Unmasking Bartonella henselae infection in the shadows of long COVID thanks to clinical metagenomics.

The diagnosis of long COVID often relies on symptoms post-COVID-19, occasionally lacking biological evidence. This case study illustrates how investigating long COVID uncovered an underlying bartonellosis through clinical metagenomics. Following mild COVID-19, a 26-year-old woman experienced persistent symptoms during 5 months, including axillary adenopathy. Pathological examination, 16 S rRNA PCR, and clinical metagenomic analysis were done on an adenopathy biopsy. The latter revealed Bartonella henselae DNA and RNA. Treatment with clarithromycin improved symptoms. This case underscores the relevance of clinical metagenomics in diagnosing hidden infections. Post-COVID symptoms warrant thorough investigation, and bartonellosis should be considered in polyadenopathy cases, regardless of a recent history of cat or flea exposures.

Failure of bamlanivimab with selection of E484K mutation in an allogeneic stem cell transplant recipient with nosocomial SARS-CoV-2 infection.

We report the case of an allogeneic stem cell transplant recipient with nosocomial acquisition of SARS-CoV-2 infection who received antispike neutralizing monoclonal antibody bamlanivimab 2 days after diagnosis of SARS-CoV-2 infection but progressed to severe COVID-19 pneumonia and died with the selection of E484K/Q resistance mutations to bamlanivimab.

Multiplex Polymerase Chain Reaction Assay to Detect Nasopharyngeal Viruses in Immunocompromised Patients With Acute Respiratory Failure.

BACKGROUND: In immunocompromised patients with acute respiratory failure (ARF), the clinical significance of respiratory virus detection in the nasopharynx remains uncertain. RESEARCH QUESTION: Is viral detection in nasopharyngeal swabs associated with causes and outcomes of ARF in immunocompromised patients? STUDY DESIGN AND METHODS: This preplanned post hoc analysis of a randomized controlled trial enrolled immunocompromised patients admitted to 32 ICUs for ARF between May 2016 and December 2017. Nasopharyngeal swabs sampled at inclusion were assessed for 23 respiratory pathogens using multiplex polymerase chain reaction (PCR) assay. Causes of ARF were established by managing physicians and were reviewed by three expert investigators masked to the multiplex PCR assay results. Associations between virus detection in nasopharyngeal swabs, causes of ARF, and composite outcome of day 28 mortality, invasive mechanical ventilation (IMV), or both were assessed. RESULTS: Among the 510 sampled patients, the multiplex PCR assay results were positive in 103 patients (20.2%), and a virus was detected in 102 samples: rhinoviruses or enteroviruses in 35.5%, coronaviruses in 10.9%, and flu-like viruses (influenza virus, parainfluenza virus, respiratory syncytial virus, human metapneumovirus) in 52.7%. The cause of ARF varied significantly according to the results of the multiplex PCR assay, especially the proportion of viral pneumonia: 50.0% with flu-like viruses, 14.0% with other viruses, and 3.6% when no virus was detected (P < .001). No difference was found in the composite outcome of day 28 mortality, IMV, or both according to positive assay findings (54.9% vs 54.7%; P = .965). In a pre-established subgroup analysis, flu-like virus detection was associated with a higher rate of day 28 mortality, IMV, or both among recipients of allogeneic hematopoietic stem cell transplantation compared with those without detected virus. INTERPRETATION: In immunocompromised patients with ARF, the results of nasopharyngeal multiplex PCR assays are not associated with IMV or mortality. A final diagnosis of viral pneumonia is retained in one-third of patients with positive assay results and in one-half of the patients with a flu-like virus.

Circulating T cell profiles associate with enterotype signatures underlying hematological malignancy relapses.

Early administration of azithromycin after allogeneic hematopoietic stem cell transplantation was shown to increase the relapse of hematological malignancies. To determine the impact of azithromycin on the post-transplant gut ecosystem and its influence on relapse, we characterized overtime gut bacteriome, virome, and metabolome of 55 patients treated with azithromycin or a placebo. We describe four enterotypes and the network of associated bacteriophage species and metabolic pathways. One enterotype associates with sustained remission. One taxon from Bacteroides specifically associates with relapse, while two from Bacteroides and Prevotella correlate with complete remission. These taxa are associated with lipid, pentose, and branched-chain amino acid metabolic pathways and several bacteriophage species. Enterotypes and taxa associate with exhausted T cells and the functional status of circulating immune cells. These results illustrate how an antibiotic influences a complex network of gut bacteria, viruses, and metabolites and may promote cancer relapse through modifications of immune cells.

Adenovirus F41 infection and liver cytolysis in adult hematopoietic stem cell transplant recipients.

Human adenoviruses (HAdVs) of the F species are commonly responsible for acute gastroenteritis. A few cases of systemic infections have been described in adults or children who have received a hematopoietic stem cell transplant (HSCT), but with no report of liver cytolysis. Since January 2022, several countries have reported an increase in cases of acute hepatitis of unknown cause in children. Adenovirus species F type 41 (HAdV-F41) infection was predominantly identified. The objective of this study is to describe HAdV-F41 infections diagnosed since January 2022 in adult HSCT recipients in two French hospitals. All four patients had diarrhea and liver cytolysis at the time of diagnosis of infection. HAdV viremia was observed in three patients (#1, #3, and #4), but no disseminated disease was reported. HAdV whole genome sequencing and metagenomics characterization were performed on stool and blood samples. The complete HAdV-F41 genome sequence was obtained for three patients and phylogenetic analysis showed that the strains consisted of similar lineage (2b). We did not identify any new HAdV-F41 strains. Metagenomics analysis found adeno-associated virus 2 and torque-teno virus infection in patient #1 and Epstein-Barr virus in patient #4. This is the first case series reporting liver cytolysis during HAdV-F41 infection in adult HSCT patients.

Higher convergence of human-great ape enteric eukaryotic viromes in central African forest than in a European zoo: a One Health analysis.

Human-animal pathogenic transmissions threaten both human and animal health, and the processes catalyzing zoonotic spillover and spillback are complex. Prior field studies offer partial insight into these processes but overlook animal ecologies and human perceptions and practices facilitating human-animal contact. Conducted in Cameroon and a European zoo, this integrative study elucidates these processes, incorporating metagenomic, historical, anthropological and great ape ecological analyses, and real-time evaluation of human-great ape contact types and frequencies. We find more enteric eukaryotic virome sharing between Cameroonian humans and great apes than in the zoo, virome convergence between Cameroonian humans and gorillas, and adenovirus and enterovirus taxa as most frequently shared between Cameroonian humans and great apes. Together with physical contact from hunting, meat handling and fecal exposure, overlapping human cultivation and gorilla pillaging in forest gardens help explain these findings. Our multidisciplinary study identifies environmental co-use as a complementary mechanism for viral sharing.

Clinical significance of human metapneumovirus detection in critically ill adults with lower respiratory tract infections.

BACKGROUND: Unlike other viruses, the pathogenicity of human metapneumovirus (hMPV) in adults remains uncertain. To address this question, a retrospective monocentric cohort including all patients admitted to ICU with hMPV infection between January 1, 2010, and June 30, 2018 was performed. The characteristics of hMPV infected patients were studied and compared to matched influenza infected patients. Consecutively, a systematic review and meta-analyses investigating PUBMED, EMBASE and COCHRANE databases was conducted to explore the hMPV infections in adult patients (PROSPERO number: CRD42018106617). Trials, case series, and cohorts published between January 1, 2008 and August 31, 2019 compiling adults presenting hMPV infections were included. Pediatric studies were excluded. Data were extracted from published reports. Primary endpoint was the rate of low respiratory tract infections (LRTIs) among all hMPV infected patients. RESULTS: During the study period, 402 patients were tested positive for hMPV. Among them 26 (6.5%) patients were admitted to the ICU, 19 (4.7%) for acute respiratory failure. Twenty-four (92%) were immunocompromised. Bacterial coinfections were frequent 53.8%. Hospital mortality rate was 30.8%. In the case-control analysis, the clinical and imaging characteristics were not different between hMPV and influenza infected patients. The systematic review identified 156 studies and 69 of them (1849 patients) were eligible for analysis. Although there was heterogeneity between the studies, the rate of hMPV LRTIs was 45% (95% CI 31-60%; I2 = 98%). Intensive care unit (ICU) admission was required for 33% (95% CI 21-45%; I2 = 99%). Hospital mortality rate was 10% (95% CI 7-13%; I2 = 83%) and ICU mortality rate was 23% (95% CI 12-34%; I2 = 65%). Underlying malignancy was independently associated with increased mortality rate. CONCLUSIONS: This preliminary work suggested that hMPV may be associated with severe infection and high mortality in patients with underlying malignancies. However, regarding the small size of the cohort and the heterogeneity of the review, more cohort studies are warranted.

BK virus genotypes and humoral response in kidney transplant recipients with BKV associated nephropathy.

BACKGROUND: Among kidney transplant recipients (KTR) with BK virus associated nephropathy (BKVN), BKV genotypes' evolution and anti-BKV humoral response are not well established. We aim to analyze BKV replication and genetic evolution following transplantation, and characterize concomitant anti-BKV-VP1 humoral response. METHODS: We retrospectively analyzed 32 cases of biopsy-proven BKVN. Stored plasma and kidney biopsies were tested for BKV viral load, and VP1 sequencing performed on positive samples. BKV-VP1 genotype-specific neutralizing antibodies (NAbs) titers were determined at transplantation and BKVN. RESULTS: At the time of BKVN diagnosis, BKV viral load was 8.2 log10 IU/106 cells and 5.4 log10 IU/mL in kidney and plasma, respectively. VP1 sequencing identified the same BKV-subtype in both compartments in 31/32 cases. At the time of transplantation, 8/20 (40%) of biopsies tested positive for BKV detection, whereas concomitant BKV viremia was negative. VP1 sequencing identified a different subtype compared to BKVN in 5/6 of these samples. This was confirmed following transplantation: 8 patients had a BKV+ biopsy before BKV viremia, and VP1 sequencing identified a different subtype compared to BKVN in all of them. After the onset of BKV viremia and prior to BKVN diagnosis, the BKV subtype in BKV+ plasma and kidney biopsy was the same as the one isolated at BKVN. BKV-VP1 NAbs titers were significantly higher at the time of BKVN compared to transplantation (p = .0031), with similar titers across genotypes. CONCLUSION: Altogether, our data suggest that among some KTR with BKVN, the BKV genotype from the donor may not be responsible for BKVN pathogenesis.

Characteristics of circulating KSHV-infected viroblasts during active KSHV+ multicentric Castleman disease.

Kaposi sarcoma-associated herpesvirus (KSHV)/human herpesvirus 8-associated multicentric Castleman disease (MCD) is a polyclonal B-cell lymphoproliferative disorder that mainly occurs in immunocompromised hosts. The diagnosis relies on lymph node biopsy demonstrating KSHV-infected cells located in the mantle zone with a marked interfollicular plasma cell infiltration. Infected cells are large cells positive for immunoglobulin M (IgM), λ light chain, and CD38, described initially as infected plasmablasts. We show that IgM+λ+CD38high cells were also detectable in the peripheral blood of 14 out of 18 (78%) patients with active KSHV-MCD and absent in 40 controls. Using immunofluorescence and flow-fluorescence in situ hybridization, we demonstrate that these cells are KSHV infected and express both latent and lytic KSHV transcripts. These KSHV-infected viroblasts (KIVs) harbor a distinct phenotype compared with conventional plasmablasts. We also identified several putative mechanisms of immune escape used by KSHV, because KIVs displayed an overall decrease of costimulatory molecules, with a remarkable lack of CD40 expression and are interleukin-10-producing cells. The identification of this specific and easily accessible KSHV+ circulating population brings new elements to the understanding of KSHV-MCD but also raises new questions that need to be clarified.

Human adenoviral (HAdV) chronic arthritis expands the infectious spectrum of primary agammaglobulinemia.

Inborn errors of immunity (IEI) are a heterogeneous entity with an increasing number of late diagnoses. Besides infections, inflammatory manifestations are a growing part of the clinical landscape of IEI. These complications are of unknown causes and often lead to the prescription of immunosuppressive agents that worsen the underlying immune defect. We here report the case of an adult patient diagnosed with chronic Human Adenovirus C-1 arthritis in the setting of primary agammaglobulinemia. Metagenomic next-generation sequencing led to the correct diagnosis and high-dose intravenous immunoglobulins resulted in complete recovery. This observation gives new insights into adenoviral immunity and underlines the importance of metagenomics in the diagnosis of inflammatory manifestations in immunocompromised patients.

Metagenomic next-generation sequencing restores the diagnosis of a rare infectious complication of B cell depletion.

A 45-year-old female patient receiving rituximab for B cell non-Hodgkin follicular lymphoma presented unexplained recurrent fever, abdominal discomfort, and pollakiuria. We performed shotgun metagenomic sequencing from peri-kidney collection that identified a co-infection with Mycoplasma hominis and Ureaplasma urealyticum. The patient recovered with sequelae after appropriate antibiotic treatment was given.

Genotypic and Phenotypic Diversity of the Replication-Competent HIV Reservoir in Treated Patients.

In HIV infection, viral rebound after treatment discontinuation is considered to originate predominantly from viral genomes integrated in resting CD4+ T lymphocytes. Replication-competent proviral genomes represent a minority of the total HIV DNA. While the quantification of the HIV reservoir has been extensively studied, the diversity of genomes that compose the reservoir was less explored. Here, we measured the genotypic and phenotypic diversity in eight patients with different treatment histories. Between 4 and 14 (mean, 8) individual viral isolates per patient were obtained using a virus outgrowth assay, and their near-full-length genomes were sequenced. The mean pairwise distance (MPD) observed in different patients correlated with the time before undetectable viremia was achieved (r = 0.864, P = 0.0194), suggesting that the complexity of the replication-competent reservoir mirrors that present at treatment initiation. No correlation was instead observed between MPD and the duration of successful treatment (mean, 8 years; range, 2 to 21 years). For 5 of the 8 patients, genotypically identical viral isolates were observed in independent wells, suggesting clonal expansion of infected cells. Identical viruses represented between 25 and 60% of the isolates (mean, 48%). The proportion of identical viral isolates correlated with the duration of treatment (r = 0.822, P = 0.0190), suggesting progressive clonal expansion of infected cells during ART. A broader range of infectivity was also observed among isolates from patients with delayed viremia control (r = 0.79, P = 0.025). This work unveiled differences in the genotypic and phenotypic features of the replication-competent reservoir from treated patients and suggests that delaying treatment results in increased diversity of the reservoir. IMPORTANCE In HIV-infected and effectively treated individuals, integrated proviral genomes may persist for decades. The vast majority of the genomes, however, are defective, and only the replication-competent fraction represents a threat of viral reemergence. The quantification of the reservoir has been thoroughly explored, while the diversity of the genomes has been insufficiently studied. Its characterization, however, is relevant for the design of strategies aiming the reduction of the reservoir. Here, we explored the replication-competent near-full-length HIV genomes of eight patients who experienced differences in the delay before viremia control and in treatment duration. We found that delayed effective treatment was associated with increased genetic diversity of the reservoir. The duration of treatment did not impact the diversity but was associated with higher frequency of clonally expanded sequences. Thus, early treatment initiation has the double advantage of reducing both the size and the diversity of the reservoir.

Prevention of SARS-CoV-2 transmission during a large, live, indoor gathering (SPRING): a non-inferiority, randomised, controlled trial.

BACKGROUND: Mass indoor gatherings were banned in early 2020 to prevent the spread of SARS-CoV-2. We aimed to assess, under controlled conditions, whether infection rates among attendees at a large, indoor gathering event would be similar to those in non-attendees, given implementation of a comprehensive prevention strategy including antigen-screening within 3 days, medical mask wearing, and optimised ventilation. METHODS: The non-inferiority, prospective, open-label, randomised, controlled SPRING trial was done on attendees at a live indoor concert held in the Accor Arena on May 29, 2021 in Paris, France. Participants, aged 18-45 years, recruited via a dedicated website, had no comorbidities, COVID-19 symptoms, or recent case contact, and had had a negative rapid antigen diagnostic test within 3 days before the concert. Participants were randomly allocated in a 2:1 ratio to the experimental group (attendees) or to the control group (non-attendees). The allocation sequence was computer-generated by means of permuted blocks of sizes three, six, or nine, with no stratification. The primary outcome measure was the number of patients who were SARS-CoV-2-positive by RT-PCR test on self-collected saliva 7 days post-gathering in the per-protocol population (non-inferiority margin <0·35%). This trial is registered with ClinicalTrials.gov, NCT04872075. FINDINGS: Between May 11 and 25, 2021, 18 845 individuals registered on the dedicated website, and 10 953 were randomly selected for a pre-enrolment on-site visit. Among 6968 who kept the appointment and were screened, 6678 participants were randomly assigned (4451 were assigned to be attendees and 2227 to be non-attendees; median age 28 years; 59% women); 88% (3917) of attendees and 87% (1947) of non-attendees complied with follow-up requirements. The day 7 RT-PCR was positive for eight of the 3917 attendees (observed incidence, 0·20%; 95% CI 0·09-0·40) and three of the 1947 non-attendees (0·15%; 0·03-0·45; absolute difference, 95% CI -0·26% to 0·28%), findings that met the non-inferiority criterion for the primary endpoint. INTERPRETATION: Participation in a large, indoor, live gathering without physical distancing was not associated with increased SARS-CoV-2-transmission risk, provided a comprehensive preventive intervention was implemented. FUNDING: French Ministry of Health. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.

Evaluation of prognostic scores for respiratory syncytial virus infection in a French multicentre cohort of allogeneic haematopoietic stem cell transplantation recipients.

Haematopoietic stem cell transplantation (HSCT) recipients are at risk for severe respiratory syncytial virus (RSV) infection. Two prognostic scores have been proposed to predict the risk of progression from upper respiratory tract infection (URTI) to lower respiratory tract infection (LRTI) and death. This was a multicentre study of allogeneic HSCT recipients diagnosed with an RSV infection between 2010 and 2019 who were retrospectively stratified by the immunodeficiency scoring index (ISI) and the severe immunodeficiency (SID) score. Endpoints were overall survival, RSV-attributable mortality and progression to LRTI after URTI. Prognostic analyses were performed using Cox regression models. We included 147 consecutive patients, including 94 (63.9%) initially diagnosed with URTI and 53 (36.1%) with LRTI. At 90 days, 14 patients had died (survival rate, 90.5%; 95% CI: 85.9-95.3), and nine deaths were attributable to RSV (attributable mortality rate, 5.4%; 95% CI: 2.5-10.0). The cumulative 90-day incidence of LRTI after URTI was 13.8% (95% CI: 7.8-21.6). Neither score showed prognostic value for mortality, while the ISI allowed the prediction of progression to LRTI (p = 0.0008). Our results do not fully replicate the results previously reported in cohorts of HSCT recipients. This may reflect the recent epidemiology of RSV infections in this HSCT cohort.

Frequent lower respiratory tract disease in hematological patients with parainfluenza virus type 3 infection.

Human parainfluenza virus type 3 (HPIV-3) may cause lower respiratory tract infection disease (LRTI-D) after hematopoietic stem cell transplantation (HSCT). Most previous have studies focused on recipients of HSCT whereas data on characteristics and outcomes in patients with hematological malignancies (HMs) compared to non-hematological patients are limited. The prognostic value of viral load in respiratory specimens remains elusive. In a 2-year retrospective study, we determined the frequencies of LRTI-D in HM, HSCT, and in non-hematological patients, and HPIV-3 levels in respiratory tract secretions. Among 98 patients with HPIV-3 infection, including 31 HSCT and 40 HM, 36 had a diagnosis of LRTI-D. LRTI-D was significantly more frequent in patients with HM or HSCT (n = 32, 45.1%) than in non-hematological patients (n = 4, 14.8%) (p = 0.006). The median HPIV-3 loads were high in upper respiratory tract secretions regardless of the presence or absence of LRTI-D (8.3 log10 vs. 7.6 log10 TCID50 /106 cells). HPIV-3 loads in respiratory tract samples in HM were not significantly higher than those found in HSCT but significantly higher than in non-hematological patients (p = 0.007). In conclusion, LRTI-D was frequent in HM patients who were diagnosed with HPIV-3 infection.

[Which drugs to treat Adenovirus infections?] / Quelles molécules pour traiter des infections à Adénovirus ?

Human adenoviruses (HAdV) infections are generally mild and resolve spontaneously in immunocompetent individuals. However, HAdV infections can have a major clinical impact in immunocompromised patients. HAdV infections are associated with high morbidity and mortality in recipients of allogeneic stem cell transplants, particularly children. There are currently no drug approved for the treatment of HAdV infections. Nevertheless, some nucleotide analogues are used under temporary authorization for use, such as cidofovir or brincidofovir. Cidofovir inhibits the replication of HAdV but its nephrotoxicity and its low tissue concentrations severely limit its use. Brincidofovir, a cidofovir prodrug, with a better bioavailability and no nephrotoxicity was evaluated in the treatment of HAdV infections, but its development was recently stopped and it is currently no longer available in ATU. Other molecules with anti-HAdV activity are still in early stages of development. Adoptive immunotherapy by adenovirus-specific T-cell transfer is an interesting option but should be anticipated in patients with high risks of disseminated infections. Given the small therapeutic panel available, it is critical to continue the search for new anti-HAdV molecules, which remains mainly conducted by academic laboratories.

Deciphering an Adenovirus F41 Outbreak in Pediatric Hematopoietic Stem Cell Transplant Recipients by Whole-Genome Sequencing.

Human adenovirus (HAdV) represents a major cause of mortality and morbidity in pediatric recipients of allogeneic hematopoietic stem cell transplants (HSCT). HAdV species F type 41 (HAdV-F41) infections in HSCT patients are scarce, whereas HAdV-F41 circulates commonly in healthy individuals. Between March and July 2018, HAdV-F41 infections were identified in four children (A, B, C, and E) who received allogeneic HSCT and one child before HSCT (D) at Robert Debré Hospital, Paris, France. We report here the clinical course of HAdV-F41 infection and the phylogenetic investigation to identify interpatient transmission. HAdV DNA was quantified in stool and plasma samples by real-time PCR. HAdV type was determined by sequencing of the fiber and hexon genes. Phylogenetic investigation was done with whole-genome sequences obtained by next-generation sequencing. HAdV loads in stool samples ranged from 6.60 to 10.10 log10 copies/ml. HAdV-F41 detection in plasma was observed in four patients, but no disseminated disease was reported. Two patients died, but neither death was attributed to HAdV. While sequencing limited to the fiber gene suggested a cluster with four patients, phylogenetic analysis with whole-genome sequencing (WGS) and HVR7 revealed a cluster that included three patients (C, D, and E), suggesting an interpatient transmission in that cluster and two other independent infections. HAdV-F41 levels in stool specimens of pediatric HSCT patients are high and represent a risk of interpatient transmission. WGS helped to identify related cases. Prompt detection of HAdV in stool and control measures are warranted to limit any risk of nosocomial transmission.

Risk factors associated with COVID-19-associated pulmonary aspergillosis in ICU patients: a French multicentric retrospective cohort.

OBJECTIVES: The main objective of this study was to determine the incidence of invasive pulmonary aspergillosis (IPA) in patients with coronavirus disease 2019 (COVID-19) admitted to the intensive care unit (ICU), and to describe the patient characteristics associated with IPA occurrence and to evaluate its impact on prognosis. METHODS: We conducted a retrospective cohort study including all successive COVID-19 patients, hospitalized in four ICUs, with secondary deterioration and one or more respiratory samples sent to the mycology department. We used a strengthened IPA testing strategy including seven mycological criteria. Patients were classified as probable IPA according to the European Organization for Research and Treatment of Cancer (EORTC)/Mycoses Study Group Education and Research Consortium (MSGERC) classification if immunocompromised, and according to the recent COVID-19-associated IPA classification otherwise. RESULTS: Probable IPA was diagnosed in 21 out of the 366 COVID-19 patients (5.7%) admitted to the ICU and in the 108 patients (19.4%) who underwent respiratory sampling for deterioration. No significant differences were observed between patients with and without IPA regarding age, gender, medical history and severity on admission and during hospitalization. Treatment with azithromycin for ≥3 days was associated with the diagnosis of probable IPA (odds ratio 3.1, 95% confidence interval 1.1-8.5, p = 0.02). A trend was observed with high-dose dexamethasone and the occurrence of IPA. Overall mortality was higher in the IPA patients (15/21, 71.4% versus 32/87, 36.8%, p < 0.01). CONCLUSION: IPA is a relatively frequent complication in severe COVID-19 patients and is responsible for increased mortality. Azithromycin, known to have immunomodulatory properties, may contribute to increase COVID-19 patient's susceptibility to IPA.

Effect of brincidofovir on adenovirus and A549 cells transcriptome profiles.

OBJECTIVES: Human adenovirus (HAdV) infections are associated with a high morbidity and mortality in transplant patients requiring the use of antiviral treatments. Brincidofovir (BCV), a cytidine analog, inhibits HAdV replication through viral DNA elongation termination and likely through other mechanisms. To elucidate if BCV regulates cellular antiviral pathways, we analyzed its impact on HAdV-infected and non-HAdV-infected lung epithelial cells. METHODS: We assessed the cellular and viral transcriptome of A549 cells infected and non-infected with HAdV C5 and treated or non-treated with BCV by RNAseq after 72 h. RESULTS: BCV treatment of HAdV infected cells resulted in a profound decrease of viral transcription associated with a relative overexpression of the early genes E1A and E4 and of the late gene L1. BCV had also a profound impact on A549 cells' transcriptome. Ontologic analysis revealed an effect of BCV on several pathways known to interact with adenovirus replication as mTor signalling and Wnt pathways. A549 cells treated with BCV demonstrated a significant inhibition of the biological function of "viral replication" including 25 dysregulated genes involved in inflammation pathways. CONCLUSION: We demonstrated that BCV alters viral gene expression and promotes the expression of antiviral cellular pathways in A549 cells. These results provide new insights how to interfere with cellular pathways to control HAdV infections.

Lack of evidence for the involvement of Merkel cell polyomavirus in pulmonary Langerhans cell histiocytosis.

Compared to control lung tissues from smokers, MCPyV DNA is rarely detected in PLCH lesions and is not associated with alterations of the MAPK pathway. A viral trigger in PLCH pathogenesis remains elusive. https://bit.ly/2xKmkIo.