Innate Response Research Articles

Recombinant fragment of human surfactant protein D to prevent neonatal chronic lung disease (RESPONSE): a protocol for a phase I safety trial in a tertiary neonatal unit

IntroductionChronic respiratory morbidity from bronchopulmonary dysplasia (BPD) remains the most common complication of preterm birth and has consequences for later respiratory, cardiovascular and neurodevelopmental outcomes. The early phases of respiratory...

NLRP3 inflammasome activation contributes to the development of the pro-fibrotic phenotype of lung fibroblasts

Idiopathic pulmonary fibrosis (IPF) is an irreversible progressive interstitial lung disease of unknown cause. The poorly understood pathophysiology of IPF poses substantial challenges to the development of effective anti-lung fibrotic drugs. The NLRP3 inflammasome, a key component of the innate immune system, has recently been linked to the pathogenesis of lung fibrosis. However, the specific contributions of NLRP3 inflammasomes to determination of the pro-fibrotic phenotype of lung fibroblasts, which play a central role in the production of extracellular matrix protein, remain to be investigated. Therefore, the present study was performed to elucidate the involvement of NLRP3 inflammasome signalling pathways in modulation of lung fibroblast proliferation and differentiation. We found that activation of NLRP3 inflammasomes increased in lung fibroblasts derived from individuals with pulmonary fibrosis and in normal lung fibroblasts stimulated with transforming growth factor β and platelet-derived growth factor. Importantly, blockage of NLRP3 inflammasome signalling, either by gene silencing of NLRP3 or using pharmacological inhibitors of NLRP3, caspase-1, or IL-1 receptor, inhibited the proliferation, differentiation, and extracellular matrix protein synthesis of activated lung fibroblasts. Moreover, induction of the reactive oxygen species/thioredoxin-interacting protein axis, an upstream signalling pathway of NLRP3 inflammasomes, was essential for maintenance of the pro-fibrotic phenotype of lung fibroblasts. Interestingly, treatments with pharmacological inhibitors of NLRP3 inflammasomes prevented the progression of bleomycin-induced pulmonary fibrosis in mice. Collectively, these findings suggest that aberrant activation of NLRP3 inflammasomes is a critical event in the pathogenesis of IPF and that targeting NLRP3 inflammasomes may serve as a therapeutic strategy for IPF.

Integrated microbiome and metabolomic analysis of Spodoptera litura under Metarhizium flavoviride qc1401 stress.

Metarhizium spp. have emerged as an alternative to chemical pesticides for protecting crops from insect pest. Here, we investigated midgut microbial community and metabolites of Spodoptera litura at three different timepoints after infection with Metarhizium flavoviride. The innate immune system of S. litura was activated with levels of polyphenol oxidase, carboxylesterase, multifunctional oxidase, and glutathione S-transferase activity significantly increasing. Exposure to the fungal pathogen also altered bacterial abundance and diversity in host's midgut, and these changes varied depending on the time elapsed since exposure. We identified more operational taxonomic units in the treated samples as compared to the control samples at all tested time points. A total of 372 metabolites were identified, and 88, 149, and 142 differentially accumulated metabolites (DAMs) were identified between the treatment and control groups at 3 timepoints after treatment, respectively. Based on the changes of DAMs in response to M. flavoviride infection at different timepoints and significantly enriched KEGG pathways, we speculated that "tyrosine metabolism," "galactose metabolism," "ATP-binding cassette transporters," "neuroactive ligand-receptor interaction," "purine metabolism," "arginine and proline metabolism," "beta-alanine metabolism," "lysosome," and "carbon metabolism" may participate in the metabolic-level defense response. An integrated pathway-level analysis of the 16S-rDNA and metabolomic data illustrated the connections and interdependencies between the metabolic responses of S. litura and the midgut microorganisms to M. flavoviride infection. This work emphasizes the value of integrated analyses of insect-pathogen interactions, provides a framework for future studies of critical microorganisms and metabolic determinants of these interactions, establishes a theoretical basis for the sustainable use of M. flavoviride.

Therapeutic Targeting of Pattern Recognition Receptors to Modulate Inflammation in Atherosclerosis.

Atherosclerosis (AS), a potentially fatal cardiovascular disease (CVD), is a chronic inflammatory condition. The disease's onset and progression are influenced by inflammatory and immunological mechanisms. The innate immune pathways are essential in the progression of AS, as they are responsible for detecting first danger signals and causing long-term changes in immune cells. The innate immune system possesses distinct receptors known as pattern recognition receptors (PRRs) which can identify both pathogen-associated molecular patterns and danger-associated molecular signals. Activation of PRRs initiates the inflammatory response in various physiological systems, such as the cardiovascular system. This review specifically examines the contribution of the innate immune response and PRRs to the formation and advancement of AS. Studying the role of these particular receptors in AS would enhance our understanding of the development of AS and offer novel approaches for directly improving the inflammatory response associated with it.

An innate immune signature induced by AS01- or AS03-adjuvanted vaccines predicts the antibody response magnitude and quality consistently over time.

Antibody-mediated protection can depend on mechanisms varying from neutralization to Fc-dependent innate immune-cell recruitment. Adjuvanted vaccine development relies on a holistic understanding of how adjuvants modulate the quantity/titer and quality of the antibody response. A Phase 2 trial (ClinicalTrials.gov: NCT00805389) evaluated hepatitis B vaccines formulated with licensed adjuvants (AS01B, AS01E, AS03, AS04 or Alum) in antigen-naïve adults. The trial investigated the role of adjuvants in shaping antibody-effector functions, and identified an innate transcriptional response shared by AS01B, AS01E and AS03. We integrated previously reported data on the innate response (gene expression, cytokine/C-reactive protein levels) and on quantitative/qualitative features of the mature antibody response (Fc-related parameters, immunoglobulin titers, avidity). Associations between the innate and humoral parameters were explored using systems vaccinology and a machine-learning framework. A dichotomy in responses between AS01/AS03 and AS04/Alum (with the former two contributing most to the association with the humoral response) was observed across all timepoints of this longitudinal study. The consistent patterns over time suggested a similarity in the impacts of the two-dose immunization regimen, year-long interval, and non-adjuvanted antigenic challenge given one year later. An innate signature characterized by interferon pathway-related gene expression and secreted interferon-γ-induced protein 10 and C-reactive protein, which was shared by AS01 and AS03, consistently predicted both the qualitative antibody response features and the titers. The signature also predicted from the antibody response quality, the group of adjuvants from which the administered vaccine was derived. An innate signature induced by AS01- or AS03-adjuvanted vaccines predicts the antibody response magnitude and quality consistently over time.

Exploration and Characterization of Antimicrobial Peptides from Shrimp Litopenaeus Vannamei by A Genomic and Transcriptomic Approach.

Antimicrobial peptides (AMPs) are crucial in the humoral immunity aspect of invertebrates' innate immune systems. However, studies on AMP discovery in the Pacific white shrimp (Litopenaeus vannamei) using omics data have been limited. Addressing the growing concern of antibiotic resistance in aquaculture, this study focused on the identification and characterization of AMPs in L. vannamei using advanced genomic and transcriptomic techniques. The genome of L. vannamei was performed to predict and identify a total of 754 AMP-derived genes, distributed across most chromosomes and spanning 24 distinct AMP families, and further identified 236 AMP-derived genes at the mRNA level in hemocytes. A subset of 20 chemically synthesized peptides, derived from these genes, exhibited significant antimicrobial activity, with over 85% showing effectiveness against key bacterial strains such as Staphylococcus aureus and Vibrio parahaemolyticus. The expression patterns of these AMPs were also investigated in different shrimp tissues and at various infection stages, revealing dynamic responses to pathogenic challenges. These findings highlight the significant potential of AMPs in L. vannamei as novel, effective alternatives to traditional antibiotics in aquaculture, offering insights into their diverse structural properties and biological functions. Together, this comprehensive characterization of the AMP repertoire in L. vannamei demonstrates the efficacy of using omics data for AMP discovery and lays the groundwork for their potential applications.

Changing expression system alters oligomerization and proinflammatory activity of recombinant human S100A9.

S100A9 is a Damage Associated Molecular Pattern (DAMP) that activates the innate immune system via Toll-like receptor 4 (TLR4). Despite many years of study, the mechanism of activation remains unknown. To date, much of the biochemical characterization of S100A9 has been performed using recombinant S100A9 expressed in E. coli (S100A9 ec ). TLR4 is the canonical receptor for LPS, a molecule found in the outer membrane of E. coli , raising the possibility of artifacts due to LPS contamination. Here we report characterization of LPS-free recombinant S100A9 expressed in insect cells (S100A9 in ). We show that S100A9 in does not activate TLR4. This difference does not appear to be due to LPS contamination, protein misfolding, purification artifacts, or differences in phosphorylation. We show instead that S100A9 in adopts an altered oligomeric state compared to S100A9 ec . Disrupting oligomer formation with the E. coli disaggregase SlyD restores activity to S100A9 in . Our results also indicate that the oligomeric state of S100A9 is a major factor in its ability to activate TLR4 and that this can be altered in unexpected ways by the recombinant expression system used to produce the protein.

Cryo-EM reconstruction of oleate hydratase bound to a phospholipid membrane bilayer

Oleate hydratase (OhyA) is a bacterial peripheral membrane protein that catalyzes FAD-dependent water addition to membrane bilayer-embedded unsaturated fatty acids. The opportunistic pathogen Staphylococcus aureus uses OhyA to counteract the innate immune system and support colonization. Many Gram-positive and Gram-negative bacteria in the microbiome also encode OhyA. OhyA is a dimeric flavoenzyme whose carboxy terminus is identified as the membrane binding domain; however, understanding how OhyA binds to cellular membranes is not complete until the membrane-bound structure has been elucidated. All available OhyA structures depict the solution state of the protein outside its functional environment. Here, we employ liposomes to solve the cryo-electron microscopy structure of the functional unit: the OhyA•membrane complex. The protein maintains its structure upon membrane binding and slightly alters the curvature of the liposome surface. OhyA preferentially associates with 20–30 nm liposomes with multiple copies of OhyA dimers assembling on the liposome surface resulting in the formation of higher-order oligomers. Dimer assembly is cooperative and extends along a formed ridge of the liposome. We also solved an OhyA dimer of dimers structure that recapitulates the intermolecular interactions that stabilize the dimer assembly on the membrane bilayer as well as the crystal contacts in the lattice of the OhyA crystal structure. Our work enables visualization of the molecular trajectory of membrane binding for this important interfacial enzyme.

The probiotic strain Bacillus subtilis CU1 primes antimicrobial innate immune response and reduces low-grade inflammation: a clinical study.

LifeinU™ Bacillus subtilis CU1 (BSCU1) has been previously shown to be effective in stimulating mucosal immune responses and supporting resistance to common infectious disease episodes in the elderly. The current clinical study aimed at exploring potential pathways by which BSCU1 could beneficially modulate the immune system and contribute to protection against infection in the general population. A total of 88 participants from three different age groups were supplemented with BSCU1 (2× 109 cfu/day) for 4 weeks. The effect of the intervention on mucosal immunity was assessed by faecal sIgA levels. In addition, a series of complementary immunoassays were selected, including immune phenotyping, gene expression, basal cytokine levels, cytokine levels in lipopolysaccharide (LPS)-stimulated whole blood and phagocytosis assay. Although no significant effect was observed on faecal sIgA levels after intervention, BSCU1 showed a positive effect on a consistent set of markers of the peripheral innate immune system in adults and the elderly. Percentages of peripheral blood myeloid cells as well as the expression of the activation marker CD69 on monocytes were significantly increased after probiotic intervention. BSCU1 supplementation resulted in significant enrichment of clusters of genes involved in response to type I interferon and phagocytosis pathway. Consistently, ex vivo stimulation of whole blood with LPS resulted in a statistically significant increase in pro-inflammatory cytokines (interleukin (IL)-1beta, IL-6, interferon-gamma, IL-12, tumour necrosis factor (TNF)-alpha, macrophage inflammatory protein (MIP)-1alpha, IL-8) and phagocytosis assays showed increased capacity of monocytes to engulf bacteria as well as higher phagosome maturation. BSCU1 supplementation also had a positive effect on low-grade inflammation as significant reduction in basal levels of several serum cytokines (IL-10, TNF-alpha, MIP-1alpha, IL-8) were observed in the elderly subgroup. Overall, BSCU1 primed immune cells for a better response to microbial challenges and reduced low-grade inflammation associated with aging. Registered at ClinicalTrials.gov with the identifier NCT05403398.

Epigenetic regulation of macrophage activation in chronic obstructive pulmonary disease.

Macrophages in the innate immune system play a vital role in various lung diseases such as asthma, chronic obstructive pulmonary disease (COPD), acute lung injury and pulmonary fibrosis. Macrophages involved in the process of immunity need to go through a process of activation, including changes in gene expression and cell metabolism. Epigenetic modifications are key factors of macrophage activation including DNA methylation, histone modification and non-coding RNA regulation. Understanding the role and mechanisms of epigenetic regulation of macrophage activation can provide insights into the function of macrophages in lung diseases and help identification of potential therapeutic targets. This review summarizes the latest progress in the epigenetic changes and regulation of macrophages in their development process and in normal physiological states, and the epigenetic regulation of macrophages in COPD as well as the influence of macrophage activation on COPD development.

Macrophage-Targeted GSH-Depleting Nanocomplexes for Synergistic Chemodynamic Therapy/Gas Therapy/Immunotherapy of Intracellular Bacterial Infection.

Intracellular pathogens can survive inside the macrophages to protect themselves from eradication by the innate immune system and conventional antibiotics, resulting in severe bacterial infections. In this work, an antibiotic-free nanocomplex (HA/GA-Fe@NO-DON), exhibiting macrophage-targeted synergistic gas therapy (nitric oxide, NO)/chemodynamic therapy/immunotherapy, was reported. HA/GA-Fe nanoparticles were synthesized by the strong coordination interactions among carboxyl groups of hyaluronic acid (HA), polyphenol groups of gallic acid (GA), and Fe(II) ions. The hydrophobic glutathione (GSH)-responsive NO donor (NO-DON) was encapsulated in HA/GA-Fe nanoparticles to form the final nanocomplexes (HA/GA-Fe@NO-DON). HA on the nanocomplexes guides the macrophage-specific uptake and intracellular accumulation. After the uptake, HA/GA-Fe@NO-DON nanocomplexes could not only generate highly toxic hydroxyl radicals (•OH) by the Fenton reaction and GSH depletion but also release NO when stimulated by intracellular GSH. Meanwhile, the nanocomplexes could trigger an efficient proinflammation immune response to reinforce the antibacterial activity. This work presents the development of antibiotic-free macrophage-targeted HA/GA-Fe@NO-DON nanocomplexes as an effective adjuvant nanomedicine with synergistic gas therapy/chemodynamic therapy/immunotherapy for eliminating intracellular bacterial infection.

ER-transiting bacterial toxins amplify STING innate immune responses and elicit ER stress.

The cGAS/STING sensor system drives innate immune responses to intracellular microbial double-stranded DNA (dsDNA) and bacterial cyclic nucleotide second messengers (e.g., c-di-AMP). STING-dependent cell-intrinsic responses can increase resistance to microbial infection and speed pathogen clearance. Correspondingly, STING activation and signaling are known to be targeted for suppression by effectors from several bacterial pathogens. Whether STING responses are also positively regulated through sensing of specific bacterial effectors is less clear. We find that STING activation through dsDNA, by its canonical ligand 2'-3' cGAMP, or the small molecule DMXAA is potentiated following intracellular delivery of the AB5 toxin family member pertussis toxin from Bordetella pertussis or the B subunit of cholera toxin from Vibrio cholerae. Entry of pertussis toxin or cholera toxin B into mouse macrophages triggers markers of endoplasmic reticulum (ER) stress and enhances ligand-dependent STING responses at the level of STING receptor activation in a manner that is independent of toxin enzymatic activity. Our results provide an example in which STING responses integrate information about the presence of relevant ER-transiting bacterial toxins into the innate inflammatory response and may help to explain the in vivo adjuvant effects of catalytically inactive toxins.

Malnutrition and Allergies: Tipping the Immune Balance towards Health.

Malnutrition, which includes macro- and micronutrient deficiencies, is common in individuals with allergic dermatitis, food allergies, rhinitis, and asthma. Prolonged deficiencies of proteins, minerals, and vitamins promote Th2 inflammation, setting the stage for allergic sensitization. Consequently, malnutrition, which includes micronutrient deficiencies, fosters the development of allergies, while an adequate supply of micronutrients promotes immune cells with regulatory and tolerogenic phenotypes. As protein and micronutrient deficiencies mimic an infection, the body's innate response limits access to these nutrients by reducing their dietary absorption. This review highlights our current understanding of the physiological functions of allergenic proteins, iron, and vitamin A, particularly regarding their reduced bioavailability under inflamed conditions, necessitating different dietary approaches to improve their absorption. Additionally, the role of most allergens as nutrient binders and their involvement in nutritional immunity will be briefly summarized. Their ability to bind nutrients and their close association with immune cells can trigger exaggerated immune responses and allergies in individuals with deficiencies. However, in nutrient-rich conditions, these allergens can also provide nutrients to immune cells and promote health.

Genetic background affects neutrophil activity and determines the severity of autoinflammatory osteomyelitis in mice.

The knowledge about the contribution of the innate immune system to health and disease is expanding. However, to obtain reliable results, it is critical to select appropriate mouse models for in vivo studies. Data on genetic and phenotypic changes associated with different mouse strains can assist in this task. Such data can also facilitate our understanding of how specific polymorphisms and genetic alterations affect gene function, phenotypes, and disease outcomes. Extensive information is available on genetic changes in all major mouse strains. However, comparatively little is known about their impact on immune response and in particular on innate immunity. Here, we analyzed a mouse model of chronic multifocal osteomyelitis (CMO), an autoinflammatory disease driven exclusively by the innate immune system, which is caused by an inactivating mutation in the Pstpip2 gene. We investigated how the genetic background of BALB/c, C57BL/6J, and C57BL/6NCrl strains alters the molecular mechanisms controlling disease progression. While all mice developed the disease, symptoms were significantly milder in BALB/c and partially also in C57BL/6J when compared to C57BL/6NCrl. Disease severity correlated with the number of infiltrating neutrophils and monocytes and with the production of chemokines attracting these cells to the site of inflammation. It also correlated with increased expression of genes associated with autoinflammation, rheumatoid arthritis, neutrophil activation, and degranulation, resulting in altered neutrophil activation in vivo. Together, our data demonstrate striking effects of genetic background on multiple parameters of neutrophil function and activity influencing the onset and course of the CMO disease.

Activation of Antiviral Host Responses against Avian Influenza Virus and Remodeling of Gut Microbiota by rLAB Vector Expressing rIL-17A in Chickens.

Low-pathogenic avian influenza virus (LPAIV) remains the most common subtype of type-A influenza virus that causes moderate to severe infection in poultry with significant zoonotic and pandemic potential. Due to high mutability, increasing drug resistance, and limited vaccine availability, the conventional means to prevent intra- or interspecies transmission of AIV is highly challenging. As an alternative to control AIV infections, cytokine-based approaches to augment antiviral host defense have gained significant attention. However, the selective application of cytokines is critical since unregulated expression of cytokines, particularly proinflammatory ones, can cause substantial tissue damage during acute phases of immune responses. Moreover, depending on the type of cytokine and its impact on intestinal microbiota, outcomes of cytokine-gut microflora interaction can have a critical effect on overall host defense against AIV infections. Our recent study demonstrated some prominent roles of chicken IL-17A (ChIL-17A) in regulating antiviral host responses against AIV infection, however, in an in vitro model. For more detailed insights into ChIL-17A function, in the present study, we investigated whether ChIL-17A-meditated elevated antiviral host responses can translate into effective immune protection against AIV infection in an in vivo system. Moreover, considering the role of gut health in fostering innate or local host responses, we further studied the contributory relationships between gut microbiota and host immunity against AIV infection in chickens. For this, we employed a recombinant lactic acid-producing bacterial (LAB) vector, Lactococcus lactis, expressing ChIL-17A and analyzed the in vivo functionality in chickens against an LPAIV (A/H9N2) infection. Our study delineates that mucosal delivery of rL. lactis expressing ChIL-17A triggers proinflammatory signaling cascades and can drive a positive shift in phylum Firmicutes, along with a marked decline in phylum Actinobacteriota and Proteobacteria, favoring effective antiviral host responses against AIV infection in chickens. We propose that ChIL-17A-mediated selective expansion of beneficial gut microbiota might form a healthy microbial community that augments the effective immune protection against AIV infections in chickens.

Infection and the Glycome─New Insights into Host Response.

Glycans play critical roles in the host-pathogen interactions leading to infection. However, we still understand very little about the dynamic nature of glycosylation in response to infection and its function in modulating host immunity. Many of the host proteins involved in immune defense are glycoproteins. Furthermore, the innate immune system recognizes glycans. The glycoform of a protein can impact proteolytic stability, receptor interactions, serum half-life, and other aspects. New, cutting-edge chemical biology tools are shedding light on the interplay between infection and the host glycome. In this review, we highlight new work on the importance of dynamic glycosylation of host proteins in the innate and adaptive immune pathways in response to infection. These include recent findings on altered glycoprofiles of mucins, complement components, and antibodies.

Complement Component C5a and Fungal Pathogen Induce Diverse Responses through Crosstalk between Transient Receptor Potential Channel (TRPs) Subtypes in Human Conjunctival Epithelial Cells.

The conjunctiva has immune-responsive properties to protect the eye from infections. Its innate immune system reacts against external pathogens, such as fungi. The complement factor C5a is an important contributor to the initial immune response. It is known that activation of transient-receptor-potential-vanilloid 1 (TRPV1) and TRP-melastatin 8 (TRPM8) channels is involved in different immune reactions and inflammation in the human body. The aim of this study was to determine if C5a and mucor racemosus e voluminae cellulae (MR) modulate Ca2+-signaling through changes in TRPs activity in human conjunctival epithelial cells (HCjECs). Furthermore, crosstalk was examined between C5a and MR in mediating calcium regulation. Intracellular Ca2+-concentration ([Ca2+]i) was measured by fluorescence calcium imaging, and whole-cell currents were recorded using the planar-patch-clamp technique. MR was used as a purified extract. Application of C5a (0.05-50 ng/mL) increased both [Ca2+]i and whole-cell currents, which were suppressed by either the TRPV1-blocker AMG 9810 or the TRPM8-blocker AMTB (both 20 µM). The N-terminal peptide C5L2p (20-50 ng/mL) blocked rises in [Ca2+]i induced by C5a. Moreover, the MR-induced rise in Ca2+-influx was suppressed by AMG 9810 and AMTB, as well as 0.05 ng/mL C5a. In conclusion, crosstalk between C5a and MR controls human conjunctival cell function through modulating interactions between TRPV1 and TRPM8 channel activity.

Characteristics and functional analysis of a novel mannose receptor in Penaeus vannamei

The mannose receptor (MR) plays a key role in the innate immune system as a pattern recognition receptor. Here, a novel type of mannose receptor, named PvMR2, was identified from Penaeus vannamei (P. vannamei). The PvMR2 coding sequence (CDS) obtained was 988 base pairs in length, encoding a protein consisting of 328 amino acids. This protein includes a signal peptide and two classical C-type lectin domains (CTLD). Quantitative real-time PCR showed that PvMR2 was distributed in all detected tissues, with the highest levels in the intestines and stomach. Following a bacterial challenge with Vibrio anguillarum (V. anguillarum), PvMR2 showed significant up-regulation in both the intestines and stomach of shrimp. To validate the function of PvMR2, recombinant proteins were extracted and purified using a His-tag. The resulting rPvMR2 demonstrated binding capability with lipopolysaccharides (LPS) and peptidoglycan (PGN) in a dose-dependent manner, affirming its binding affinity. The purified rPvMR2 demonstrated calcium-independent binding activity towards both Gram-positive bacteria (V. anguilliarum and Vibrio parahaemolyticus) and Gram-negative bacteria (Escherichia coli and Aeromonas Veronii). Antibacterial assays confirmed that rPvMR2 inhibits bacterial growth. Intestinal adhesion and adhesion inhibition experiments confirmed that the rPvMR2 can be used to reduce the adhesion capacity of harmful bacteria in the gut. Phagocytosis experiments have shown that rPvMR2 promotes phagocytosis in hemocytes and protects the host from external infection. Treatment with recombinant PvMR2 significantly bolstered bacterial clearance within the hemolymph and markedly augmented shrimp survival post-infection with V. anguillarum. These results suggest that PvMR2 has agglutination, growth inhibition, adhesion inhibition, clearance promotion, and phagocytosis effects on harmful bacteria, and plays a crucial role in the antimicrobial immune response of P. vannamei.

The Role of Retrotransposons and Endogenous Retroviruses in Age-Dependent Neurodegenerative Disorders.

Over 40% of the human genome is composed of retrotransposons, DNA species that hold the potential to replicate via an RNA intermediate and are evolutionarily related to retroviruses. Retrotransposons are most studied for their ability to jump within a genome, which can cause DNA damage and novel insertional mutations. Retrotransposon-encoded products, including viral-like proteins, double-stranded RNAs, and extrachromosomal circular DNAs, can also be potent activators of the innate immune system. A growing body of evidence suggests that retrotransposons are activated in age-related neurodegenerative disorders and that such activation causally contributes to neurotoxicity. Here we provide an overview of retrotransposon biology and outline evidence of retrotransposon activation in age-related neurodegenerative disorders, with an emphasis on those involving TAR-DNA binding protein-43 (TDP-43) and tau. Studies to date provide the basis for ongoing clinical trials and hold promise for innovative strategies to ameliorate the adverse effects of retrotransposon dysregulation in neurodegenerative disorders.

Fungal Pneumonia in a Diabetic Female Masquerading as Primary Lung Cancer

Abstract Aspergillus is a ubiquitous saprophytic mold that humans and animals constantly inhale. In health, the conidia are eliminated by the innate immune system. However, a subset of individuals with risk factors such as neutropenia, receiving high doses of glucocorticoids or certain biologicals, and recipients of hematopoietic or solid-organ transplants develop invasive aspergillosis. The mortality associated with invasive aspergillosis is 42%–64%. The early diagnosis of invasive pulmonary aspergillosis in patients without classical risk factors remains challenging. We present a case of an elderly female with uncontrolled diabetes mellitus who presented with acute-onset chest pain, breathlessness, and cough without expectoration. On evaluation, her chest radiograph showed a mass lesion in the right upper zone. 18Fluorodeoxyglucose (FDG)-positron emission tomography-computed tomography showed two FDG-avid lesions in the apical and medial segment of the right upper lobe. The lung biopsy was negative for malignancy; however, she was diagnosed with invasive pulmonary aspergillosis based on serum and bronchoalveolar fluid galactomannan positivity. She was managed with voriconazole with complete resolution of the lesion.