Persistent Infection Research Articles

Host and Viral Factors Influencing Chronic Hepatitis B Infection Across Three Generations in a Family.

Chronic hepatitis B (CHB) infection is influenced by both virological and host factors. A total of 5,920 CHB patients were classified into four groups based on HBV seromarkers: three-generation families (CHB grandmother, mother, and child), two-generation families (CHB mother/child pairs), individuals recovered from HBV infection, and a control group. Serological markers, viral load, liver function tests (LFT), HBV mutations, HLA-DQ variations, cytokine polymorphisms, and liver stiffness measurements (LSM) were analyzed using FibroScan. Point mutations in genes such as core/pre-core (G1896A/G1899A), polymerase (H248N, H267Q, N263D), S (G145R, S143L), and X (C1500T, T1464C) were observed in 30% of three-generation pairs and 20% of two-generation pairs. The three-generation group exhibited the highest mean liver stiffness measurement (LSM) (4.94 ± 1.24kPa), which is considered a predictor for the development of hepatocellular carcinoma (HCC). Subsequent HLA allele analysis identified HLA-DQB105:01 (OR = 0.27) as a risk factor for treatment resistance, while HLA-DQB105 (OR = 0.98), HLA-DQB103 (OR = 0.80), and HLA-DQB104:01 (OR = 0.70) were associated with HBV persistence in both three- and two-generation groups. Higher frequencies of specific polymorphisms, including G/G (TNF-α: 75%; IL-18: 74%), A/A (IL-10: 74.28%), and C/C (IL-1ß: 80%), were significantly linked to persistent infection. Analysis of viral sequences, HLA-DQB1 variations, cytokine polymorphisms, and genetic relationships within the phylogenetic tree revealed that 40% of CHB patients from three-generation families were infected by a shared source of transmission, as indicated by the presence of the same HBV genotype. This study underscores the complex interplay of host and viral factors that influence hepatitis B infection outcomes and suggests potential familial transmission pathways.

Ivacaftor ameliorates mucus burden, bacterial load, and inflammation in acute but not chronic P. aeruginosa infection in hG551D rats

BackgroundNewly approved highly effective modulation therapies (HEMT) have been life-changing for people with CF. Although these drugs have resulted in significant improvements in lung function and exacerbation rate, bacterial populations in the lung have not been eradicated. The mechanisms behind the continued colonization are not completely clear.MethodsWe used a humanized rat to assess the effects of ivacaftor therapy on infection outcomes. Rats harbor an insert expressing humanized CFTR cDNA, including the G551D mutation. hG551D rats were treated with ivacaftor either during or before infection with P. aeruginosa. The response to infection was assessed by bacterial burden in the lung and mucus burden in the lung.ResultsWe found that hG551D rats treated with ivacaftor had reduced bacteria present in the lung in the acute phase of the infection but were not different than vehicle control in the chronic phase of the infection. Similarly, the percentage of neutrophils in the airways were reduced at the acute, but not chronic, timepoints. Overall weight data indicated that the hG551D rats had significantly better weight recovery during the course of infection when treated with ivacaftor. Potentiation of the G551D mutation with ivacaftor resultant in short-circuit current measurements equal to WT, even during the chronic phase of the infection. Despite the persistent infection, hG551D rats treated with ivacaftor had fewer airways with mucus plugs during the chronic infection.ConclusionsThe data indicate that the hG551D rats have better outcomes during infection when treated with ivacaftor compared to the vehicle group. Rats have increased weight gain, increased CFTR protein function, and decreased mucus accumulation, despite the persistence of infection and inflammation. These data suggest that ivacaftor improves tolerance of infection, rather than eradication, in this rat model.

ISG15 Drives Immune Pathology and Respiratory Failure during Systemic Lymphocytic Choriomeningitis Virus Infection.

ISG15, an IFN-stimulated gene, plays a crucial role in modulating immune responses during viral infections. Its upregulation is part of the host's defense mechanism against viruses, contributing to the antiviral state of cells. However, altered ISG15 expression can also lead to immune dysregulation and pathological outcomes, particularly during persistent viral infections. Understanding the balance of ISG15 in promoting antiviral immunity while avoiding immune-mediated pathology is essential for developing targeted therapeutic interventions against viral diseases. In this article, using Usp18-deficient, USP18 enzymatic-inactive and Isg15-deficient mouse models, we report that a lack of USP18 enzymatic function during persistent viral infection leads to severe immune pathology characterized by hematological disruptions described by reductions in platelets, total WBCs, and lymphocyte counts; pulmonary cytokine amplification; lung vascular leakage; and death. The lack of Usp18 in myeloid cells mimicked the pathological manifestations observed in Usp18-/- mice and required Isg15. Mechanistically, interrupting the enzymes that conjugate/deconjugate ISG15, using Uba7-/- or Usp18C61A mice, respectively, led to accumulation of ISG15 that was accompanied by inflammatory neutrophil accumulation, lung pathology, and death similar to that observed in Usp18-deficient mice. Moreover, myeloid cell depletion reversed pathological manifestations, morbidity, and mortality in Usp18C61A mice. Our results suggest that dysregulated ISG15 production and signaling during persistent lymphocytic choriomeningitis virus infection can produce lethal immune pathology and could serve as a therapeutic target during severe viral infections with pulmonary pathological manifestations.

FoxK1 and FoxK2 cooperate with ORF45 to promote late lytic replication of Kaposi's sarcoma-associated herpesvirus.

Lytic replication is essential for persistent infection of Kaposi's sarcoma-associated herpesvirus (KSHV) and the pathogenesis of related diseases, and many cellular pathways are hijacked by KSHV proteins to initiate and control the lytic replication of this virus. However, the mechanism involved in KSHV lytic replication from the early to the late phases remains largely undetermined. We previously revealed that KSHV open reading frame 45 (ORF45) plays important roles in late transcription and translation. In the present study, we revealed that the Forkhead box proteins FoxK1 and FoxK2 are ORF45-binding proteins and are essential for KSHV lytic gene expression and virion production, and that depletion of FoxK1 or FoxK2 significantly suppresses the expression of many late viral genes. FoxK1 and FoxK2 directly bind to the promoters of several late viral genes, ORF45 augments the promoter binding and transcriptional activity of FoxK1 and FoxK2, and then FoxK1 or FoxK2 cooperates with ORF45 to promote late viral gene expression. Our findings suggest that ORF45 interacts with FoxK1 and FoxK2 and promotes their occupancy on a cluster of late viral promoters and their subsequent transcriptional activity; consequently, FoxK1 and FoxK2 promote late viral gene expression to facilitate KSHV lytic replication.IMPORTANCEThe forkhead box proteins FoxK1 and FoxK2 can act as transcriptional inhibitors or activators to regulate several important processes, including aerobic glycolysis, metabolism, autophagy, and antiviral responses. However, the subversion and functions of FoxK1 and FoxK2 during KSHV infection and the pathogenesis of related diseases remain unknown. Here, we revealed that ORF45 binds to FoxK1 and FoxK2 and increases their transcriptional activity during KSHV lytic replication; consequently, FoxK1 and FoxK2 bind to late viral promoters and cooperate with ORF45 to promote late lytic gene expression. Our findings reveal two new ORF45 partners and a new function of ORF45 in which it utilizes FoxK1 and FoxK2 to promote transcription during late KSHV lytic replication.

Middle Lobe Syndrome: A Case Report and Literature Review

Background: Middle lobe syndrome (MLS) is a distinct clinical and radiographic entity characterized by recurrent or chronic collapse of the middle lobe of the right lung, but it can also involve the lingula of the left lung. Case Study: This study presents a rare case of MLS caused by a vascular ring never described in the literature until now and provides physicians with the clinical and instrumental tools in order to early recognize and promptly treat this condition. The case report was reported according to CARE guidelines. A literature research on PubMed/MEDLINE was also performed using the MeSH terms “Middle lobe syndrome OR MLS AND double aortic arch” “Middle lobe syndrome OR MLS AND vascular rings”. No case described in the literature was found. In most cases, MLS presents non-specific respiratory symptoms, which unfortunately is responsible for the diagnostic delay that patients with this pathology often suffer. The diagnostic delay is estimated to be 8 months (range 3 to 36 months). A history of dysphagia and regurgitation can be indirect signs of a vascular compression, such as vascular rings, which can cause MLS. Conclusion: To date, the reported case is the only case in the literature of MLS caused by double aortic arch. The key point for the diagnosis of MLS is diagnostic suspicion. Early recognition of MLS is essential to quickly start a targeted therapeutic program avoiding the persistence of vicious circle atelectasis-recurrent respiratory infections, and this could significantly improve the long-term outcome of these patients.

Biofilm Production in Intensive Care Units: Challenges and Implications

The prevalence of infections amongst intensive care unit (ICU) patients is inevitably high, and the ICU is considered the epicenter for the spread of multidrug-resistant bacteria. Multiple studies have focused on the microbial diversity largely inhabiting ICUs that continues to flourish despite treatment with various antibiotics, investigating the factors that influence the spread of these pathogens, with the aim of implementing sufficient monitoring and infection control methods. Despite joint efforts from healthcare providers and policymakers, ICUs remain a hub for healthcare-associated infections. While persistence is a unique strategy used by these pathogens, multiple other factors can lead to persistent infections and antimicrobial tolerance in the ICU. Despite the recognition of the detrimental effects biofilm-producing pathogens have on ICU patients, overcoming biofilm formation in ICUs continues to be a challenge. This review focuses on various facets of ICUs that may contribute to and/or enhance biofilm production. A comprehensive survey of the literature reveals the apparent need for additional molecular studies to assist in understanding the relationship between biofilm regulation and the adaptive behavior of pathogens in the ICU environment. A better understanding of the interplay between biofilm production and antibiotic resistance within the environmental cues exhibited particularly by the ICU may also reveal ways to limit biofilm production and indivertibly control the spread of antibiotic-resistant pathogens in ICUs.

Spatially controllable fluid hydrogel with in-situ electrospinning PCL/chitosan fiber for treating irregular wounds

Skin injuries sustained during exercise are often irregular in shape and frequently accompanied by infections. Bacteria residing in the crevices of these wounds can lead to persistent infections. Routine wound monitoring, which requires removing the wound dressing to assess recovery, is inconvenient and increases the risk of infection. To address this, we prepared a polyvinyl alcohol/polyhydroxylated fullerenes ((PVA/PHF) hydrogel with good fluidity and photothermal antibacterial properties, which can penetrate into the crevices of irregular wounds. After the hydrogel was applied to the wound, the hydrogel was locally defined by the polycaprolactone/Chitosan (PCL/CS) membrane of in-situ electrospinning, which effectively killed bacteria, and the healing efficiency was increased by 240 % in the wound healing experiment. The PVA/PHF hydrogel exhibits excellent electrical conductivity, making it suitable for real-time monitoring of human body motion as a strain sensor. This capability provides doctors with an accurate basis for wound assessment. At the same time, the hydrogel can achieve self-healing within 1.5 s and withstand up to 2200 % tensile strain, which can be used for large-scale motion monitoring of the human body. This flowable hydrogel, capable of penetrating wound crevices, offers a dual function of both treatment and monitoring.

From acute to persistent infection: revealing phylogenomic variations in Salmonella Agona.

Salmonella enterica serovar Agona (S. Agona) has been increasingly recognised as a prominent cause of gastroenteritis. This serovar is a strong biofilm former that can undergo genome rearrangement and enter a viable but non-culturable state whilst remaining metabolically active. Similar strategies are employed by S. Typhi, the cause of typhoid fever, during human infection, which are believed to assist with the transition from acute infection to chronic carriage. Here we report S. Agona's ability to persist in people and examine factors that might be contributing to chronic carriage. A review of 2233 S. Agona isolates from UK infections (2004-2020) and associated carriage was undertaken, in which 1155 had short-read sequencing data available. A subset of 207 isolates was selected from different stages of acute and persistent infections within individual patients. The subset underwent long-read sequencing and genome structure (GS) analysis, as well as phenotyping assays including carbon source utilisation and biofilm formation. Associations between genotypes and phenotypes were investigated to compare acute infections to those which progress to chronic. GS analysis revealed the conserved arrangement GS1.0 in 195 isolates, and 8 additional GSs in 12 isolates. These rearranged isolates were typically associated with early, convalescent carriage (3 weeks- 3 months). We also identified an increase in SNP variation during this period of infection. We believe this increase in genome-scale and SNP variation reflects a population expansion after acute S. Agona infection, potentially reflecting an immune evasion mechanism which enables persistent infection to become established.

Prospectives of developing therapeutic HPV vaccines

Human papillomavirus (HPV) represents one of the most serious global public health problems. Malignant female and male diseases mainly result from persistent HPV infection. Cancer belongs to a high mortality rate disease. It has been established that HPV infection causes about 70% vaginal cancer, 50% male genital cancer, 90% anal cancer and 60% head-and-neck cancer. Annually, a large number of people develop various HPV-caused cancer types, dominated by cervical cancer, one of the most common and aggressive types of cancer that threatens health holding the fourth place among most female common cancer worldwide. According to the World Health Organization (WHO), in 2020, about 600 cases of cervical cancer are recorded daily in different countries. Emergence of cervical cancer is closely related to factors such as long-term (persistent) HPV infection and somatic mutations of the host genome. Although HPV infection can be detected and cured early with highly effective screening methods and surgical procedures, the carcinogenic risk of HPV related diseases constantly increases, which elimination faces certain difficulties, especially in low- and mid-developed countries. The most acceptable solution to this is development and implementation of therapeutic vaccines for prevention and treatment of HPV related diseases. Three licensed HPV vaccines based on L1 type virus-like particles (L1-VLPs) technology are available globally: bivalent (HPV-2), quadrivalent (HPV-4) and nonavalent (HPV-9) vaccines. These vaccines demonstrated effectiveness in reducing HPV-related cervical cancer rate by up to 90% worldwide. However, the therapeutic effect of these vaccines on persistent HPV infection and lesions has not been observed. Therapeutic HPV vaccines candidates targeted Ye6/Ye7 cancer proteins activate cellular immunity that eliminates existing HPV infection. Here we review types, mechanisms of action and clinical effects of therapeutic HPV vaccines, as well as current and future developments in the field for prevention and treatment of HPV related diseases.

Influence of vitamin D supplementation and the vaginal microenvironment on human papillomavirus infection

This was a retrospective study, mainly explored the mediating role of vaginal microenvironment and the influence of vitamin D addition on human papillomavirus (HPV) infection. Five hundred and twelve participants were chosen in this study, followed by dividing into HPV positive (212 cases) and negative groups (300 cases) based on HPV 23 typing results. The high-risk human papillomavirus (HR-HPV) positive group showed higher abnormal rates of lactobacillus, catalase, cleanliness, sialidosidase, and proline aminopeptidase than the HPV negative group. No significant differences were found in pH value, leukocyte esterase, and Acetylglucosaminidase abnormality between 2 groups. The HR-HPV positive group presented a higher percentage of patients with cleanliness III and IV. Relative to low-grade squamous intraepithelial lesion (LSIL) group, HSIL group presented a higher HPV positive infection rate. Mould infection, Gardnerella infection, and catalase were identified as independent risk elements for HR-HPV infection. Vitamin D supplementation was found to potentially reduce HR-HPV infection persistence post-Loop Electrosurgical Excision Procedure (LEEP), improve nutritional health, reduce insulin, insulin resistance (HOMA-IR) and triglyceride levels, as well as reduce high-sensitivity C-reactive protein (hs-CRP) along with malondialdehyde (MDA) levels. Our results indicate that HR-HPV infection is intimately associated with the condition of the vaginal microenvironment, and vitamin D addition potentially reduces the persistence of HR-HPV infection post-LEEP, improves nutritional and metabolic health, reduces inflammation, and be well-tolerated.

HPV and HCMV in Cervical Cancer: A Review of Their Co-Occurrence in Premalignant and Malignant Lesions

Cervical cancer remains a significant global health concern, particularly in low- and middle-income countries. While persistent infection with high-risk human papillomavirus (HR-HPV) is essential for cervical cancer development, it is not sufficient on its own, suggesting the involvement of additional cofactors. The human cytomegalovirus (HCMV) is a widespread β-herpesvirus known for its ability to establish lifelong latency and reactivate under certain conditions, often contributing to chronic inflammation and immune modulation. Emerging evidence suggests that HCMV may play a role in various cancers, including cervical cancer, through its potential to influence oncogenic pathways and disrupt host immune responses. This review explores clinical evidence regarding the co-presence of HR-HPV and HCMV in premalignant lesions and cervical cancer. The literature reviewed indicates that HCMV is frequently detected in cervical lesions, particularly in those co-infected with HPV, suggesting a potential synergistic interaction that could enhance HPV’s oncogenic effects, thereby facilitating the progression from low-grade squamous intraepithelial lesions (LSIL) to high-grade squamous intraepithelial lesions (HSIL) and invasive cancer. Although the precise molecular mechanisms were not thoroughly investigated in this review, the clinical evidence suggests the importance of considering HCMV alongside HPV in the management of cervical lesions. A better understanding of the interaction between HR-HPV and HCMV may lead to improved diagnostic, therapeutic, and preventive strategies for cervical cancer.

SARS-CoV-2 persistence: A potential catalyst for age-associated neurodegenerative diseases

The persistence of RNA viruses in the brain is increasingly recognized as a significant factor in the progression of age-related neurodegenerative diseases. This phenomenon is particularly evident in infections caused by various neurotropic and non-neurotropic viruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The COVID-19 pandemic has underscored the urgent need to explore the complex relationship between viral persistence and neurological decline. Growing evidence indicates that SARS-CoV-2 affects brain structure and function, although the precise molecular mechanisms remain poorly understood. Chronic neuroinflammation induced by viral infections is thought to accelerate age-related neurodegeneration. While the immune system typically clears many viral infections in the brain, some viruses establish chronic infections, leading to restricted viral replication. These persistent infections can exacerbate neuroinflammation and contribute to ongoing neuronal damage, key drivers of age-related neurodegeneration. This review explores current knowledge on how SARS-CoV-2 infiltrates the brain, evades immune defenses, and persists within brain cells, potentially using them as viral reservoirs. As individuals age, the cumulative effects of such viral infections may accelerate cognitive decline and increase vulnerability to neurodegenerative diseases such as Alzheimer’s and Parkinson’s. Understanding the molecular mechanisms of viral persistence and its long-term impact on brain health is crucial for developing targeted therapies to combat these age-related diseases.

Virulence genes and antibiotic susceptibility patterns of Escherichia coli isolated from nosocomial urinary tract infections in the northwest of Iran during 2022-2023: A cross-sectional study.

Urinary tract infections (UTIs) are prevalent among hospitalized patients, constituting the most frequent health-care infections. Uropathogenic Escherichia coli (UPEC) is leading causative agent of UTIs. The present study was aimed to examine the susceptibility of UPEC isolates obtained from nosocomial cases to antibiotics, as well as their biofilm formation capability and frequency of virulence genes. A total of 100 UPEC isolates were collected from nosocomial UTIs at Imam Reza Hospitals in Tabriz, Iran, spanning from April 2022 to January 2023. The antimicrobial susceptibility patterns were evaluated using the disk diffusion method, along with the detection of broad-spectrum β-lactam enzymes (ESBLs) and carbapenemases. The ability of isolates to form biofilms was assessed using the microtiter-plate method, while the PCR method was employed to identify the presence of virulence genes. The highest resistance was observed toward piperacillin (82%), followed by aztreonam and ciprofloxacin (81%), while the lowest resistance was found against piperacillin/tazobactam (12%) and meropenem (9%). ESBLs were detected in 62% of the isolates. The microtiter-plate results revealed strong, moderate, and weak biofilm formation abilities in 32%, 33%, and 24% of the isolates, respectively. The most prevalent virulence gene was fimA (74%) followed by hlyF (68%), papA (44%), papC (32%), iroN (26%), and cnf (20%). The elevated levels of resistance to multiple antimicrobial agents, coupled with the co-presence of virulence genes and biofilm formation abilities, contribute to the persistence of UPEC-related infections, particularly in hospitalized patients. These findings underscore the necessity of implementing an effective program to control nosocomial UTIs caused by UPEC in the healthcare centers.

HPV Vaccines

Human papillomavirus (HPV) is a double-stranded DNA virus and a source of infection that primarily affects the skin and mucous membranes. It can be transmitted through sexual contact and contaminated surfaces. There are over 200 genotypes of HPV, approximately 40 of which infect the anogenital region. High-risk HPV types, such as HPV-16 and HPV-18, can lead to the development of various cancers, particularly cervical cancer. Factors that increase the risk of transmission include having multiple sexual partners, early initiation of sexual activity, and having an uncircumcised male partner. Low socioeconomic status, poor nutrition, immunosuppression, and co-infections with HIV, genital herpes, or chlamydia can result in persistent and severe HPV infection. Three types of vaccines have been developed against HPV: bivalent, quadrivalent, and nonavalent vaccines. The bivalent vaccine provides protection against HPV-16 and HPV-18; the quadrivalent vaccine is effective against HPV-16, HPV-18, as well as HPV-6 and HPV-11. The nonavalent vaccine offers the broadest protection, covering nine different types of HPV. All vaccines are approved for males and females aged 9 and older. Vaccination before the onset of sexual activity significantly increases protection against cervical cancer.

Development of KSHV vaccine platforms and chimeric MHV68-K-K8.1 glycoprotein for evaluating the in vivo immunogenicity and efficacy of KSHV vaccine candidates.

Kaposi's sarcoma-associated herpesvirus (KSHV)/human herpesvirus 8 is an etiological agent of Kaposi's Sarcoma, multicentric Castleman's disease, and primary effusion lymphoma. Considering the high seroprevalence reaching up to 80% in sub-Saharan Africa, an effective vaccine is crucial for preventing KSHV infection. However, vaccine development has been limited due to the lack of an effective animal model that supports KSHV infection. Murine Herpesvirus 68 (MHV68), a natural mouse pathogen persisting lifelong post-infection, presents a promising model for KSHV infection. In this study, we developed KSHV vaccine and a chimeric MHV68 carrying the KSHV glycoprotein, serving as a surrogate challenge virus for testing KSHV vaccines in a mouse model. Among KSHV virion glycoproteins, K8.1 is the most abundant envelope glycoprotein with the highest immunogenicity. We developed two K8.1 vaccines: K8.1 mRNA-lipid nanoparticle (LNP) vaccine and K8.126-87-Ferritin (FT) nanoparticle vaccines. Both induced humoral responses in immunized mice, whereas K8.1 mRNA LNP also induced T cell responses. Using BACmid-mediated homologous recombination, the MHV68 M7 (gp150) gene was replaced with KSHV K8.1 gene to generate chimeric MHV68-K-K8.1. MHV68-K-K8.1 established acute and latent infection in the lungs and spleens of infected mice, respectively. Mice immunized with K8.1 mRNA LNP or K8.126-87-FT showed a reduction of MHV68-K-K8.1 titer but not MHV68 wild type (WT) titer in the lung. In addition, viral reactivation of MHV68-K-K8.1 was also significantly reduced in K8.1 mRNA LNP-immunized mice. This study demonstrates the effectiveness of two vaccine candidates in providing immunity against KSHV K8.1 and introduces a surrogate MHV68 system for evaluating vaccine efficacy in vivo.IMPORTANCEKaposi's sarcoma-associated herpesvirus (KSHV) is a prevalent virus that establishes lifelong persistent infection in humans and is linked to several malignancies. While antiretroviral therapy has reduced Kaposi's Sarcoma (KS) complications in people with HIV, KS still affects individuals with well-controlled HIV, older men without HIV, and transplant recipients. Despite its significant impact on human health, however, research on KSHV vaccine has been limited, mainly due to the lack of interest and the absence of a suitable animal model. This study addresses these challenges by developing KSHV K8.1 vaccine with two platforms, mRNA lipid nanoparticle (LNP) and FT nanoparticle. Additionally, chimeric virus, MHV68-K-K8.1, was created to evaluate KSHV vaccine efficacy in vivo. Vaccination of K8.1 mRNA LNP or K8.126-87-FT significantly reduced MHV68-K-K8.1 titers. Developing an effective KSHV vaccine requires an innovative approach to ensure safety and efficacy, especially for the immunocompromised population and people with limited healthcare resources. This study could be a potential blueprint for future KSHV vaccine development.

Lassa virus persistence with high viral titers following experimental infection in its natural reservoir host, Mastomys natalensis

Lassa virus (LASV) outbreaks in West Africa pose a significant public health threat. We investigated the infection phenotype and transmission (horizontal and vertical) of LASV strain Ba366 in its natural host, Mastomys natalensis. Here we analyze viral RNA levels in body fluids, virus titers in organs and antibody presence in blood. In adults and 2-week-old animals, LASV causes transient infections with subsequent seroconversion. However, mice younger than two weeks exhibit persistent infections lasting up to 16 months despite antibody presence. LASV can be detected in various body fluids, organs, and cell types, primarily in lung, kidney, and gonadal epithelial cells. Despite the systemic virus presence, no pathological alterations in organs are observed. Infected animals efficiently transmit the virus throughout their lives. Our findings underscore the crucial role of persistently infected individuals, particularly infected females and their progeny, in LASV dissemination within the host population.

Small hepatitis B virus surface antigen (SHBs) induces dyslipidemia by suppressing apolipoprotein-AII expression through ER stress-mediated modulation of HNF4α and C/EBPγ.

Persistent infection with hepatitis B virus (HBV) often leads to disruptions in lipid metabolism. Apolipoprotein AII (apoAII) plays a crucial role in lipid metabolism and is implicated in various metabolic disorders. However, whether HBV could regulate apoAII and contribute to HBV-related dyslipidemia and the underlying mechanism remain unclear. This study revealed significant reductions in apoAII expression in HBV-expressing cell lines, the serum, and liver tissues of HBV-transgenic mice. The impact of HBV on apoAII is related to small hepatitis B virus surface antigen (SHBs). Overexpression of SHBs decreased apoAII levels in SHBs-expressing hepatoma cells, transgenic mice, and the serum of HBV-infected patients, whereas suppression of SHBs increased apoAII expression. Mechanistic investigations demonstrated that SHBs repressed the apoAII promoter activity through a HNF4α- and C/EBPγ-dependent manner; SHBs simultaneously upregulated C/EBPγ and downregulated HNF4α by inhibiting the PI3K/AKT signaling pathway through activating endoplasmic reticulum (ER) stress. Serum lipid profile assessments revealed notable decreases in high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC), and triglycerides (TG) in SHBs-transgenic mice compared to control mice. However, concurrent overexpression of apoAII in these mice effectively counteracted these reductions in lipid levels. In HBV patients, SHBs levels were negatively correlated with serum levels of HDL-C, LDL-C, TC, and TG, whereas apoAII levels positively correlated with lipid content. This study underscores that SHBs contributes to dyslipidemia by suppressing the PI3K/AKT pathway via inducing ER stress, leading to altered expression of HNF4α and C/EBPγ, and subsequently reducing apoAII expression.IMPORTANCEThe significance of this study lies in its comprehensive examination of how the hepatitis B virus (HBV), specifically through its small hepatitis B virus surface antigen (SHBs), impacts lipid metabolism-a key aspect often disrupted by chronic HBV infection. By elucidating the role of SHBs in regulating apolipoprotein AII (apoAII), a critical player in lipid processes and associated metabolic disorders, this research provides insights into the molecular pathways contributing to HBV-related dyslipidemia. Discovering that SHBs downregulates apoAII through mechanisms involving the repression of the apoAII promoter via HNF4α and C/EBPγ, and the modulation of the PI3K/AKT signaling pathway via endoplasmic reticulum (ER) stress, adds critical knowledge to HBV pathogenesis. The research also shows an inverse correlation between SHBs expression and key lipid markers in HBV-infected individuals, suggesting that apoAII overexpression could counteract the lipid-altering effects of SHBs, offering new avenues for understanding and managing the metabolic implications of HBV infection.

Synergistic potential of Leu10-teixobactin and cefepime against multidrug-resistant Staphylococcus aureus

Staphylococcus aureus (S. aureus) is a significant Gram-positive opportunistic pathogen behind many debilitating infections. β-lactam antibiotics are conventionally prescribed for treating S. aureus infections. However, the adaptability of S. aureus in evolving resistance to multiple β-lactams contributed to the persistence and spread of infections, exemplified in the emergence of methicillin-resistant S. aureus (MRSA). In the present study, we investigated the efficacies of the synthetic teixobactin analogue, Leu10-teixobactin, combined with the penicillinase-resistant cephalosporin cefepime against MRSA strains. The Leu10-teixobactin and cefepime combination exerted synergism against most strains tested in broth microdilution assay. Time-kill profiles showed that both Leu10-teixobactin and cefepime predominantly exhibited synergistic activity, with > 2.0-log10CFU decrease compared to monotherapy at 24 h. Moreover, biofilm assays revealed a significant inhibition of biofilm production in ATCC™43300 cells treated with sub-MICs of Leu10-teixobactin and cefepime. Subsequent electron microscopy studies showed more extensive damage with the combination therapy compared to monotherapies, including aberrant bacterial morphology, vesicle formation and substantial lysis, indicating combined damage to the cell wall. Quantitative real-time PCR revealed marked perturbation of genes mecA, sarA, atlA, and icaA, substantiating the apparent mode of combined antibacterial action of both antibiotics against peptidoglycan synthesis and initial biofilm production. Hence, the study highlights the prospective utility of the Leu10-teixobactin-cefepime combination in treating MRSA infections via β-lactam potentiation.

Tracing the path of Quorum sensing molecules in cystic fibrosis mucus in a biomimetic in vitro permeability platform

P. aeruginosa employs specific quorum sensing (QS) mechanisms to orchestrate biofilm formation, enhancing resistance to host defences. In physiological conditions, QS molecules permeate the lung environment and cellular membrane to reach the cytoplasmic Aryl Hydrocarbon Receptor (AhR) that is pivotal for activating the immune response against infection. In pathological conditions like cystic fibrosis (CF) this interkingdom communication is altered, favouring P. aeruginosa persistence and chronic infection. Here, we aim to investigate the molecular journey of QS molecules from CF-like environments to the cytoplasm by quantifying via HPLC-MS the permeability of selected QS molecules (quinolones, lactones, and phenazines) through in vitro models of the two main biological lung barriers: CF-mucus and cellular membrane. While QS molecules not activating AhR exhibit intermediate permeability through the cellular membrane model (PAMPA) (1.0–4.0 × 10−6 cm/s), the AhR-activating molecule (pyocyanin) shows significantly higher permeability (8.6 ± 1.4 × 10−6 cm/s). Importantly, combining the CF mucus model with PAMPA induces a 50% decrease in pyocyanin permeability, indicating a strong mucus-shielding effect with pathological implications in infection eradication. This study underscores the importance of quantitatively describing the AhR-active bacterial molecules, even in vitro, to offer new perspectives for understanding P. aeruginosa virulence mechanisms and for proposing new antibacterial therapeutic approaches.

Challenging frontiers in neuroplastic cranial reconstruction: addressing neurosurgical wound healing complications through interdisciplinary collaboration – an observational study

Background and objectivesAlthough rare, complications like skin dehiscence and necrosis after neurosurgery pose significant challenges by increasing the risk of infections spreading to the epidural, subdural, or intracerebral spaces. This retrospective, single-center study aims to assess the prior clinical courses, neuroplastic repair, and outcomes of patients with skin defects following cranial neurosurgical procedures, and to outline our interdisciplinary reconstructive protocol.MethodsA retrospective analysis was performed on cranial surgeries conducted at the Department of Neurosurgery, spanning from 2017 to 2023. Patients with skin defects requiring the combined expertise of neurosurgery and plastic surgery for effective treatment were included. The sizes of the skin defects were measured using intraoperative photographs analyzed with the freeware ImageJ software, version 2018. All patients provided informed consent for the surgeries. If informed consent was not possible due to neurological deterioration, consent was sought from adult representatives or next of kin except for acute circumstances. All patients admitted to our hospital agree to the pseudonymized use of their medical data and tissue specimens for research purposes in their treatment contract.ResultsA cohort of 24 patients experiencing wound healing complications after neurosurgical procedures underwent a total of 29 interdisciplinary surgeries for the reconstruction of skin, dural, and bone defects. After the neuroplastic surgery, 8 out of 24 patients (33.3%) developed surgical complications, with 6 of these requiring revision surgeries due to persistent cranial infection. In all cases, permanent wound closure was successfully achieved following adherence to the proposed treatment algorithm.ConclusionsOur study underscores the necessity of an integrated neurosurgical and plastic surgical approach to effectively manage wound healing complications in a single stage surgery. Key interventions include differentiation between necrosis and gaping lesions, alongside precise management of neurosurgical issues like cerebrospinal fluid fistulas and hydrocephalus. Plastic surgical expertise in assessing the possibilities and limitations of both local and free flap surgeries is essential.