Publications by authors named "Michel Huerre"

105 Publications

Co-Infection of Mosquitoes with Chikungunya and Dengue Viruses Reveals Modulation of the Replication of Both Viruses in Midguts and Salivary Glands of Aedes aegypti Mosquitoes.

Int J Mol Sci 2017 Aug 4;18(8). Epub 2017 Aug 4.

Unité Environnement et Risques Infectieux, Institut Pasteur, 75015 Paris, France.

Arthropod-borne virus (arbovirus) infections cause several emerging and resurgent infectious diseases in humans and animals. Chikungunya-affected areas often overlap with dengue-endemic areas. Concurrent dengue virus (DENV) and chikungunya virus (CHIKV) infections have been detected in travelers returning from regions of endemicity. CHIKV and DENV co-infected have also been collected in the vicinity of co-infected human cases, emphasizing the need to study co-infections in mosquitoes. We thus aimed to study the pathogen-pathogen interaction involved in these co-infections in DENV/CHIKV co-infected mosquitoes. In mono-infections, we detected CHIKV antigens as early as 4 days post-virus exposure in both the midgut (MG) and salivary gland (SG), whereas we detected DENV serotype 2 (DENV-2) antigens from day 5 post-virus exposure in MG and day 10 post-virus exposure in SG. Identical infection rates were observed for singly and co-infected mosquitoes, and facilitation of the replication of both viruses at various times post-viral exposure. We observed a higher replication for DENV-2 in SG of co-infected mosquitoes. We showed that mixed CHIKV and DENV infection facilitated viral replication in . The outcome of these mixed infections must be further studied to increase our understanding of pathogen-pathogen interactions in host cells.
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http://dx.doi.org/10.3390/ijms18081708DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5578098PMC
August 2017

Interferon-γ promotes gastric lymphoid follicle formation but not gastritis in -infected BALB/c mice.

Gut Pathog 2016 21;8:61. Epub 2016 Nov 21.

Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Monash University, 27-31 Wright Street, Clayton, VIC 3123 Australia ; Department of Microbiology, Monash University, Clayton, VIC Australia.

Background: Mouse infection studies have shown that interferon-γ (IFN-γ), a T helper 1 (Th1) cytokine, is required for the development of severe pathology induced by chronic infection. This finding is largely based on studies performed using mice that have polarised Th1 responses i.e. C57BL/6 animals. The current work aims to investigate the role of IFN-γ in -induced inflammation in BALB/c mice which have Th2-polarised immune responses.

Results: At 7 months post-infection with IFN-γ deficiency in BALB/c mice had no significant effect on colonisation levels in the gastric mucosa, nor on humoral responses, or gastritis severity. animals with chronic infection did, however, develop significantly fewer lymphoid follicle lesions, as well as increased IL-4 splenocyte responses, when compared with infected mice (P = 0.015 and P = 0.0004, respectively).

Conclusions: The work shows that in mice on a BALB/c background, IFN-γ is not required for bacterial clearance, antibody responses, nor gastric inflammation. Conversely, IFN-γ appears to play a role in the development of gastric lymphoid follicles, which are precursor lesions to mucosa-associated lymphoid tissue (MALT) lymphoma. This study highlights the importance of mouse host background on the susceptibility to -induced pathologies.
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http://dx.doi.org/10.1186/s13099-016-0142-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5117576PMC
November 2016

Ligand-receptor dissociated expression explains high TSLP without prognostic impact in human primary head and neck squamous cell carcinoma.

Oncoimmunology 2016 Jul 7;5(7):e1179414. Epub 2016 Jun 7.

Institut Curie, Laboratoire d'Immunologie Clinique, Paris, France; Institut National de la Santé et de la Recherche Médicale, U932, Institut Curie, Paris, France; Inserm Center of Clinical Investigation, CIC IGR Curie 1428, Paris, France.

Thymic stromal lymphopoietin (TSLP) is an interleukin (IL)-7-like cytokine expressed by epithelial cells during allergic inflammation, and activating dendritic cells (DC). Its expression and functional role in cancer remain controversial. We conducted retrospective (n = 89), and prospective studies including patients with untreated primary head and neck squamous cell carcinoma (HNSCC). We found that TSLP was overexpressed by HNSCC tumor cells, and associated with a highly differentiated status. However, no significant difference in overall and recurrence-free survival was found between patients bearing a tumor with high and low TSLP levels, respectively. Surprisingly, there was no significant association between the levels of TSLP expression, and the number of tumor-infiltrating mature DCLAMP(+) DC. In order to explain the apparent lack of TSLP-induced DC activation, we performed phenotypic and functional experiments on freshly resected tumors. Tumor-infiltrating immune cells, including DC, did not express the TSLP receptor heterodimer (TSLPR chain, IL-7Ralpha chain). Furthermore, freshly sorted blood CD11c(+) DC from healthy donors cultured with tumor-conditioned supernatant exhibited an activated profile, but this was not affected by an anti-TSLP blocking antibody, suggesting a DC activation pathway independent of tumor-derived TSLP. Overall, our results demonstrate that TSLP is overexpressed in HNSCC but its function is hampered by the lack of TSLPR-expressing cells in the tumor microenvironment. Such a dissociated ligand-receptor expression may impact intercellular communication in other immune activation pathways, and tumor types.
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http://dx.doi.org/10.1080/2162402X.2016.1179414DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5006899PMC
July 2016

Cytokine and Chemokine Expression in Kidneys during Chronic Leptospirosis in Reservoir and Susceptible Animal Models.

PLoS One 2016 24;11(5):e0156084. Epub 2016 May 24.

Institut Pasteur International Network, Institut Pasteur de Nouvelle-Calédonie, Leptospirosis Research and Expertise Unit, Noumea, New Caledonia.

Leptospirosis is caused by pathogenic spirochetes of the genus Leptospira. Humans can be infected after exposure to contaminated urine of reservoir animals, usually rodents, regarded as typical asymptomatic carriers of leptospires. In contrast, accidental hosts may present an acute form of leptospirosis with a range of clinical symptoms including the development of Acute Kidney Injury (AKI). Chronic Kidney Disease (CKD) is considered as a possible AKI-residual sequela but little is known about the renal pathophysiology consequent to leptospirosis infection. Herein, we studied the renal morphological alterations in relation with the regulation of inflammatory cytokines and chemokines, comparing two experimental models of chronic leptospirosis, the golden Syrian hamster that survived the infection, becoming carrier of virulent leptospires, and the OF1 mouse, a usual reservoir of the bacteria. Animals were monitored until 28 days after injection with a virulent L. borgpetersenii serogroup Ballum to assess chronic infection. Hamsters developed morphological alterations in the kidneys with tubulointerstitial nephritis and fibrosis. Grading of lesions revealed higher scores in hamsters compared to the slight alterations observed in the mouse kidneys, irrespective of the bacterial load. Interestingly, pro-fibrotic TGF-β was downregulated in mouse kidneys. Moreover, cytokines IL-1β and IL-10, and chemokines MIP-1α/CCL3 and IP-10/CXCL-10 were significantly upregulated in hamster kidneys compared to mice. These results suggest a possible maintenance of inflammatory processes in the hamster kidneys with the infiltration of inflammatory cells in response to bacterial carriage, resulting in alterations of renal tissues. In contrast, lower expression levels in mouse kidneys indicated a better regulation of the inflammatory response and possible resolution processes likely related to resistance mechanisms.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0156084PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4878748PMC
July 2017

Physical Sequestration of Bacillus anthracis in the Pulmonary Capillaries in Terminal Infection.

J Infect Dis 2016 07 14;214(2):281-7. Epub 2016 Mar 14.

Institut Pasteur, Histopathologie Humaine et Modèles Animaux Pathogénie des Toxi-Infections Bactériennes.

The lung is the terminal target of Bacillus anthracis before death, whatever the route of infection (cutaneous, inhalational, or digestive). During a cutaneous infection in absence of toxins, we observed encapsulated bacteria colonizing the alveolar capillary network, bacteria and hemorrhages in alveolar and bronchiolar spaces, and hypoxic foci in the lung (endothelial cells) and brain (neurons and neuropil). Circulating encapsulated bacteria were as chains of approximately 13 µm in length. Bacteria of such size were immediately trapped within the lung capillary network, but bacteria of shorter length were not. Controlling lung-targeted pathology would be beneficial for anthrax treatment.
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http://dx.doi.org/10.1093/infdis/jiw098DOI Listing
July 2016

Rainbow trout (Oncorhynchus mykiss) muscle satellite cells are targets of salmonid alphavirus infection.

Vet Res 2016 Jan 8;47. Epub 2016 Jan 8.

INRA, Unité de Virologie et d'Immunologie Moléculaires, Jouy-en-Josas, France.

Sleeping disease in rainbow trout is characterized by an abnormal swimming behaviour of the fish which stay on their side at the bottom of the tanks. This sign is due to extensive necrosis and atrophy of red skeletal muscle induced by the sleeping disease virus (SDV), also called salmonid alphavirus 2. Infections of humans with arthritogenic alphaviruses, such as Chikungunya virus (CHIKV), are global causes of debilitating musculoskeletal diseases. The mechanisms by which the virus causes these pathologies are poorly understood due to the restrictive availability of animal models capable of reproducing the full spectrum of the disease. Nevertheless, it has been shown that CHIKV exhibits a particular tropism for muscle stem cells also known as satellite cells. Thus, SDV and its host constitute a relevant model to study in details the virus-induced muscle atrophy, the pathophysiological consequences of the infection of a particular cell-type in the skeletal muscle, and the regeneration of the muscle tissue in survivors together with the possible virus persistence. To study a putative SDV tropism for that particular cell type, we established an in vivo and ex vivo rainbow trout model of SDV-induced atrophy of the skeletal muscle. This experimental model allows reproducing the full panel of clinical signs observed during a natural infection since the transmission of the virus is arthropod-borne independent. The virus tropism in the muscle tissue was studied by immunohistochemistry together with the kinetics of the muscle atrophy, and the muscle regeneration post-infection was observed. In parallel, an ex vivo model of SDV infection of rainbow trout satellite cells was developed and virus replication and persistence in that particular cell type was followed up to 73 days post-infection. These results constitute the first observation of a specific SDV tropism for the muscle satellite cells.
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http://dx.doi.org/10.1186/s13567-015-0301-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4705810PMC
January 2016

Dissociation of Tissue Destruction and Bacterial Expansion during Bubonic Plague.

PLoS Pathog 2015 Oct 20;11(10):e1005222. Epub 2015 Oct 20.

Unité de Recherche Yersinia, Institut Pasteur, Paris, France.

Activation and/or recruitment of the host plasmin, a fibrinolytic enzyme also active on extracellular matrix components, is a common invasive strategy of bacterial pathogens. Yersinia pestis, the bubonic plague agent, expresses the multifunctional surface protease Pla, which activates plasmin and inactivates fibrinolysis inhibitors. Pla is encoded by the pPla plasmid. Following intradermal inoculation, Y. pestis has the capacity to multiply in and cause destruction of the lymph node (LN) draining the entry site. The closely related, pPla-negative, Y. pseudotuberculosis species lacks this capacity. We hypothesized that tissue damage and bacterial multiplication occurring in the LN during bubonic plague were linked and both driven by pPla. Using a set of pPla-positive and pPla-negative Y. pestis and Y. pseudotuberculosis strains in a mouse model of intradermal injection, we found that pPla is not required for bacterial translocation to the LN. We also observed that a pPla-cured Y. pestis caused the same extensive histological lesions as the wild type strain. Furthermore, the Y. pseudotuberculosis histological pattern, characterized by infectious foci limited by inflammatory cell infiltrates with normal tissue density and follicular organization, was unchanged after introduction of pPla. However, the presence of pPla enabled Y. pseudotuberculosis to increase its bacterial load up to that of Y. pestis. Similarly, lack of pPla strongly reduced Y. pestis titers in LNs of infected mice. This pPla-mediated enhancing effect on bacterial load was directly dependent on the proteolytic activity of Pla. Immunohistochemistry of Pla-negative Y. pestis-infected LNs revealed extensive bacterial lysis, unlike the numerous, apparently intact, microorganisms seen in wild type Y. pestis-infected preparations. Therefore, our study demonstrates that tissue destruction and bacterial survival/multiplication are dissociated in the bubo and that the primary action of Pla is to protect bacteria from destruction rather than to alter the tissue environment to favor Y. pestis propagation in the host.
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http://dx.doi.org/10.1371/journal.ppat.1005222DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4615631PMC
October 2015

Disruption of Parasite hmgb2 Gene Attenuates Plasmodium berghei ANKA Pathogenicity.

Infect Immun 2015 Jul 27;83(7):2771-84. Epub 2015 Apr 27.

Sorbonne Universités, Centre d'Immunologie et des Maladies Infectieuses (CIMI-Paris), Paris, France INSERM, U1135, CIMI-Paris, Paris, France CNRS, ERL 8255, CIMI-Paris, Paris, France

Eukaryotic high-mobility-group-box (HMGB) proteins are nuclear factors involved in chromatin remodeling and transcription regulation. When released into the extracellular milieu, HMGB1 acts as a proinflammatory cytokine that plays a central role in the pathogenesis of several immune-mediated inflammatory diseases. We found that the Plasmodium genome encodes two genuine HMGB factors, Plasmodium HMGB1 and HMGB2, that encompass, like their human counterparts, a proinflammatory domain. Given that these proteins are released from parasitized red blood cells, we then hypothesized that Plasmodium HMGB might contribute to the pathogenesis of experimental cerebral malaria (ECM), a lethal neuroinflammatory syndrome that develops in C57BL/6 (susceptible) mice infected with Plasmodium berghei ANKA and that in many aspects resembles human cerebral malaria elicited by P. falciparum infection. The pathogenesis of experimental cerebral malaria was suppressed in C57BL/6 mice infected with P. berghei ANKA lacking the hmgb2 gene (Δhmgb2 ANKA), an effect associated with a reduction of histological brain lesions and with lower expression levels of several proinflammatory genes. The incidence of ECM in pbhmgb2-deficient mice was restored by the administration of recombinant PbHMGB2. Protection from experimental cerebral malaria in Δhmgb2 ANKA-infected mice was associated with reduced sequestration in the brain of CD4(+) and CD8(+) T cells, including CD8(+) granzyme B(+) and CD8(+) IFN-γ(+) cells, and, to some extent, neutrophils. This was consistent with a reduced parasite sequestration in the brain, lungs, and spleen, though to a lesser extent than in wild-type P. berghei ANKA-infected mice. In summary, Plasmodium HMGB2 acts as an alarmin that contributes to the pathogenesis of cerebral malaria.
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http://dx.doi.org/10.1128/IAI.03129-14DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4468538PMC
July 2015

Hyperactivation of Alk induces neonatal lethality in knock-in AlkF1178L mice.

Oncotarget 2014 May;5(9):2703-13

Inserm U830, Paris, France;

The ALK (Anaplastic Lymphoma Kinase) gene encodes a tyrosine kinase receptor preferentially expressed in the central and peripheral nervous systems. A syndromic presentation associating congenital neuroblastoma with severe encephalopathy and an abnormal shape of the brainstem has been described in patients harbouring de novo germline F1174V and F1245V ALK mutations. Here, we investigated the phenotype of knock-in (KI) mice bearing the AlkF1178L mutation (F1174L in human). Although heterozygous KI mice did not reproduce the severe breathing and feeding difficulties observed in human patients, behavioral tests documented a reduced activity during dark phases and an increased anxiety of mutated mice. Matings of heterozygotes yielded the expected proportions of wild-type, heterozygotes and homozygotes at birth but a high neonatal lethality was noticed for homozygotes. We documented Alk expression in several motor nuclei of the brainstem involved in the control of sucking and swallowing. Evaluation of basic physiological functions 12 hours after birth revealed slightly more apneas but a dramatic reduced milk intake for homozygotes compared to control littermates. Overall, our data demonstrate that Alk activation above a critical threshold is not compatible with survival in mice, in agreement with the extremely severe phenotype of patients carrying aggressive de novo ALK germline mutations.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4058038PMC
http://dx.doi.org/10.18632/oncotarget.1882DOI Listing
May 2014

Colorectal cancer metastasis: the DNA repair inhibitor Dbait increases sensitivity to hyperthermia and improves efficacy of radiofrequency ablation.

Radiology 2014 Mar 14;270(3):736-46. Epub 2013 Dec 14.

From the Department of Research, Institut Curie, Bat 11215 Georges Clémenceau, Orsay 91405, France (F.D., M.H., A.C., M.D.); CNRS, Unit UMR3347, Orsay, France (M.D.); INSERM, Unit U1021, Orsay, France (M.D.); DNA Therapeutics, Evry, France (F.D., A.C., J.S.S.); Department of Radiotherapy, Centre Jean Perrin, Clermont-Ferrand, France (J.B.); Department of Pathology, Institut Pasteur, Paris, France (M.H.); Muséum National d'Histoire Naturelle USM503, Paris, France (J.S.S.); Université Paris-Sud, Paris, France (M.D.); and Department of Radiology and Interventional Radiology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland (A.D.).

Purpose: To assess the usefulness of combining hyperthermia with a DNA repair inhibitor (double-strand break bait [Dbait]) and its potential application to radiofrequency ablation (RFA) in a preclinical model of human colorectal cancer.

Materials And Methods: The local ethics committee of animal experimentation approved all investigations. First, the relevance was assessed by studying the survival of four human colorectal adenocarcinoma cell cultures after 1 hour of hyperthermia at 41°C or 43°C with or without Dbait. Human colon adenocarcinoma cells (HT-29) were grafted subcutaneously into nude mice (n = 111). When tumors reached approximately 500 mm(3), mice were treated with Dbait alone (n = 20), sublethal RFA (n = 21), three different Dbait schemes and sublethal RFA (n = 52), or a sham treatment (n = 18). RFA was performed to ablate the tumor center alone. To elucidate antitumor mechanisms, 39 mice were sacrificed for blinded pathologic analysis, including assessment of DNA damage, cell proliferation, and tumor necrosis. Others were monitored for tumor growth and survival. Analyses of variance and log-rank tests were used to evaluate differences.

Results: When associated with mild hyperthermia, Dbait induced cytotoxicity in all tested colon cancer cell lines. Sublethal RFA or Dbait treatment alone moderately improved survival (median, 40 days vs 28 days for control; P = .0005) but combination treatment significantly improved survival (median, 84 days vs 40 days for RFA alone, P = .0004), with approximately half of the animals showing complete tumor responses. Pathologic studies showed that the Dbait and RFA combination strongly enhances DNA damage and coagulation areas in tumors.

Conclusion: Combining Dbait with RFA sensitizes the tumor periphery to mild hyperthermia and increases RFA antitumor efficacy.
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http://dx.doi.org/10.1148/radiol.13130805DOI Listing
March 2014

Mutant mice lacking the p53 C-terminal domain model telomere syndromes.

Cell Rep 2013 Jun 13;3(6):2046-58. Epub 2013 Jun 13.

Genetics of Tumor Suppression, Institut Curie, Centre de Recherche, 26 rue d'Ulm, 75248 Paris Cedex 05, France.

Mutations in p53, although frequent in human cancers, have not been implicated in telomere-related syndromes. Here, we show that homozygous mutant mice expressing p53Δ31, a p53 lacking the C-terminal domain, exhibit increased p53 activity and suffer from aplastic anemia and pulmonary fibrosis, hallmarks of syndromes caused by short telomeres. Indeed, p53Δ31/Δ31 mice had short telomeres and other phenotypic traits associated with the telomere disease dyskeratosis congenita and its severe variant the Hoyeraal-Hreidarsson syndrome. Heterozygous p53+/Δ31 mice were only mildly affected, but decreased levels of Mdm4, a negative regulator of p53, led to a dramatic aggravation of their symptoms. Importantly, several genes involved in telomere metabolism were downregulated in p53Δ31/Δ31 cells, including Dyskerin, Rtel1, and Tinf2, which are mutated in dyskeratosis congenita, and Terf1, which is implicated in aplastic anemia. Together, these data reveal that a truncating mutation can activate p53 and that p53 plays a major role in the regulation of telomere metabolism.
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http://dx.doi.org/10.1016/j.celrep.2013.05.028DOI Listing
June 2013

Expression of follicle-stimulating hormone receptor by the vascular endothelium in tumor metastases.

BMC Cancer 2013 May 20;13:246. Epub 2013 May 20.

Inserm Equipe Angiogenèse Tumorale, Institut Curie, Centre de Recherche, Département Recherche Translationnelle, 26 rue d'Ulm, 75005, Paris, France.

Background: The Follicle Stimulating Hormone receptor (FSHR) is expressed by the vascular endothelium in a wide range of human tumors. It was not determined however if FSHR is present in metastases which are responsible for the terminal illness.

Methods: We used immunohistochemistry based on a highly FSHR-specific monoclonal antibody to detect FSHR in cancer metastases from 6 major tumor types (lung, breast, prostate, colon, kidney, and leiomyosarcoma ) to 6 frequent locations (bone, liver, lymph node, brain, lung, and pleura) of 209 patients.

Results: In 166 patients examined (79%), FSHR was expressed by blood vessels associated with metastatic tissue. FSHR-positive vessels were present in the interior of the tumors and some few millimeters outside, in the normally appearing tissue. In the interior of the metastases, the density of the FSHR-positive vessels was constant up to 7 mm, the maximum depth available in the analyzed sections. No significant differences were noticed between the density of FSHR-positive vessels inside vs. outside tumors for metastases from lung, breast, colon, and kidney cancers. In contrast, for prostate cancer metastases, the density of FSHR-positive vessels was about 3-fold higher at the exterior of the tumor compared to the interior. Among brain metastases, the density of FSHR-positive vessels was highest in lung and kidney cancer, and lowest in prostate and colon cancer. In metastases of breast cancer to the lung pleura, the percentage of blood vessels expressing FSHR was positively correlated with the progesterone receptor level, but not with either HER-2 or estrogen receptors. In normal tissues corresponding to the host organs for the analyzed metastases, obtained from patients not known to have cancer, FSHR staining was absent, with the exception of approx. 1% of the vessels in non tumoral temporal lobe epilepsy samples.

Conclusion: FSHR is expressed by the endothelium of blood vessels in the majority of metastatic tumors.
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http://dx.doi.org/10.1186/1471-2407-13-246DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3663659PMC
May 2013

A novel murine model of rhinoscleroma identifies Mikulicz cells, the disease signature, as IL-10 dependent derivatives of inflammatory monocytes.

EMBO Mol Med 2013 Apr;5(4):516-30

Institut Pasteur, Génotypage des Pathogènes et Santé Publique, Paris Cedex, France.

Rhinoscleroma is a human specific chronic disease characterized by the formation of granuloma in the airways, caused by the bacterium Klebsiella pneumoniae subspecies rhinoscleromatis, a species very closely related to K. pneumoniae subspecies pneumoniae. It is characterized by the appearance of specific foamy macrophages called Mikulicz cells. However, very little is known about the pathophysiological processes underlying rhinoscleroma. Herein, we characterized a murine model recapitulating the formation of Mikulicz cells in lungs and identified them as atypical inflammatory monocytes specifically recruited from the bone marrow upon K. rhinoscleromatis infection in a CCR2-independent manner. While K. pneumoniae and K. rhinoscleromatis infections induced a classical inflammatory reaction, K. rhinoscleromatis infection was characterized by a strong production of IL-10 concomitant to the appearance of Mikulicz cells. Strikingly, in the absence of IL-10, very few Mikulicz cells were observed, confirming a crucial role of IL-10 in the establishment of a proper environment leading to the maturation of these atypical monocytes. This is the first characterization of the environment leading to Mikulicz cells maturation and their identification as inflammatory monocytes.
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http://dx.doi.org/10.1002/emmm.201202023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3628109PMC
April 2013

HTLV-1-associated inflammatory myopathies: low proviral load and moderate inflammation in 13 patients from West Indies and West Africa.

J Clin Virol 2013 May 30;57(1):70-6. Epub 2013 Jan 30.

Institut Pasteur, 75015 Paris, France.

Background: The Human T-cell Leukemia Virus type 1 (HTLV-1) is the causative agent of several inflammatory diseases, including HTLV-1-associated inflammatory myopathies (HAIM). Little is known about the virological and immunological characteristics of this viral disease.

Objectives: To characterize the histological and virological features of HAIM patients, in order to better understand the pathogenetic mechanisms and unravel new biological markers of this disease.

Study Design: We conducted a retrospective study on 13 patients with HAIM, based on blood and muscle samples. We included blood samples from HTLV-1-infected individuals without myopathy as controls. Muscle biopsies were used for a broad immunohistological evaluation of tissue damage and inflammation, as well as identification of infected cells through in situ hybridization. DNA extracted from patients' PBMC was used to identify the virus genotype by sequencing and to assess the proviral load by quantitative PCR. Anti-viral antibodies in plasma samples were titrated by indirect immunofluorescence.

Results: Patients originate from HTLV-1 endemic areas, the West Indies and West Africa. Histological alterations and inflammation in patients muscles were mostly moderate, with classical features of idiopathic myositis and rare HTLV-1-infected infiltrating cells. In all patients, HTLV-1 belonged to the A subtype, transcontinental subgroup. Anti-HTLV-1 antibodies titers were high, but the proviral load was not elevated compared to asymptomatic HTLV-1 carriers.

Conclusion: We show here that muscle inflammation is moderate in HAIM, and accompanied by a low HTLV-1 proviral load, suggesting that the pathogenetic events do not exactly mirror those of other HTLV-1-associated inflammatory diseases.
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http://dx.doi.org/10.1016/j.jcv.2012.12.016DOI Listing
May 2013

Visualizing non infectious and infectious Anopheles gambiae blood feedings in naive and saliva-immunized mice.

PLoS One 2012 13;7(12):e50464. Epub 2012 Dec 13.

Unité de Biochimie et de Biologie Moléculaire des Insectes, Institut Pasteur, Paris, France.

Background: Anopheles gambiae is a major vector of malaria and lymphatic filariasis. The arthropod-host interactions occurring at the skin interface are complex and dynamic. We used a global approach to describe the interaction between the mosquito (infected or uninfected) and the skin of mammals during blood feeding.

Methods: Intravital video microscopy was used to characterize several features during blood feeding. The deposition and movement of Plasmodium berghei sporozoites in the dermis were also observed. We also used histological techniques to analyze the impact of infected and uninfected feedings on the skin cell response in naive mice.

Results: The mouthparts were highly mobile within the skin during the probing phase. Probing time increased with mosquito age, with possible effects on pathogen transmission. Repletion was achieved by capillary feeding. The presence of sporozoites in the salivary glands modified the behavior of the mosquitoes, with infected females tending to probe more than uninfected females (86% versus 44%). A white area around the tip of the proboscis was observed when the mosquitoes fed on blood from the vessels of mice immunized with saliva. Mosquito feedings elicited an acute inflammatory response in naive mice that peaked three hours after the bite. Polynuclear and mast cells were associated with saliva deposits. We describe the first visualization of saliva in the skin by immunohistochemistry (IHC) with antibodies directed against saliva. Both saliva deposits and sporozoites were detected in the skin for up to 18 h after the bite.

Conclusion: This study, in which we visualized the probing and engorgement phases of Anopheles gambiae blood meals, provides precise information about the behavior of the insect as a function of its infection status and the presence or absence of anti-saliva antibodies. It also provides insight into the possible consequences of the inflammatory reaction for blood feeding and pathogen transmission.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0050464PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3521732PMC
June 2013

Neutrophil elastase degrades cystic fibrosis transmembrane conductance regulator via calpains and disables channel function in vitro and in vivo.

Am J Respir Crit Care Med 2013 Jan 6;187(2):170-9. Epub 2012 Dec 6.

Institut Pasteur,Unité de Défense Innée et Inflammation, 25 rue du Dr Roux, 75724 Paris, France.

Rationale: Cystic fibrosis transmembrane conductance regulator (CFTR) protein is a chloride channel regulating fluid homeostasis at epithelial surfaces. Its loss of function induces hypohydration, mucus accumulation, and bacterial infections in CF and potentially other lung chronic diseases.

Objectives: To test whether neutrophil elastase (NE) and neutrophil-mediated inflammation negatively impact CFTR structure and function, in vitro and in vivo.

Methods: Using an adenovirus-CFTR overexpression approach, we showed that NE degrades wild-type (WT)- and ΔF508-CFTR in vitro and WT-CFTR in mice through a new pathway involving the activation of intracellular calpains.

Measurements And Main Results: CFTR degradation triggered a loss of function, as measured in vitro by channel patch-clamp and in vivo by nasal potential recording in mice. Importantly, this mechanism was also shown to be operative in a Pseudomonas aeruginosa lung infection murine model, and was NE-dependent, because CFTR integrity was significantly protected in NE(-/-) mice compared with WT mice.

Conclusions: These data provide a new mechanism and show for the first time a link between NE-calpains activation and CFTR loss of function in bacterial lung infections relevant to CF and to other chronic inflammatory lung conditions.
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http://dx.doi.org/10.1164/rccm.201205-0875OCDOI Listing
January 2013

The four and a half LIM-only protein 2 regulates liver homeostasis and contributes to carcinogenesis.

J Hepatol 2012 Nov 11;57(5):1029-36. Epub 2012 Jul 11.

Institut Pasteur, Unité d'Oncogenèse et Virologie Moléculaire, France.

Background & Aims: The four and a half LIM-only protein 2 (FHL2) is upregulated in diverse pathological conditions. Here, we analyzed the effects of FHL2 overexpression in the liver of FHL2 transgenic mice (Apo-FHL2).

Methods: We first examined cell proliferation and apoptosis in Apo-FHL2 livers and performed partial hepatectomy to investigate high FHL2 expression in liver regeneration. Expression of FHL2 was then analyzed by real time PCR in human hepatocellular carcinoma and adjacent non-tumorous livers. Finally, the role of FHL2 in hepatocarcinogenesis was assessed using Apo-FHL2;Apc(lox/lox) mice.

Results: Six-fold increase in cell proliferation in transgenic livers was associated with concomitant apoptosis, resulting in normal liver mass. In Apo-FHL2 livers, both cyclin D1 and p53 were markedly increased. Evidence supporting a p53-dependent cell death mechanism was provided by the findings that FHL2 bound to and activated the p53 promoter, and that a dominant negative p53 mutant compromised FHL2-induced apoptosis in hepatic cells. Following partial hepatectomy in Apo-FHL2 mice, hepatocytes displayed advanced G1 phase entry and DNA synthesis leading to accelerated liver weight restoration. Interestingly, FHL2 upregulation in human liver specimens showed significant association with increasing inflammation score and cirrhosis. Finally, while Apo-FHL2 mice developed no tumors, the FHL2 transgene enhanced hepatocarcinogenesis induced by liver-specific deletion of the adenomatous polyposis coli gene and aberrant Wnt/β-catenin signaling in Apc(lox/lox) animals.

Conclusions: Our results implicate FHL2 in the regulation of signaling pathways that couple proliferation and cell death machineries, and underscore the important role of FHL2 in liver homeostasis and carcinogenesis.
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http://dx.doi.org/10.1016/j.jhep.2012.06.035DOI Listing
November 2012

Prolonged myalgia in Sindbis virus infection: case description and in vitro infection of myotubes and myoblasts.

J Infect Dis 2012 Aug 21;206(3):407-14. Epub 2012 May 21.

Infection Biology Research Program, Research Programs Unit, Department of Virology, Haartman Institute, Faculty of Medicine, University of Helsinki, Helsinki, Finland.

Background: Sindbis virus (SINV) is a mosquito-borne alphavirus found in Eurasia, Africa, and Oceania. Clinical SINV infection is characterized by febrile rash and arthritis and sometimes prolonged arthralgia and myalgia. The pathophysiological mechanisms of musculoskeletal and rheumatic disease caused by SINV are inadequately understood.

Methods: We studied the muscle pathology of SINV infection ex vivo by examining a unique muscle biopsy obtained from a patient with chronic myalgia and arthralgia 6 months after acute SINV infection and assessed potential genetic predisposing factors by determining the human leukocyte antigen (HLA) and complement factor C4 genes and proteins. In addition, we performed in vitro SINV infections of primary human myoblasts and myotubes.

Results: In the muscle biopsy we found evidence of muscle regeneration due to previous necrotic lesions likely caused by earlier SINV infection. We showed that human myoblasts and myotubes were susceptible in vitro for SINV infection as the cells became immunoreactive for viral antigens and cytopathic effect was observed. The patient was homozygous for HLA-B*35 alleles and heterozygous for HLA-DRB1*01 and HLA-DRB1*03 alleles and had total deficiency of C4B protein.

Conclusions: This study provides new insights concerning pathological processes leading to chronic symptoms in SINV infection and demonstrates for the first time the susceptibility of human myogenic cells to SINV infection.
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http://dx.doi.org/10.1093/infdis/jis358DOI Listing
August 2012

Docosahexaenoic acid inhibits Helicobacter pylori growth in vitro and mice gastric mucosa colonization.

PLoS One 2012 17;7(4):e35072. Epub 2012 Apr 17.

Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal.

H. pylori drug-resistant strains and non-compliance to therapy are the major causes of H. pylori eradication failure. For some bacterial species it has been demonstrated that fatty acids have a growth inhibitory effect. Our main aim was to assess the ability of docosahexaenoic acid (DHA) to inhibit H. pylori growth both in vitro and in a mouse model. The effectiveness of standard therapy (ST) in combination with DHA on H. pylori eradication and recurrence prevention success was also investigated. The effects of DHA on H. pylori growth were analyzed in an in vitro dose-response study and n in vivo model. We analized the ability of H. pylori to colonize mice gastric mucosa following DHA, ST or a combination of both treatments. Our data demonstrate that DHA decreases H. pylori growth in vitro in a dose-dependent manner. Furthermore, DHA inhibits H. pylori gastric colonization in vivo as well as decreases mouse gastric mucosa inflammation. Addition of DHA to ST was also associated with lower H. pylori infection recurrence in the mouse model. In conclusion, DHA is an inhibitor of H. pylori growth and its ability to colonize mouse stomach. DHA treatment is also associated with a lower recurrence of H. pylori infection in combination with ST. These observations pave the way to consider DHA as an adjunct agent in H. pylori eradication treatment.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0035072PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3328494PMC
November 2012

An encapsulated Yersinia pseudotuberculosis is a highly efficient vaccine against pneumonic plague.

PLoS Negl Trop Dis 2012 14;6(2):e1528. Epub 2012 Feb 14.

Unité de Recherche Yersinia, Institut Pasteur, Paris, France.

Background: Plague is still a public health problem in the world and is re-emerging, but no efficient vaccine is available. We previously reported that oral inoculation of a live attenuated Yersinia pseudotuberculosis, the recent ancestor of Yersinia pestis, provided protection against bubonic plague. However, the strain poorly protected against pneumonic plague, the most deadly and contagious form of the disease, and was not genetically defined.

Methodology And Principal Findings: The sequenced Y. pseudotuberculosis IP32953 has been irreversibly attenuated by deletion of genes encoding three essential virulence factors. An encapsulated Y. pseudotuberculosis was generated by cloning the Y. pestis F1-encoding caf operon and expressing it in the attenuated strain. The new V674pF1 strain produced the F1 capsule in vitro and in vivo. Oral inoculation of V674pF1 allowed the colonization of the gut without lesions to Peyer's patches and the spleen. Vaccination induced both humoral and cellular components of immunity, at the systemic (IgG and Th1 cells) and the mucosal levels (IgA and Th17 cells). A single oral dose conferred 100% protection against a lethal pneumonic plague challenge (33×LD(50) of the fully virulent Y. pestis CO92 strain) and 94% against a high challenge dose (3,300×LD(50)). Both F1 and other Yersinia antigens were recognized and V674pF1 efficiently protected against a F1-negative Y. pestis.

Conclusions And Significance: The encapsulated Y. pseudotuberculosis V674pF1 is an efficient live oral vaccine against pneumonic plague, and could be developed for mass vaccination in tropical endemic areas to control pneumonic plague transmission and mortality.
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http://dx.doi.org/10.1371/journal.pntd.0001528DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3279354PMC
June 2012

Early systemic bacterial dissemination and a rapid innate immune response characterize genetic resistance to plague of SEG mice.

J Infect Dis 2012 Jan 16;205(1):134-43. Epub 2011 Nov 16.

Yersinia Research Unit, Institut Pasteur, Paris, France.

Background: Although laboratory mice are usually highly susceptible to Yersinia pestis, we recently identified a mouse strain (SEG) that exhibited an exceptional capacity to resist bubonic plague and used it to identify immune mechanisms associated with resistance.

Methods: The kinetics of infection, circulating blood cells, granulopoiesis, lesions, and cellular populations in the spleen, and cytokine production in various tissues were compared in SEG and susceptible C57BL/6J mice after subcutaneous infection with the virulent Y. pestis CO92.

Results: Bacterial invasion occurred early (day 2) but was transient in SEG/Pas mice, whereas in C57BL/6J mice it was delayed but continuous until death. The bacterial load in all organs significantly correlated with the production of 5 cytokines (granulocyte colony-stimulating factor, keratinocyte-derived chemokine (KC), macrophage cationic peptide-1 (MCP-1), interleukin 1α, and interleukin 6) involved in monocyte and neutrophil recruitment. Indeed, higher proportions of these 2 cell types in blood and massive recruitment of F4/80(+)CD11b(-) macrophages in the spleen were observed in SEG/Pas mice at an early time point (day 2). Later times after infection (day 4) were characterized in C57BL/6J mice by destructive lesions of the spleen and impaired granulopoiesis.

Conclusion: A fast and efficient Y. pestis dissemination in SEG mice may be critical for the triggering of an early and effective innate immune response necessary for surviving plague.
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http://dx.doi.org/10.1093/infdis/jir696DOI Listing
January 2012

Expansion of European vacA and cagA alleles to East-Asian Helicobacter pylori strains in Cambodia.

Infect Genet Evol 2011 Dec 17;11(8):1899-905. Epub 2011 Aug 17.

Unité de Bactériologie Médicale et Environnementale, Institut Pasteur, 36 Avenue Pasteur, BP 220, Dakar, Senegal.

Helicobacter pylori infection is associated with gastric cancer (GC). The highest incidence rates have been described in Asia, but regional variations exist that do not match the distribution of infection prevalence rates. The aim of the study was to examine the possible contribution of H. pylori virulence factors to geographic differences in the incidence of GC across East and Southeast Asia. We studied 66 isolates from Cambodian patients that had previously been assigned to two genetic populations based on sequences of seven housekeeping genes, namely hpEurope (n = 34, 51.5%) and hpEastAsia, subpopulation hspEAsia (n = 32, 48.5%). These strains were characterized with respect to vacA polymorphism and cagA status by PCR, and the CagA C-terminal region was sequenced. We also sequenced the complete cagA gene from 10 hpEurope and 10 hspEAsia strains chosen at random. The cagA gene was present in 92.4% of the 66 isolates and was mainly of Western type (n = 36, 59.0%). hspEAsia strains carrying East-Asian CagA and the m1-type vacA allele (15.2%) were less frequent among the 66 Cambodian isolates than reported in East Asian countries, a finding that might partly explain the intermediate incidence of GC in Cambodia, and by extension, in Southeast Asia (except for Vietnam). The observed high prevalence of s1a alleles (34.4%) and Western CagA (28.1%) among hspEAsia strains indicates frequent introgression of European vacA and cagA alleles into East Asian H. pylori strains. This expansion might have severe consequences for individual disease outcome.
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http://dx.doi.org/10.1016/j.meegid.2011.08.007DOI Listing
December 2011

Evolutionary history of Helicobacter pylori sequences reflect past human migrations in Southeast Asia.

PLoS One 2011 19;6(7):e22058. Epub 2011 Jul 19.

Unité de Biologie Médicale et Environnementale, Institut Pasteur, Dakar, Senegal.

The human population history in Southeast Asia was shaped by numerous migrations and population expansions. Their reconstruction based on archaeological, linguistic or human genetic data is often hampered by the limited number of informative polymorphisms in classical human genetic markers, such as the hypervariable regions of the mitochondrial DNA. Here, we analyse housekeeping gene sequences of the human stomach bacterium Helicobacter pylori from various countries in Southeast Asia and we provide evidence that H. pylori accompanied at least three ancient human migrations into this area: i) a migration from India introducing hpEurope bacteria into Thailand, Cambodia and Malaysia; ii) a migration of the ancestors of Austro-Asiatic speaking people into Vietnam and Cambodia carrying hspEAsia bacteria; and iii) a migration of the ancestors of the Thai people from Southern China into Thailand carrying H. pylori of population hpAsia2. Moreover, the H. pylori sequences reflect iv) the migrations of Chinese to Thailand and Malaysia within the last 200 years spreading hspEasia strains, and v) migrations of Indians to Malaysia within the last 200 years distributing both hpAsia2 and hpEurope bacteria. The distribution of the bacterial populations seems to strongly influence the incidence of gastric cancer as countries with predominantly hspEAsia isolates exhibit a high incidence of gastric cancer while the incidence is low in countries with a high proportion of hpAsia2 or hpEurope strains. In the future, the host range expansion of hpEurope strains among Asian populations, combined with human motility, may have a significant impact on gastric cancer incidence in Asia.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0022058PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3139604PMC
December 2011

Mycobacterium bovis Bacillus Calmette-Guérin killed by extended freeze-drying reduces colitis in mice.

Gastroenterology 2011 Aug 14;141(2):642-52, 652.e1-4. Epub 2011 May 14.

Institut Pasteur, Laboratoire d'Immunothérapie, Paris, France.

Background & Aims: Mycobacterium bovis Bacillus Calmette-Guérin (BCG), killed by extended freeze-drying (EFD), induces secretion of interleukin-10 and reduces lung inflammation in a mouse model of asthma. We investigated the effects of EFD BCG in mouse models of inflammatory bowel disease.

Methods: EFD BCG was administered subcutaneously to mice with colitis induced by dextran sodium sulfate (DSS), oxazolone, or adoptive transfer of CD4(+)CD45RB(high)Foxp3(-) T cells from C57Bl/6 Foxp3GFP mice to RAG2(-/-) mice.

Results: EFD BCG, administered either before induction of DSS and oxazolone colitis or after development of acute or chronic DSS-induced colitis, reduced symptom scores, loss of body weight, and inflammation. Although transfer of CD4(+)CD45RB(high)Foxp3(-) cells induced colitis in RAG2(-/-) mice, administration of EFD BCG at the time of the transfer converted Foxp3(-) T cells to Foxp3(+) T cells and the mice did not develop colitis. EFD BCG protected mice from colitis via a mechanism that required expansion of T regulatory cells and production of interleukin-10 and transforming growth factor β. EFD BCG activated the retinoid X receptor (RXR)-α-peroxisome proliferator-activated receptor (PPAR)-γ heterodimer, blocked translocation of nuclear factor κB to the nucleus, and reduced colonic inflammation; it did not increase the number of colon tumors that formed in mice with chronic DSS-induced colitis.

Conclusions: EFD BCG controls severe colitis in mice by expanding T regulatory cell populations and PPAR-γ and might be developed to treat patients with inflammatory bowel disease.
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http://dx.doi.org/10.1053/j.gastro.2011.05.002DOI Listing
August 2011

Noninvasive imaging technologies reveal edema toxin as a key virulence factor in anthrax.

Am J Pathol 2011 Jun;178(6):2523-35

Pathogenesis of Bacterial Toxi-Infections Laboratory, Pasteur Institute (Institut Pasteur), Paris, France.

Powerful noninvasive imaging technologies enable real-time tracking of pathogen-host interactions in vivo, giving access to previously elusive events. We visualized the interactions between wild-type Bacillus anthracis and its host during a spore infection through bioluminescence imaging coupled with histology. We show that edema toxin plays a central role in virulence in guinea pigs and during inhalational infection in mice. Edema toxin (ET), but not lethal toxin (LT), markedly modified the patterns of bacterial dissemination leading, to apparent direct dissemination to the spleen and provoking apoptosis of lymphoid cells. Each toxin alone provoked particular histological lesions in the spleen. When ET and LT are produced together during infection, a specific temporal pattern of lesion developed, with early lesions typical of LT, followed at a later stage by lesions typical of ET. Our study provides new insights into the complex spatial and temporal effects of B. anthracis toxins in the infected host, suggesting a greater role than previously suspected for ET in anthrax and suggesting that therapeutic targeting of ET contributes to protection.
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http://dx.doi.org/10.1016/j.ajpath.2011.02.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3124019PMC
June 2011

Type II secretion system of Pseudomonas aeruginosa: in vivo evidence of a significant role in death due to lung infection.

J Infect Dis 2011 May;203(10):1369-77

Department of Medicine, University of Florida, Gainesville, USA.

Background: The role of toxins secreted by the type II secretion system (T2SS) of Pseudomonas aeruginosa during lung infection has been uncertain despite decades of research.

Methods: Using a model of pneumonia in Toll-like receptor (TLR) 2,4(-/-) mice, we reexamined the role of the T2SS system. Flagellin-deficient mutants of P. aeruginosa, with mutations in the T2SS and/or T3SS, were used to infect mice. Mice were followed up for survival, with some killed at different intervals to study bacterial clearance, inflammatory responses, and lung pathology.

Results: Strains carrying either secretion system were lethal for mice. Double mutants were avirulent. The T3SS(+) strains killed mice within a day, and the T2SS(+) strains killed them later. Mice infected with a strain that had only the T2SS were unable to eradicate the organism from the lungs, whereas those infected with a T2SS-T3SS double deletion were able to clear this mutant. Death caused by the T2SS(+) strain was accompanied by a >50-fold increase in bacterial counts and higher numbers of viable intracellular bacteria.

Conclusions: The T2SS of P. aeruginosa may play a role in death from pneumonia, but its action is delayed. These data suggest that antitoxin strategies against this organism will require measures against the toxins secreted by both T2SS and T3SS.
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http://dx.doi.org/10.1093/infdis/jir045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3080898PMC
May 2011

[Pseudotumoral toxoplasmic cystitis revealing acquired immunodeficiency syndrome].

Ann Pathol 2011 Feb 26;31(1):46-9. Epub 2011 Jan 26.

Service d'anatomie et de cytologie pathologiques, université Paris-Sud, hôpital de Bicêtre, Le Kremlin-Bicêtre, France.

A case of bladder toxoplasmosis in a 57-year-old male Caucasian patient was diagnosed with difficulty due to misleading clinical presentation. The patient presented with pollakiuria and urination burning. Imagery showed pseudotumoral thickening of the vesicle wall. Previously unknown status of HIV infection was found positive through the diagnosis of bladder toxoplasmosis. The patient died rapidly from neurological complications. This is the second published case in which bladder toxoplasmosis reveals an HIV infection.
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http://dx.doi.org/10.1016/j.annpat.2010.11.001DOI Listing
February 2011

Pulmonary bacteriophage therapy on Pseudomonas aeruginosa cystic fibrosis strains: first steps towards treatment and prevention.

PLoS One 2011 Feb 15;6(2):e16963. Epub 2011 Feb 15.

Molecular Biology of the Gene in Extremophiles Unit, Department of Microbiology, Institut Pasteur, Paris, France.

Multidrug-resistant bacteria are the cause of an increasing number of deadly pulmonary infections. Because there is currently a paucity of novel antibiotics, phage therapy--the use of specific viruses that infect bacteria--is now more frequently being considered as a potential treatment for bacterial infections. Using a mouse lung-infection model caused by a multidrug resistant Pseudomonas aeruginosa mucoid strain isolated from a cystic fibrosis patient, we evaluated bacteriophage treatments. New bacteriophages were isolated from environmental samples and characterized. Bacteria and bacteriophages were applied intranasally to the immunocompetent mice. Survival was monitored and bronchoalveolar fluids were analysed. Quantification of bacteria, bacteriophages, pro-inflammatory and cytotoxicity markers, as well as histology and immunohistochemistry analyses were performed. A curative treatment (one single dose) administrated 2 h after the onset of the infection allowed over 95% survival. A four-day preventive treatment (one single dose) resulted in a 100% survival. All of the parameters measured correlated with the efficacy of both curative and preventive bacteriophage treatments. We also showed that in vitro optimization of a bacteriophage towards a clinical strain improved both its efficacy on in vivo treatments and its host range on a panel of 20 P. aeruginosa cystic fibrosis strains. This work provides an incentive to develop clinical studies on pulmonary bacteriophage therapy to combat multidrug-resistant lung infections.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0016963PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3039662PMC
February 2011

Cutting edge: intravenous Ig inhibits invariant NKT cell-mediated allergic airway inflammation through FcγRIIIA-dependent mechanisms.

J Immunol 2011 Mar 11;186(6):3289-93. Epub 2011 Feb 11.

Unité Mixte de Recherche 8147, Centre National de la Recherche Scientifique, Hôpital Necker, Paris 75783, France.

Despite their increasing use in autoimmune, inflammatory, and allergic conditions, the mechanism of action of i.v. Igs (IVIg) is poorly understood. On the basis of the critical role of invariant NKT (iNKT) cells in allergic airway inflammation (AAI) and their constitutive expression of the low-affinity IgG receptor FcγRIIIA, we surmised that IVIg targets iNKT cells to exert their anti-inflammatory effect. We found that IVIg treatment significantly inhibited AAI in OVA-sensitized C57BL/6 mice and downregulated α-galactosylceramide-induced iNKT cell activation and cytokine production. Allergic responses were restored in iNKT cell-deficient mice by transferring iNKT cells from PBS- but not from IVIg-treated mice, suggesting that IVIg acts directly on activated iNKT cells that have a critical role in AAI. The inhibitory effects of IVIg on both iNKT cell activation/function and OVA-driven AAI were lost in FcγRIIIA(-/-) mice. Our data unravel an FcγRIIIA-dependent inhibitory effect of IVIg on activated iNKT cells that confers protection in AAI.
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http://dx.doi.org/10.4049/jimmunol.1003076DOI Listing
March 2011

Cutting Edge: The murine high-affinity IgG receptor FcγRIV is sufficient for autoantibody-induced arthritis.

J Immunol 2011 Feb 19;186(4):1899-903. Epub 2011 Jan 19.

Département d’Immunologie, Institut Pasteur, Unité d’Allergologie Moléculaire et Cellulaire, F-75015 Paris, France.

K/BxN serum-induced passive arthritis was reported to depend on the activation of mast cells, triggered by the activating IgG receptor FcγRIIIA, when engaged by IgG1 autoantibodies present in K/BxN serum. This view is challenged by the fact that FcγRIIIA-deficient mice still develop K/BxN arthritis and because FcγRIIIA is the only activating IgG receptor expressed by mast cells. We investigated the contribution of IgG receptors, IgG subclasses, and cells in K/BxN arthritis. We found that the activating IgG2 receptor FcγRIV, expressed only by monocytes/macrophages and neutrophils, was sufficient to induce disease. K/BxN arthritis occurred not only in mast cell-deficient W(sh) mice, but also in mice whose mast cells express no activating IgG receptors. We propose that at least two autoantibody isotypes, IgG1 and IgG2, and two activating IgG receptors, FcγRIIIA and FcγRIV, contribute to K/BxN arthritis, which requires at least two cell types other than mast cells, monocytes/macrophages, and neutrophils.
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http://dx.doi.org/10.4049/jimmunol.1003642DOI Listing
February 2011