-level cross-reactivity toward certain strains became apparent. To test the efficacy of these responses for protection against subsequent challenge, CEACAM1-humanized mice exposed to strain 90/18311 were then rechallenged with different N. meningitidis strains. As expected, the mice were immune to challenge with the same strain and with a closely related ST-11 strain, 38VI, while H44/76 (ST-32) could still colonize these animals. Notably, however, despite the paucity of detectable humoral response against strain 196/87 (ST-32), this strain was unable to colonize the 90/18311-exposed mice. Combined, our data suggest that current approaches may underestimate the actual breadth of mucosal protection gained through natural exposure to N. meningitidis strains. N eisseria meningitidis is the causative agent of meningococcal meningitis and septicemia. Both manifestations of invasive meningococcal disease (IMD) primarily affect infants and toddlers and are characterized by a rapid course of progression (1). The fatality rate is particularly high in meningococcal sepsis, and treatment options are limited, especially when patients present in hospitals with late-stage disease (2). Therefore, preemptive measures such as vaccination are pivotal in the defense against this human-specific pathogen.Although mainly recognized because of its devastating invasive potential, N. meningitidis bacteria are normal inhabitants of the human upper respiratory tract, as about 10% of the general population carry these bacteria in their throats (3, 4). Overall, progression into disease is uncommon and is limited to certain hypervirulent lineages of this diverse species (5, 6). One key aspect in meningococcal virulence is the polysaccharide capsule, which shields the bacteria against the bactericidal activities of the host through phagocytosis and the complement system and which allows for their survival and multiplication in the blood. In order to overcome this protective function, immunoglobulin specific for surface antigens is required to facilitate Fc receptor-mediated phagocytosis and ser...

Distinct roles of the anaphylatoxin receptors C3aR, C5aR1 and C5aR2 in experimental meningococcal infections

“…Thus, we wanted to test whether complement and the anaphylatoxins as important attractors of phagocytes impact on Nme mucosal colonization in vivo. We, therefore, used our CEACAM1-humanized mouse model [42][43][44] in combination with deficiencies in C3 (C3 −/-), C5 (C5 −/-), C3aR1 (C3ar1 -/-) C5aR1 (C5ar1 −/-) or C5aR2 (C5ar2 −/-) to monitor Nme nasal colonization following intranasal infection with 10 5 CFU. Colonization levels of the mice were similar across all genotypes at day 1 and day 3 ( Figure 1(a,b)).…”

Complement C5a Receptor 1 Exacerbates the Pathophysiology ofN. meningitidisSepsis and Is a Potential Target for Disease Treatment

“…infection by comparing wild-type (WT) mice with C3 −/− mice (completely devoid of complement effector functions) and Hc ° / ° mice lacking C5 (allowing C3b opsonization but devoid of MAC and C5a formation). Although humans represent the only natural host of these bacteria ( 18 ), several mouse models have been developed that allow in vivo investigation of IMD ( 19 – 21 ) as well as colonization ( 22 , 23 ). Congenic Hc ° / ° mice were obtained by 10 generations of backcrossing of the Hc° allele from FVB mice onto the C57BL/6J background.…”

Exploring the Ability of Meningococcal Vaccines to Elicit Mucosal Immunity: Insights from Humans and Mice

“…Colonization of hCEACAM1 mice is variable for different strains in terms of rate of colonization (number of mice colonized) and burden of colonization (CFU recovered per mouse). Some strains tested will colonize upward of 90% of infected mice, while others will colonize as few as 20–30% of mice ([ 17 , 20 , 21 ] and unpublished data). Colonization is also short-term, with most transgenic mice clearing nasal infection within 10–14 days post inoculation, corresponding with the time required for the emergence of an adaptive immune response [ 17 ].…”

“…Colonization is quantified by the number of colony-forming units (CFU) recovered from the mouse nose at various time points following infection [ 17 ]. A diverse array of meningococcal strains are capable of colonizing hCEACAM1 mice, including historically relevant lab strains [ 17 , 20 ], as well as low-passage clinical strains [ 21 ]. N. meningitidis binds to hCEACAM1 via its colony opacity-associated (Opa) proteins [ 17 ].…”