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Echoviruses are amongst the most common causative agents of aseptic meningitis worldwide and are particularly devastating in the neonatal population, where they are associated with severe hepatitis, neurological disease, including meningitis and encephalitis, and even death. Here, we identify the neonatal Fc receptor (FcRn) as a pan-echovirus receptor. We show that loss of expression of FcRn or its binding partner beta 2 microglobulin (β2M) renders cells resistant to infection by a panel of echoviruses at the stage of virus attachment, and that a blocking antibody to β2M inhibits echovirus infection in cell lines and in primary human intestinal epithelial cells. We also show that expression of human, but not mouse, FcRn renders nonpermissive human and mouse cells sensitive to echovirus infection and that the extracellular domain of human FcRn directly binds echovirus particles and neutralizes infection. Lastly, we show that neonatal mice expressing human FcRn are more susceptible to echovirus infection by the enteral route. Our findings thus identify FcRn as a pan-echovirus receptor, which may explain the enhanced susceptibility of neonates to echovirus infections.

Am J Manag Care. 2025;31(9):In Press _____ Takeaway Points * This propensity-matched study evaluated the impact of syndromic real-time reverse transcriptase–polymerase chain reaction (RT-PCR) tests for oropharyngeal infections and respiratory tract infections on subsequent health care resource use (HCRU) and costs in a large US population. * Past research shows that the use of PCR tests to diagnose respiratory infections in clinical practice in the US is low despite high sensitivity and specificity in identifying causative pathogens. * This study demonstrates that using syndrome-driven RT-PCR tests for patients with oropharyngeal infections and respiratory tract infections is associated with lower HCRU and costs through lower utilization of outpatient services. * Lower HCRU and costs may be reflective of improved patient care. _____ Respiratory tract infections (RTIs) including acute oropharyngeal/respiratory infections are a serious health care concern in the US, with an age-standardized incidence of 339,703 per 100,000 people and accounting for 13.6 per 100,000 deaths (~2% of all deaths) in 2019.1 Oropharyngeal infections and RTIs also result in substantial health care resource utilization (HCRU): almost one-fifth of all outpatient visits (193 visits per 1000 people)2 and more than $1 billion in health care expenditures in the US.3,4 Oropharyngeal infections, such as pharyngitis, characterized by sore throat, sneezing, cough, and/or fever,2,5 can be caused by both viral and bacterial etiologies. Yet observational research has shown that, despite low overall utilization, antibiotic use is significantly lower in patients who received PCR testing (34.6%) compared with those with no testing (57.1%), indicating that identifying the causative pathogen can help guide appropriate treatment.13 Improved accuracy of diagnostic tests could have a considerable benefit for the patient population by enabling quicker and more accurate diagnosis, which may result in more timely treatment effectiveness and reduced symptom duration and severity. METHODS Study Design, Data Source, and Funding This retrospective, propensity-matched study aimed to compare the HCRU and costs among patients with oropharyngeal infections and RTIs during the 6 months after receiving a syndromic RT-PCR test (with next-day test results) with those among matched patients receiving other diagnostic tests or no laboratory tests for their respective infections. Comorbidities, including the Charlson Comorbidity Index (CCI) score14 and select non-CCI comorbidities, presence of similar previous infection, and total health care costs, as well as pharmacy, outpatient medical/emergency department (ED), and inpatient costs, were assessed during the 6-month baseline period.

This study compared all-cause health care resource use (HCRU) and costs between patients with acute oropharyngeal infections and respiratory tract infections (RTIs) receiving targeted syndromic real-time polymerase chain reaction (RT-PCR) tests with next-day results vs matched patients receiving other/no diagnostic tests. Propensity-matched, retrospective study. Two cohorts with International Classification of Diseases, Tenth Revision, Clinical Modification codes for diagnosis or symptom(s) of oropharyngeal infection or RTI (first diagnosis = index) on an outpatient claim were identified in the IQVIA PharMetrics Plus database (July 2020-October 2023). HCRU and costs were examined over 6 months post index across 5 subcohorts: patients receiving syndromic RT-PCR and 4 matched subcohorts (other PCR, point-of-care [POC] only, culture, or no test). The mean (SD) costs for postindex total outpatient services ($2598 [$7564] vs $2970 [$8417]; P < .0001), physician office visit ($624 [$1150] vs $689 [$1082]; P = .0002), emergency department (ED) ($290 [$1145] vs $397 [$1630]; P = .0192), and other medical services ($1684 [$6799] vs $1883 [$7568]; P < .0001) were significantly lower for the oropharyngeal RT-PCR subcohort than the matched culture subcohort. The mean (SD) postindex costs for any outpatient medical services ($2796 [$11,453] vs $3221 [$7873]; P < .0001), physician office visits ($525 [$974] vs $703 [$2635]; P = .0057), ED visits ($253 [$1036] vs $355 [$1300]; P = .0011), and other medical services ($2018 [$10,986] vs $2163 [$6458]; P < .0001) were significantly lower for the RTI RT-PCR subcohort than the matched culture subcohort. Patients in both RT-PCR subcohorts had lower utilization of other medical services and any outpatient services compared with all matched comparator subcohorts. This propensity-matched study provides evidence on the economic impact of syndromic RT-PCR tests for respiratory infections, highlighting their advantages over traditional diagnostic methods.

Advancements in pathogen identification by diagnostic testing may improve patient outcomes. This study evaluated healthcare utilization and costs following diagnostic testing for acute oropharyngeal and respiratory tract infections (RTIs). Healthcare utilization and costs were evaluated in patients with acute oropharyngeal infections (n=1,172,693), and RTIs (n=4,005,228) who received a syndromic panel-based PCR test with next-day results (HealthTrackRx, Denton, TX), or no test in the IQVIA PharMetrics Plus adjudicated claims database. Statistically significant differences were observed between patients who received the PCR test compared to those who received no test. The PCR test cohort had lower total healthcare costs (mean = $5,601±$29,170, median = $807) versus the no test cohort (mean = $7,460±$40,817, median = $1,163) (p = 0.0014) over 6 months, and fewer outpatient visits, other medical service visits, emergency room visits, and inpatient stays (p<0.0001). Similarly, those who received the PCR test for oropharyngeal infection trended towards lower total healthcare costs (mean = $4,393±$13,524, median=$844) than those who received no test (mean = $5,503±$34,141, median = $956) (p=0.0525) and had fewer outpatient and other medical services (p<0.0001). Next-day molecular testing for respiratory and oropharyngeal infection lowers healthcare utilization and costs, suggesting improved patient care through reduced need for healthcare resources.

Enteroviruses manipulate host membranes to form replication organelles, which concentrate viral and host factors to allow for efficient replication. However, this process has not been well-studied in living cells throughout the course of infection. To define the dynamic process of enterovirus membrane remodeling of major secretory pathway organelles, we have developed plasmid-based reporter systems that utilize viral protease-dependent release of a nuclear-localized fluorescent protein from the endoplasmic reticulum (ER) membrane during infection, while retaining organelle-specific fluorescent protein markers such as the ER and Golgi. This system thus allows for the monitoring of organelle-specific changes induced by infection in real-time. Using long-term time-lapse imaging of living cells infected with coxsackievirus B3 (CVB), we detected reporter translocation to the nucleus beginning ~4 h post-infection, which correlated with a loss of Golgi integrity and a collapse of the peripheral ER. Lastly, we applied our system to study the effects of a calcium channel inhibitor, 2APB, on virus-induced manipulation of host membranes. We found that 2APB treatment had no effect on the kinetics of infection or the percentage of infected cells. However, we observed aberrant ER structures in CVB-infected cells treated with 2APB and a significant decrease in viral-dependent cell lysis, which corresponded with a decrease in extracellular virus titers. Thus, our system provides a tractable platform to monitor the effects of inhibitors, gene silencing, and/or gene editing on viral manipulation of host membranes, which can help determine the mechanism of action for antivirals.

Advancements in diagnostic technologies for the evaluation of infectious disease complaints in the outpatient setting have improved the speed and accuracy of pathogen detection and created the opportunity for higher accuracy in treatment planning. The benefits of these advanced diagnostics insights can be optimized when coupled with robust shared decision-making between the patient and clinician during the clinical encounter. This manuscript describes the process for the integration of results from molecular testing for respiratory tract infection into a shared decision-making framework. It also explores how this synergy may lead to improved patient outcomes, enhanced health care delivery, and more collaborative care, while enhancing diagnosis and treatment of respiratory infections in various clinical settings.

Background/Objectives: Vaginitis is a common infection among women of reproductive age. Although various diagnostic methodologies exist, diagnosis without the utilization of available diagnostic tests remains prevalent. This study aimed to assess downstream healthcare utilization and the cost of patients with and without diagnostic testing. Methods: This retrospective, observational study utilized the IQVIA PharMetrics® Plus database from July 2020 to October 2023. Patients with an index claim (ICD-10 code indicating vaginitis) were categorized into two cohorts: those who received a syndromic polymerase chain reaction (PCR) test and those who had no documented test on the index date or within two days. Total and service-specific healthcare resource utilization and costs were assessed for 6 months following the index event. This study was designed to inform how Syndromic Vaginitis PCR testing is used to make treatment decisions and to track outpatient and inpatient healthcare utilization for 6 months post index date represented by cost. Results: Patients who received a Syndromic Vaginitis PCR test had significantly fewer outpatient medical services in the 6 months following initial diagnosis compared to those who received no diagnostic test. This was largely attributed to a substantial decrease in other medical service visits, resulting in mean cost savings of USD 2067 (Syndromic PCR = USD 6675, SD = USD 17,187; No Test = USD 8742, SD = USD 29,894) (p-value 0.0009). Conclusions: Many vaginitis patients do not receive testing, but Syndromic Vaginitis PCR testing may be an effective diagnostic tool for reducing costs associated with vaginitis infections.

The lifecycle of positive strand RNA viruses occurs in close association to host intracellular membranes as a mechanism to isolate viral replication from cellular restriction factors and innate immune detection. Distinct virus families rely on different membrane sources, each employing unique strategies to manipulate host membranes for their own advantage. One major source of these membranes is the endoplasmic reticulum (ER), which functions at the center of many cellular processes, including secretory pathway and autophagy vesicle trafficking. We have identified Bactericidal/permeability-increasing protein (BPI) fold-containing family B3 (BPIFB3) as a host endoplasmic reticulum (ER) localized protein that differentially controls the replication of two distinct virus families, enteroviruses and flaviviruses, through a non-canonical autophagy pathway. BPIFB3 belongs to the BPIFB protein family which have predicted lipid binding and transfer abilities. This family of proteins has been largely uncharacterized, and their intracellular function has remained to be elucidated. Here we expand on our previous work and address the cellular function of BPIFB3 in two parts. First, we focus on the effects of BPIFB3 induced autophagy on the replication of two flaviviruses, dengue virus (DENV) and Zika virus (ZIKV), and determine that the reticulophagy mediated turnover of ER membranes during BPIFB3 depletion inhibits DENV and ZIKV replication. Second, we identify two unique BPIFB3 binding partners, ADP Ribosylation Factor GTPase Activating Protein 1 (ARFGAP1) and Transmembrane emp24 domain-containing protein 9 (TMED9), that are required for the induction of BPIFB3si mediated non-canonical autophagy. Lastly, we expand on the work presented here in the context of what is known about non-canonical autophagy regulation and present a novel model for BPIFB3 function. We further discuss the downstream effects of BPIFB3 depletion on autophagy regulation and positive strand RNA virus replication. This work defines BPIFB3 as a novel regulator of flavivirus replication and provides meaningful insights into the mechanisms of non-canonical autophagy regulation and their impact on positive strand RNA virus replication.

Autophagy is a degradative cellular pathway that targets cytoplasmic contents and organelles for turnover by the lysosome. Various autophagy pathways play key roles in the clearance of viral infections, and many families of viruses have developed unique methods for avoiding degradation. Some positive stranded RNA viruses, such as enteroviruses and flaviviruses, usurp the autophagic pathway to promote their own replication. We previously identified the endoplasmic reticulum-localized protein BPIFB3 as an important regulator of non-canonical autophagy that uniquely impacts the replication of enteroviruses and flaviviruses. Here, we find that many components of the canonical autophagy machinery are not required for BPIFB3-regulated autophagy and identify the host factors that facilitate its role in the replication of enteroviruses and flaviviruses. Using proximity-dependent biotinylation (BioID) followed by mass spectrometry, we identify ARFGAP1 and TMED9 as two cellular components that interact with BPIFB3 to regulate autophagy and viral replication. Importantly, our data demonstrate that non-canonical autophagy in mammalian cells can be controlled outside of the traditional pathway regulators and define the role of two proteins in BPIFB3-mediated non-canonical autophagy.

Mastermind-like 1 (MAML1) is well characterized for its involvement in the Notch signaling pathway where it functions as a transcriptional co-activator and facilitates the degradation of the Notch intracellular domain (NICD). MAML1 has recently been implicated as a multifunctional protein that interacts with a variety of other signaling pathways, including Wnt-β-catenin, NF-B, and MEF2C (myocyte enhancer factor 2C). MEF2C is a member of the family of transcription factors involved in muscle cell differentiation and proliferation. MAML1 has previously been shown to activate MEF2C transcription. Given that MAML1 is responsible for degradation of the NICD, we wanted to know if MAML1 could also induce degradation of MEF2C. Here we show that full length MAML1 induces degradation of MEF2C. MEF2C is not degraded when co-expressed with MAML1 deletion constructs, MAML1 1-301 and MAML1 Δ75-300, suggesting the entire c-terminus is needed for degradation. In addition, treatment with the proteasome inhibitor MG132 stabilized MEF2C expression both in the absence and presence of MAML1 when compared to dimethyl sulfoxide (DMSO) controls. Immuno-preciptations of MEF2C in the presence of MAML1 with MG132 treatment showed an increase in the amount of ubiquitin detected. Serine 98 and 110 in MEF2C appear to be essential for ubiquitination. In order to determine if S98 and S110 are required for MAML1 degradation of MEF2C, we cloned the double serine mutant MEF2C S98A S110A. However, co-expression of the mutant with MAML1 still resulted in decreased protein levels. Our results showed MAML1-induced degradation of MEF2C occurs through the proteasomal pathway and that S98 and S110 are not required for degradation.