[[Emerging Infectious Diseases]
[Volume 4 No. 2 / April - June 1998]

Perspectives

Campylobacter jejuni Strains from Patients with Guillain-Barr Syndrome

Ban Mishu Allos,* Frank T. Lippy,* Andrea Carlsen,* Ronald G. Washburn,
and Martin J. Blaser*
*Vanderbilt University School of Medicine, The Department of Veterans
Affairs Medical Center, Nashville, Tennessee, USA; and The Bowman Gray
School of Medicine, Winston-Salem, North Carolina, USA

---------------------------------------------------------------------------
      Guillain-Barr syndrome (GBS), an acute demyelinating
      peripheral neuropathy, may be triggered by an acute infectious
      illness; infection with Campylobacter jejuni is the most
      frequently reported antecedent event. In Japan, O:19 is the
      most common serotype among GBS-associated C. jejuni strains. To
      determine whether serotype O:19 occurs among GBS-associated
      strains in the United States and Europe, we serotyped seven
      such strains and found that two (29%) of seven GBS-associated
      strains from patients in the United States and Germany were
      serotype O:19. To determine whether GBS-associated strains may
      be resistant to killing by normal human serum (NHS), we studied
      the serum susceptibility of 17 GBS- and 27 enteritis-associated
      strains (including many O:19 and non-O:19 strains) using C.
      jejuni antibody positive (pool 1) or negative (pool 2) human
      serum. Using pool 1 serum we found that one (6%) of 18 serotype
      O:19 strains compared with 11 (42%) of 26 non-O:19 strains were
      killed; results using pool 2 serum were nearly identical.
      Finally, 8 O:19 and 8 non-O:19 strains were not significantly
      different in their ability to bind complement component C3.
      Serotype O:19 C. jejuni strains were overrepresented among
      GBS-associated strains in the United States and Germany and
      were significantly more serum-resistant than non-O:19 strains.
      The mechanism of this resistance appears unrelated to C3
      binding.

Guillain-Barr syndrome (GBS) is an acute demyelinating polyneuropathy
characterized by an immunologic attack upon peripheral nerve myelin (1,2).
The trigger for this immune attack is unknown; however, GBS is frequently
preceded by an acute infectious illness (3). In recent years, infection
with Campylobacter jejuni has emerged as one of the most common antecedent
events associated with GBS. Up to 40% of patients with GBS have culture or
serologic evidence of C. jejuni infection when neurologic symptoms begin
(4-6). The many variants of GBSincluding acute motor axonal neuropathy,
acute inflammatory demyelinating neuropathy, and Miller Fisher
syndromehave also been associated with preceding C. jejuni infection
(7-9).

C. jejuni infections are common in the United States, affecting
approximately 1% of the population each year (10). Typically, they cause a
self-limited gastrointestinal illness characterized by diarrhea, abdominal
pain, and fever. However, approximately 1 in 2,000 C. jejuni infections may
be complicated by GBS (11). Because C. jejuni infections occur far more
commonly than GBS, either host (12) or strain (5,13) characteristics may
determine which infected persons contract GBS. Several reports from Japan
showed that a particular serotype, O:19, was overrepresented among C.
jejuni strains isolated from GBS patients (5,13). Among 12 Japanese
patients with GBS and culture-confirmed C. jejuni infection, 10 (83%) were
infected with strains of O:19, a serotype that accounts for only 2% of
randomly selected C. jejuni isolates in Japan (5). However, in England,
none of four C. jejuni strains isolated from patients with GBS were
serotype O:19 (6). Other Campylobacter serotypes predominate among GBS
patients in other parts of the world. All nine C. jejuni strains isolated
from GBS patients in South Africa were serotype O:41 (14); this serotype
accounts for fewer than 2% of isolates from South African children with
uncomplicated enteritis. With Lior typing (a serotyping system based upon
heat-labile antigens), all four GBS-associated C. jejuni strains in Germany
were serotype O:11 (15).

Whether the predominance of O:19 strains among GBS patients is limited to
Japan is not clear. Furthermore, the reason for the O:19 overrepresentation
among Japanese GBS strains is unknown, but their resistance to host
bacterial clearance mechanisms is one possibility. C. jejuni strains vary
in their susceptibility to the bactericidal activity in normal human serum
(NHS) (16). Bacteria that are more resistant to nonspecific serum killing
may elicit more extensive specific responses to eliminate the organism;
such elicited immune responses may have the potential of greater tissue
injury and myelin damage.

To determine whether C. jejuni serotype O:19 is an important cause of GBS
outside Japan, we serotyped GBS-associated strains from the United States
and Germany. To investigate the immunologic response to GBS-associated C.
jejuni strains, we performed two additional sets of experiments. First, we
examined the susceptibility of C. jejuni strains to NHS. Our hypothesis was
that GBS-associated Campylobacter strains, more specifically O:19 strains,
are more serum-resistant than those from patients with uncomplicated
enteritis. To further characterize the mechanism of resistance, we
determined whether C. jejuni strains isolated from GBS patients differ in
their capacity to bind complement component C3.

Statistical Analysis

We determined mean values, standard deviations, odds ratios, p-values,
paired T-tests, 95% confidence limits, and interquartile ranges. Software
included Lotus 123 and EpiInfo (a statistical software package designed by
the Centers for Disease Control and Prevention [CDC]).

Serotyping of Strains

Seven GBS-associated strains were serotyped with the O (formerly
heat-stable) serotyping scheme of Penner and Hennessy (17) and the
heat-labile serotyping scheme of Lior (18). Serotyping was conducted (19)
at the CDC Campylobacter Reference Laboratory. A GBS-associated strain was
defined as one isolated from a patient with GBS (n = 6) or from a patient
infected during an outbreak in which at least one infected person
contracted GBS (n = 1). Four strains were from patients in the United
States, and three were from patients in Germany; four of these were
isolated from women.

Serotype O:19 was present in one of four U.S. GBS-associated C. jejuni
isolates and one of three German isolates. Thus, 2 (29%) of 7
GBS-associated C. jejuni isolates from patients in the United States and
Germany were O:19. The O and heat-labile serotypes of the seven
GBS-associated strains are shown in Table 1.

Table 1. Serotypes of Guillain-Barr syndromeassociated Campylobacter jejuni
strains from the United States and Germany

----------------------------------------------------------------------
                          
   Strain designation   (O)(sup a)(HL)(sup b)
-----------------------    sero-    sero-                      Age/
CDC(sup c)Vanderbilt(sup d)type     type    Location           sex
----------------------------------------------------------------------
D459          93-002        19       77     Florida            79F
D2769         93-006         2        4     Maine              F
D4262         84-158        19       84     Germany            59F
D4266         84-196         2        4     Germany            24M
D4267         84-197         8,17    40     Germany            71F
D4271         86-381         2        4     Wisconsin          30M
D4808         93-001         1        4     Washington         57M
----------------------------------------------------------------------
(sup a)O = heat-stable.
(sup b)HL = heat-labile.
(sup c)Designated strain number assigned by the Centers for Disease Control and
Prevention Campylobacter Reference Laboratory.
(sup d)Designated strain number in the Vanderbilt Campylobacter/Helicobacter
strain collection.

Serum Bactericidal Assays

We studied 44 GBS- and enteritis-associated strains from all over the
world. We divided C. jejuni isolates into two major groups. Group 1 (17
GBS-associated strains) was divided into two subgroups. Subgroup 1A
(GBS-associated/type O:19) consisted of seven C. jejuni O:19 isolates:
three from the United States, three from Japan, and one from Germany.
Subgroup 1B (GBS-associated/non-O:19 serotype) consisted of 10 C. jejuni
isolates with serotypes other than O:19: three from the United States, two
from Germany, and five from England. Group 2 (27 enteritis-associated
strains from patients with uncomplicated enteritis but no known GBS
association) was also divided into two subgroups. Subgroup 2A (not
GBS-associated/type O:19) consisted of 11 C. jejuni O:19 isolates: 10 from
the United States and one from Japan. Subgroup 2B (not
GBS-associated/non-O:19 serotype) consisted of 16 C. jejuni isolates from
U.S. patients with serotypes other than O:19. Serum-resistant C. fetus
strain 23D and its spontaneous serum-susceptible mutant, 23B, were used as
controls (20).

Strains were grown on trypticase soy blood agar plates (BBL Cockeysville,
MD, USA) at 37C for 48 hours in an incubator containing 10% CO2, 5% O2,
and 85% N2. The bacteria were harvested in 0.15M saline and centrifuged at
8,000 g for 15 minutes. The supernatant was discarded, the pellet was
resuspended in 300 l of saline, and 10-fold serial dilutions were
performed in saline. From the 10(sup -4), 10(sup -5), and 10-6 dilutions, 
400 l aliquots of cells were added to 1.2 ml of Hanks balanced salt solution
(HBSS).

Two sources of NHS were used in these assays. Pool 1 consisted of serum
from five healthy adults that was pooled, aliquotted, and frozen at -70C.
The level of C. jejuni antibodies in pool 1 serum was determined by
enzyme-linked immunosorbent assay (ELISA) (4). The optical density ratio
(ODR) for immunoglobulin G (IgG) was 5.14; the ODR for IgM was 0.66.
Documentation of previous C. jejuni infection was not required to be
included in this pool. In contrast, pool 2 consisted of serum from two
healthy adults with only low-titer antibody. The ODR for pool 2 serum in
the IgG assay was 0.37; and the ODR in the IgM assay was 0.30. As a
control, the NHS was heated to 56oC for 30 minutes (heat inactivated NHS
[HINHS]) to ablate all complement activity.

The assay to determine susceptibility to NHS was performed in sterile,
disposable 96-well microtiter U-bottom plates (Falcon MICROTEST III, Becton
Dickinson & Co., Franklin Lakes, NJ, USA). From each of the bacterial
suspensions, a 150 l aliquot was added to duplicate wells. In addition, 50
l of NHS or HINHS (diluted to 40% with HBSS) was added; the final serum
concentration in the suspension was 10%. After the assay plate was
incubated at 37C for 1 hour, 50 l of the suspension from each well was
poured onto blood agar plates and incubated for 48 hours; the number of
CFUs was then calculated. The difference between the counts for cells
incubated with NHS and HINHS was expressed as median log(sub 10) kill for each
strain; greater than 1 log10 kill was considered a serum-susceptible strain
(21). If less than 1 log10 kill occurred, the strain was considered
serum-resistant. The identical procedure was performed using pool 1 and
pool 2 serum.

The resistance of the 44 C. jejuni strains studied to killing by NHS is
shown in Table 2. Of these strains, 12 (27%) were resistant to killing by
C. jejuni antibody-positive pool 1 serum and 10 (23%) were resistant to
killing by C. jejuni antibody-negative pool 2 serum; thus, as described
previously (22), antibodies to C. jejuni had little impact on
serum-killing. The GBS-associated strains were no more likely to be
resistant to serum-killing than were the strains from patients with
uncomplicated enteritis. However, O:19 strains were significantly more
likely than other C. jejuni serotypes to resist serum-killing, regardless
of GBS-association and serum pool used (Table 2). In serum pool 1, only 1
of 18 O:19 strains was serum-susceptible compared with 11 (42%) of 26
non-O:19 strains (odds ratio = 12.5, p = 0.008). Similarly, in serum pool
2, no O:19 strain was serum-susceptible compared with 10 (38%) of the
non-O:19 isolates.

Table 2. Susceptibility of Campylobacter jejuni strains to killing by normal
human serum (NHS)

---------------------------------------------------------------------------------                           
                   	        No. (%) with                Median log kill
                    No. of    >1 log kill(sup a,b)     (interquartile range) 
		  O    strains  ------------------------- -----------------------
Illness   serotype studied Pool 1(sup c) Pool 2(sup c)  Pool 1     Pool 2
---------------------------------------------------------------------------------

GBS(sup d)   19      7     1 (14)           0 (0)       0.53        0.39 
                                                    (0.18-0.63) (0.08-0.52)
Enteritis    19     11      0 (0)           0 (0)       0.37        0.48 
                                                    (0.09-0.47) (0.29-0.50)
GBS          non-19 10     3 (30)           3 (30)      0.70        0.43 
                                                    (0.44-1.18) (0.03-1.32)
Enteritis    non-19 16     8 (50)           7 (44)      0.90        0.59 
                                                    (0.24-2.00) (0.35-2.53)
All          19     18     1 (6)            0 (0)       0.38        0.45 
                                                    (0.17-0.58) (0.23-0.52)
All          non-19 26    11 (42)          10 (38)      0.70        0.54 
                                                    (0.26-1.86) (0.17-2.27)
---------------------------------------------------------------------------------
(sup a)Bacterial suspensions were incubated in either NHS or heat inactivated NHS
at 37C for 1 hr as described in text, and net CFU (NHS minus HINHS)
determined. Values greater than 1 log(sub 10) kill were considered to denote a
serum-susceptible strain.
(sup b)Comparison of O:19 strains with non-O:19 strains: Pool 1, odds ratio = 12.5,
p = 0.008; Pool 2, odds ratio = undefined, p = 0.003.
(sup c)Pool 1 consists of C. jejuni-antibody positive serum from five healthy
adults; Pool 2 consists of C. jejuni-antibody negative serum from two healthy
adults.
(sup d)GBS = Guillain-Barr syndrome.

(sup 125)I-C3 Binding Assays

Eight strains from Group 1 (four randomly selected from each subgroup) and
eight from Group 2 (four randomly selected from each subgroup) were grown
on blood agar plates as described above. C. fetus strains 23D and 23B again
served as controls and the assays were conducted (21). In brief, bacteria
from each plate were harvested in 1.5 ml of HBSS and were centrifuged at
8,000 g for 15 minutes; the pellet was resuspended in 0.5 ml HBSS and
adjusted to OD(sub 450)0 = 3.0. For each strain studied, a suspension of 4 l
(sup 125)I-C3 (with 20,000 cpm to 65,000 cpm) and 2.5 l of either NHS or HINHS
from pool 2 and 100 l of the bacteria-HBSS suspension were incubated at
37oC for 15 minutes. (sup 125)I-C3 was prepared in the laboratory of one of the
authors (RGW) (21). The suspensions were then centrifuged twice at 175xg
for 5 minutes, the pellet was resuspended in HBSS, and the supernatant was
discarded. The bottom 5 mm (containing the pellet) of each tube was
clipped, and emissions were determined in a gamma counter. The counts in
the negative control mixtures containing HINHS were subtracted from the NHS
counts. An assay was considered valid only if the net pellet counts (NHS
minus HINHS) for control strain 23B were at least four times higher than
for 23D. To control for nonspecific binding, the counts for each strain
studied were expressed as the ratio of net counts relative to the serum
susceptible control (23B). Each strain was assayed two to four times.

Mean binding of serum-susceptible control strain 23B was 497 cpm, whereas
mean binding of serum-resistant control strain 23D was 54. The mean ratio
of C3-binding for strain 23D to 23B of 0.114 was as expected (21). In
contrast, the mean ratio for C3 binding to C. jejuni strains in comparison
with strain 23B was 0.022 to 0.464 (mean 0.216). The eight O:19 strains
were not significantly different from the eight non-O:19 strains in their
ability to bind (sup 125)I-C3 (Table 3).

Table 3. Comparison of (sup 125)I-C3 binding to Campylobacter
jejuni strains
--------------------------------------------------------------
Measure                   Serotype of      C. jejuni strain
--------------------------------------------------------------
                             O:19              non-O:19
                            (n = 8)             (n = 8)
Counts per minute(sup a)   85 +/-51            98 +/- 48
Mean binding ratio(sup b)  0.187 +/-           0.245 +/-
                            0.116               0.130
--------------------------------------------------------------
(sup a)Bacterial cells were incubated with pool 2 normal human
serum or heat inactivated normal human serum and (sup 125)I-C3
(mean 40,416 [range 20,234-63,503]. cpm) at 37C for 15
minutes. The cells were centrifuged and washed; net (NHS
minus HINHS) 125I binding was measured as counts per minute.
p-value = 0.20 (paired T-test, 1-tailed).
(sup b)The mean binding ratio is an average of the ratio of the net
counts for each study strain relative to the net counts of
the serum-susceptible control (23B). p-value = 0.31 (paired
T-test, 1-tailed).

Conclusion

This study of GBS patients in the United States and Germany confirms the
observation made in Japan that serotype O:19 is overrepresented among
patients with C. jejuni-induced GBS. Of 298 randomly collected
Campylobacter isolates from patients with enteritis in the United States,
only 3% were serotype O:19 (19). A similarly low prevalence of O:19 strains
is found in all parts of the world, including North and South America,
Asia, and Europe (5,6,19,23). Although specific serotyping surveys have not
been done in Germany, it is unlikely that serotype O:19 is more frequent
among German C. jejuni isolates. Thus, the GBS-associated strains in our
study were more than 11 times as likely to belong to this serotype (p =
0.03). Although the association among GBS and C. jejuni serotype O:19 was
not as marked as in Japan (where more than 80% of GBS-associated isolates
are O:19), this serotype clearly is overrepresented among GBS-associated
strains in other countries. We conclude that the association of O:19
strains with GBS is not just a local phenomenon in Japan but likely
reflects a fundamental characteristic of O:19 strains. O-serotype 2 and
heat-labile serotype 4, which were common among the GBS strains, are
commonly represented among infected persons in the United States (23).

Despite the frequency of Campylobacter infections in GBS patients, such
strains are difficult to obtain for several reasons. First, in most C.
jejuni-infected patients, stools are clear before neurologic symptoms
begin. Second, most neurologists do not culture stool samples when GBS is
first diagnosed. And finally, even if a stool culture is ordered and
Campylobacter is present, few microbiology laboratories save their
isolates; by the time the case is reported, the strain has been discarded.
Thus, these seven strains represent one of the largest collections of
GBS-associated strains described. Additionally, these are likely to be
representative of the population of GBS-associated C. jejuni strains.
Unless serotype O:19 strains persist in stools longer, are more easily
cultured, or are less likely to be discarded by microbiology laboratories
(and no data support any of these possibilities), these strains probably
are not different in any systematic way from other GBS-associated isolates.

Most C. jejuni strains are susceptible to killing by human serum (22), but
because we studied highly selected strains (most either serotype O:19 or
from GBS patients), a high proportion of strains in this investigation were
resistant. In this context, the finding that C. jejuni strains from GBS
patients were no more likely than the strains from patients with
uncomplicated enteritis to be serum resistant is not surprising. Even when
the analysis was limited only to serotype O:19 strains, no differences were
found between GBS- and enteritis-associated strains. However, serotype O:19
strains were substantially less serum-susceptible than strains of other
serotypes and were 12 times as likely to be serum-resistant. Although
serotype O:19 represents only a small percentage of C. jejuni strains from
patients with uncomplicated enteritis in the United States or Japan, it is
the most common serotype identified in GBS patients in both locales. The
relatively small variation in serum susceptibility of the O:19 strains is
consistent with the close genetic relationship observed among these strains
(24).

To better understand the basis for the relative serum-resistance among the
O:19 strains, we compared their ability to bind C3 in relation to non-O:19
strains. Because C3 binding occurs after activation by either the
alternative or classical complement pathways, it is a screen for
differences in these early steps. The serum-resistance of C. fetus is
explained by the inability of C3 to bind to the cell surface (25). In
contrast, C3 binding is normal in serum-resistant Salmonella, but the C5-9
membrane attack complex does not insert properly (26). In the present
study, the lack of substantial C3 binding differences among O:19 and
non-O:19 C. jejuni strains suggests that the early steps in complement
activation are similar among strains. However, clear differences in
serum-susceptibility bespeak either rapid inactivation of C3 or reduced
assembly or function of the membrane attack complex in the more resistant
strains. Future studies should address this point.

The increasing awareness of the importance of C. jejuni infection in
triggering GBS is another example of how previously well-described diseases
have emerged as sequelae of acute infectious illnesses. This study attempts
to begin to characterize the nature of this association; however, there is
much to learn about how an acute gastrointestinal infection results in
ascending paralysis. One fact is quite clear: many more people are infected
with C. jejuni than contract GBS subsequently. Perhaps some persons are
predisposed to contracting GBS after infection with campylobacters that
might cause only uncomplicated enteritis in another patient. Conversely, as
we have suggested in this paper, some strains may be more likely than
others to trigger GBS. No associations between human leukocyte antigen
(HLA) types and GBS have been found (27,28). However, in Great Britain and
Japan, an association between HLA type and C. jejuni-associated GBS has
been suggested (9,29). Perhaps some combination of familial susceptibility,
HLA type, strain serotype, or other host or strain characteristics together
play a role in the pathogenesis of C. jejuni-induced GBS.

The relative serum-resistance of O:19 strains correlates with mechanism.
Furthermore, the relevance of these in vitro assays to the susceptibility
of organisms in vivo cannot be known with certainty. We speculate that the
relative insensitivity of these strains to the lytic effects of complement
allows them to trigger a heightened specific immunologic response. We
further speculate that this heightened immunologic response leads to injury
of peripheral nerve structures. Since only a small fraction of infections
caused by C. jejuni O:19 lead to GBS (estimated incidence 1 in 158) (30),
additional factors also must be involved in vivo.

Acknowledgments

We thank Charlotte Patton for serotyping the strains and Manfred Kist for
supplying the strains from Germany.

This work was supported by grant NIH-1-K08-NS01709 of the NINDS, NIH (BMA);
NIH grant KO4-AI01036 (RGW); and the Medical Research Service of the
Department of Veterans Affairs (MJB).

Ban Mishu Allos is an assistant professor of medicine in the Division of
Infectious Diseases, Department of Medicine and the Department of
Preventive Medicine at Vanderbilt University School of Medicine in
Nashville, Tennessee. Her clinical work relates to HIV and other infectious
diseases; her research has focused on foodborne illness in general and
Campylobacter jejuni as a cause of Guillain-Barr syndrome in particular.

Address for correspondence: Ban Mishu Allos, A-3310 MCN, Division of
Infectious Diseases, Vanderbilt University School of Medicine, Nashville,
TN 37232, USA; fax: 615-343-6160; e-mail:
Ban.mishu.allos@mcmail.vanderbilt.edu.

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Emerging Infectious Diseases
National Center for Infectious Diseases
Centers for Disease Control and Prevention
Atlanta, GA

URL: http://www.cdc.gov/ncidod/EID/vol4no2/allos.htm

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