FEMS Microbiology Reviews 19 (1997) 209^217
Coxiella burnetii
: the `query' fever bacterium
A model of immune subversion by a strictly intracellular microorganism Jean-Louis Mege, Max Maurin, Christian Capo, Didier Raoult *
Uniteè des Rickettsies, CNRS UPRESA 6020, Faculteè de Meèdecine, 27 Bd Jean Moulin, 13385 Marseille Cedex 05, France Received 20 February 1996 ; revised 8 November 1996 ; accepted 10 December 1996
Abstract Although substantial progress occurred in the knowledge of
Coxiella burnetii
during the past years, the pathophysiology of Q
fever is still obscure. Emerging evidence from clinical investigations suggested that certain disorders of cell-mediated immunity play a pivotal role in Q fever and especially in its chronic form. This review analyses the potential stategies that
C. burnetii
, a
strictly intracellular pathogen, use to divert microbicidal mechanisms of macrophages and to depress protective T-cell mediated immunity. The role of monocytes in the induction of Q fever is specifically discussed.
Keywords: Coxiella burnetii
; Q fever ; Macrophage ; Immunosuppression ; Cytokine
Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
209
2. What kind of bacterium is
210
3. How does
Coxiella burnetii
? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Coxiella burnetii C. burnetii Coxiella burnetii Coxiella burnetii . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . C. burnetii divert microbicidal mechanisms ?
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
211
in acidic vacuoles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
211
targeting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
212
depress T cell-mediated immunity ? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
213
3.1. Survival of
3.2. Cell receptors and
3.3. Immunomodulation by 4. How does
212
5. Monocytes and Q fever endocarditis : a hypothesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
214
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
215
1. Introduction
rium, is the etiologic agent of Q fever, a zoonosis
Coxiella burnetii
, an obligate intracellular bacte-
of worldwide distribution [1]. The precise prevalence of
C. burnetii
infections in humans is unknown as its
clinical picture is non-speci¢c and diagnosis is usu* Corresponding author. Tel : +33 (4) 91 83 43 75 ; fax : +33 (4) 91 83 03 90 ; e-mail :
[email protected]
ally based on serology. In Southern France, the prevalence of acute Q fever is 50 per 100,000 inhabitants.
0168-6445 / 97 / $32.00 ß 1997 Federation of European Microbiological Societies. Published by Elsevier Science B.V.
PII
S0168-6445(96)00030-7
210
J.-L. Mege et al. / FEMS Microbiology Reviews 19 (1997) 209^217
Large outbreaks of Q fever have been also reported in Switzerland, Great Britain and Canada [2]. Q fever is characterized by two major evolutive forms with distinct prognosis. The clinical expression of the acute form is wide with acute febrile illness, pneumonia, hepatitis and meningoencephalitis. During acute infection, doughnut granulomas consisting of macrophages and lymphocytes have been found in liver and bone marrow biopsy specimens [3] whereas the alveolar exsudates of C. burnetii-induced pneumonia were composed of histiocytes [4]. All these lesions result from an e¤cient cell-mediated immune response limiting bacterial multiplication and leading to a favorable prognosis. On the other hand, the chronic form of Q fever may occur several months to years after acute infection and is usually expressed as an endocarditis with severe prognosis and more rarely as vascular infection. Q fever endocarditis is the main cause of culture-negative endocarditis, and represents approximatively 10% of all diagnosed endocarditis cases. In situ studies showed many microorganisms without granulomatous formation in heart valves [4]. Bone infection or chronic hepatitis may also indicate chronic Q fever. Clinical and epidemiological investigations demonstrated that the development of chronic Q fever is often associated with immunosuppression caused by Human Immunode¢ciency Virus (HIV) infection, cancer, lymphoma, chronic renal failure or pregnancy [5^8]. Hence, it is likely that some disorders of cell-mediated immunity play a pivotal role in chronic infection. Three main questions will be evoked in this review. First, what kind of bacterium is C. burnetii ? Second, how does C. burnetii divert microbicidal mechanisms and escape immune response? Third, how does C. burnetii cause endocarditis? 2. What kind of bacterium is
Coxiella burnetii ?
C. burnetii, a Gram-negative bacterium, is the only species of the genus Coxiella. It was initially classi¢ed in the Rickettsiaceae family and Rickettsiale order because of its obligate intracellular life and because it is transmitted by ticks. More recently, molecular biology techniques including 16S rRNA
gene sequence analysis have placed C. burnetii, Wolbachia persica and Legionella pneumophila in the
gamma
subdivision
of
Proteobacteria,
and
Rickettsia, Ehrlichia and Bartonella spp. in the alpha group [9,10]. Whereas C. burnetii and L. pneumophila
survive in soil and water and are most often transmitted to humans by aerosols, only C. burnetii is a strictly intracellular bacterium. The reservoirs of C. burnetii may be multiple. Its transmission to humans by tick bite is rare. Pets, speci¢cally pregnant females at the time of delivery, may be responsible for infection by C. burnetii since it displays high tropism for the female reproductive system, thus causing abortions. Humans are also infected by inhalation of infected fomites or, less frequently, after ingestion of contaminated dairy products such as milk [11]. Envelopes of C. burnetii contain outer membrane proteins, lipopolysaccharide (LPS) and A-1-gamma type peptidoglycan. Mutational variation in the LPS is linked to shifts in antigenicity and virulence, termed `phase variation'. Phase I C. burnetii are recovered from infected humans and animals, and are characterized by smooth-type LPS and high virulence. Conversely, phase II C. burnetii are obtained after serial passages in embryonated eggs or cell cultures, and express rough-type LPS and dramatically reduced virulence. In addition, the sugar composition of each LPS is quite di¡erent. LPS in phase I contains sugars such as L-virenose, dihydrohydroxystreptose and galactosamine uronyl-K-(1^6)-glucosamine which are lacking in phase II LPS [12,13]. Although phenotype reversion upon passage of phase II microorganisms through laboratory animals had been suspected, it is now evident that there is a selection for few phase I remaining in uncloned phase II bacteria [14]. In addition, C. burnetii undergoes a complex intracellular cycle leading to the formation of variants of di¡erent size and to sporulation under speci¢c environmental conditions. Although few genetic studies have been conducted, it is known that the genome of C. burnetii contains about 1600 kb [15]. Only a few chromosomal genes have been cloned and expressed in Escherichia coli : the gltA citrate synthase gene [16], the superoxide dismutase gene [17], the genes coding for the heat shock proteins htpA and htpB [18], and a gene coding for a 27 kDa surface antigen [19]. Base composition and codon usage have been analyzed to com-
J.-L. Mege et al. / FEMS Microbiology Reviews 19 (1997) 209^217 pare C. burnetii with other microorganisms. A codon bias is probable in C. burnetii since an inordinate use of U or A in the ¢rst and the third codons has been described. In contrast to the previous theory concerning codon usage, C. burnetii has a preference for A or U in the ¢rst and the third positions regardless the nucleotide in the second position [20]. In addition, three plasmids in di¡erent strains of C. burnetii have been described: QpH1, QpRS, and QpDG [21]. QpH1 and QpRS plasmids were tentatively associated with the onset of acute and chronic diseases respectively. The Nine Mile and Henzerling strains, recovered from ticks and humans su¡ering from acute disease, contained the QpH1 plasmid and were considered as the reference strains for acute Q fever. The Priscilla and Q212 strains, recovered from a goat chronically infected and from a patient with endocarditis, contained the QpRS plasmid and were considered as reference strains for chronic Q fever [22]. More recent investigations, using an enlarged panel of C. burnetii strains which were mainly obtained from infected patients, did not however con¢rm such hypothesis [23]. It is likely that these plasmids remain cryptic.
3. How does Coxiella mechanisms?
211
burnetii
divert microbicidal
3.1. Survival of C. burnetii in acidic vacuoles The maintenance of C. burnetii infection depends on the multiplication of the pathogen inside an acidic vacuole and the avoidance of microbicidal activities in host macrophages. In contrast to other intracellular bacteria such as Legionella or Mycobacteria, the adaptation of C. burnetii to the intracellular environment is a prerequisite for its survival and its multiplication [1]. The acidic environment allows the penetration of nutrients necessary for the metabolism of C. burnetii [24]. It also protects C. burnetii from antibiotic treatment since the activity of antibiotics is altered by acidic pH. This may account for Q fever relapses despite antibacterial treatment. When lysosomotropic agents such as chloroquine which alkalinize the phagolysosomal compartment were combined with doxycycline, macrophage microbicidal machinery towards C. burnetii was stimulated [25]. Several features characterize C. burnetii parasitism
Fig. 1. Intracellular fate of Coxiella burnetii. The virulent bacteria in phase I (CB I) are recognized by the LRI-IAP complex on human monocytes but are poorly phagocytozed. The avirulent bacteria in phase II (CB II) also bind CR3 of phagocytes accounting for an e¤cient phagocytosis. The survival and the multiplication of Coxiella burnetii is observed in mature phagolysosomes, i.e., expressing membrane proton ATPase and lysosomal markers LAMP1 and LAMP2, and containing lysosomal enzymes. Golgi vesicles are not engaged in the intracellular fate of C. burnetii. It is probable that the acidic pH of phagolysosomes protects C. burnetii of the activity of antibiotics. Oxygen scavengers expressed by C. burnetii impair the oxidative response, a major antimicrobial defense of macrophages.
J.-L. Mege et al. / FEMS Microbiology Reviews 19 (1997) 209^217
212
sistent infection of ¢broblastic cell lines such as
Legionella pneumophila or Mycobacterium tuberculosis [32]. The interaction of C. burnetii with
Vero, L929 and HEL cells and myeloid cells such
human monocytes and macrophages involves anoth-
as P388D1 cells. But, in vivo, its multiplication is
er class of integrins. The binding of
apparently restricted to cells belonging to the mono-
human monocytes is mediated by the complex con-
nuclear phagocyte system [26]. Second, infected mur-
sisting of LRI (Leukocyte Response Integrin,
ine macrophage-like cells show a single vacuole ¢lled
and IAP (Integrin Associated Protein) [33]. While
with microorganisms, which is able to fuse with ly-
phase I (virulent form) which is weakly internalized
sosomes. Vacuoles containing
only engages the integrin complex,
(Fig. 1). First,
C. burnetii can establish in vitro per-
C. burnetii ful¢lled the
spp.,
C. burnetii
KvL3)
C. burnetii L2
to
in
criteria of mature phagolysosomes including the se-
phase II (avirulent form) also bind
integrins,
questration of £uid phase markers, the expression of
thus accounting for its more e¤cient phagocytosis
proton ATPase and lysosomal glycoproteins LAMP-
(manuscript in preparation). It is tempting to spec-
1 and LAMP-2, and lysosomal enzymes such as
ulate that LRI and IAP are required for the adhesion
cathepsin D and acid phosphatase. In addition, these
of
vacuoles do not interact with Golgi-derived vesicles
C. burnetii to several cell types but the fate of C. burnetii in monocytes and macrophages is in£uenced
containing
by the engagement of speci¢c coreceptors (Fig. 1).
newly
synthesized
sphingolipids
Third, phagolysosomes containing
C. burnetii
[27]. have
a pH of 5.2 [26,27]. It has been suggested that the
3.3. Immunomodulation by Coxiella burnetii
acidi¢cation of a maturing phagosome depends upon the delivery to the phagosome of the vacuolar proton
The subversion of macrophage microbicidal mech-
C. burnetii to survive in acidic
pump which is present in early and late endosomes
anisms is required for
[28]. This ATPase is lacking in phagosomes contain-
vacuoles. First of all, limiting the microbicidal e¡ects
ing mycobacteria, known to inhibit phagosome-ly-
of reactive oxygen intermediates is a strategy used by
some fusion and to survive in alkaline environment
occasionally intracellular pathogens such as
[29].
Leishmania spp. and C. burnetii share the prop-
Mycobacteria spp. and Legionella spp. [34,35]. C. burnetii
erty of surviving and multiplying in acidic phagoly-
possesses oxygen scavengers such as superoxide dis-
sosomes. While particles such as yeasts,
mutase and catalase [36] which can blunt the oxida-
L glucan and
C. burnetii did not induce superoxide
latex beads were easily transferred to vacuoles con-
C. burnetii in CHO cells, the e¤ciency of the
tive response.
taining
by itself and did not depress agonist-induced super-
vectorial transfer was dampened in cells infected with
oxide generation in human monocytes (unpublished
Leishmania amazonensis [30]. Although C. burnetii and L. amazonensis were con¢ned within the same
data). Second, the decreased generation of macrophage cytotoxic cytokines such as Tumor Necrosis
K is bene¢cial for the survival of intra-
vacuoles in double infected cells, it is likely that the
Factor (TNF)
speci¢c behavior of
cellular pathogens. For instance, lipoarabinomannan
C. burnetii
depends on cellular
from virulent isolates of
events upstream from phagosome formation.
3.2. Cell receptors and Coxiella burnetii targeting During the past few years, it has become evident
gers TNF
K
M. tuberculosis poorly trig-
production whereas that from avirulent
isolates markedly increases TNF
burnetii
K
release [37].
C.
exhibits a distinct behavior. Virulent phase
I bacteria highly stimulated the synthesis and the
K
that numerous microorganisms use speci¢c eucary-
secretion of TNF
otic receptors such as integrins to invade host cells.
avirulent phase II bacteria were less e¤cient (manu-
Integrins
script
are
heterodimeric
glycoproteins
whose
in
in human monocytes whereas
preparation).
Cytokines
such
as
K
TNF
C. burnetii,
binding speci¢city is generated by varied combina-
probably favor the ingestion of phase I
tions of 14
which is poorly internalized, by upregulating adhe-
K
subunits and 8
L
subunits identi¢ed
to date [31] (Fig. 1). One of these receptors, CR3 (
KM L2)
is known to be one of the most important
sion
receptors
Moreover, TNF
on
K
monocytes
and
macrophages.
may also trigger pathophysiologi-
phagocyte receptors involved in the binding and the
cal responses associated with acute infection such as
uptake of bacteria and parasites such as
the development of granulomas [3]. Third, mainte-
Leishmania
J.-L. Mege et al. / FEMS Microbiology Reviews 19 (1997) 209^217 nance of C. burnetii infection probably involves either the depression of speci¢c T cell responses and/or the down-modulation of macrophage responsiveness. The decrease in cell-mediated immunity by ionizing radiations, corticosteroids, or parturition modi¢es the natural resistance of mice to C. burnetii [38]. Athymic mice became chronically infected by bacteria in phase I whereas euthymic mice were able to kill them [39]. The onset of chronic Q fever is largely determined by the immunological status of human recipients. Several sporadic cases of Q fever have been reported in patients immunocompromised by Crohn's disease, alcoholism, or immunosuppressive treatment [5,40]. Q fever also occurred as a complication of hematologic and solid neoplasms [41]. A higher percentage of HIV-infected individuals were positive for Q fever antibodies as compared with blood donors [8]. It is probable that antigen-presenting defect of monocytes and dendritic cells, an initial event in HIV infection [42], favors the persistence of C. burnetii in macrophages without the development of protective immune response. In addition, Q fever is reactivated during pregnancy [43,44], suggesting that the fetalplacental unit secretes Th2 cytokines to divert the maternal Th1-mediated response [45]. On the other hand, the down-modulation of macrophage responses to lymphokines may create a protected environment for the pathogen. The priming of microbicidal functions of macrophages by interferon (IFN) Q [46] limits the multiplication of intracellular parasites and bacteria including C. burnetii [47,48]. However, we recently found that monocytes infected with C. burnetii cannot be primed by IFNQ for oxidative metabolism (unpublished data). This de¢ciency is reminiscent of defective IFNQ-mediated priming for cytotoxicity observed in macrophages from A/J mice which are highly susceptible to C. burnetii infection [49]. 4. How does C. immunity?
burnetii depress T cell-mediated
In addition to subverted microbicidal functions of macrophages, the survival of C. burnetii requires the impairment of protective T cell responses. Di¡erent strategies may be used: down-modulation of Th1
213
lymphokine production, alteration of antigen processing and/or presentation, and induction of suppressor factors. Ine¤cient antigen presentation and down-modulation of MHC Class II molecules have been reported in M. tuberculosis-infected monocytes [50] and may be operative in C. burnetii infection. They may result from inhibition of the intracellular tra¤c of MHC Class II molecules or peptides and/or secretion of cytokines depressing antigen-presenting activity, such as interleukin (IL)-10. Moreover, leishmanial or mycobacterial infection down-modulated the expression of B7 and ICAM-1 antigens [51] which are cosignal molecules necessary for T cell activation [52]. To date, it is not possible to establish either hypothesis. The mechanisms of antigen-dependent suppression are more documented. Peripheral blood lymphocytes (PBL) from patients who have convalesced from acute Q fever and patients with active Q fever hepatitis manifested a marked proliferative response when cultured in vitro with C. burnetii antigen [53]. Similarly, a high percentage of individuals exposed to low infection risk exhibited speci¢c lymphoproliferative response early after vaccination with formalin-inactivated C. burnetii [54,55]. A large percentage of antigen-stimulated PBL secreted IFNQ [56]. In contrast, PBL from patients with Q fever endocarditis did not proliferate in the presence of C. burnetii antigen while their response to Candida albicans antigen or mitogens was maintained [57]. This suppression is not mediated by CD8 T cells since their removal did not restore lymphoproliferation, in contrast to lepromatous leprosis [57]; it seems that prostaglandins (PG) depress T-cell mediated immunity against C. burnetii. High amounts of PGE2 were produced in response to C. burnetii by peripheral blood mononuclear cells (PBMC) from patients with endocarditis; PBL proliferation was restored by indomethacine [57]. Cytokines such as Transforming Growth Factor (TGF) L and IL-10 are produced in excess by PBMC and monocytes from patients with Q fever endocarditis, and we showed that the increase in IL-10 production was associated with the occurrence of Q fever relapses [58]. These mediators may also be involved in the down-modulation of speci¢c T cell responses. We also found that T cell compartment may be a¡ected in chronic Q fever. Indeed, these patients exhibited CD4 T cell lym-
J.-L. Mege et al./FEMS Microbiology Reviews 19 (1997) 209^217
214
Coxiella burnetii
Fig. 2. A model for Q fever endocarditis. stimulated the secretion of proin£ammatory cytokines such as TNFK, known to up-regulate adhesion molecules, possibly integrins and selectins. The interaction between infected macrophages and endothelium is favored by this up-regulation of adhesion molecules and chemokine synthesis, leading to the colonization of valvular tissues. On the other hand, the infection is characterized by a defective cell-mediated immunity probably driven by a cytokine such as IL-10. The resulting impaired production of IFNQ by lymphocytes limits the microbicidal response of macrophages and then favors the intracellular survival of .
C. burnetii C. burnetii
phopenia related to the activity of the disease. The study of CD45RO and CD45RA expression by CD4 T cells provided evidence that lymphopenia preferentially a¡ected unprimed lymphocytes [59]. The induction of suppressive mediators by monocytes may result from the action of speci¢c bacterial determinants. Indeed, lipoarabinomannan isolated from and inhibited T cell proliferation responses, the expression of IL-2 gene in human T cells and the IFNQ-mediated activation of macrophages [60]. Growing monocytes and T cells from vaccinated individuals with phase I led to residual production of IFNQ whereas phase II bacteria stimulated strong IFNQ production. Pretreatment of phase I LPS with periodate, which yields an arti¢cial phase II LPS, restored IFNQ production [56]. In addition, treating phase I with trichloroacetic acid yielded a soluble antigen consisting of LPS and proteins, and a residue with low amounts of LPS. While the residue clearly elicited lympho-proliferative response, the soluble antigen was weakly e¡ective [61]. Hence, LPS probably promotes the suppression of IFNQ production by
M. tuberculosis
M. leprae
C. burnetii C. burnetii
PBL from patients with Q fever endocarditis by masking bacterial determinants critical for lymphokine production. Indeed, the extended structure of phase I LPS might sterically block the access of speci¢c antibodies to surface proteins [62]. 5. Monocytes and Q fever endocarditis: a hypothesis
Q fever endocarditis is one of the rare endocardites caused by an intracellular pathogen; most of the infections of endocardial heart surfaces are caused by extracellular microorganisms, such as streptococci or staphylococci [63]. This endocarditis is atypical because it is associated with rare vegetations and negative blood culture. These cause diagnosis delay, accounting for the especially severe prognosis [2]. Clearly, the occurrence of Q fever endocarditis does not depend on the sub-type of isolate (see Section 2). It is now accepted that the onset of Q fever endocarditis requires previous valvular lesions and/or defective cell-mediated immunity [5]. induced valvular endocar-
C.
burnetii
C. burnetii
J.-L. Mege et al. / FEMS Microbiology Reviews 19 (1997) 209^217 ditis in mice treated by cyclophosphamide but not in immunocompetent mice without preinjury of cardiac valves [64]. Clinical investigations of chronic Q fever have revealed suppression of speci¢c T cell responses [57] and activation of circulating monocytes, assessed by the release of in£ammatory cytokines [65] (Fig. 2). The strictly intracellular behavior of C. burnetii, excluding a direct colonization of valvular tissues, implies its vectorization by monocytes. Nevertheless, the infection of circulating monocytes cannot account for their activation and their speci¢c targeting since few monocytes from patients with endocarditis harbor the pathogen. Since the interaction between these few infected cells and valvular tissue would be rare, additional factors are probably required for valvular colonization. As it is established that immune complexes are constantly found in chronic Q fever [2], we hypothesize that immune complexes play a crucial role in the initiation of C. burnetii endocarditis. They would elicit the release of eicosanoids and cytokines by monocytes [66] and suppress protective cell-mediated immunity via the induction of IL-10 [67]. In the context of Q fever, once circulating monocytes are activated by immune complexes, they release TNFK and IL-1L which upregulate the expression of cell adhesion molecules including L integrins. Monocytes can then ¢rmly attach to modi¢ed valvular tissue. Its modi¢cation may result in the release of chemoattractants, such as L chemokines, which may favor the tra¤c of monocytes, thus creating the conditions for the targeting of the minority of monocytes containing C. burnetii. Our hypothesis will now be tested in dynamic conditions with infected monocytes and modi¢ed endothelium.
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