Capsule switching of <em>Neisseria meningitidis</em>

J Swartley

A Marfin

S Edupuganti

L Liu

Departments of ^{Medicine and}^{Microbiology and Immunology, Emory University School of Medicine, and}^{Laboratories of Microbial Pathogenesis, Research Service, Veterans Administration Medical Center, Atlanta, GA 30303;}^{Health Division, Oregon Department of Human Resources, and}^{Department of Medicine, Oregon Health Sciences University, Portland, OR 97232; and}^{Division of Bacterial and Mycotic Diseases, Centers for Disease Control and Prevention, Atlanta, GA 30333}

^{To whom reprint requests should be addressed at: Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, 69 Butler Street, SE, Atlanta, GA 30303. e-mail:}ude.yrome@10petsd.

Emil C. Gotschlich, The Rockefeller University, New York, NY

Received 1996 Aug 7; Accepted 1996 Oct 31.

Abstract

The different sialic acid (serogroups B, C, Y, and W-135) and nonsialic acid (serogroup A) capsular polysaccharides expressed by Neisseria meningitidis are major virulence factors and are used as epidemiologic markers and vaccine targets. However, the identification of meningococcal isolates with similar genetic markers but expressing different capsular polysaccharides suggests that meningococcal clones can switch the type of capsule they express. We identified, except for capsule, isogenic serogroups B [(α2→8)-linked polysialic acid] and C [(α2→9)-linked polysialic acid] meningococcal isolates from an outbreak of meningococcal disease in the U. S. Pacific Northwest. We used these isolates and prototype serogroup A, B, C, Y, and W-135 strains to define the capsular biosynthetic and transport operons of the major meningococcal serogroups and to show that switching from the B to C capsule in the outbreak strain was the result of allelic exchange of the polysialyltransferase. Capsule switching was probably the result of transformation and horizontal DNA exchange in vivo of a serogroup C capsule biosynthetic operon. These findings indicate that closely related virulent meningococcal clones may not be recognized by traditional serogroup-based surveillance and can escape vaccine-induced or natural protective immunity by capsule switching. Capsule switching may be an important virulence mechanism of meningococci and other encapsulated bacterial pathogens. As vaccine development progresses and broader immunization with capsular polysaccharide conjugate vaccines becomes a reality, the ability to switch capsular types may have important implications for the impact of these vaccines.

Abstract

Neisseria meningitidis is a leading worldwide cause of meningitis and rapidly fatal sepsis in otherwise healthy individuals (1); over 350,000 cases of meningococcal disease were estimated to have occurred in 1995 (2). The problem of meningococcal disease is emphasized by the recurrence of major epidemics due to serogroups A, B, and C N. meningitidis over the last 20 years (3–9) [such as the devastating serogroup A outbreak in sub-Saharan Africa this year (W.H.O., 1996, unpublished bulletin); the recent dramatic increases in the incidence of serogroups B and C meningococcal disease in parts of North America (6–8); and the emergence in Europe and elsewhere of meningococci with decreased susceptibility to antibiotics (10)].

Differences in capsular polysaccharide chemical structure determine the meningococcal serogroups (11, 12). Meningococci of serogroups B, C, Y, and W-135 express capsules composed entirely of polysialic acid or sialic acid linked to glucose or galactose (12, 13), while the capsule of group A N. meningitidis is composed of N-acetyl mannosamine-1-phosphate (11). The currently available capsular polysaccharide vaccines for serogroups A, C, Y, or W-135 N. meningitidis are effective for control of meningococcal outbreaks in older children and adults. However, because of poor immunogenicity in young children and short-lived immunity (14), these vaccines are not routinely used for long-term prevention of meningococcal disease. In the case of group B N. meningitidis, whose (α2→8)-linked polysialic capsule is an immunotolerized self-antigen, a reliable polysaccharide vaccine is not yet available. However, rapid progress is being made in development of polysaccharide–protein conjugate vaccines, and it is hoped that, following the example of newly licensed Haemophilus influenzae type b vaccines, widespread introduction of the polysaccharide conjugates will lead to elimination of disease.

In some epidemic settings, simultaneous or closely linked meningococcal outbreaks have occurred in the same population due to different serogroups (5, 6, 15). Further, Caugant et al. (3, 16) have noted that meningococcal isolates of different serogroups may be members of the same enzyme type (ET)-5, ET-37, or ET-4 clonal complexes.

Since 1993 the number of cases of serogroup B meningococcal disease in Oregon and adjacent counties in Washington has doubled, and the overall incidence has been fivefold higher than rates observed in other parts of the United States (6). This increase was due to the first appearance in the United States of serogroup B meningococcal strains belonging to the ET-5 complex. ET-5 complex strains have been responsible for major epidemics in Norway, Iceland, Cuba, and South America over the last 20 years (3, 17, 18). Since 1994, cases of serogroup C meningococcal disease due to ET-5 complex strains were also noted in Oregon and Washington. Recent advances (19–27) in understanding the genetic basis for meningococcal capsule expression allowed us to carefully analyze the serogroup B and C ET-5 meningococcal strains responsible for the outbreak in the Pacific Northwest.

Acknowledgments

We thank Dr. Nigel Raymond for help with the PFGE studies and Lane Pucko for manuscript preparation. This work was supported by an interagency agreement and by the Emerging Infections Program of the Centers for Disease Control and Prevention, by Public Health Service Grant A140247 from the National Institutes of Allergy and Infectious Diseases, and by the Research Service of the Department of Veterans Affairs

Acknowledgments

Footnotes

Abbreviations: ET, enzyme type; PFGE, pulsed-field gel electrophoresis.

Data deposition: The sequence reported in this paper has been deposited in the GenBank data base (accession no. {"type":"entrez-nucleotide","attrs":{"text":"U75650","term_id":"2072796"}}U75650 {"type":"entrez-nucleotide","attrs":{"text":"U75650","term_id":"2072796"}}U75650).

Footnotes

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