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Background: Q fever has become a major public health problem in The Netherlands. Infection with Coxiella burnetii (Q fever) during pregnancy has resulted in adverse pregnancy outcome in the majority of reported cases. Therefore, we aimed to quantify this risk by examining the earliest periods corresponding to the epidemic in The Netherlands., Methods: Serum samples that had been collected from the area of highest incidence by an existing national prenatal screening programme and data from the Netherlands Perinatal Registry (PRN) on diagnosis and outcome were used. We performed indirect immunofluorescence assay to detect the presence of IgM and IgG antibodies against C. burnetii in the samples. The serological results were analyzed to determine statistical association with recorded pregnancy outcome., Results: Evaluation of serological results for 1174 women in the PRN indicated that the presence of IgM and IgG antibodies against phase II of C. burnetii was not significantly associated with preterm delivery, low birth weight, or several other outcome measures., Conclusion: The present population-based study showed no evidence of adverse pregnancy outcome among women who had antibodies to C. burnetii during early pregnancy.

Coxiella burnetii is a Gram-negative obligate intracellular pathogen and the causative agent of Q fever in humans. Q fever causes acute flu-like symptoms and may develop into a chronic disease leading to endocarditis. Its potential as a bioweapon has led to its classification as a category B select agent. An effective inactivated whole-cell vaccine (WCV) currently exists but causes severe granulomatous/necrotizing reactions in individuals with prior exposure, and is not licensed for use in most countries. Current efforts to reduce or eliminate the deleterious reactions associated with WCVs have focused on identifying potential subunit vaccine candidates. Both humoral and T cell-mediated responses are required for protection in animal models. In this study, nine novel immunogenic C. burnetii proteins were identified in extracted whole-cell lysates using 2D electrophoresis, immunoblotting with immune guinea pig sera, and tandem MS. The immunogenic C. burnetii proteins elicited antigen-specific IgG in guinea pigs vaccinated with whole-cell killed Nine Mile phase I vaccine, suggesting a T cell-dependent response. Eleven additional proteins previously shown to react with immune human sera were also antigenic in guinea pigs, showing the relevance of the guinea pig immunization model for antigen discovery. The antigens described here warrant further investigation to validate their potential use as subunit vaccine candidates.

Coxiella burnetii is the etiological agent of human Q fever. In this study, adaptive transfer of mouse bone marrow-derived dendritic cells (BMDCs) stimulated with C. burnetii antigen, phase I whole-cell antigen (PIAg), lipopolysaccharide (LPS)-removed PIAg (PIIAg), protein antigen Com1, or SecB significantly reduced coxiella burden in recipient mice compared with control mice. Mice that received PIIAg-pulsed BMDCs displayed substantially lower coxiella burden than recipient mice of PIAg-pulsed BMDCs after C burnetii challenge. The protection offered by the antigen-activated BMDCs was correlated with the increased proliferation of helper T (T(H)) T(H)1 CD4(+) cells, preferential development of T(H)17 cells, and impaired expansion of regulatory T lymphocytes. Our results suggest that PIIAg is far superior to PIAg in activating BMDCs to confer protection against C. burnetii in vivo, whereas Com1 and SecB are protective antigens because Com1- or SecB-pulsed BMDCs confer partial protection.

In the Netherlands, the number of notified human Q fever cases showed a steep increase over the last three years and is not expected to disappear in the next few years. Since vaccination might be an option to prevent Q fever cases in the general population, evidence is needed about its effectiveness. We therefore conducted a meta-analysis to determine the evidence base for effectiveness for Q fever vaccination in human populations. We calculated Mantel-Haenszel risk ratios and we used the following formula to calculate the vaccines effectiveness: (1-mhRR) × 100%. Although individual and the pooled estimates showed a high effectiveness of Q fever vaccine, conclusions for the general population cannot be confidently drawn about vaccine effectiveness due to potential flaws in the design of the studies and the selected group of study participants., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Objective: The aim of this study was to assess the clinical significance of serological profiles suggestive of chronic Q fever after acute infection., Methods: A prospective follow-up study consisting of two separate cohorts was conducted to monitor the serological evolution of Q fever. The first cohort comprised subjects with acute Q fever diagnosed in 2004-2007 and the second enrolled subjects whose infection occurred in 2009. The indirect immunofluorescence assay was used for serological monitoring, with serum PCR testing added for subjects whose serological profiles revealed high titers of anti-phase I IgG≥800, titers suggestive of chronic Q fever., Results: In the first cohort of 92 persons, seventeen (18%) subjects had serological profiles suggestive of chronic Q fever (titers of anti-phase I IgG: 1280-5120, median: 1280) after a median follow-up period of 606.5 days. After a further follow-up (median period: 592 days) exclusively for those seventeen subjects, serological resolution with fourfold decrease of titers of anti-phase I IgG was noted in five of them. In the second cohort, only one (4%) of the twenty-eight subjects had high levels of anti-phase I IgG 180 days after acute infection. All the eighteen subjects with high levels of anti-phase I IgG were asymptomatic and had negative serum PCR testing. The different prevalence of subjects with high titers of anti-phase I IgG in the two cohorts was associated with duration of follow-up period (P < .01)., Conclusions: Subjects with high titers of anti-phase I IgG≥800 was not uncommon and might not be detected until more than six months after acute Q fever infection. Asymptomatic subjects with high levels of anti-phase I IgG alone should not be treated as chronic Q fever and might not need continued serological monitoring in the absence of predisposing factors to chronic Q fever., (Copyright © 2010 The British Infection Association. Published by Elsevier Ltd. All rights reserved.)

The present study investigated the prevalence of antibodies to Coxiella burnetii and the possible factors predisposing students of veterinary medicine to C. burnetii infections. IgG antibodies to phase I and phase II C. burnetii antigens were determined by ELISA. Out of 77 students examined, 13 were positive for phase I and 45 were positive for phase II antibodies. The titres determined were in the range of 1 : 100-1 : 3200. Some risk factors may have contributed to the high seroprevalence found in these subjects. For example, there were positive associations with rural life and exposure to the breeding of farm animals, and in addition, work in a dusty environment, such as on fields, gardens, stables and construction sites were also connected to high seroprevalence.

Background: Q fever is a zoonosis caused by the obligate intracellular bacterium Coxiella burnetii. The two long-term complications, after primary infection, are chronic Q fever in ∼1% of patients, and a chronic fatigue syndrome in 10-20%. However, the existence of a protracted decreased health status after Q fever remains controversial., Aim: To determine the health status of the patients of the Q fever outbreak in The Netherlands in 2007, 1 year after primary infection., Design: Cross-sectional case-control study., Methods: Health status of the patients from the 2007 Dutch Q fever outbreak was compared to age-, sex- and geographically matched and Q fever seronegative controls. Health status of both patients and controls was assessed with the Nijmegen Clinical Screening Instrument (NCSI)., Results: Fifty-four Q fever patients provided 34 years of age- and sex-matched controls from the same neighbourhood. Eleven controls had positive Q fever serology and were excluded. Q fever patients had significantly more problems on the subdomains of symptoms and functional impairment. Overall quality of life was decreased in both patients and controls, 59% vs. 39%, respectively, ns). Severe fatigue levels were present in 52% of patients vs. 26% in controls (P < 0.05)., Conclusion: These data support a sustained decrease in many aspects of health status in Q fever patients in The Netherlands, 1 year after primary infection.

Coxiella burnetii and Legionella pneumophila are evolutionarily related pathogens with different intracellular infection strategies. C. burnetii persists within and is transmitted by mammalian hosts, whereas, L. pneumophila is found primarily in the environment associated with protozoan hosts. Although a type IV secretion system encoded by the defect in organelle trafficking (dot) and intracellular multiplication (icm) genes is a virulence determinant that remains highly conserved in both bacteria, the two pathogens encode a different array of effector proteins that are delivered into host cells by the Dot/Icm machinery. This difference suggests that adaptations to evolutionarily distinct hosts may be reflected in the effector protein repertoires displayed by these two pathogens. Here we provide evidence in support of this hypothesis. We show that a unique C. burnetii effector from the ankyrin repeat (Ank) family called AnkG interferes with the mammalian apoptosis pathway. AnkG was found to interact with the host protein gC1qR (p32). Either the addition of AnkG to the repertoire of L. pneumophila effector proteins or the silencing of p32 in mouse dendritic cells resulted in a gain of function that allowed intracellular replication of L. pneumophila in these normally restrictive mammalian host cells by preventing rapid pathogen-induced apoptosis. These data indicate that p32 regulates pathogen-induced apoptosis and that AnkG functions to block this pathway. Thus, emergence of an effector protein that interferes with a proapoptotic signaling pathway directed against intracellular bacteria correlates with adaptation of a pathogen to mammalian hosts.

Background: Previous studies of inciting factors for a prolonged post-infection fatigue syndrome after Q fever (variously termed QFS or Q fever associated CFS/ME in the literature) showed that after the acute infection a high proportion of asymptomatic and QFS patients had Q fever antibody and also low levels in PBMC and bone marrow of Coxiella burnetii (C.b.) DNA with PCR assays directed against three different target sequences in different parts of the coxiella genome. Attempts to isolate a strain of C.b. in A/J mice, and cell culture from PCR positive PBMC and bone marrow were consistently negative. The detailed composition of the persisting coxiella residues remains to be defined., Aim: To retest and provide detailed results on selected PCR positive samples from the Birmingham Q fever outbreak patients tested by a highly sensitive method to detect viable organisms and to determine the nature of the residual coxiella cell components., Design: Laboratory case study., Methods: NOD/SCID mice were inoculated with samples from the 1989 Q fever outbreak in Birmingham and followed for evidence of infection and the presence of coxiella DNA and specific antigens in spleen and liver macrophages. A significant, unexpected finding of specific antigen was followed by assessment of its ability to provoke production of inflammatory and non-inflammatory cytokines in mice, in THP-1 human macrophage cell cultures and to induce inflammatory lesions in the skin of guinea pigs hyperimmunized against Q fever vaccine., Results: Culture of samples from 10 Birmingham Q fever patients in NOD/SCID mice, 12 years from infection did not yield viable Coxiella burnetii, as shown earlier. However complexes of material with coxiella antigens were found in mouse spleens in all cases but in significantly greater amounts in samples from those with post Q fever fatigue syndrome. The antigenic complexes [now designated 'immunomodulatory complexes' (IMC)] were shown to stimulate cytokine release in the mice and in the THP-1 macrophages and to provoke an inflammatory reaction on intradermal injection into the skin of Q fever hyperimmunized guinea pigs., Conclusion: The study identifies a non-infective complex of C.b. antigens able to survive in the host and provoke aberrant humoral and cell medicated immunity responses - a possible pathogenic link between initial infection and a subsequent long-term post Q fever fatigue syndrome.

There is little information on human Q fever in Iran and other Middle East countries. The aim of this study was to determine apparent Q fever seropositivity among febrile patients with suspected brucellosis in southeast Iran. Coxiella burnetii phases I and II specific IgG antibodies were measured by a commercial enzyme-linked immunosorbent assay (ELISA) in sera from 75 febrile patients. Phase I antibodies were detected in 18 subjects (24%) and phase II antibodies in 27 subjects (36%). This is the first report of human Q fever seropositivity in Iran after 3 decades and demonstrated a high prevalence of C. burnetii exposure in the sampled febrile patients., (Copyright 2010 Royal Society of Tropical Medicine and Hygiene. Published by Elsevier Ltd. All rights reserved.)

Q fever is a zoonotic infection caused by Coxiella burnetii that is endemic worldwide. Domestic ruminants are a source of infection for humans. Given the suggestion that the bacterium recrudesces during pregnancy in cattle, this study was designed to determine whether C. burnetii infection affects hormonal patterns, such as progesterone, cortisol, pregnancy associated glycoproteins (PAG), and prolactin during gestation in lactating cows. Possible interactions with Neospora caninum were also explored. The study was performed on 58 gestating non-aborting cows. Blood samples for hormone determinations were collected on Days 40, 90, 120, 150, 180, and 210 of gestation. For antibody determinations, blood was collected at day 40 postinsemination and postpartum. By GLM repeated measures analysis of variance, we established the effects of production and reproductive variables as well as Coxiella and Neospora seropositivity related to changes on cortisol, PAG, progesterone, and prolactin levels. Coxiella antibody levels were significantly related to cortisol, PAG, and plasma progesterone concentrations, whereas Neospora seropositivity was linked to plasma progesterone concentrations. The interaction between Coxiella and Neospora seropositivity was correlated with cortisol and plasma progesterone levels, whereas the interaction seropositivity against C. burnetii-plasma cortisol concentration was related to plasma PAG levels. Finally, an effect of lactation number only was observed on plasma prolactin. Our findings suggest that both the N. caninum and C. burnetii infection or the presence of both modify endocrine patterns throughout gestation. Cows seropositive to both, Neospora and Coxiella, showed higher plasma progesterone levels than the remaining animals examined. Seropositivity to C. burnetii was associated with placental damage and diminishing PAG levels throughout the second half of gestation, along with increased plasma cortisol levels on Day 180 of gestation., (Copyright 2010 Elsevier Inc. All rights reserved.)

Background: Q fever is a zoonosis distributed worldwide that is caused by Coxiella burnetii infection and the defervescence usually occurs within few days of appropriate antibiotic therapy. Whether the changes of cytokine levels are associated with acute Q fever with persistent fever despite antibiotic therapy had not been investigated before., Case Presentation: We report a rare case of acute Q fever granulomatous hepatitis remained pyrexia despite several antibiotic therapy and 6-day course of oral prednisolone. During the 18-month follow-up, the investigation of the serum cytokines profile and procalcitonin (PCT) revealed that initially elevated levels of interleukin-2 (IL-2), IL-8, IL-10, and PCT decreased gradually, but the IL-6 remained in low titer. No evidence of chronic Q fever was identified by examinations of serum antibodies against C. burnetii and echocardiography., Conclusions: The changes of cytokine levels may be associated with acute Q fever with poor response to treatment and PCT may be an indicator for monitoring the response to treatment.

The mechanisms of the primary adaptive immune response to Coxiella burnetii are not well known. Following inoculation of the lungs with C. burnetii Nine Mile phase I (NMI), SCID mice developed pneumonia and splenomegaly and succumbed to infection, whereas wild-type mice cleared the infection by 24 days. SCID mice reconstituted with either CD4+ T cells or CD8+ T cells alone were able to control the infection, indicating that the presence of either type of T cells was sufficient to control infection, and B cells were not necessary for primary immunity. Similarly, wild-type mice depleted of either CD4+ T cells or CD8+ T cells controlled infections in their lungs, but these mice were highly susceptible if they were depleted of both types of T cells. However, compared to CD4+ T-cell-dependent protection, CD8+ T-cell-dependent protection resulted in less inflammation in the lungs and less growth of bacteria in the spleens.

Comprehensive evaluation of the humoral immune response to Coxiella burnetii may identify highly needed diagnostic antigens and potential subunit vaccine candidates. Here we report the construction of a protein microarray containing 1901 C. burnetii ORFs (84% of the entire proteome). This array was probed with Q-fever patient sera and naïve controls in order to discover C. burnetii-specific seroreactive antigens. Among the 21 seroreactive antigens identified, 13 were significantly more reactive in Q-fever cases than naïve controls. The remaining eight antigens were cross-reactive in both C. burnetii infected and naïve patient sera. An additional 64 antigens displayed variable seroreactivity in Q-fever patients, and underscore the diversity of the humoral immune response to C. burnetii. Nine of the differentially reactive antigens were validated on an alternative immunostrip platform, demonstrating proof-of-concept development of a consistent, safe, and inexpensive diagnostic assay alternative. Furthermore, we report here the identification of several new diagnostic antigens and potential subunit vaccine candidates for the highly infectious category B alphaproteobacteria, C. burnetii.

Background: Q fever is a worldwide zoonotic disease caused by Coxiella burnetii. Epidemiologically, animals are considered reservoirs and humans incidental hosts., Methodology/principal Findings: We investigated Q fever in rural Senegal. Human samples (e.g., sera, saliva, breast milk, feces) were screened in the generally healthy population of two villages of the Sine-Saloum region. Ticks were collected in four regions. Seroprevalence was studied by immunofluorescence, and all other samples were tested by two qPCR systems for detection of C. burnetii. Positive samples were genotyped (multispacer typing) by amplification and sequencing of three spacers. Strains were isolated by cell culture. We found that the seroprevalence may be as high as 24.5% (59 of 238 studied) in Dielmo village. We identified spontaneous excretion of C. burnetii by humans through faeces and milk. Hard and soft ticks (8 species) were infected in 0-37.6%. We identified three genotypes of C. burnetii. The previously identified genotype 6 was the most common in ticks in all studied regions and the only one found in human samples. Three strains of genotype 6 of C. burnetii were also recovered from soft tick Ornithodoros sonrai. Two other genotypes found in ticks, 35 and 36, were identified for the first time., Conclusions/significance: Q fever should be considered a significant public health threat in Senegal. Humans, similar to other mammals, may continuously excrete C. burnetii.

Objectives: Q fever is a worldwide zoonosis caused by Coxiella burnetii. Its presentation can be atypical, delaying and complicating the diagnosis. We report 7 cases of Q fever mimicking vasculitis, systemic inflammatory disease, or auto-immune disorder., Methods: Seven cases of Q fever diagnosed between 1995 and 2007 in Nantes University Hospital (France) are described. They occurred in a nonendemic region and were selected on the basis of initial clinical presentation suggesting systemic immune disease. C. burnetii was detected using indirect immunofluorescence serology., Results: Q fever was acute in 4 of the 7 patients and chronic in 3. None had endocarditis. The initial presentations suggested Crohn's disease, Goodpasture's syndrome, polymyalgia rheumatica, adult-onset Still's disease, polyarteritis nodosa, giant-cell arteritis, and essential type II cryoglobulinemia. Two patients had antiphospholipid antibodies, 1 had transient IgG kappa monoclonal gammopathy, and 1 had polyclonal T CD8+ large granular lymphocyte expansion., Conclusion: Clinicians must be aware of the potential diagnosis of Q fever, and C. burnetii serology is a helpful diagnostic tool in the investigation of fever of unknown origin with atypical systemic symptoms suggesting vasculitis or inflammatory disease., (Copyright 2010 Elsevier Inc. All rights reserved.)

An epidemiological study was carried out to determine the herd prevalence of Chlamydophila abortus and Coxiella burnetii antibodies in goats covered by a milk recording program in Poland. The survey took place in 2007 and 48 herds located in different parts of the country were involved. A representative sample from each herd was taken by a simple random sampling allowing to detect seropositivity of a herd on a 95% level of confidence. In total 918 goats were tested for specific antibodies against both germs with the use of enzyme-linked immunosorbent assays. In addition, history of reproductive failures was recorded in these herds. The survey revealed that the herd prevalence of C. abortus was 4.2% (2 herds) while no C. burnetii antibodies were found. Abortions were reported to be a problem in 80% of herds while repeating estrus was encountered in 46% of herds. Reproductive failure concerned two seropositive herds as well. Since the germ is present in the population, it has to be taken into consideration in diagnostic process. Nevertheless, the results of the present study indicate that C. abortus infection occurs infrequently in Polish goats. As no antibodies against C. burnetii were detected in the screened sample the risk of goat-to-human transmission of both bacteria in Poland seems to be very low.

Little information is available in Turkey on Q fever, a zoonose caused by Coxiella burnetii and transmitted from domestic ruminants. This study aimed at investigating the seroprevalence in sheep flocks from three provinces (Bursa, Balikesir and Canakkale). Serosurvey was undertaken on 42 flocks, which were categorised by sizes. Sera were collected randomly from specific age groups within the young population. CHEKIT Q-fever ELISA kit was used to identify the infection in sheep. The results showed that 20% (n=151) of sheep were seropositive. A total of 34 flocks (81%) revealed at least one seropositive animal. Higher seroprevalence was observed in Balikesir region. Larger flocks resulted more infected than medium and small flocks. An association was found between seropositivity and age, when the primiparous ewes (1-year old) had higher antibodies rates than newborn sheep (aged less than 10 months) or biparous ewes (2 years old). These results showed that Q fever infection was common and circulating in the studied region, hence encourage efforts to propose measures that could reduce the spread and the zoonotic risk.

The aim of this study was to identify candidate proteins for serodiagnostics of Q fever by monoclonal antibodies (MAbs), and to clone, express, and purify the selected proteins for use as antigens in ELISA. The reactivity of three MAbs to Coxiella burnetii (C. b.) Nine Mile strain and one MAb to Priscilla strain was tested using SDS-PAGE, 2-D gel electrophoresis, immunoblot analysis, and mass spectrometry. Three immunoreactive Q fever-specific proteins discriminated by MAbs, namely the CBU&#95;0937 protein, outer membrane Com1 (CBU&#95;1910) protein, and elongation factor Tu (CBU&#95;0236) were identified. Successful PCR-amplification, cloning, expression, and purification of the recombinant proteins Com1 and CBU&#95;0937 allowed their use for the screening of sera from patients with Q fever endocarditis (18) or acute Q fever (16) in ELISA. The recombinant protein CBU&#95;0937 with unknown biological function proved to be a more applicable diagnostic tool for Q fever ELISA as compared to the Com1 protein.

Q fever is a zoonotic disease of worldwide significance caused by the obligate intracellular bacterium Coxiella burnetii. Humans with Q fever may experience an acute flu-like illness and pneumonia and/or chronic hepatitis or endocarditis. Various markers demonstrate significant phylogenetic separation between and clustering among isolates from acute and chronic human disease. The clinical and pathological responses to infection with phase I C. burnetii isolates from the following four genomic groups were evaluated in immunocompetent and immunocompromised mice and in guinea pig infection models: group I (Nine Mile, African, and Ohio), group IV (Priscilla and P), group V (G and S), and group VI (Dugway). Isolates from all of the groups produced disease in the SCID mouse model, and genogroup-consistent trends were noted in cytokine production in response to infection in the immunocompetent-mouse model. Guinea pigs developed severe acute disease when aerosol challenged with group I isolates, mild to moderate acute disease in response to group V isolates, and no acute disease when infected with group IV and VI isolates. C. burnetii isolates have a range of disease potentials; isolates within the same genomic group cause similar pathological responses, and there is a clear distinction in strain virulence between these genomic groups.

Background: Our previous studies of persistence of Coxiella burnetii in humans after an initial acute Q fever infection revealed raised, maintained antibody levels and low levels of coxiella genomic DNA at the age of 5 years from onset in Australian patients and at 12 years in patients in the 1989 Birmingham UK Q fever outbreak. Attempts to isolate the coxiella in standard cell culture and susceptible mice by serial passage of PCR positive PBMC and bone marrow were negative., Aim: To retest PCR positive patient samples by more sensitive methods for viable coxiellas and for the coxiella cell components of antigen and specific lipopolysaccharide (LPS). To re-interpret the previous results in the light of the new information. To review the pertinent literature for a concept of an immuno-modulatory complex generated by the current studies., Design: Laboratory case study., Methods: Stored patient samples were inoculated into SCID mice that were followed for 60 days. Mouse spleen and liver samples were then examined by PCR assay for targets in the COM1 and IS1111a sequences and for antigens by IFA with a polyclonal rabbit antiserum to C. burnetii Phase 1 and a monoclonal antiserum to Phase 1 LPS (details; O. Sukocheva et al., unpublished data)., Results: All specimens, including a recently excised heart valve from a Birmingham patient with late developing endocarditis, were infection negative in SCID mice. Dilutions of SCID mouse spleen and liver homogenates titrated in PCR assays were negative at dilutions attained by control mice inoculated with an endpoint dilution of a viable prototype strain of C. burnetii. Sections of the spleens from all specimens showed a complex of coxiella antigen-LPS by IFA. DISCUSSION/REVIEW: We advance a concept of long-term persistence of a non-infective, non-biodegraded complex of coxiella cell components with its antigens and specific LPS [so called Immunomodulatory complex (IMC)] associated with traces of genomic DNA that signalled its presence in our earlier studies. The IMC's survival in patients for at least 12 years, and in one patient for 70 years implies a capacity for serial passage in macrophages with effective down-regulation of their biodegrading functions. The review assesses the compatibility of the IMC concept in relation to cogent literature on C. burnetii interactions with macrophage and cell-mediated immunity. Some remaining gaps in our knowledge of the organ sites and duration of carriage of viable coxiellas after initial infection are also identified.

Background: The obligate intracellular bacterial pathogen Coxiella burnetii causes the zoonosis Q fever. The intracellular niche of C. burnetii has led to the assumption that cell-mediated immunity is the most important immune component for protection against this pathogen. However, passive immunization with immune serum can protect naïve animals from challenge with virulent C. burnetii, indicating a role for antibody (Ab) in protection. The mechanism of this Ab-mediated protection is unknown. Therefore, we conducted a study to determine whether Fc receptors (FcR) or complement contribute to Ab-mediated immunity (AMI) to C. burnetii., Results: Virulent C. burnetii infects and replicates within human dendritic cells (DC) without inducing their maturation or activation. We investigated the effects of Ab opsonized C. burnetii on human monocyte-derived and murine bone marrow-derived DC. Infection of DC with Ab-opsonized C. burnetii resulted in increased expression of maturation markers and inflammatory cytokine production. Bacteria that had been incubated with naïve serum had minimal effect on DC, similar to virulent C. burnetii alone. The effect of Ab opsonized C. burnetii on DC was FcR dependent as evidenced by a reduced response of DC from FcR knockout (FcR k/o) compared to C57Bl/6 (B6) mice. To address the potential role of FcR in Ab-mediated protection in vivo, we compared the response of passively immunized FcR k/o mice to the B6 controls. Interestingly, we found that FcR are not essential for AMI to C. burnetii in vivo. We subsequently examined the role of complement in AMI by passively immunizing and challenging several different strains of complement-deficient mice and found that AMI to C. burnetii is also complement-independent., Conclusion: Despite our data showing FcR-dependent stimulation of DC in vitro, Ab-mediated immunity to C. burnetii in vivo is FcR-independent. We also found that passive immunity to this pathogen is independent of complement.

Coxiella burnetii, the causative agent of Q fever, is an obligate intracellular bacterium and a highly infectious pathogen. The disease is a widespread zoonosis and is endemic throughout the world. An easy aerosol dissemination, environmental persistence, and high infectivity make the bacterium a serious threat for humans and animals. Lipopolysaccharide is considered one of the major factors of virulence expression and infection of the bacterium. Detailed glycomic studies enabled to better understand structural and functional peculiarities of this biopolymer and its role in pathogenesis and immunity of Q fever. Recent proteomic studies of C. burnetii have brought new approaches in accurate detection of the infectious agent and offered new insights into the inter- or intra-species relatedness. Thus, structure/function relationship studies are currently of utmost importance in the field. This paper will focus on glycomic and proteomic approaches providing information on unique glycan and protein species of the microorganism as the candidate molecules for the use in detection/diagnosis, therapy, and prophylaxis.

Coxiella burnetii, the agent of Q fever, is an obligate intracellular bacterium that is considered a potential biological weapon of category B. C. burnetii survives within myeloid cells by subverting receptor-mediated phagocytosis and preventing phagosome maturation. The intracellular fate of C. burnetii also depends on the functional state of myeloid cells. This review describes the mechanisms used by C. burnetii to circumvent uptake and trafficking events, and the role of cytokines on C. burnetii survival in myeloid cells.

To estimate the prevalence of Coxiella burnetii in the dairy sheep population from the Basque Country (northern Spain), a study was carried out combining molecular and serological techniques. First, bulk-tank milk samples from 154 flocks belonging to the Latxa Breed Farmers Association were analyzed by PCR, with 22% of flocks testing positive for C. burnetii. Then, a selection of 34 flocks (7 PCR positive and 17 negative) was investigated for the presence of serum antibodies by ELISA test on 1,011 ewes (approximately 30 ewes per flock). A total of 8.9% of the animals were seropositive, 67.6% of the flocks had at least one seropositive animal, but only in 14.7% of them was seroprevalence greater than 25%. Older ewes showed a significantly greater prevalence (17.5%) compared with yearlings (7.5%) or replacement lambs (1.5%). A marginally significant association was found between seroprevalence and PCR detection of C. burnetii in bulk-tank milk. The widespread distribution of C. burnetii in the region advocates for the implementation of Q fever control strategies and highlights the potential risk of sheep as a reservoir and infection source for other domestic and wildlife species and the human population.

Background: Endocarditis is the main clinical manifestation of chronic Q fever, a challenging disease due to Coxiella burnetii. The recommended treatment for Q fever endocarditis is a combination of doxycycline and hydroxychloroquine for at least 18 months. However, there is considerable heterogeneity in the biological response to this regimen as measured by the rate of decrease of dilutions of phase I antibodies against C. burnetii. Previous studies have demonstrated that this response heterogeneity was due to variations in the serum concentration of doxycycline in patients when compared with MICs for the isolates., Objectives: The objective of this study was to evaluate retrospectively the evolution of phase I antibodies in patients with an initial slow serological change, who received higher doses of doxycycline., Results: Among 17 patients with definitive diagnosis of Q fever endocarditis, 12 were defined as slow responders [mean (+/- SD) decrease of dilutions of phase I antibodies of 0.42 +/- 0.51 and mean (+/-SD) serum doxycycline level of 3.44 +/- 1.06 mg/L after 1 year of treatment] and received increased doses of doxycycline. After 1 year of treatment with increased dose, the mean (+/-SD) serum doxycycline concentration increased to 4.86 +/- 1.14 mg/L (P<0.05) and the mean (+/-SD) decrease of dilutions of phase I antibodies increased to 3.42 +/- 1.78 (P<0.05)., Conclusions: During the treatment of Q fever endocarditis, serum concentrations of doxycycline should be monitored concomitantly with phase I antibodies in order to adjust the dose of doxycycline to achieve a higher concentration for patients with slow serological evolution.

Q fever is a worldwide zoonosis caused by Coxiella burnetii bacterium. Two clinical forms are present: acute Q fever and chronic disease, including endocarditis. Currently, the diagnosis of Q fever endocarditis is based on the detection of anti-phase I antibodies. The objective of the study was to identify candidate proteins for the serological diagnosis of endocarditis due to C. burnetii. The immunoreactivities of sera from 12 patients with C. burnetii infections, including the sera from patients with endocarditis and with the acute clinical form of Q fever, were compared with those of three control subjects who did not have Q fever. We identified 29 candidate antigenic proteins by mass spectrometry. Two proteins, arginine repressor and OmpH, were recognised exclusively by the sera of patients with Q fever endocarditis. These proteins are promising candidates for the development of serodiagnostic assays for Q fever endocarditis.

Coxiella burnetii is an obligate intracellular bacterial pathogen that causes the zoonosis Q fever. While an effective whole-cell vaccine (WCV) against Q fever exists, the vaccine has limitations in being highly reactogenic in sensitized individuals. Thus, a safe and effective vaccine based on recombinant protein antigen (Ag) is desirable. To achieve this goal, a better understanding of the host response to primary infection and the precise mechanisms involved in protective immunity to C. burnetii are needed. This review summarizes our current understanding of adaptive immunity to C. burnetii with a focus on recent developments in the field.

Background: Query-fever (Q-fever) is a zoonotic infection caused by the intracellular Gram-negative coccobacillus Coxiella burnetii. A large ongoing outbreak of Q-fever has been reported in the Netherlands. We studied various markers of infection in inpatients (hospitalised) and outpatients (treated by a general physician) with acute Q-fever in relation to disease severity., Methods: Leukocyte counts, C-reactive protein (CRP) and procalcitonin (PCT) concentrations were measured in 25 inpatients and 40 outpatients upon presentation with acute Q-fever. Chest X-rays, if available, were analysed and confusion, urea, respiratory rate, blood pressure-age 65 (CURB-65) scores, indicating severity of pneumonia, were calculated., Results: CRP was the only marker that significantly differentiated between inpatients and outpatients. It was increased in all patients from both groups. Leukocyte counts and PCT concentrations did not differ between inpatients and outpatients. Overall, only 13/65 patients had an increased leukocyte count and only 11/65 patients presented with PCT concentrations indicative of possible bacterial respiratory tract infection. Infiltrative changes on the chest X-ray were observed in the majority of patients. CURB-65 score was 0+/-1 (mean+/-SD)., Conclusions: Acute Q-fever, a relatively mild pneumonia with low CURB-65 scores, specifically induces a response in CRP, while PCT concentrations and leukocytes are within the normal range or increased only marginally.

A mononuclear phagocyte derived from B1b cells (B1CDP) has been described. As these cells migrate from the peritoneal cavity to non-specific inflammatory lesion sites and are highly phagocytic via Fc and mannose receptors, their microbicidal ability of these cells was investigated using the Coxiella burnetii cell infection model in vitro. In this report, the pattern of infection and C. burnetii phase II survival in B1CDP phagosomes was compared with the pattern of infection of peritoneal macrophages from Xid mice (PMphi) and bone marrow derived macrophages (BMMphi). Infection was assessed by determining the large parasitophorous vacuole formation, the relative focus forming units and the quantification of DAPI (4',6-diamino-2-phenylindole) fluorescence images acquired by confocal microscopy. When compared to macrophages, B1CDP are more permissive to the bacterial infection and less effective to kill them. Further, results suggest that IL-10 secreted by B1 cells are involved in their susceptibility to infection by C. burnetti, since B1CDP from IL-10 KO mice are more competent to control C. burnetii infection than cells from wild type mice. These data contribute further to characterize B1CDP as a novel mononuclear phagocyte.

Q fever is a widespread zoonosis caused by Coxiella burnetii. Diagnosis of Q fever is usually based on serological testing of patient serum. The diagnostic antigen of test kits is formalin-fixed phase I and phase II organisms of the Nine Mile reference strain. Deficiencies of this antigen include (i) potential for cross-reactivity with other pathogens; (ii) an inability to distinguish between C. burnetii strains; and (iii) a need to propagate and purify C. burnetii, a difficult and potentially hazardous process. Consequently, there is a need for sensitive and specific serodiagnostic tests utilizing defined antigens, such as recombinant C. burnetii protein(s). Here we describe the use of a C. burnetii protein microarray to comprehensively identify immunodominant antigens recognized by antibody in the context of human C. burnetii infection or vaccination. Transcriptionally active PCR products corresponding to 1,988 C. burnetii open reading frames (ORFs) were generated. Full-length proteins were successfully synthesized from 75% of the ORFs by using an Escherichia coli-based in vitro transcription and translation system (IVTT). Nitrocellulose microarrays were spotted with crude IVTT lysates and probed with sera from acute Q fever patients and individuals vaccinated with Q-Vax. Immune sera strongly reacted with approximately 50 C. burnetii proteins, including previously identified immunogens, an ankyrin repeat-domain containing protein, and multiple hypothetical proteins. Recombinant protein corresponding to selected array-reactive antigens was generated, and the immunoreactivity was confirmed by enzyme-linked immunosorbent assay. This sensitive and high-throughput method for identifying immunoreactive C. burnetii proteins will aid in the development of Q fever serodiagnostic tests based on recombinant antigen.

Background: Functional polymorphisms in immune response genes are increasingly recognized as important contributors to the marked individual differences in susceptibility to and outcomes of infectious disease. The acute sickness response is a stereotypical set of illness manifestations mediated by the proinflammatory cytokines induced by many different pathogens. The genetic determinants of severity of the acute sickness response have not previously been explored., Methods: We examined the impact of functional polymorphisms in cytokine genes with critical roles in the early immune response (tumor necrosis factor-alpha, interleukin-6, interleukin-10, and interferon-gamma) on the severity and duration of illness following acute infection with Epstein-Barr virus, Coxiella burnetii (the causative agent of Q fever), or Ross River virus., Results: We found that the interferon-gamma +874T/A and the interleukin-10 -592C/A polymorphisms significantly affected illness severity, cytokine protein levels, and the duration of illness. These cytokine genotypes acted in synergy to potentiate their influence on disease outcomes., Conclusions: These findings suggest that genetically determined variations in the intensity of the inflammatory response underpin the severity of the acute sickness response and predict the recovery time across varied infections.

The aims of this study were to determine the prevalence of Coxiella burnetii antibodies among blood donors and to examine the epidemiological characteristics of C. bumetii infection in Ankara, Turkey. A total of 601 serum samples were collected from blood donors aged 18-61 years. Donor samples were stratified by age, sex, and residence (rural or urban). IgG and IgM antibodies to the C. bumetii phase II antigen were determined using a commercial ELISA. Blood samples reactive in the ELISA were also analysed using a commercial indirect immunofluorescence assay (IFA). The prevalence of anti-phase II IgG was 32.3%, and 17 (2.8%) were IgM positive. Seropositivity in men was higher than in women (33.2% vs. 21.7%, OR:1.88; 95% CI: 0.88-4.14) and the difference in seroprevalence rates between genders was not related to occupational exposure to domestic animals. 87.6% of seropositive donors reported no contact with farm animals. Our results revealed that C. burnetii infection is highly endemic in Ankara and that the majority of seropositive cases are not linked to specific occupational exposure in this area. In conclusion, the high rate of C. burnetii phase II antibodies among blood donors is a reflection of the high prevalence of Q fever in this area of Turkey and indicates the need for further studies, not only to determine the risk of transfusion-transmitted Q fever, but also to elucidate the epidemiology of Q fever in Turkey. These studies should be conducted through improved collaboration between the veterinary and medical services.

We report here a patient with acute Q fever-related acalculous cholecystitis, who presented with prolonged fever, valvular abnormalities, and positive serology for Q fever phase 1 antigens, features suggesting chronic Q fever endocarditis. The pathogenesis of this rare presentation of Q fever is discussed.

High seroprevalence rates for Anaplasma phagocytophilum (8.8%), Coxiella burnetii (6.4%), Bartonella henselae (9.6%), and Rickettsia typhi (4.1%) in 365 farm workers near Tianjin, People's Republic of China, suggest that human infections with these zoonotic bacteria are frequent and largely unrecognized. Demographic features of seropositive persons suggest distinct epidemiology, ecology, and risks.

Patients with valvulopathy have the highest risk to develop infective endocarditis (IE), although the relationship between valvulopathy and IE is not clearly understood. Q fever endocarditis, an IE due to Coxiella burnetii, is accompanied by immune impairment. Patients with valvulopathy exhibited increased levels of circulating apoptotic leukocytes, as determined by the measurement of active caspases and nucleosome determination. The binding of apoptotic cells to monocytes and macrophages, the hosts of C. burnetii, may be responsible for the immune impairment observed in Q fever endocarditis. Apoptotic lymphocytes (AL) increased C. burnetii replication in monocytes and monocyte-derived macrophages in a cell-contact dependent manner, as determined by quantitative PCR and immunofluorescence. AL binding induced a M2 program in monocytes and macrophages stimulated with C. burnetii as determined by a cDNA chip containing 440 arrayed sequences and functional tests, but this program was in part different in monocytes and macrophages. While monocytes that had bound AL released high levels of IL-10 and IL-6, low levels of TNF and increased CD14 expression, macrophages that had bound AL released high levels of TGF-beta1 and expressed mannose receptor. The neutralization of IL-10 and TGF-beta1 prevented the replication of C. burnetii due to the binding of AL, suggesting that they were critically involved in bacterial replication. In contrast, the binding of necrotic cells to monocytes and macrophages led to C. burnetii killing and typical M1 polarization. Finally, interferon-gamma corrected the immune deactivation induced by apoptotic cells: it prevented the replication of C. burnetii and re-directed monocytes and macrophages toward a M1 program, which was deleterious for C. burnetii. We suggest that leukocyte apoptosis associated with valvulopathy may be critical for the pathogenesis of Q fever endocarditis by deactivating immune cells and creating a favorable environment for bacterial persistence.

Coxiella burnetii is an obligate intracellular bacterium, responsible for Q fever, which survives in macrophages by interfering with their microbicidal competence. As functional polarization of macrophages is critical for their microbicidal activity, we studied the activation program of monocyte-derived macrophages (MDM) stimulated with C. burnetii. This program was markedly distinct from that induced by lipopolysaccharides (LPS), a canonical inducer of M1 polarization. Indeed, C. burnetii up-regulated the expression of genes associated with M2 polarization, including TGF-beta1, IL-1 receptor antagonist (IL-1ra), CCL18, the mannose receptor and arginase-1, and only up-regulated the expression of two genes associated with M1 polarization, namely IL-6 and CXCL8. In contrast, C. burnetii down-regulated the expression of genes associated with M1 polarization such as TNF, CD80, CCR7 and TLR-2. Functional analyses showed that C. burnetii-stimulated MDM produced high levels of TGF-beta1 and CCL18, and expressed the mannose receptor and arginase-1, the latter being associated with the prevention of nitric oxide production by MDM. Finally, C. burnetii induced the release of IL-6 and CXCL8 at a lower level than LPS-stimulated MDM. Our results suggest that C. burnetii stimulated an atypical M2 activation program that may account for the persistence of C. burnetii in macrophages.

Interleukin (IL)-10 increases host susceptibility to microorganisms and is involved in intracellular persistence of bacterial pathogens. IL-10 is associated with chronic Q fever, an infectious disease due to the intracellular bacterium Coxiella burnetii. Nevertheless, accurate animal models of chronic C. burnetii infection are lacking. Transgenic mice constitutively expressing IL-10 in macrophages were infected with C. burnetti by intraperitoneal and intratracheal routes and infection was analyzed through real-time PCR and antibody production. Transgenic mice exhibited sustained tissue infection and strong antibody response in contrast to wild-type mice; thus, bacterial persistence was IL-10-dependent as in chronic Q fever. The number of granulomas was low in spleen and liver of transgenic mice infected through the intraperitoneal route, as in patients with chronic Q fever. Macrophages from transgenic mice were unable to kill C. burnetii. C. burnetii-stimulated macrophages were characterized by non-microbicidal transcriptional program consisting of increased expression of arginase-1, mannose receptor, and Ym1/2, in contrast to wild-type macrophages in which expression of inducible NO synthase and inflammatory cytokines was increased. In vivo results emphasized macrophage data. In spleen and liver of transgenic mice infected with C. burnetii by the intraperitoneal route, the expression of arginase-1 was increased while microbicidal pathway consisting of IL-12p40, IL-23p19, and inducible NO synthase was depressed. The overexpression of IL-10 in macrophages prevents anti-infectious competence of host, including the ability to mount granulomatous response and microbicidal pathway in tissues. To our knowledge, this is the first efficient model for chronic Q fever pathogenesis.

Short information about significance of Q-fever in human pathology is represented. Necessity of vaccination is proved. The row of vaccines, developed in Czechoslovakia and Romania and identified as small-effective, was considered. Live vaccine from M-44 strain, was made in USSR, still remains in Russia. However, experimental data of American and Russian authors showed persistency of Q-fever agents in vaccinated animals, abortions and other pathology. WHO recommended declining to use live vaccines. Inactivated corpuscular combined vaccine against Q-fever was development under leadership of I. V. Tarasevich. The method of vaccine production is protected by industrial patent #2094057 from 31.01.94, concomitant studies--by 9 author's certificates. The vaccine is harmless, are actogenic, and high immunogenic after single injection. Antibodies of vaccinated persons remain more than in 75% during one year. The vaccine assists in resolving of actual problems of fight against Q-fever.

Coxiella burnetii is a highly infectious obligate intracellular bacterium. The phase I form is responsible for Q fever, a febrile illness with flu-like symptoms that often goes undiagnosed. The attenuated C. burnetii phase II (having a truncated "O" chain of its lipopolysaccharide) does not cause disease in immunocompetent animals; however, phase II organisms remain infectious, and we questioned whether disease could be produced in immunodeficient mice. To study C. burnetii phase II infections, febrile responses in gamma interferon knockout (IFN-gamma(-/-)), BALB/c, Toll-like receptor 2 knockout (TLR2(-/-)), and C57BL/6 mice were measured using the Nine Mile phase II (NMII) strain of C. burnetii. Immunocompetent mice showed minimal febrile responses, unlike those obtained with IFN-gamma(-/-) and TLR2(-/-) mice, which showed elevated rectal temperatures that were sustained for approximately 15 days with transient increases in splenic weights. Reinfection of IFN-gamma(-/-) and TLR2(-/-) mice with C. burnetii NMII 30 days after primary infection protected mice as evident by reduced febrile responses and a lack of splenic inflammation. Although minimal detection of Coxiella in TLR2(-/-) mouse spleens was observed, greater colonization was evident in the IFN-gamma(-/-) mice. Cytokine analysis was performed on infected peritoneal macrophages isolated from these mice, and immunocompetent macrophages showed robust tumor necrosis factor alpha, IFN-gamma, and granulocyte-macrophage colony-stimulating factor (GM-CSF) but no interleukin-12 (IL-12) responses. IFN-gamma(-/-) macrophages produced elevated levels of IL-6, IL-10, and IL-12, while TLR2(-/-) macrophages produced GM-CSF, IL-12, and minimal IL-10. To distinguish immunity conferred by innate or adaptive systems, adoptive transfer studies were performed and showed that immune lymphocytes obtained from immunocompetent mice protected against a subsequent challenge with NMII, indicating that adaptive immunity mediates the observed protection. Thus, our data show that NMII is capable of eliciting disease in immunocompromised mice, which may help in evaluation of vaccine candidates as well as the study of host-pathogen interactions.

Coxiella burnetii is a macrophage-tropic, Gram-negative organism, which causes acute Q fever infection in humans. This zoonotic infection causes illness ranging from asymptomatic seroconversion to severe and protracted disease featuring hepatitis and pneumonia. Interactions between C. burnetii lipopolysaccharide (LPS) and host Toll-like receptors (TLR)-2 and -4 have been implicated in pathogen recognition, phagocytosis and signaling responses. Nonconservative single nucleotide polymorphisms in the coding regions of TLR-2 (Arg677Trp and Arg753Gln) and TLR-4 (Asp299Gly) have been found to correlate with mycobacterial infections and Gram-negative sepsis respectively. Associations between the TLR-2 and -4 polymorphisms, illness characteristics and immune response parameters were examined in subjects with acute Q fever (n=85) and comparison subjects with viral infections (n=162). No correlation was demonstrated between these polymorphisms and susceptibility to Q fever, illness severity or illness course.

Designation as a Category B biothreat agent has propelled Coxiella burnetii from a relatively obscure, underappreciated, "niche" microorganism on the periphery of bacteriology, to one of possibly great consequence if actually used in acts of bioterrorism. Advances in the study of this microorganism proceeded slowly, primarily because of the difficulty in studying this obligate intracellular pathogen that must be manipulated under biosafety level-3 conditions. The dogged determination of past and current C. burnetii researchers and the application of modern immunological and molecular techniques have more clearly defined the host and bacterial response to infection. This review is intended to provide a basic introduction to C. burnetii and Q fever, while emphasizing immunomodulatory properties, both positive and negative, of Q fever vaccines and C. burnetii infections.

The objective of this study was to investigate the effects of age on infection with Coxiella burnetii, the agent of Q fever. Bacterial burden and granuloma number were increased in the spleens of 14-month-old as compared with 1-month-old mice. This increase was not the result of an anti-inflammatory macrophage response, because inflammatory and anti-inflammatory cytokines were induced in macrophages from young mice but were repressed in mature mice. In addition, macrophage microbicidal competence was similar in mature and young mice. These results suggest the importance of individual host factors in the pathophysiology of an infectious disease such as Q fever.

Aims: To determine the proportion of notifiable cases of Q fever attributable to occupational and community exposures and to identify missed opportunities for Q fever vaccination in notifications of occupational exposures., Methods: A review of Q fever notifications to the BSPHU from January 2000 to September 2006 was undertaken. Notifications were categorised according to probable exposure source. Occupational exposures were further categorised according to reported past exposure to Q fever and Q fever vaccination status., Results: One hundred and ninety-one Q fever notifications were identified, with occupational exposure reported in 106 cases and community exposure reported in 69 cases. In the occupational exposures, 76 cases (71%) were not vaccinated, 15 (14%) reported past exposure to Q fever and eight reported vaccination prior to illness onset, but vaccination status could not be independently verified. Community acquired Q fever was most commonly attributed to living or working near a high-risk industry (26, 38%), incidental exposures such as farm visits, or attending sale yards (27, 39%)., Conclusions: Occupationally acquired cases of Q fever continue to be reported in significant numbers and opportunities for vaccination are being missed. There is an ongoing need to ensure that all employees in high-risk industries are screened and vaccinated. The proportion of community acquired notifications of Q fever has increased since the National Q fever Management Program started, commensurate with the decline in occupationally acquired cases. These proportions may be expected to change with the cessation of the program in Queensland in December 2006.

Background: Q fever remains an important occupational zoonosis in rural Australia. Although Q fever vaccine is recommended in high-risk occupational groups, its availability has been limited in recent years., Method: A literature review of the efficacy of the human Q fever vaccine registered in Australia was conducted., Results: Seven relevant vaccine efficacy studies were identified but no large double-blind, randomised, placebo-controlled studies have been conducted. Vaccine efficacy has ranged from 83-100% but limitations of study designs hamper a precise estimate of vaccine efficacy., Conclusion: Despite the shortcomings of efficacy studies, the Q fever vaccine available in Australia has considerable protective benefit in established high-risk environments, particularly of an occupational nature.

Coxiella burnetii, the etiological agent of Q fever, has two phase variants. Phase I has a complete lipopolysaccharide (LPS), is highly virulent, and causes Q fever in humans and pathology in experimental animals. Phase II lacks an LPS O side chain, is avirulent, and does not grow well in immunocompetent animals. To understand the pathogenicity of Q fever, we investigated the roles of immune components in animals infected with Nine Mile phase I (NM I) or Nine Mile phase II (NM II) bacteria. Immunodeficient mice, including SCID mice (deficient in T and B cells), SCIDbg mice (deficient in T, B, and NK cells), nude mice (deficient in T cells), muMT mice (deficient in B cells), bg mice (deficient in NK cells), mice deficient in tumor necrosis factor alpha (TNF-alpha(-/-) mice), and mice deficient in gamma interferon (IFN-gamma(-/-) mice), were compared for their responses to infection. SCID, SCIDbg, nude, and IFN-gamma(-/-) mice showed high susceptibility to NM I, and TNF-alpha(-/-) mice showed modest susceptibility. Disease caused by NM I in SCID, SCIDbg, and nude mice progressed slowly, while disease in IFN-gamma(-/-) and TNF-alpha(-/-) mice advanced rapidly. B- and NK-cell deficiencies did not enhance clinical disease development or alter bacterial clearance but did increase the severity of histopathological changes, particularly in the absence of B cells. Mice infected with NM II showed no apparent clinical disease, but T-cell-deficient mice had histopathological changes. These results suggest that T cells are critical for clearance of C. burnetii, either NM I or NM II, that IFN-gamma and TNF-alpha are essential for the early control of infection, and that B cells are important for the prevention of tissue damage.