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Monogenic IFN-mediated autoinflammatory diseases present in infancy with systemic inflammation, an IFN response gene signature, inflammatory organ damage, and high mortality. We used the JAK inhibitor baricitinib, with IFN-blocking activity in vitro, to ameliorate disease. Between October 2011 and February 2017, 10 patients with CANDLE (chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperatures), 4 patients with SAVI (stimulator of IFN genes-associated [STING-associated] vasculopathy with onset in infancy), and 4 patients with other interferonopathies were enrolled in an expanded access program. The patients underwent dose escalation, and the benefit was assessed by reductions in daily disease symptoms and corticosteroid requirement. Quality of life, organ inflammation, changes in IFN-induced biomarkers, and safety were longitudinally assessed. Eighteen patients were treated for a mean duration of 3.0 years (1.5-4.9 years). The median daily symptom score decreased from 1.3 (interquartile range [IQR], 0.93-1.78) to 0.25 (IQR, 0.1-0.63) (P < 0.0001). In 14 patients receiving corticosteroids at baseline, daily prednisone doses decreased from 0.44 mg/kg/day (IQR, 0.31-1.09) to 0.11 mg/kg/day (IQR, 0.02-0.24) (P < 0.01), and 5 of 10 patients with CANDLE achieved lasting clinical remission. The patients' quality of life and height and bone mineral density Z-scores significantly improved, and their IFN biomarkers decreased. Three patients, two of whom had genetically undefined conditions, discontinued treatment because of lack of efficacy, and one CANDLE patient discontinued treatment because of BK viremia and azotemia. The most common adverse events were upper respiratory infections, gastroenteritis, and BK viruria and viremia. Upon baricitinib treatment, clinical manifestations and inflammatory and IFN biomarkers improved in patients with the monogenic interferonopathies CANDLE, SAVI, and other interferonopathies. Monitoring safety and efficacy is important in benefit-risk assessment. ClinicalTrials.gov NCT01724580 and NCT02974595. This research was supported by the Intramural Research Program of the NIH, NIAID, and NIAMS. Baricitinib was provided by Eli Lilly and Company, which is the sponsor of the expanded access program for this drug.

The objective of this study was to examine the association between serum tacrolimus trough levels and the detection of BK viruria in kidney transplant recipients. We conducted a retrospective study and included kidney transplant recipients who underwent BK viruria screening during 2018–2021. Serum tacrolimus trough levels, urine BK viral load, and potential risk factors were collected. Statistical analysis was performed to identify the association between the serum tacrolimus trough levels and the detection of BK virus in urine (defined as positive BK viruria), as well as to determine the cumulative incidence and risk factors for BK viruria. Out of 243 recipients, 76 had positive BK viruria. The average serum tacrolimus trough level was significantly higher among the positive BK viruria group compared to the BK viruria-negative group. High HLA mismatch was identified as a risk factor for BK viruria. Approximately half of the recipients with average serum tacrolimus trough levels exceeding 10 ng/mL would develop BK viruria early. This study found an association between the average serum tacrolimus trough level and the detection of BK viruria. High HLA mismatch and an average serum tacrolimus trough level exceeding 10 ng/mL should be regarded as a risk for BK viruria.

Postoperative JC viruria is common in kidney transplant recipients, however there remains a dearth of research on perioperative JCV infection in this population. The clinical significance of JCV monitoring in kidney transplant recipients remains unclear. Based on JCV urine monitoring during the perioperative phase, renal transplant recipients who underwent perioperative and postoperative monitoring at our center were categorized into two groups: the perioperative JC virus infection group and the control group consisting of recipients without detectable JCV DNA in plasma or urine during the two-year follow-up period. A comparative analysis of baseline data was initially performed, followed by a 1:1 propensity score matching of 80 cases from each group. Within the first month after transplantation, the JC viruria group exhibited a significant decrease in the incidence of delayed graft function compared to the control group (P = 0.031).Over the two-year postoperative period, the JC viruria group displayed a significantly lower rate of acute rejection (P = 0.027). Notably, the JC viruria group demonstrated higher estimated glomerular filtration rate levels compared to the control group, particularly within the first year post-transplantation. Moreover, recipient and transplant kidney survival rates did not significantly differ between the two groups (P = 0.642). Perioperative JC viruria in kidney transplant recipients may persist beyond the initial two postoperative years. The presence of JCV is associated with lower rates of DGF and acute rejection, indicating a favorable post-transplant recovery. These findings provide novel insights into the importance of postoperative JCV monitoring.

Zika virus (ZIKV), an emerging flavivirus, has recently spread explosively through the Western hemisphere. In addition to symptoms including fever, rash, arthralgia, and conjunctivitis, ZIKV infection of pregnant women can cause microcephaly and other developmental abnormalities in the fetus. We report herein the results of ZIKV infection of adult rhesus macaques. Following subcutaneous infection, animals developed transient plasma viremia and viruria from 1-7 days post infection (dpi) that was accompanied by the development of a rash, fever and conjunctivitis. Animals produced a robust adaptive immune response to ZIKV, although systemic cytokine response was minimal. At 7 dpi, virus was detected in peripheral nervous tissue, multiple lymphoid tissues, joints, and the uterus of the necropsied animals. Notably, viral RNA persisted in neuronal, lymphoid and joint/muscle tissues and the male and female reproductive tissues through 28 to 35 dpi. The tropism and persistence of ZIKV in the peripheral nerves and reproductive tract may provide a mechanism of subsequent neuropathogenesis and sexual transmission.

Zika virus (ZIKV) is a mosquito-borne flavivirus that predominantly circulates between humans and Aedes mosquitoes. Clinical studies have shown that Zika viruria in patients persists for an extended period, and results in infectious virions being excreted. Here, we demonstrate that Aedes mosquitoes are permissive to ZIKV infection when breeding in urine or sewage containing low concentrations of ZIKV. Mosquito larvae and pupae, including from field Aedes aegypti can acquire ZIKV from contaminated aquatic systems, resulting in ZIKV infection of adult females. Adult mosquitoes can transmit infectious virions to susceptible type I/II interferon receptor-deficient ( ifnagr-/- ) C57BL/6 (AG6) mice. Furthermore, ZIKV viruria from infected AG6 mice can causes mosquito infection during the aquatic life stages. Our studies suggest that infectious urine could be a natural ZIKV source, which is potentially transmissible to mosquitoes when breeding in an aquatic environment. Here the authors show that Aedes mosquitoes can acquire ZIKV by breeding in contaminated aquatic systems, and that these infected mosquitoes can transmit ZIKV to susceptible mice. This suggests that human urine containing aquatic environments could contribute to ZIKV transmission.

Background. Cytomegalovirus (CMV) urinary shedding in pregnant women infected with human immunodeficiency virus (HIV) was evaluated to determine whether it poses an increased risk for congenital CMV infection (cCMV). Methods. A subset of mother-infant pairs enrolled in the perinatal NICHD HPTN 040 study (distinguished by no antiretroviral use before labor) was evaluated. Maternal and infant urines were tested by qualitative real-time polymerase chain reaction (RT-PCR) for CMV DNA with quantitative RT-PCR performed on positive specimens. Results. Urine specimens were available for 260 women with 85.4% from the Americas and 14.6% from South Africa. Twenty-four women (9.2%) had detectable CMV viruria by qualitative PCR. Maternal CMV viruria was not associated with mean CD4 cell counts or HIV viral load but was associated with younger maternal age (P = .02). Overall, 10 of 260 infants (3.8%) had cCMV. Women with detectable peripartum CMV viruria were more likely to have infants with cCMV than those without: 20.8% (5/24) versus 2.1% (5/236), (P = .0001). Women with CMV viruria had significantly higher rates of HIV perinatal transmission (29.2% vs. 8.1%, P= .002). They were 5 times (adjusted odds ratio [aOR] = 5.6, 95% confidence interval [CI] 1.9–16.8) and nearly 30 times (aOR, 29.7; 95% CI, 5.4–164.2) more likely to transmit HIV and CMV to their infants, respectively. Maternal gonorrhea (aOR, 19.5; 95% CI, 2.5–151.3) and higher maternal HIV log10 viral load (OR, 2.8; 95% CI, 1.3–6.3) were also significant risk factors for cCMV. Conclusion. In this cohort of HIV-infected pregnant women not on antiretrovirals, urinary CMV shedding was a significant risk factor for CMV and HIV transmission to infants. Clinical Trials Registration Number. NCT00099359.

Limited understanding of bladder cancer aetiopathology hampers progress in reducing incidence. Mutational signatures show the anti-viral apolipoprotein B mRNA editing enzyme catalytic polypeptide (APOBEC) enzymes are responsible for the preponderance of mutations in bladder tumour genomes, but no causative viral agent has been identified. BK polyomavirus (BKPyV) is a common childhood infection that remains latent in the adult kidney, where reactivation leads to viruria. This study provides missing mechanistic evidence linking reactivated BKPyV-infection to bladder cancer risk. We used a mitotically-quiescent, functionally-differentiated model of normal human urothelium to examine BKPyV-infection. BKPyV-infection led to significantly elevated APOBEC3A and APOBEC3B protein, increased deaminase activity and greater numbers of apurinic/apyrimidinic sites in the host urothelial genome. BKPyV Large T antigen (LT-Ag) stimulated re-entry from G0 into the cell cycle through inhibition of retinoblastoma protein and activation of EZH2, E2F1 and FOXM1, with cells arresting in G2. The single-stranded DNA displacement loops formed in urothelial cells during BKPyV-infection interacted with LT-Ag to provide a substrate for APOBEC3-activity. Addition of interferon gamma (IFNγ) to infected urothelium suppressed expression of the viral genome. These results support reactivated BKPyV infections in adults as a risk factor for bladder cancer in immune-insufficient populations.

Background BK virus allograft nephropathy is a serious complication after kidney transplantation, and the effect of pre-emptive intervention for high-level BK viruria has been verified, but protocols after kidney transplantation for early identification of high-level viruria are lacking. Methods This was a single-center study. The clinical data of the kidney transplant recipients and their donors in our center from January 1, 2015 to December 31, 2018, were collected. The patients were divided into the high-level BK viruria group (Group A) and a non-high-level BK viruria group (Group B) according to the qPCR results of BK virus DNA loads in urine samples. Significant variables were screened out by univariate analysis, and then the results were incorporated into a multivariate logistic regression model to analyze the independent risk factors for high-level BK viruria. Results A total of 262 recipients were included in the study. The incidence of high-level BK viruria was 13.4% (n = 35), and the median time of detection was 181 (range 91–1119) days. Univariate analysis showed that donor type ( χ 2  = 21.770, P  < 0.001), history of ATG/ATG-F application ( χ 2  = 4.543, P  = 0.033), acute rejection (AR) ( χ 2  = 8.313, P  = 0.004) and delayed graft function (DGF) ( χ 2  = 21.170, P  < 0.001) were related to high-level BK viruria. After the inclusion of the multivariate logistic regression model, the results showed deceased brain and cardiac donors ( P  = 0.032, OR = 3.927, 95% CI 1.122–13.746), AR ( P  = 0.022, OR = 4.709, 95% CI 1.253–17.697) and DGF ( P  = 0.001, OR = 6.682, 95% CI 2.288–19.518). Conclusions Donation by deceased brain and cardiac patients, history of AR and DGF were independent risk factors for high-level BK viruria after kidney transplantation.

During its most recent outbreak across the Americas, Zika virus (ZIKV) was surprisingly shown to cause fetal loss and congenital malformations in acutely and chronically infected pregnant women. However, understanding the underlying pathogenesis of ZIKV congenital disease has been hampered by a lack of relevant in vivo experimental models. Here we present a candidate New World monkey model of ZIKV infection in pregnant marmosets that faithfully recapitulates human disease. ZIKV inoculation at the human-equivalent of early gestation caused an asymptomatic seroconversion, induction of type I/II interferon-associated genes and proinflammatory cytokines, and persistent viremia and viruria. Spontaneous pregnancy loss was observed 16–18 days post-infection, with extensive active placental viral replication and fetal neurocellular disorganization similar to that seen in humans. These findings underscore the key role of the placenta as a conduit for fetal infection, and demonstrate the utility of marmosets as a highly relevant model for studying congenital ZIKV disease and pregnancy loss.

Although hemorrhagic cystitis (HC) is a common complication of allogeneic hematopoietic cell transplantation (alloHCT), its risk factors and effects on survival are not well known. We evaluated HC in a large cohort ( n =1321, 2003–2012) receiving alloHCT from all graft sources, including umbilical cord blood (UCB). We compared HC patients with non-HC (control) patients and examined clinical variables at HC onset and resolution. Of these 1321 patients, 219 (16.6%) developed HC at a median of 22 days after alloHCT. BK viruria was detected in 90% of 109 tested HC patients. Median duration of HC was 27 days. At the time of HC diagnosis, acute GVHD, fever, severe thrombocytopenia and steroid use were more frequent than at the time of HC resolution. In univariate analysis, male sex, age <20 years, myeloablative conditioning with cyclophosphamide and acute GVHD were associated with HC. In multivariate analysis, HC was significantly more common in males and HLA-mismatched UCB graft recipients. Severe grade HC (grade III–IV) was associated with increased treatment-related mortality but not with overall survival at 1 year. HC remains hazardous and therefore better prophylaxis, and early interventions to limit its severity are still needed.