Integrative systems biology reveals NKG2A-biased immune responses correlate with protection in infectious disease, autoimmune disease, and cancer.

Infection, autoimmunity, and cancer are principal human health challenges of the 21st century. Often regarded as distinct ends of the immunological spectrum, recent studies hint at potential overlap between these diseases. For example, inflammation can be pathogenic in infection and autoimmunity. T resident memory (TRM) cells can be beneficial in infection and cancer. However, these findings are limited by size and scope; exact immunological factors shared across diseases remain elusive. Here, we integrate large-scale deeply clinically and biologically phenotyped human cohorts of 526 patients with infection, 162 with lupus, and 11,180 with cancer. We identify an NKG2A+ immune bias as associative with protection against disease severity, mortality, and autoimmune/post-acute chronic disease. We reveal that NKG2A+ CD8+ T cells correlate with reduced inflammation and increased humoral immunity and that they resemble TRM cells. Our results suggest NKG2A+ biases as a cross-disease factor of protection, supporting suggestions of immunological overlap between infection, autoimmunity, and cancer.

A four-part guide to lung immunology: Invasion, inflammation, immunity, and intervention.

Lungs are important respiratory organs primarily involved in gas exchange. Lungs interact directly with the environment and their primary function is affected by several inflammatory responses caused by allergens, inflammatory mediators, and pathogens, eventually leading to disease. The immune architecture of the lung consists of an extensive network of innate immune cells, which induce adaptive immune responses based on the nature of the pathogen(s). The balance of immune responses is critical for maintaining immune homeostasis in the lung. Infection by pathogens and physical or genetic dysregulation of immune homeostasis result in inflammatory diseases. These responses culminate in the production of a plethora of cytokines such as TSLP, IL-9, IL-25, and IL-33, which have been implicated in the pathogenesis of several inflammatory and autoimmune diseases. Shifting the balance of Th1, Th2, Th9, and Th17 responses have been the targets of therapeutic interventions in the treatment of these diseases. Here, we have briefly reviewed the innate and adaptive i3mmune responses in the lung. Genetic and environmental factors, and infection are the major causes of dysregulation of various functions of the lung. We have elaborated on the impact of inflammatory and infectious diseases, advances in therapies, and drug delivery devices on this critical organ. Finally, we have provided a comprehensive compilation of different inflammatory and infectious diseases of the lungs and commented on the pros and cons of different inhalation devices for the management of lung diseases. The review is intended to provide a summary of the immunology of the lung, with an emphasis on drug and device development.

Ophthalmic and immunopathological characterization of systemic infectious diseases in cats.

Ocular involvement in systemic diseases is frequent in cats; however, without concurrent clinical and ophthalmic examinations with gross and/or histologic analysis of the eye, these findings can be underdiagnosed. This article aims to provide gross, histologic, and immunohistochemical characteristics of ocular lesions from cats submitted to necropsy, focusing on those caused by systemic infectious agents. Cats that died due to a systemic infectious disease were selected based on necropsy diagnosis and presence of ocular lesions. Gross, histologic, and immunohistochemical findings were recorded. From April 2018 to September 2019, 849 eyes of 428 cats were evaluated. Histologic abnormalities were seen in 29% of cases, which were classified as inflammatory (41%), neoplastic (32%), degenerative (19%), and metabolic/vascular (8%). Macroscopic changes were present in one-third of eyes with histologic lesions. Of these, 40% were attributed to inflammatory or neoplastic diseases associated with infectious agents. The most important infectious agents causing ocular disease in this study were feline leukemia virus, feline infectious peritonitis virus, and Cryptococcus sp. The most common ocular abnormalities associated with infectious agents were uveitis (anterior, posterior, or panuveitis), optic neuritis, and meningitis of the optic nerve. Ocular lesions secondary to systemic infections in cats are frequent; however, these are not always diagnosed because gross lesions are less common than histologic lesions. Therefore, both gross and histologic evaluation of the eyes of cats is recommended, mainly for cases in which the clinical suspicion or necropsy diagnosis suggests that an infectious agent might be related to the cause of death.

Endoplasmic reticulum stress mediates the myeloid-derived immune suppression associated with cancer and infectious disease.

Myeloid-derived suppressor cells (MDSCs), which are immature heterogeneous bone marrow cells, have been described as potent immune regulators in human and murine cancer models. The distribution of MDSCs varies across organs and is divided into three subpopulations: granulocytic MDSCs or polymorphonuclear MDSCs (G-MDSCs or PMN-MDSCs), monocytic MDSCs (M-MDSCs), as well as a recently identified early precursor MDSC (eMDSCs) in humans. Activated MDSCs induce the inactivation of NK cells, CD4+, and CD8+ T cells through a variety of mechanisms, thus promoting the formation of tumor immunosuppressive microenvironment. ER stress plays an important protecting role in the survival of MDSC, which aggravates the immunosuppression in tumors. In addition, ferroptosis can promote an anti-tumor immune response by reversing the immunosuppressive microenvironment. This review summarizes immune suppression by MDSCs with a focus on the role of endoplasmic reticulum stress-mediated immune suppression in cancer and infectious disease, in particular leprosy and tuberculosis.

The differential expression of toll like receptors and RIG-1 correlates to the severity of infectious diseases.

The toll like receptors (TLRs) and RIG-1 are proteins involved in the initial reaction of the innate immune system to infectious diseases and, thus, can provide much information to the surgical pathologist in terms of the molecular dynamics of the infection. The TLRs (TLR1, 2, 3, 4, 7, 8) and RIG-1 distribution as determined by immunohistochemistry was examined in the following diseases: human papillomavirus (n = 30 including 15 squamous intraepithelial lesions (SIL), 5 cancers, and 10 controls); molluscum contagiosum (n = 8 including 4 controls), SARS-CoV2 (n = 52 including 20 mild, 5 fatal, and 27 controls) and reovirus infection as oncolytic therapy. Mild, regressing infection (molluscum contagiosum, mild SARS-CoV2 and low grade SIL) each showed the same pattern: marked up regulation of at least three of the TLRs/RIG-1 with decreased expression of none compared to the controls. Severe infection (fatal SARS-CoV2, and cervical cancer) each showed marked decrease expression in at least three of the TLRs/RIG-1. We recently documented an equivalent marked decrease expression of the TLRs/RIG-1 in the placenta in fatal in utero infections. The reoviral infected tissues showed an overall pattern of marked increase expression of TLRs/RIG-1, consistent with a strong anti-viral response. Thus, the in situ testing of infectious diseases by a panel of these early infectious disease recognition proteins may allow the surgical pathologist to predict the outcome of the disease which, in turn, may assist in the understanding of the role of the TLRs/RIG-1 in determining the fate of a given infectious process.

Breast imaging of infectious disease.

Infectious diseases of the breast can demonstrate a wide variety of clinical presentations and imaging appearances. Breast abscesses are often a complication of infectious mastitis of the breast. Puerperal mastitis is the most common cause of breast abscess, typically affecting postpartum females. Often diagnosed clinically, it is usually treated with antibiotics without need for imaging. Non-puerperal mastitis is relatively uncommon and typically subareolar in location. Patients can present with asymmetric breast thickening, a palpable lump, nipple discharge, or axillary adenopathy. These presentations can mimic malignancy. Herein, this pictorial review demonstrates imaging findings of common and uncommon infectious processes of the breast and clinically important mimickers of breast infection.

Aborto infectocontagioso em éguas: uma revisão bibliográfica / Infectious-contagious abortion in mares: a literature review / Aborto infecto-contagioso en yeguas: una revisión de la literatura

O aborto infectocontagioso em éguas é um tema de grande relevância e interesse para os médicos veterinários e criadores de equinos. Além dos impactos econômicos decorrentes de perdas e redução das taxas reprodutivas, os surtos de abortos causados por doenças infectocontagiosas representam uma ameaça significativa para a saúde equina. Neste trabalho, realizamos uma revisão bibliográfica abrangente sobre as principais doenças que causam abortos infecciosos em éguas. Nosso objetivo é fornecer uma visão geral das patologias mais relevantes nesse contexto, abordando suas características clínicas, epidemiologia, diagnóstico e medidas de controle. Para isso, realizamos uma busca em bancos de dados renomados, como o PubMed e o Scopus, por artigos científicos relevantes publicados nos últimos dez anos. As informações selecionadas foram cuidadosamente analisadas, comparadas e sintetizadas, com o intuito de identificar as principais doenças e suas implicações na saúde reprodutiva das éguas. Esta revisão pretende auxiliar veterinários, pesquisadores e profissionais da área a compreenderem melhor essas doenças e desenvolverem estratégias eficazes de prevenção e controle.(AU)

El aborto infeccioso en yeguas es un tema de gran relevancia e interés para veterinarios y criadores de equinos. Además de las repercusiones económicas derivadas de las pérdidas y la reducción de las tasas reproductivas, los brotes de aborto causados por enfermedades infecciosas representan una importante amenaza para la salud equina. En este artículo, realizamos una revisión exhaustiva de la literatura sobre las principales enfermedades que causan abortos infecciosos en yeguas. Nuestro objetivo es ofrecer una visión general de las patologías más relevantes en este contexto, abordando sus características clínicas, epidemiología, diagnóstico y medidas de control. Para ello, buscamos en bases de datos de renombre como PubMed y Scopus artículos científicos relevantes publicados en los últimos diez años. La información seleccionada fue cuidadosamente analizada, comparada y sintetizada con el fin de identificar las principales enfermedades y sus implicaciones en la salud reproductiva de las yeguas. El objetivo de esta revisión es ayudar a veterinarios, investigadores y profesionales del sector a comprender mejor estas enfermedades y desarrollar estrategias eficaces de prevención y control.(AU)

Infectious abortion in mares is a topic of great relevance and interest for veterinarians and equine breeders. In addition to economic impacts from losses and reduced reproductive rates, abortion outbreaks caused by infectious diseases represent a significant threat to equine health. In this paper, we conduct a comprehensive literature review on the major diseases that cause infectious abortions in mares. Our goal is to provide an overview of the most relevant pathologies in this context, addressing their clinical features, epidemiology, diagnosis, and control measures. To this end, we searched renowned databases such as PubMed and Scopus for relevant scientific articles published in the last ten years. The selected information was carefully analyzed, compared and synthesized in order to identify the main diseases and their implications in the reproductive health of mares. This review aims to assist veterinarians, researchers, and professionals in the field to better understand these diseases and develop effective prevention and control strategies.(AU)

Kidney Pathology of Tropical and Nontropical Infectious Diseases in the Pediatric Population.

OBJECTIVES: To review kidney pathology of tropical and nontropical infectious diseases in the pediatric population. METHODS: We review 4 tropical and 2 nontropical infectious diseases that affect the kidneys of children in terms of their direct and indirect pathogenetic mechanism in inducing kidney damage. RESULTS: We demonstrate clinical manifestations, pathogenesis, kidney pathology, and laboratory diagnostic methods for (1) renal cryptococcosis, which represents involvement of a pure direct pathway; (2) schistosomiasis and dengue fever as examples of dual direct and indirect pathways; and (3) congenital syphilis, visceral leishmaniasis, and Chagas disease, which represent indirect pathways. CONCLUSIONS: Infective agents affect the kidneys of children mainly through indirect mechanisms, such as through immunological mechanisms as part of an antigenic response. A direct mechanism of kidney injury, however, is less known within the medical community simply because the direct mechanism is rarely encountered in nontropical countries. In some infectious diseases, both indirect and direct pathways are responsible in inducing 2 sets of morphologically separate kidney lesions.

Biofilm in sino-nasal infectious diseases: the role nasal cytology in the diagnostic work up and therapeutic implications.

BACKGROUD: Biofilm formation has been recently recognised as one of the most important etiopathological mechanisms underlying chronic rhinosinusitis (CRS) and its recalcitrance. In this context, nasal cytology (NC) has become an integral part of diagnostic work up of patients suffering from sino-nasal diseases, since it is an easy-to-apply, reproducible and non-invasive diagnostic tool that allows to assess both the nasal inflammatory infiltrate and the presence of biofilms on nasal mucosal surface, further orienting the therapeutic choices in case of infectious diseases for eradicating infections and biofilms. Nevertheless, biofilms are typically resistant to common antibiotic treatments and may trigger or maintain chronic inflammation. Hence, the importance of correctly detecting the presence of biofilm and identifying new effective treatments. PURPOSE: The aim of this brief review is to better clarify the role of biofilm in the pathogenesis and recurrence of sino-nasal disorders and to highlight the role of nasal cytology (NC) in the rhino-allergologic diagnostic path and in the evaluation of the effectiveness of new treatments.

Sífilis mimetizando lúpus eritematoso sistêmico: um relato de caso / Syphilis mimicking systemic lupus erythematosus: a case report / Sífilis que simula lupus eritematoso sistémico: informe de un caso

O Lúpus Eritematoso Sistêmico (LES) é uma patologia crônica, de origem autoimune e inflamatória. As diversas manifestações clínicas existentes em pacientes acometidos pelo LES, sejam elas sistêmicas ou órgãos-alvo, possibilitam variados diagnósticos diferenciais. Dentre as manifestações clínicas que possibilitam estes diagnósticos está o acometimento cutâneo, com vasta variabilidade de apresentação. Da mesma forma, a sífilis também possui apresentação cutânea, tornando possível o diferencial de diagnóstico com outras patologias, inclusive o próprio LES. O presente estudo tem como objetivo relatar um caso de sífilis mimetizando lúpus eritematoso sistêmico, descrever o quadro clínico apresentado pelo paciente, bem como as ferramentas utilizadas para diagnóstico, e a posterior abordagem terapêutica. O caso relatado refere-se a um paciente de 29 anos, do sexo masculino, procedente de Campos Novos (SC), que apresentou um quadro clínico e laboratorial de lúpus-like induzido por uma infecção aguda de sífilis. A resolução completa de critérios inflamatórios de LES ocorreu após tratamento correto da doença infecciosa, com total melhora clínica e sorológica.

Systemic lupus erythematosus (SLE) is a chronic autoimmune inflammatory disease. The various clinical manifestations in SLE patients, both systemic and in target organs, allow for various differential diagnoses. Among the clinical manifestations that aid in diagnosis are the cutaneous injuries, which have a wide range of presentations. Syphilis also has cutaneous manifestations, which aid in the differential diagnosis from other pathologies, including SLE. The present study aims to report a case of syphilis mimicking SLE, describe the clinical condition presented by the patient, the tools used for diagnosis, and the therapeutic approach. The case reported refers to a 29- year-old male patient from Campos Novos (SC), who showed a clinical and laboratory lupus-like condition induced by an acute syphilis infection. The full resolution of SLE inflammatory criteria occurred following appropriate treatment for the infectious disease, with complete clinical and serological improvement.

El lupus eritematoso sistémico (LES) es una enfermedad inflamatoria autoinmune crónica. Las diversas manifestaciones clínicas de los pacientes con LES, tanto sistémicas como en órganos diana, permiten realizar varios diagnósticos diferenciales. Entre las manifestaciones clínicas que ayudan al diagnóstico se encuentran las lesiones cutáneas, que tienen una amplia gama de presentaciones. La sífilis también tiene manifestaciones cutáneas, que ayudan al diagnóstico diferencial con otras patologías, incluido el LES. El presente estudio tiene como objetivo comunicar un caso de sífilis que simula un LES, describir el cuadro clínico presentado por la paciente, las herramientas utilizadas para el diagnóstico y el abordaje terapéutico. El caso relatado se refiere a un paciente masculino de 29 años, natural de Campos Novos (SC), que presentó un cuadro clínico y de laboratorio semejante al lupus, inducido por una infección aguda por sífilis. La resolución completa de los criterios inflamatorios del LES ocurrió tras el tratamiento adecuado de la enfermedad infecciosa, con mejoría clínica y serológica completa.

Is Alzheimer's disease an infectious neurological disease? A review of the literature.

INTRODUCTION: Alzheimer's disease (AD) is a leading cause of dementia around the globe. Its pathogenesis is characterized primarily by the extracellular deposition of amyloid ß peptides and intracellular neurofibrillary tangles. Despite the significant investments in neurological research, the exact molecular mechanism of AD pathogenesis is still not fully elucidated. Several studies converge on a hypothesis that pathogenic microbes might play a role in AD progression. Although this hypothesis has been considered relatively weak for decades, it has recently received considerable attention due to increasing evidence on the association between microorganisms and AD. There is a lack of experimental and scientific arguments conveying that these microorganisms engender cognitive and neuropathological deficits and modifications specific to AD, challenging the theory that it could be an infectious neurological disease. This review focuses on recent advances in the infection hypothesis and provides an overview of new findings portraying the significance of pathogenic microbes in AD and the challenges confronting the validity of the hypothesis. METHODOLOGY: Data were collected from medical journals published on PubMed, Ovid MEDLINE, ScienceDirect, and Embase bibliographical databases with a predefined search strategy. All articles considering neurological disorders, especially AD associated with infectious diseases, were included. RESULTS: This work focused on providing an overview of new findings around the relationship between microorganisms and AD, challenges facing the validity of the theory, and recommendations on how the scientific community can best develop alternative approaches to address the pathophysiology of AD. CONCLUSION: While many studies reinforce the suspicion of an infectious etiology of AD, it is important to note that it is yet not validated how microorganisms' presence in the brain can develop AD due to the limited available evidence. Certainly, ground-breaking work is mandatory in this field of research, and these reports so far warrant a thorough investigation into how a chronic infection may remain silent while progressing its neuroinflammation. Amid this uncertainty arises the hope that many researchers will take on this challenge and join this endeavor to benefit AD patients worldwide.

Spatial Metabolomics Reveals Localized Impact of Influenza Virus Infection on the Lung Tissue Metabolome.

The influenza virus (IAV) is a major cause of respiratory disease, with significant infection increases in pandemic years. Vaccines are a mainstay of IAV prevention but are complicated by IAV's vast strain diversity and manufacturing and vaccine uptake limitations. While antivirals may be used for treatment of IAV, they are most effective in early stages of the infection, and several virus strains have become drug resistant. Therefore, there is a need for advances in IAV treatment, especially host-directed therapeutics. Given the spatial dynamics of IAV infection and the relationship between viral spatial distribution and disease severity, a spatial approach is necessary to expand our understanding of IAV pathogenesis. We used spatial metabolomics to address this issue. Spatial metabolomics combines liquid chromatography-tandem mass spectrometry of metabolites extracted from systematic organ sections, 3D models, and computational techniques to develop spatial models of metabolite location and their role in organ function and disease pathogenesis. In this project, we analyzed serum and systematically sectioned lung tissue samples from uninfected or infected mice. Spatial mapping of sites of metabolic perturbations revealed significantly lower metabolic perturbation in the trachea compared to other lung tissue sites. Using random forest machine learning, we identified metabolites that responded differently in each lung position based on infection, including specific amino acids, lipids and lipid-like molecules, and nucleosides. These results support the implementation of spatial metabolomics to understand metabolic changes upon respiratory virus infection. IMPORTANCE The influenza virus is a major health concern. Over 1 billion people become infected annually despite the wide distribution of vaccines, and antiviral agents are insufficient to address current clinical needs. In this study, we used spatial metabolomics to understand changes in the lung and serum metabolome of mice infected with influenza A virus compared to uninfected controls. We determined metabolites altered by infection in specific lung tissue sites and distinguished metabolites perturbed by infection between lung tissue and serum samples. Our findings highlight the utility of a spatial approach to understanding the intersection between the lung metabolome, viral infection, and disease severity. Ultimately, this approach will expand our understanding of respiratory disease pathogenesis.

Early IFN-ß administration protects cigarette smoke exposed mice against lethal influenza virus infection without increasing lung inflammation.

During influenza A virus (IAV) infection, it is unclear whether type I interferons (IFNs) have defensive antiviral effects or contribute to immunopathology in smokers. We treated nonsmoking (NS) and cigarette smoke (CS)-exposed mice intranasally with early (prophylactic) or late (therapeutic) IFN-ß. We compared the mortality and innate immune responses of the treated mice following challenge with IAV. In NS mice, both early and late IFN-ß administration decreased the survival rate in mice infected with IAV, with late IFN-ß administration having the greatest effect on survival. In contrast, in CS-exposed mice, early IFN-ß administration significantly increased survival during IAV infection while late IFN-ß administration did not alter mortality. With regards to inflammation, in NS mice, IFN-ß administration, especially late administration, significantly increased IAV-induced inflammation and lung injury. Early IFN-ß administration to CS-exposed mice did not increase IAV-induced inflammation and lung injury as occurred in NS mice. Our results demonstrate, although IFN-ß administration worsens the susceptibility of NS mice to influenza infection with increased immunopathology, early IFN-ß administration to CS-exposed mice, which have suppression of the intrinsic IFN response, improved outcomes during influenza infection.

A contextual exploration of healthcare service use in urban slums in Nigeria.

INTRODUCTION: Many urban residents in low- and middle-income countries live in unfavorable conditions with few healthcare facilities, calling to question the long-held view of urban advantage in health, healthcare access and utilization. We explore the patterns of healthcare utilization in these deprived neighborhoods by studying three such settlements in Nigeria. METHODS: The study was conducted in three slums in Southwestern Nigeria, categorized as migrant, indigenous or cosmopolitan, based on their characteristics. Using observational data of those who needed healthcare and used in-patient or out-patient services in the 12 months preceding the survey, frequencies, percentages and odds-ratios were used to show the study participants' environmental and population characteristics, relative to their patterns of healthcare use. RESULTS: A total of 1,634 residents from the three slums participated, distributed as 763 (migrant), 459 (indigenous) and 412 (cosmopolitan). Residents from the migrant (OR = 0.70, 95%CI: 0.51 to 0.97) and indigenous (OR = 0.65, 95%CI: 0.45 to 0.93) slums were less likely to have used formal healthcare facilities than those from the cosmopolitan slum. Slum residents were more likely to use formal healthcare facilities for maternal and perinatal conditions, and generalized pains, than for communicable (OR = 0.50, 95%CI: 0.34 to 0.72) and non-communicable diseases (OR = 0.61, 95%CI: 0.41 to 0.91). The unemployed had higher odds (OR = 1.45, 95%CI: 1.08 to 1.93) of using formal healthcare facilities than those currently employed. CONCLUSION: The cosmopolitan slum, situated in a major financial center and national economic hub, had a higher proportion of formal healthcare facility usage than the migrant and indigenous slums where about half of families were classified as poor. The urban advantage premise and Anderson behavioral model remain a practical explanatory framework, although they may not explain healthcare use in all possible slum types in Africa. A context-within-context approach is important for addressing healthcare utilization challenges in slums in sub-Saharan Africa.

Simple epidemic models with segmentation can be better than complex ones.

Given a sequence of epidemic events, can a single epidemic model capture its dynamics during the entire period? How should we divide the sequence into segments to better capture the dynamics? Throughout human history, infectious diseases (e.g., the Black Death and COVID-19) have been serious threats. Consequently, understanding and forecasting the evolving patterns of epidemic events are critical for prevention and decision making. To this end, epidemic models based on ordinary differential equations (ODEs), which effectively describe dynamic systems in many fields, have been employed. However, a single epidemic model is not enough to capture long-term dynamics of epidemic events especially when the dynamics heavily depend on external factors (e.g., lockdown and the capability to perform tests). In this work, we demonstrate that properly dividing the event sequence regarding COVID-19 (specifically, the numbers of active cases, recoveries, and deaths) into multiple segments and fitting a simple epidemic model to each segment leads to a better fit with fewer parameters than fitting a complex model to the entire sequence. Moreover, we propose a methodology for balancing the number of segments and the complexity of epidemic models, based on the Minimum Description Length principle. Our methodology is (a) Automatic: not requiring any user-defined parameters, (b) Model-agnostic: applicable to any ODE-based epidemic models, and (c) Effective: effectively describing and forecasting the spread of COVID-19 in 70 countries.

VEuPathDB: the eukaryotic pathogen, vector and host bioinformatics resource center.

The Eukaryotic Pathogen, Vector and Host Informatics Resource (VEuPathDB, https://veupathdb.org) represents the 2019 merger of VectorBase with the EuPathDB projects. As a Bioinformatics Resource Center funded by the National Institutes of Health, with additional support from the Welllcome Trust, VEuPathDB supports >500 organisms comprising invertebrate vectors, eukaryotic pathogens (protists and fungi) and relevant free-living or non-pathogenic species or hosts. Designed to empower researchers with access to Omics data and bioinformatic analyses, VEuPathDB projects integrate >1700 pre-analysed datasets (and associated metadata) with advanced search capabilities, visualizations, and analysis tools in a graphic interface. Diverse data types are analysed with standardized workflows including an in-house OrthoMCL algorithm for predicting orthology. Comparisons are easily made across datasets, data types and organisms in this unique data mining platform. A new site-wide search facilitates access for both experienced and novice users. Upgraded infrastructure and workflows support numerous updates to the web interface, tools, searches and strategies, and Galaxy workspace where users can privately analyse their own data. Forthcoming upgrades include cloud-ready application architecture, expanded support for the Galaxy workspace, tools for interrogating host-pathogen interactions, and improved interactions with affiliated databases (ClinEpiDB, MicrobiomeDB) and other scientific resources, and increased interoperability with the Bacterial & Viral BRC.

COVID-19 Toes and Other Skin Lesions During the Pandemic: Emerging Entities?

There is accumulating evidence to indicate an association between coronavirus infectious disease 2019 (COVID-19) and clusters of incident cutaneous eruptions. Of these, chilblains-like perniosis have received widespread medical and media attention. These typically affect the toes, and have been called "COVID-toes." Other acral lesions such as large bullae have also been reported. However, a definitive causal relationship with the severe acute respiratory syndrome coronavirus 2 has not yet been definitively proven, nor has a pathogenic mechanism been established. These episodes are self-limiting, but we need to know whether long-term sequelae exist.

Characterization of Keterah orthonairovirus and evaluation of therapeutic candidates against Keterah orthonairovirus infectious disease.

The species Keterah orthonairovirus is a member of the genus Orthonairovirus. Few studies have focused on this species, and there remains no treatment for Issyk-Kul fever, an infectious disease caused by a Keterah orthonairovirus. This study was performed to characterize this species using two viruses, Issyk-Kul virus (ISKV) and Soft tick bunyavirus (STBV), in cell culture and type I interferon receptor knockout (IFNAR-/-) mice and to evaluate the efficacy of serum transfusion using a mouse model of ISKV infection. The two viruses replicated in many kinds of mammal- and tick-derived cell lines but showed few different characteristics in tropism and antigenicity against anti-viral sera in cell culture. Neither virus caused clinical signs in wild-type mice, but both caused lethal infection in IFNAR-/- mice. ISKV caused more acute death than STBV in IFNAR-/- mice. In both viral infections in IFNAR-/- mice, macroscopic abnormalities were prominent in the liver. Similar levels of viral genome between ISKV- and STBV-infected IFNAR-/- mice were observed in blood, liver, lymphoid tissues and adrenal gland at moribund stages. Hematologic abnormalities in IFNAR-/- mice infected with these viruses, including leukopenia and thrombocytopenia, and biochemical abnormalities indicating liver damage were prominent. In addition, blood levels of many kinds of cytokines and chemokines such as granulocyte colony-stimulating factor, interleukin-6, tumor necrosis factor-α, interferon gamma-induced protein 10 and monocyte chemoattractant protein-1 were elevated. ISKV-immunized serum transfusion after infection delayed the time to death of IFNAR-/- mice. Thus, the present study showed that the species Keterah orthonairovirus could proliferate in most mammal-derived cell lines and cause severe liver lesions and death in IFNAR-/- mice and that serum transfusion might be effective in treatment against Issyk-Kul fever.

Precision-cut lung slices: A powerful ex vivo model to investigate respiratory infectious diseases.

Respiratory infections are a leading cause of mortality worldwide. Most of the research on the underlying disease mechanisms is based on cell culture, organoid, or surrogate animal models. Although these provide important insights, they have limitations. Cell culture models fail to recapitulate cellular interactions in the lung and animal models often do not permit high-throughput analysis of drugs or pathogen isolates; hence, there is a need for improved, scalable models. Precision-cut lung slices (PCLS), small, uniform tissue slices generated from animal or human lungs are increasingly recognized and employed as an ex vivo organotypic model. PCLS retain remarkable cellular complexity and the architecture of the lung, providing a platform to investigate respiratory pathogens in a near-native environment. Here, we review the generation and features of PCLS, their use to investigate the pathogenesis of viral and bacterial pathogens, and highlight their potential to advance respiratory infection research in the future.

PANoptosis: A New Insight Into Oral Infectious Diseases.

The oral microbiome, one of the most complex and intensive microbial ecosystems in the human body, comprises bacteria, archaea, fungi, protozoa, and viruses. Dysbiosis of the oral microbiome is the initiating factor that leads to oral infectious diseases. Infection is a sophisticated biological process involving interplay between the pathogen and the host, which often leads to activation of programmed cell death. Studies suggest that pyroptosis, apoptosis, and necroptosis are involved in multiple oral infectious diseases. Further understanding of crosstalk between cell death pathways has led to pyroptosis, apoptosis, and necroptosis being integrated into a single term: PANoptosis. PANoptosis is a multifaceted agent of the immune response that has important pathophysiological relevance to infectious diseases, autoimmunity, and cancer. As such, it plays an important role in innate immune cells that detect and eliminate intracellular pathogens. In addition to the classical model of influenza virus-infected and Yersinia-infected macrophages, other studies have expanded the scope of PANoptosis to include other microorganisms, as well as potential roles in cell types other than macrophages. In this review, we will summarize the pathophysiological mechanisms underlying inflammation and tissue destruction caused by oral pathogens. We present an overview of different pathogens that may induce activation of PANoptosis, along with the functional consequences of PANoptosis in the context of oral infectious diseases. To advance our understanding of immunology, we also explore the strategies used by microbes that enable immune evasion and replication within host cells. Improved understanding of the interplay between the host and pathogen through PANoptosis will direct development of therapeutic strategies that target oral infectious diseases.