Predictive signature of murine and human host response to typical and atypical pneumonia.

BACKGROUND: Pneumonia due to typical bacterial, atypical bacterial and viral pathogens can be difficult to clinically differentiate. Host response-based diagnostics are emerging as a complementary diagnostic strategy to pathogen detection. METHODS: We used murine models of typical bacterial, atypical bacterial and viral pneumonia to develop diagnostic signatures and understand the host's response to these types of infections. Mice were intranasally inoculated with Streptococcus pneumoniae, Mycoplasma pneumoniae, influenza or saline as a control. Peripheral blood gene expression analysis was performed at multiple time points. Differentially expressed genes were used to perform gene set enrichment analysis and generate diagnostic signatures. These murine-derived signatures were externally validated in silico using human gene expression data. The response to S. pneumoniae was the most rapid and robust. RESULTS: Mice infected with M. pneumoniae had a delayed response more similar to influenza-infected animals. Diagnostic signatures for the three types of infection had 0.94-1.00 area under the receiver operator curve (auROC). Validation in five human gene expression datasets revealed auROC of 0.82-0.96. DISCUSSION: This study identified discrete host responses to typical bacterial, atypical bacterial and viral aetiologies of pneumonia in mice. These signatures validated well in humans, highlighting the conserved nature of the host response to these pathogen classes.

A 3-month-old male infant with Goldenhar syndrome: A clinical case report from Woldia, Northeast Ethiopia.

Goldenhar syndrome is a multifactorial congenital anomaly that involves structures that develop from the first and second pharyngeal arches. In this report, we present a clinical case of a 3-month-old male infant diagnosed with Goldenhar syndrome, born to a known retro-viral infected mother who was receiving antiretroviral therapy. The baby was brought to the hospital with complaints related to upper respiratory system. On examination, he had typical signs and symptoms of Goldenhar syndrome: an asymmetrical face with small left facial bones, a low-set ear, left anophthalmia, an atretic left ear with only small ear appendages, and a complete cleft lip and palate. His family had no history of birth defects or exposure to the known causes of birth defects. The baby was treated for severe community-acquired pneumonia, the diagnosis for his current presentation to our hospital, and he is now on multidisciplinary follow-up for possible medical and surgical management of the Goldenhar syndrome.

Single-cell RNA-sequencing reveals a profound immune cell response in human cytomegalovirus-infected humanized mice.

Human cytomegalovirus (HCMV) is a common herpesvirus that persistently infects a large portion of the world's population. Despite the robust host immune response, HCMV is able to replicate, evade host defenses, and establish latency throughout the lifespan by developing multiple immunomodulatory strategies, making the studies on the interaction between HCMV infection and host response particularly important. HCMV has a strict host specificity that specifically infects humans. Therefore, most of the in vivo researches of HCMV rely on clinical samples. Fortunately, the establishment of humanized mouse models allows for convenient in-lab animal experiments involving HCMV infection. Single-cell RNA sequencing enables the study of the relationship between viral and host gene expressions at the single-cell level within host cells. In this study, we assessed the gene expression alterations of PBMCs at the single-cell level within HCMV-infected humanized mice, which sheds light onto the virus-host interactions in the context of HCMV infection of humanized mice and provides a valuable dataset for the related researches.

The dual nature of TDC - bridging dendritic and T cells in immunity.

TDC are hematopoietic cells with unique features that provide intriguing insights into the interplay between innate and adaptive immunity. They express a combination of conventional dendritic cell (DC) and T-cell markers and are found in secondary lymphoid organs (SLOs), lungs and liver of naïve mice, as well as in human blood. When analyzed ex vivo, TDC can behave either as DCs or as T cells, depending on the provided stimuli. Notably, TDC numbers and activation significantly increase in SLOs following viral infection, suggesting a potential role for TDC in antiviral immune responses. In this review, we discuss the properties of these fascinating cells, which call for more investigation on their physiological role during immune responses to both pathogens and tumors.

An Atypical Presentation of Molluscum Contagiosum in a Newborn.

Molluscum contagiosum (MC) is a skin infection caused by a poxvirus that is highly contagious and common among children. When MC does occur in children less than one year old, it is suspected to be a result of vertical transmission through maternal MC infection. In this report, we describe a case of MC on the scalp of a 10-month-old child that started shortly after birth via Cesarean delivery. To our knowledge, this is the first case of MC in a neonate born via Cesarean delivery without evidence of maternal vertical transmission.

Damage-associated molecular patterns in viral infection: potential therapeutic targets.

Frequent viral infections leading to infectious disease outbreaks have become a significant global health concern. Fully elucidating the molecular mechanisms of the immune response against viral infections is crucial for epidemic prevention and control. The innate immune response, the host's primary defense against viral infection, plays a pivotal role and has become a breakthrough in research mechanisms. A component of the innate immune system, damage-associated molecular patterns (DAMPs) are involved in inducing inflammatory responses to viral infections. Numerous DAMPs are released from virally infected cells, activating downstream signaling pathways via internal and external receptors on immune cells. This activation triggers immune responses and helps regulate viral host invasion. This review examines the immune regulatory mechanisms of various DAMPs, such as the S100 protein family, high mobility group box 1 (HMGB1), and heat shock proteins, in various viral infections to provide a theoretical basis for designing novel antiviral drugs.

Multifocal epithelial hyperplasia: an understudied infectious disease affecting ethnic groups. A mini review.

Focal Epithelial Hyperplasia or Multifocal Epithelial Hyperplasia (MEH), also known as Heck's disease, is considered a rare pathology of the oral mucosa associated with human papillomavirus types 13 and 32. For reasons not fully understood, MEH disproportionally affects specific populations of indigenous groups around the world. After the first reports in Native Americans, the epidemiology of the disease has been described in different geographical regions mainly related to particular indigenous populations, the majority of the studies are clinical case reports, but the biological determinants are still unknown. Some suggested risk factors include chronic irritation caused by smoking, a galvanic current, vitamin A deficiency, and/or a familial-genetic predisposition; however, the scientific evidence is not solid due the scarcity of case-control studies or longitudinal cohorts. In light of the evidence, further study of the pathology of MEH should be considered and proper clinical trials for effective treatments should be designed. The disease warrants further study as it is considered as neglected by research and it affects rural/remote population groups usually living in adverse socioeconomic conditions.

Activation of neurotoxic A1-reactive astrocytes by SFTS virus infection accelerates fatal brain damage in IFNAR1-/- mice.

Severe fever with thrombocytopenia syndrome (SFTS) has a high mortality rate compared to other infectious diseases. SFTS is particularly associated with a high risk of mortality in immunocompromised individuals, while most patients who die of SFTS exhibit symptoms of severe encephalitis before death. However, the region of brain damage and mechanisms by which the SFTS virus (SFTSV) causes encephalitis remains unknown. Here, we revealed that SFTSV infects the brainstem and spinal cord, which are regions of the brain associated with respiratory function, and motor nerves in IFNAR1-/- mice. Further, we show that A1-reactive astrocytes are activated, causing nerve cell death, in infected mice. Primary astrocytes of SFTSV-infected IFNAR1-/- mice also induced neuronal cell death through the activation of A1-reactive astrocytes. Herein, we showed that SFTSV induces fatal neuroinflammation in the brain regions important for respiratory function and motor nerve, which may underlie mortality in SFTS patients. This study provides new insights for the treatment of SFTS, for which there is currently no therapeutic approach.

The divergent effects of G3BP orthologs on human stress granule assembly imply a centric role for the core protein interaction network.

Liquid-liquid phase separation (LLPS) mediated by G3BP1/2 proteins and non-translating mRNAs mediates stress granule (SG) assembly. We investigated the phylogenetic evolution of G3BP orthologs from unicellular yeast to mammals and identified both conserved and divergent features. The modular domain organization of G3BP orthologs is generally conserved. However, invertebrate orthologs displayed reduced capacity for SG assembly in human cells compared to vertebrate orthologs. We demonstrated that the protein-interaction network facilitated by the NTF2L domain is a crucial determinant of this specificity. The evolution of the G3BP1 network coincided with its exploitation by certain viruses, as evident from the interaction between viral proteins and G3BP orthologs in insects and vertebrates. We revealed the importance and divergence of the G3BP interaction network in human SG formation. Leveraging this network, we established a 7-component in vitro SG reconstitution system for quantitative studies. These findings highlight the significance of G3BP network divergence in the evolution of biological processes.

Herpes Simplex Virus Type 1 Infection of Human Periodontal Ligament.

The periodontal ligament (PDL) is a complex connective tissue that connects the tooth root to the dental alveolar bone and plays crucial mechanical roles. PDL also exhibits regenerative roles and regulatory functions to maintain periodontium integrity and homeostasis. While PDL exposure to oral microbial pathogens is common, virtually nothing is known regarding viral infections of PDL. In particular, human herpes simplex virus type 1 (HSV-1) persistently infects the oral cavity through infections of the oral epithelium, connective tissue and neurons. While the oral spread of HSV-1 is generally asymptomatic, this virus has also been implicated in various oral pathologies. In this study, using a primary cell model derived from PDL (PDL cells), and whole surgical fragments of PDL, we provide evidence supporting the efficient infection of PDL by HSV-1 and the promotion of cytopathic effects. Infection of PDL by HSV-1 was also associated with an acute innate inflammatory response, as illustrated by the production of antiviral interferons and pro-inflammatory cytokines. Furthermore, this inflammatory response to HSV-1 was exacerbated in the presence of bacterial-derived products, such as peptidoglycans. This work therefore highlights the ability of HSV-1 to infect mesenchymal cells from PDL, suggesting that PDL may serve as a viral reservoir for the periodontal spread of HSV-1. Moreover, this raises questions about HSV-1 oral pathogenesis, as HSV-1-associated cytopathic and inflammatory effects may contribute to profound alterations of PDL integrity and functioning.

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Neonates, particularly preterm infants, are a susceptible population to respiratory viral infections. Currently, aside from influenza, there are no antiviral medications specifically approved for the treatment of respiratory viral infections in neonates; therefore, prevention of these viral infections is particularly crucial for neonates. The Neonatal HealthCare Committee of Chinese Maternal and Child Health Association, based on domestic and international clinical evidence and combined with clinical practice experience, and after thorough discussion by relevant experts, has developed eight expert recommendations. These include preventive strategies against influenza virus, respiratory syncytial virus, and severe acute respiratory syndrome coronavirus 2 infections, intended for reference in clinical practice.

Rare pediatric case of two episodes of fulminant myocarditis and cardiac dysfunction after viral infection.

Myocarditis presents with a broad spectrum of clinical severity, ranging from subclinical illness to sudden death. Children with fulminant myocarditis often require inotropic or mechanical circulatory support; however, recurrent acute myocarditis is extremely rare. There is limited evidence to guide the management of recurrent acute myocarditis because the relevant literature is sparse. Here, we present a rare pediatric case of recurrent acute myocarditis. This patient experienced two episodes of fulminant myocarditis and two episodes of suspected myocarditis over an eight-year period; each episode fully resolved with preserved cardiac function. Three episodes were associated with influenza virus infection. During each episode, the electrocardiography, echocardiogram, and laboratory findings improved. Autoimmune and chronic myocarditis were not suspected because of the rapid onset of myocarditis associated with viral infection. Genetic testing by next-generation sequencing was performed; however, no underlying genetic illnesses were identified. Human leukocyte antigen genotyping was performed, and the results determined the genotype to be HLA-DQB1*0302/0303, which reports indicate might be involved in the development of myocarditis in mice or humans. The combination of these genotypes in myocardial cells may be associated with susceptibility to influenza infection or acute myocarditis. Learning objective: There is little evidence regarding susceptibility to myocarditis. We present a pediatric patient who experienced two episodes of fulminant myocarditis and two episodes of suspected myocarditis associated with influenza infection and a specific human leukocyte antigen genotype. This case highlights the importance of understanding myocarditis susceptibility.

Advancement in the development of mRNA-based vaccines for respiratory viruses.

Acute respiratory infections are the leading cause of death and illness in children under 5 years old and represent a significant burden in older adults. Primarily caused by viruses infecting the lower respiratory tract, symptoms include cough, congestion, and low-grade fever, potentially leading to bronchiolitis and pneumonia. Messenger ribonucleic acid (mRNA)-based vaccines are biopharmaceutical formulations that employ mRNA molecules to induce specific immune responses, facilitating the expression of viral or bacterial antigens and promoting immunization against infectious diseases. Notably, this technology had significant relevance during the COVID-19 pandemic, as these formulations helped to limit SARS-CoV-2 virus infections, hospitalizations, and deaths. Importantly, mRNA vaccines promise to be implemented as new alternatives for fighting other respiratory viruses, such as influenza, human respiratory syncytial virus, and human metapneumovirus. This review article analyzes mRNA-based vaccines' main contributions, perspectives, challenges, and implications against respiratory viruses.

Nasal microRNA signatures for disease severity in infants with respiratory syncytial virus bronchiolitis: a multicentre prospective study.

BACKGROUND: Respiratory syncytial virus (RSV) bronchiolitis contributes to a large morbidity and mortality burden globally. While emerging evidence suggests that airway microRNA (miRNA) is involved in the pathobiology of RSV infection, its role in the disease severity remains unclear. METHODS: In this multicentre prospective study of infants (aged<1 year) hospitalised for RSV bronchiolitis, we sequenced the upper airway miRNA and messenger RNA (mRNA) at hospitalisation. First, we identified differentially expressed miRNAs (DEmiRNAs) associated with higher bronchiolitis severity-defined by respiratory support (eg, positive pressure ventilation, high-flow oxygen therapy) use. We also examined the biological significance of miRNAs through pathway analysis. Second, we identified differentially expressed mRNAs (DEmRNAs) associated with bronchiolitis severity. Last, we constructed miRNA-mRNA coexpression networks and determined hub mRNAs by weighted gene coexpression network analysis (WGCNA). RESULTS: In 493 infants hospitalised with RSV bronchiolitis, 19 DEmiRNAs were associated with bronchiolitis severity (eg, miR-27a-3p, miR-26b-5p; false discovery rate<0.10). The pathway analysis using miRNA data identified 1291 bronchiolitis severity-related pathways-for example, regulation of cell adhesion mediated by integrin. Second, 1298 DEmRNAs were associated with bronchiolitis severity. Last, of these, 190 DEmRNAs were identified as targets of DEmiRNAs and negatively correlated with DEmiRNAs. By applying WGCNA to DEmRNAs, four disease modules were significantly associated with bronchiolitis severity-for example, microtubule anchoring, cell-substrate junction. The hub genes for each of these modules were also identified-for example, PCM1 for the microtubule anchoring module, LIMS1 for the cell-substrate junction module. CONCLUSIONS: In infants hospitalised for RSV bronchiolitis, airway miRNA-mRNA coexpression network contributes to the pathobiology of bronchiolitis severity.

The Prevention of Viral Infections: The Role of Intestinal Microbiota and Nutritional Factors.

Viral infections pose significant global challenges due to their rapid transmissibility. Therefore, preventing and treating these infections promptly is crucial to curbing their spread. This review focuses on the vital link between nutrition and viral infections, underscoring how dietary factors influence immune system modulation. Malnutrition, characterized by deficiencies in essential nutrients such as vitamins A, C, D, E, and zinc, can impair the immune system, thereby increasing vulnerability to viral infections and potentially leading to more severe health outcomes that complicate recovery. Additionally, emerging evidence highlights the role of commensal microbiota in immune regulation, which can affect hosts' susceptibility to infections. Specific dietary components, including bioactive compounds, vitamins, and probiotics, can beneficially modify gut microbiota, thus enhancing immune response and offering protection against viral infections. This review aims to elucidate the mechanisms by which dietary adjustments and gut microbiota impact the pathogenesis of viral infections, with a particular focus on strengthening the immune system.

Geminivirus C4/AC4 proteins hijack cellular COAT PROTEIN COMPLEX I for chloroplast targeting and viral infections.

Geminiviruses infect numerous crops and cause extensive agricultural losses worldwide. During viral infection, geminiviral C4/AC4 proteins relocate from the plasma membrane to chloroplasts, where they inhibit the production of host defense signaling molecules. However, mechanisms whereby C4/AC4 proteins are transported to chloroplasts are unknown. We report here that tomato (Solanum lycopersicum) COAT PROTEIN COMPLEX I (COPI) components play a critical role in redistributing Tomato yellow leaf curl virus C4 protein to chloroplasts via an interaction between the C4 and ß subunits of COPI. Coexpression of both proteins promotes the enrichment of C4 in chloroplasts that is blocked by a COPI inhibitor. Overexpressing or downregulating gene expression of COPI components promotes or inhibits the viral infection, respectively, suggesting a proviral role of COPI components. COPI components play similar roles in C4/AC4 transport and infections of two other geminiviruses: Beet curly top virus and East African cassava mosaic virus. Our results reveal an unconventional role of COPI components in protein trafficking to chloroplasts during geminivirus infection and suggest a broad-spectrum antiviral strategy in controlling geminivirus infections in plants.

Risk and impact of cytomegalovirus infection in lymphoma patients treated with bendamustine.

Bendamustine is used to treat lymphoma with excellent efficacy but is known for its immunosuppressive effect. Cytomegalovirus (CMV) reactivation after bendamustine use has been reported. We aim to address the impact of CMV infection in lymphoma patients treated with bendamustine-containing regimens. We retrospectively analyzed lymphoma patients at Taipei Veterans General Hospital in Taiwan between September 1, 2010, and April 30, 2022. Clinically significant CMV infection (CS-CMVi) was defined as the first CMV reactivation after bendamustine use necessitating CMV therapy. Patients' baseline characteristics and laboratory data were recorded. The primary endpoint of the study was CS-CMVi. A time-dependent covariate Cox regression model was used to estimate the risk factors of CS-CMVi and mortality. A total of 211 lymphoma patients treated with bendamustine were enrolled. Twenty-seven (12.8%) had CS-CMVi. The cumulative incidence was 10.1 per 100 person-years during the three-year follow-up period. In the multivariate analysis, lines of therapy before bendamustine ≥ 1 (95% CI 1.10-24.76), serum albumin < 3.5 g/dL (95% CI 2.63-52.93), and liver disease (95% CI 1.51-28.61) were risk factors for CS-CMVi. In conclusion, CS-CMVi (95% confidence interval [CI] 1.23-10.73) was one of the major independent risk factors of mortality. Lines of therapy before bendamustine ≥ 1, hypoalbuminemia, and liver disease were risk factors for CS-CMVi in lymphoma patients treated with bendamustine.

STING recognition of viral dsDNA by nociceptors mediates pain in mice.

Pain is often one of the initial indicators of a viral infection, yet our understanding of how viruses induce pain is limited. Immune cells typically recognize viral nucleic acids, which activate viral receptors and signaling, leading to immunity. Interestingly, these viral receptors and signals are also present in nociceptors and are associated with pain. Here, we investigate the response of nociceptors to nucleic acids during viral infections, specifically focusing on the role of the viral signal, Stimulator of Interferon Genes (STING). Our research shows that cytosolic double-stranded DNA (dsDNA) from viruses, like herpes simplex virus 1 (HSV-1), triggers pain responses through STING expression in nociceptors. In addition, STING agonists alone can elicit pain responses. Notably, these responses involve the direct activation of STING in nociceptors through TRPV1. We also provided a proof-of-concept showing that STING and TRPV1 significantly contribute to the mechanical hypersensitivity induced by HSV-1 infection. These findings suggest that STING could be a potential therapeutic target for relieving pain during viral infections.

Inhalable dry powders of a monoclonal antibody against SARS-CoV-2 virus made by thin-film freeze-drying.

Monoclonal antibodies (mAbs) represent a promising modality for the prevention and treatment of viral infections. For infections that initiate from the respiratory tract, direct administration of specific neutralizing mAbs into lungs has advantages over systemic injection of the same mAbs. Herein, using AUG-3387, a human-derived mAb with high affinity to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its various variants, as a model mAb, we formulated the mAb into dry powders by thin-film freeze-drying, confirmed that the AUG-3387 mAb reconstituted from the dry powders retained their integrity, high affinity to the SARS-CoV-2 spike protein receptor binding domain (RBD), as well as ability to neutralize RBD-expressing pseudoviruses. Finally, we showed that one of the AUG-3387 mAb dry powders had desirable aerosol properties for pulmonary delivery into the lung. We concluded that thin-film freeze-drying represents a viable method to prepare inhalable powders of virus-neutralizing mAbs for pulmonary delivery into the lung.