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Alpha herpesvirus (α-HV) particles enter their hosts from mucosal surfaces and efficiently maintain fast transport in peripheral nervous system (PNS) axons to establish infections in the peripheral ganglia. The path from axons to distant neuronal nuclei is challenging to dissect due to the difficulty of monitoring early events in a dispersed neuron culture model. We have established well-controlled, reproducible, and reactivateable latent infections in compartmented rodent neurons by infecting physically isolated axons with a small number of viral particles. This system not only recapitulates the physiological infection route but also facilitates independent treatment of isolated cell bodies or axons. Consequently, this system enables study not only of the stimuli that promote reactivation but also the factors that regulate the initial switch from productive to latent infection. Adeno-associated virus (AAV)-mediated expression of herpes simplex-1 (HSV-1) VP16 alone in neuronal cell bodies enabled the escape from silencing of incoming pseudorabies virus (PRV) genomes. Furthermore, the expression of HSV VP16 alone reactivated a latent PRV infection in this system. Surprisingly, the expression of PRV VP16 protein supported neither PRV escape from silencing nor reactivation. We compared transcription transactivation activity of both VP16 proteins in primary neurons by RNA sequencing and found that these homolog viral proteins produce different gene expression profiles. AAV-transduced HSV VP16 specifically induced the expression of proto-oncogenes including c-Jun and Pim2. In addition, HSV VP16 induces phosphorylation of c-Jun in neurons, and when this activity is inhibited, escape of PRV silencing is dramatically reduced.IMPORTANCEDuring latency, alpha herpesvirus genomes are silenced yet retain the capacity to reactivate. Currently, host and viral protein interactions that determine the establishment of latency, induce escape from genome silencing or reactivation are not completely understood. By using a compartmented neuronal culture model of latency, we investigated the effect of the viral transcriptional activator, VP16 on pseudorabies virus (PRV) escape from genome silencing. This model recapitulates the physiological infection route and enables the study of the stimuli that regulate the initial switch from a latent to productive infection. We investigated the neuronal transcriptional activation profiles of two homolog VP16 proteins (encoded by HSV-1 or PRV) and found distinct gene activation signatures leading to diverse infection outcomes. This study contributes to understanding of how alpha herpesvirus proteins modulate neuronal gene expression leading to the initiation of a productive or a latent infection.

Inducing tertiary lymphoid structure (TLS) formation can fuel antitumor immunity. It is necessary to create mouse models containing TLS to explore strategies of TLS formation. Oncolytic herpes simplex virus‐1 (oHSV) exhibited intense effects in preclinical and clinical trials. However, the role of oHSV in TLS formation remains to be elucidated. Here, we observed the presence of TLS in 4MOSC1 and MC38 subcutaneous tumour models. Interestingly, oHSV evoked TLS formation, and increased infiltration of B cells and stem‐like TCF1+CD8+ T cells proliferation. Mechanistically, oHSV increased the expression of TLS‐related chemokines, along with upregulated CXCL10/CXCR3 to facilitate TLS formation. Notably, CXCL10 and CXCR3 were favourable prognostic factors for cancer patients, and closely related with immune cells infiltration. Inhibiting CXCL10/CXCR3 reduced TCF1+CD8+ T cells and granzyme B expression, and impaired oHSV‐mediated TLS formation. Furthermore, oHSV‐mediated TLS formation revealed superior response and survival rate when combined with αPD‐1 treatment. Collectively, these findings indicate that oHSV recruits stem‐like TCF1+CD8+ T cells through CXCL10/CXCR3 pathway to propagate TLS formation, and warrants future antitumor immunity development. [ABSTRACT FROM AUTHOR]

Evolving evidence suggests that Janus Kinase Inhibitors (JAKi) may predispose to certain infections, including tuberculosis and human herpes viruses. This review aimed to compare the infection risk in patients on a systemic JAKi for a dermatologic indication to a placebo. A systematic review was carried out from inception to June 2023, using the EMBASE, Medline, SCOPUS, and Cochrane Library of Registered Trials databases. Eligible studies included placebo‐controlled randomized trials that investigated the incidence of infection in patients with a dermatologic indication. Primary outcomes included the most commonly reported infections pertaining to serious and opportunistic infections, upper respiratory tract infections, nasopharyngitis, herpes simplex, varicella zoster, tuberculosis, neutropenia, and lymphopenia. A meta‐analysis of incidence ratios was conducted to determine odds ratios (OR), with a 95% confidence interval (CI) analysis. The meta‐analysis found no increased risk of serious (OR: 0.92, 95% CI: 0.61–1.43, P = 0.74) or opportunistic infections (OR: 0.65, 95% CI: 0.32–1.31, P = 0.23). The incidence of varicella‐zoster infections was significantly higher in the JAKi cohort (OR: 1.72, 95% CI: 1.08–2.72, P = 0.022). From 25 studies, there was no overall increased risk of herpes simplex infections (OR: 1.43, 95% CI: 0.93–2.23, P = 0.102) to placebo; however, a significantly higher risk in those with atopic dermatitis to alopecia areata was demonstrated (OR: 1.73, 95% CI: 1.13–2.69, P = 0.013). The results of this analysis do not suggest an increased risk of serious and opportunistic infections in those on JAKi compared to placebo. However, they support an increased risk of varicella‐zoster infections and a higher risk of herpes simplex infections in those with atopic dermatitis to alopecia areata. The results of this report support these agents' short‐term safety but signal that vigilance should be practiced in patients at risk for serious or recurrent herpes virus infections. [ABSTRACT FROM AUTHOR]

Fetal limb anomaly presentation varies greatly. It can present as amelia (complete absence of skeletal part of one or more limb), meromelia (partial absence of skeletal part of one or more limb), phocomelia (only rudimentary limb formed), and minor limb disorders like polydactyly. The complete absence of the four fetal limbs is extremely rare. Incidence of tetra‐amelia is not well known, but it is mentioned to be 1–4 in 100,000 births in different literature. Etiopathogenesis of fetal tetra‐amelia remains speculative. Tetra‐amelia occurs either as tetra‐amelia syndrome (when other organ systems are affected too) or isolated tetra‐amelia. Tetra‐amelia syndrome is more common than isolated tetra‐amelia. It occurs secondary to genetic aberration or is sporadic. Genetic inheritance of tetra‐amelia may present as autosomal dominance, autosomal recessive, or X‐linked recessive. The protein coded on WTN 3 on chromosome 17q21 is important for fetal limb and other organ system formation. Mutation associated with the WTN 3 gene is a known cause for fetal limb malformation. Maternal diabetes, amniotic band syndrome, TORCH (toxoplasmosis, rubella cytomegalovirus, herpes simplex, and HIV) infection, alcohol consumption, and intrauterine exposure to some drugs like thalidomide, glucocorticoids, and sedatives are risk factors for limb malformation. Tetra‐amelia can be diagnosed as early as the first trimester of pregnancy. Ultrasound imaging is a gold standard investigation to detect tetra‐amelia. Tetra‐amelia syndrome is associated with high mortality and morbidity than isolated tetra‐amelia. In this case report, we present an extremely rare case, isolated tetra‐amelia, born to G3P2 (Gravida 3, Para 2) mother at 36 weeks of gestation. It was diagnosed late in pregnancy at 34 weeks. The fetal organs (kidney, lung, abdominal wall, heart, vertebrae, and brain) were evaluated with ultrasound and were found healthy. She gave birth by cesarean section at 36 weeks of gestation for other obstetric indication. Isolated tetra‐amelia is an extremely rare case. Early antenatal ultrasound fetal evaluation should be promoted. Early detection of tetra‐amelia helps to provide parental counselling and option of management timely. Parental counselling should involve how to care for the neonate with tetra‐amelia. Community awareness creation is important to decrease social stigma against babies with tetra‐amelia. In such rare cases, it is important to alert public health researchers for possible further epidemiological study. [ABSTRACT FROM AUTHOR]