Factors associated with coinfections in invasive aspergillosis: a retrospective cohort study.

OBJECTIVES: To describe the coinfections in invasive aspergillosis (IA), to identify factors associated with coinfections, and to evaluate the impact of coinfection on mortality. PATIENTS AND METHODS: We conducted a monocentric retrospective study of consecutive putative, probable, or proven IA that occurred between 1997 and 2017. All coinfections, with an onset within 7 days before or after the first sign of aspergillosis, were identified. Factors associated with coinfections and mortality were analysed by multivariable analysis. RESULTS: Among the 690 patients with IA included in the study, the median age was 57 years (range 7 days to 90 years). A coinfection was diagnosed in 272/690 patients (39.4%, 95%CI 35.8-43.2). The location of this coinfection was pulmonary only in 131/272 patients (48%), bloodstream only in 66/272 patients (24%) and other/multiple sites in 75/272 patients (28%). Coinfections were bacterial (110/272 patients, 40%), viral (58/272, 21%), fungal (57/272, 21%), parasitic (5/272, 2%) or due to multiple types of pathogens (42/272, 15%). Factors associated with a coinfection in adjusted analysis were: allogeneic haematopoietic stem-cell transplantation (OR 2.3 (1.2-4.4)), other haematological malignancies (OR 2.1 (1.2-3.8)), other underlying diseases (OR 4.3 (1.4-13.6)), lymphopenia (OR 1.7 (1.1-2.5)), C-reactive protein >180 mg/L (OR 1.9 (1.2-3.0)), fever (OR 2.4 (1.5-4.1)), tracheal intubation (OR 2.6 (1.5-4.7)), isolation of two or more different Aspergillus species (OR 2.7 (1.1-6.3)), and the presence of non-nodular lesions on chest computed tomography (OR 2.2 (1.3-3.7) and OR 2.2 (1.2-4.0)). Coinfections were independently associated with a higher mortality at week 12 (adjusted HR 1.5 (1.1-1.9), p < 0.01). CONCLUSIONS: Coinfections are frequent in IA patients and are associated with higher mortality.

Locally acquired infection with Dibothriocephalus nihonkaiense (=Diphyllobothrium nihonkaiense) in France: the importance of molecular diagnosis.

Diphyllobothriasis is a parasitic fish-borne disease caused by tapeworms of the genus Dibothriocephalus (=Diphyllobothrium). The majority of reported cases are attributed to D. latum, based on morphological identification of eggs or proglottids. However, numerous reports in recent years suggested that other Dibothriocephalus species could be involved in human infections, mainly after consumption of salmonid fish. Among these, D. nihonkaiense has been predominantly reported from Eastern Asia and probably underestimated in the rest of the world. We report here a clinical case of D. nihonkaiense in a French patient (without history of travel abroad) after consumption of salmon. Suspected on morphological characteristics, the final identification of D. nihonkaiense was performed using molecular methods by sequencing nad1, cox1, and 5.8S rRNA (containing ITS1 and 2) genes sequences. The patient was successfully treated by a single dose of praziquantel. Reports of diphyllobothriasis due to D. nihonkaiense are rare outside Asia, but worldwide demand of seafood could lead to the globalization of cases and reflect the need to monitor the distribution of Dibothriocephalus species. Thus, clinical parasitologists should be aware of this risk and able to raise the possibility of infections by non-endemic Dibothriocephalus species in order to use the proper molecular tools.

Cestode infections in non-human primates suggest the existence of zoonotic cycles in the area surrounding the Strasbourg primatology center.

BACKGROUND: Several cases of infections due to Echinococcus multilocularis, Taenia martis and Taenia crassiceps were recently described in various species of captive non-human primates (NHPs) harbored in the Strasbourg Primate Center (SPC). Furthermore, one of the first cases of human cysticercosis due to T. martis was described in the Strasbourg region. These data suggest the existence of zoonotic cycles of tapeworm infections in the direct environment of the SPC. The aim of our study was to assess the prevalence of larval cestode infections among intermediate and definitive hosts in the close neighborhood of the center. We analyzed carnivore mammal fecal samples as well as rodent carcasses, collected inside or near the SPC, using PCR. Furthermore, we performed serology for Echinococcus spp. and Taenia spp. on NHP sera. RESULTS: We found that 14.5% (95% CI [8.6; 20.4]) of 138 carnivore feces were positive for E. multilocularis-DNA, as well as 25% (95% CI [5.5; 57.2]) of 12 rodent carcasses, and 5.1% (95% CI [1.4; 8.7]) for T. martis or T. crassiceps. Of all NHPs tested, 10.1% (95% CI [3.8; 16.4]) were seropositive for Echinococcus spp. and 8.2% (95% CI [1.3; 15.1]) for Taenia spp. CONCLUSIONS: Our data support the existence of zoonotic cycles of larval cestode infections in the direct environment of the primatology center affecting NHPs harbored in the SPC, potentially threatening the human population living in this area. Since this zoonotic risk is borne by local wildlife, and given the severity of these infections, it seems necessary to put in place measures to protect captive NHPs, and further studies to better assess the risk to human populations.

In Vitro Amoebicidal Activity of Titanium Dioxide/UV-A Combination Against Acanthamoeba.

Purpose: To assess the amoebicidal effect of titanium dioxide (TiO2)/UV-A combination against Acanthamoeba sp trophozoites and cysts. Methods: The amoebicidal effect of the TiO2/UV-A combination was tested on trophozoites and cysts of clinical isolates of Acanthamoeba hatchetti and Acanthamoeba sp genotype T4, obtained from two severe cases of ulcerative keratitis. Samples of cultured Acanthamoeba were transferred to a 96-well plate. We tested the effect of sterile water (blank control), TiO2 alone, UV-A alone, TiO2 and additional UV-A exposure, chlorhexidine 0.02% alone, chlorhexidine 0.02% and TiO2, chlorhexidine and UV-A, chlorhexidine 0.02% and TiO2, and additional UV-A exposure. Cell viability assessment was done using the trypan blue dye exclusion method. Results: The combination of TiO2 with UV-A demonstrated antitrophozoite and anticyst activity (P < 0.05). This in vitro study showed a synergistic effect of the association of chlorhexidine with TiO2 and UV-A on cysts (P < 0.001). Conclusions: Given the in vitro synergistic effectiveness of the association of chlorhexidine with TiO2 and UV-A against cysts, the treatment of Acanthamoeba keratitis could be improved by this new therapeutic approach.

Evaluation of Two Commercial Real-Time PCR Kits for Aspergillus DNA Detection in Bronchoalveolar Lavage Fluid in Patients with Invasive Pulmonary Aspergillosis.

Invasive pulmonary aspergillosis (IPA) is a common complication of immunosuppression. Rapid diagnosis using molecular techniques is essential to improve patient survival. PCR techniques are promising in enhancing Aspergillus detection in blood and respiratory samples. We evaluate for the first time the performances of two commercial real-time PCR kits, the A. fumigatus Bio-Evolution and the MycoGENIE A. fumigatus for the detection of A. fumigatus DNA in bronchoalveolar lavage (BAL) from patients with and without IPA. Seventy-three BAL samples were included. Thirty-one of them corresponded to patients with probable IPA, 11 to patients with possible IPA, and 31 to patients without aspergillosis, according to the 2008 European Organization for Research and Treatment of Cancer/Mycoses Study Group criteria. In the probable IPA group, A. fumigatus Bio-Evolution and the MycoGENIE A. fumigatus real-time PCR kits showed a specificity of 100% and a sensitivity of 81% and 71%, respectively. The A. fumigatus Bio-Evolution detected Aspergillus DNA in the 14 BAL samples with a positive Aspergillus culture result, whereas the MycoGENIE A. fumigatus PCR result was positive only for 12. In the possible IPA group, there were no positive real-time PCR or positive Aspergillus culture results. For the patients without aspergillosis, no positive result was observed for real-time PCR kit, despite the presence of various other non-Aspergillus pathogens in this group. Our study demonstrates an excellent specificity and a good sensitivity of A. fumigatus DNA detection in BAL samples with both kits.

Intraocular Cytokine Levels in Post-Cataract Endophthalmitis and their Association with Visual Outcome.

PURPOSE: The host immune reaction during endophthalmitis, studied in particular through the intraocular cytokine network, is essential for the comprehension of the disease and the development of new therapies. Therefore, the purpose of this study was to elucidate the cytokine composition of aqueous humor during endophthalmitis. METHODS: In a multicenter case-control study, forty-nine patients with postoperative endophthalmitis and 60 controls (cataract surgery) were included. Visual acuity, local inflammatory grading, medical history and intraocular levels of 27 cytokines and chemokines (measured by multiplex immunoassay) were recorded. RESULTS: During endophtalmitis, an increase in total cytokines was observed. The raise of Th1 cytokines was particularly noticeable. Chemokines, such as IL-8, MIP-1 ß, MCP-1, G-CSF and IP-10, also increased. Pearson's correlation analyses showed a poor visual prognosis with high levels of IL-8, MCP-1 and VEGF and a low level of IL-10 at admission. CONCLUSION: An increase in inflammatory cytokines is noticeable during endophthalmitis, with a particular emphasis on IL-8, MCP-1 and VEGF. Targeted anti-inflammatory and anti-VEGF treatments may be of interest in the future.

Surgical treatment of Metarhizium anisopliae sclerokeratitis and endophthalmitis.

A 55-year-old nurse was referred with a 5-month history of right eye corneal abscess. The initial injury occurred when doing lawn work. The infection worsened despite multiple antibiotic, antiviral, and steroid treatments. Visual acuity was limited to hand motion. On examination, there was keratitis, ocular hypertension, and a secondary cataract. Corneal scrapings grew a filamentous fungus, identified as Metarhizium anisopliae (MA). Despite intensive antifungal treatment with topical, intravitreous, and systemic voriconazole, purulent corneal melting and scleritis with endophthalmitis rapidly appeared. An emergency surgical procedure including sclerocorneal transplantation, cataract surgery, a pars plana vitrectomy using temporary keratoprosthesis, and scleral crosslinking was necessary. One year after the surgery, there was no recurrence of infection. Functional outcome remained very poor. This is the first case of sclerokeratitis and endophthalmitis caused by MA ever reported. The infection was successfully treated with an aggressive combination of medical and surgical treatments.

First case of Arthrographis kalrae fungemia in a patient with cystic fibrosis.

Arthrographis kalrae is a hyalin fungus. It is a saprophyte of the environment, mainly found in soil and compost. In recent years, cases of opportunistic infections attributed to this pathogen have been described. Our patient was a 19-year-old woman with cystic fibrosis. She presented a bacterial and fungal pulmonary colonization with Aspergillus fumigatus and Arthrographis. kalrae. After her lung transplantation, she developed an A. kalrae fungemia, treated with caspofungin 50 mg/day associated to liposomal amphotericin B i.v. 3 mg/kg/day. The patient died 8 months after her transplantation as the result of a bacterial septic shock.

HIC1 controls cellular- and HIV-1- gene transcription via interactions with CTIP2 and HMGA1.

Among many cellular transcriptional regulators, Bcl11b/CTIP2 and HGMA1 have been described to control the establishment and the persistence of HIV-1 latency in microglial cells, the main viral reservoir in the brain. In this present work, we identify and characterize a transcription factor i.e. HIC1, which physically interacts with both Bcl11b/CTIP2 and HMGA1 to co-regulate specific subsets of cellular genes and the viral HIV-1 gene. Our results suggest that HIC1 represses Tat dependent HIV-1 transcription. Interestingly, this repression of Tat function is linked to HIC1 K314 acetylation status and to SIRT1 deacetylase activity. Finally, we show that HIC1 interacts and cooperates with HGMA1 to regulate Tat dependent HIV-1 transcription. Our results also suggest that HIC1 repression of Tat function happens in a TAR dependent manner and that this TAR element may serve as HIC1 reservoir at the viral promoter to facilitate HIC1/TAT interaction.

Description of vertebral and liver alveolar echinococcosis cases in Cynomolgus monkeys (Macaca fascicularis).

BACKGROUND: Echinococcus multilocularis, the causative agent of alveolar echinococcosis, is a fox tapeworm widely distributed in Europe with an increase of endemic area in recent years. Many mammal species including humans and non-human primates can be infected by accidental ingestion of eggs. CASE PRESENTATION: In March 2011, a 5-year-old zoo-raised male cynomolgus macaque (Macaca fascicularis) presented a paresis of the lower limbs which evolved into paralysis. Lesions in liver and vertebra were observed on tomography scan. E. multilocularis infection was diagnosed post-mortem by morphological and histological examination and detection of Em DNA by polymerase chain reaction. Serodiagnosis of other primates of the colony using enzyme-linked immunosorbent assay (ELISA) was negative. In June 2013, at necroscopy, a hepatic and a paravertebral masses were detected in a second cynomolgus macaque of the same colony. Serology and DNA isolated from hepatic and abdominal cysts confirmed E. multilocularis infection. CONCLUSIONS: We described hear vertebral and liver localization of alveolar echinococcosis in non-human primates. The animals lived in an indoor/outdoor housing facility, where the probable mode of contamination is by ingestion of food foraging around the enclosure which could be contaminated with fox feces. Serological survey in the facility should allow us to estimate the risk of human contamination and the zoonotic risk of monkey infection due to environmental contamination.

First Case of Human Cerebral Taenia martis Cysticercosis.

Taenia martis is a tapeworm affecting mustelids, with rodents serving as intermediate hosts. The larval stage (cysticercus) has been found before only rarely in humans or primates. We hereby describe a case of cerebral T. martis cysticercosis in a French immunocompetent patient, confirmed by DNA analyses of biopsy material.

Pseudozyma aphidis fungemia after abdominal surgery: First adult case.

Pseudozyma aphidis is an environmental Basidiomycete yeast, and has been involved in the ten past years in rare cases of invasive infection. Pseudozyma species are naturally resistant to caspofungin and often present decreased susceptibility or resistance to fluconazole. This fungus may be difficult to recognize and misidentifications are reported with conventional phenotypical methods. We report a case of P. aphidis invasive infection in an adult with a metastatic ampulloma who had gone through digestive surgery.

Interleukin-6-driven inflammatory response induces retinal pathology in a model of ocular toxoplasmosis reactivation.

Ocular inflammation is one of the consequences of infection with the protozoan parasite Toxoplasma gondii. Even if lesions are self-healing in immunocompetent persons, they pose a lifetime risk of reactivation and are a serious threat to vision. As there are virtually no immunological data on reactivating ocular toxoplasmosis, we established a model of direct intravitreal injection of parasites in previously infected mice with a homologous type II strain. Two different mouse strains with variable ability to control retinal infection were studied in order to describe protective and deleterious reaction patterns. In Swiss-Webster mice, which are already relatively resistant to primary infection, no peak of parasite load was observed upon reinfection. In contrast, the susceptible inbred strain C57BL/6 showed high parasite loads after 7 days, as well as marked deterioration of retinal architecture. Both parameters were back to normal on day 21. C57BL/6 mice also reacted with a strong local production of inflammatory and Th1-type cytokines, like interleukin-6 (IL-6), IL-17A, and gamma interferon (IFN-γ), while Swiss-Webster mice showed only moderate expression of the Th2 cytokine IL-31. Interestingly, rapid intraocular production of anti-Toxoplasma antibodies was observed in Swiss-Webster but not in C57BL/6 mice. We then localized the cellular source of different immune mediators within the retina by immunofluorescence. Finally, neutralization experiments of IFN-γ or IL-6 demonstrated the respective protective and deleterious roles of these cytokines for parasite control and retinal integrity during reinfection. In conclusion, we developed and immunologically characterized a promising mouse model of reactivating ocular toxoplasmosis.

Diversity and prevalence of gastrointestinal parasites in seven non-human primates of the Taï National Park, Côte d'Ivoire.

Parasites and infectious diseases are well-known threats to primate populations. The main objective of this study was to provide baseline data on fecal parasites in the cercopithecid monkeys inhabiting Côte d'Ivoire's Taï National Park. Seven of eight cercopithecid species present in the park were sampled: Cercopithecus diana, Cercopithecus campbelli, Cercopithecus petaurista, Procolobus badius, Procolobus verus, Colobus polykomos, and Cercocebus atys. We collected 3142 monkey stool samples between November 2009 and December 2010. Stool samples were processed by direct wet mount examination, formalin-ethyl acetate concentration, and MIF (merthiolate, iodine, formalin) concentration methods. Slides were examined under microscope and parasite identification was based on the morphology of cysts, eggs, and adult worms. A total of 23 species of parasites was recovered including 9 protozoa (Entamoeba coli, Entamoeba histolytica/dispar, Entamoeba hartmanni, Endolimax nana, Iodamoeba butschlii, Chilomastix mesnili, Giardia sp., Balantidium coli, and Blastocystis sp.), 13 nematodes (Oesophagostomum sp., Ancylostoma sp., Anatrichosoma sp., Capillariidae Gen. sp. 1, Capillariidae Gen. sp. 2, Chitwoodspirura sp., Subulura sp., spirurids [cf Protospirura muricola], Ternidens sp., Strongyloides sp., Trichostrongylus sp., and Trichuris sp.), and 1 trematode (Dicrocoelium sp.). Diversity indices and parasite richness were high for all monkey taxa, but C. diana, C. petaurista, C. atys, and C. campbelli exhibited a greater diversity of parasite species and a more equitable distribution. The parasitological data reported are the first available for these cercopithecid species within Taï National Park.

An unusual case of hematuria in a French family returning from Corsica.

Urinary schistosomiasis caused by Schistosoma haematobium worms is endemic to tropical regions where it is the most common cause of hematuria. However, the intermediate snail hosts, Bulinus truncatus, have been described in Portugal, Spain, Sardinia, and Corsica. S. haematobium has long remained exotic to Europe, however, an outbreak of urinary schistosomiasis in Corsica started in 2011 with B. truncatus as the primary intermediate host. We describe the case of a 12-year-old French boy presenting hematuria and dysuria who was diagnosed with urinary schistosomiasis. Urine examination confirmed the presence of viable parasitic ova. He also had a positive serology. Since there was no history of travel to a schistosomiasis endemic region, the probable area of contamination was identified as the south of Corsica where the family had spent their summer holidays 7 months earlier. Two other family members had a positive serology without ova excretion in urine. The patients were treated with praziquantel. In light of these recent locally acquired cases in France, schistosomiasis should be considered in the differential diagnosis of hematuria, especially in patients who have recently visited Corsica.

First case of peritoneal cysticercosis in a non-human primate host (Macaca tonkeana) due to Taenia martis.

BACKGROUND: Infections with larval stages (metacestodes) of a variety of taeniid species have been described in primates, including humans, with partial to severe clinical consequences. Taenia martis is a tapeworm of mustelids, and martens are mainly their definitive hosts in Central Europe. In the rodent intermediate host cysticerci develop in the pleural and peritoneal cavities. The present report describes a case of T. martis peritoneal cysticercosis in a Tonkean macaque. FINDINGS: An abdominal mass was detected in a 3-year-old male Tonkean macaque (Macaca tonkeana) born and raised in a primate colony in France. Examination of the mass after laparotomy showed numerous vesicles identified as cysticerci of T. martis, based on the morphology of scolex and hooks, with confirmation by PCR amplification and sequence analysis of the mitochondrial cytochrome c oxidase subunit 1 (cox1) and NADH dehydrogenase subunit 1 (nad1) genes. Exeresis of the lesion was not possible and praziquantel (5.7 mg/kg) was given twice at an interval of 3 days. The abdominal mass was greatly diminished upon examination 2 months later and no signs of recurrence were noticed during the following 4 years. CONCLUSIONS: This is the first report of T. martis cysticercosis in a monkey. This record and the recent first description of an ocular T. martis cysticercosis in a human show the susceptibility of primates to T. martis and its zoonotic potential. This taeniid species must be considered in the differential diagnosis of cysticercosis in primates.

Ocular cytokinome is linked to clinical characteristics in ocular toxoplasmosis.

PURPOSE: To determine the cytokine levels in aqueous humor (AH) of Colombian patients with active ocular toxoplasmosis (OT), and to correlate them with their clinical characteristics. METHODS: 27 Cytokines/chemokines were assayed in 15 AH samples (nine patients with diagnosis of OT biologically-confirmed and six controls that underwent cataract surgery). Correlations were assessed between cytokine/chemokine levels, type of inflammatory response (Th1, Th2, Th17, Treg), and clinical characteristics. RESULTS: Th2 predominant response was related to more severe clinical features. The presence of VEGF and IL-5 was related to higher number of recurrences. Growth factors (VEGF, FGF, PDGF-ß), were related to higher number of lesions. Patients infected by type-I/III strains had a particular intraocular cytokine-pattern. CONCLUSIONS: Th2 response was related to more severe clinical characteristics in patients infected by Type I/III strains. IL-5 and VEGF were associated with recurrences. We correlate for the first time, specific cytokine-patterns with clinical characteristics and with the infecting Toxoplasma strain.

Severe South American ocular toxoplasmosis is associated with decreased Ifn-γ/Il-17a and increased Il-6/Il-13 intraocular levels.

In a cross sectional study, 19 French and 23 Colombian cases of confirmed active ocular toxoplasmosis (OT) were evaluated. The objective was to compare clinical, parasitological and immunological responses and relate them to the infecting strains. A complete ocular examination was performed in each patient. The infecting strain was characterized by genotyping when intraocular Toxoplasma DNA was detectable, as well as by peptide-specific serotyping for each patient. To characterize the immune response, we assessed Toxoplasma protein recognition patterns by intraocular antibodies and the intraocular profile of cytokines, chemokines and growth factors. Significant differences were found for size of active lesions, unilateral macular involvement, unilateral visual impairment, vitreous inflammation, synechiae, and vasculitis, with higher values observed throughout for Colombian patients. Multilocus PCR-DNA sequence genotyping was only successful in three Colombian patients revealing one type I and two atypical strains. The Colombian OT patients possessed heterogeneous atypical serotypes whereas the French were uniformly reactive to type II strain peptides. The protein patterns recognized by intraocular antibodies and the cytokine patterns were strikingly different between the two populations. Intraocular IFN-γ and IL-17 expression was lower, while higher levels of IL-13 and IL-6 were detected in aqueous humor of Colombian patients. Our results are consistent with the hypothesis that South American strains may cause more severe OT due to an inhibition of the protective effect of IFN-γ.

Is a Plasmodium lactate dehydrogenase (pLDH) enzyme-linked immunosorbent (ELISA)-based assay a valid tool for detecting risky malaria blood donations in Africa?

BACKGROUND: Malaria is a leading cause of mortality in southern Benin. The main causative agent, Plasmodium falciparum, poses a threat on critical transfusions in pregnant women and children. This study's objective was to compare the performance of different malaria screening methods in blood donors in southern Benin, a malaria-endemic country. METHODS: Blood from 2,515 voluntary blood donors in Benin was collected over a period of 10 months in ethylenediaminetetraacetic acid (EDTA) tubes, which were then classified according to extraction time: long rainy season, short dry season, short rainy season, and long dry season. Microscopic examination was used to count parasites. Parasite density (PD) was expressed as the number of parasites per µL of blood. Pan Plasmodium pLDH detection was assessed by an ELISA-malaria antigen test. Using crude soluble P. falciparum antigens, an ELISA-malaria antibody test detected anti-Plasmodium antibodies. RESULTS: Among the 2,515 blood donors (2,025 males and 488 females) screened, the rate of asymptomatic Plasmodium carriage was 295/2,515 (11.72%, 95% CI: 10.5-13.1%). Males had a higher infection rate (12.4%) than did females (8.8%). Parasite density was very low: between seven and100 parasites per µL of blood was reported in 80% of donors with parasitaemia. Three Plasmodium species were diagnosed: P. falciparum in 280/295 patients (95.0%), Plasmodium malariae in 14/295 (5.0%), and Plasmodium ovale in 1/295 (0.34%). Malaria prevalence in donors was higher during the rainy seasons (13.7%) compared with the dry seasons (9.9%). The use of a highly sensitive assay enabled pan Plasmodium pLDH detection in 966/2,515 (38.4%, 95% CI: 36.5%-40.3%). Malaria antibody prevalence was 1,859/2,515 (73.9%, 95% CI: 72.16-75.6%). Donors' antigenaemia and antibody levels varied significantly (P <0.05) over the course of the four seasons. The highest antigenaemia rate 323/630 (51.3%), was observed during the short rainy season, while the highest antibody prevalence, 751/886 (84.7%), was recorded during the long dry season. CONCLUSION: Blood donations infected with Plasmodium can transmit malaria to donation recipients. Malaria diagnostic methods are currently available, but the feasibility criteria for mass screening in endemic areas become preponderant. Detection of the pLDH antigen seems to be an adequate screening tool in endemic areas, for this antigen indicates parasite presence. Routine screening of all donated blood would prevent infected blood donations and reduce P. falciparum transmission in critical patients, such as children and pregnant women. This tool would also decrease medical prophylaxis in donation recipients and contribute to lower Plasmodium resistance.

CTIP2 is a negative regulator of P-TEFb.

The positive transcription elongation factor b (P-TEFb) is involved in physiological and pathological events including inflammation, cancer, AIDS, and cardiac hypertrophy. The balance between its active and inactive form is tightly controlled to ensure cellular integrity. We report that the transcriptional repressor CTIP2 is a major modulator of P-TEFb activity. CTIP2 copurifies and interacts with an inactive P-TEFb complex containing the 7SK snRNA and HEXIM1. CTIP2 associates directly with HEXIM1 and, via the loop 2 of the 7SK snRNA, with P-TEFb. In this nucleoprotein complex, CTIP2 significantly represses the Cdk9 kinase activity of P-TEFb. Accordingly, we show that CTIP2 inhibits large sets of P-TEFb- and 7SK snRNA-sensitive genes. In hearts of hypertrophic cardiomyopathic mice, CTIP2 controls P-TEFb-sensitive pathways involved in the establishment of this pathology. Overexpression of the ß-myosin heavy chain protein contributes to the pathological cardiac wall thickening. The inactive P-TEFb complex associates with CTIP2 at the MYH7 gene promoter to repress its activity. Taken together, our results strongly suggest that CTIP2 controls P-TEFb function in physiological and pathological conditions.