The Roles of Neuropeptide Y in Respiratory Disease Pathogenesis via the Airway Immune Response.

The lungs are very complex organs, and the respiratory system performs the dual roles of repairing tissue while protecting against infection from various environmental stimuli. Persistent external irritation disrupts the immune responses of tissues and cells in the respiratory system, ultimately leading to respiratory disease. Neuropeptide Y (NPY) is a 36-amino-acid polypeptide and a neurotransmitter that regulates homeostasis. The NPY receptor is a seven-transmembrane-domain G-protein-coupled receptor with six subtypes (Y1, Y2, Y3, Y4, Y5, and Y6). Of these receptors, Y1, Y2, Y4, and Y5 are functional in humans, and Y1 plays important roles in the immune responses of many organs, including the respiratory system. NPY and the Y1 receptor have critical roles in the pathogenesis of asthma, chronic obstructive pulmonary disease, and idiopathic pulmonary fibrosis. The effects of NPY on the airway immune response and pathogenesis differ among respiratory diseases. This review focuses on the involvement of NPY in the airway immune response and pathogenesis of various respiratory diseases.

From "Immunity Debt" to "Immunity Theft"-How COVID-19 Might Be Tied to Recent Respiratory Disease Surges.

This Medical News story discusses the relationship between the COVID-19 pandemic and recent increases in other respiratory diseases.

Co-administration of chicken IL-2 alleviates clinical signs and replication of the ILTV chicken embryo origin vaccine by pre-activating natural killer cells and cytotoxic T lymphocytes.

IMPORTANCE: Chickens immunized with the infectious laryngotracheitis chicken embryo origin (CEO) vaccine (Medivac, PT Medion Farma Jaya) experience adverse reactions, hindering its safety and effective use in poultry flocks. To improve the effect of the vaccine, we sought to find a strategy to alleviate the respiratory reactions associated with the vaccine. Here, we confirmed that co-administering the CEO vaccine with chIL-2 by oral delivery led to significant alleviation of the vaccine reactions in chickens after immunization. Furthermore, we found that the co-administration of chIL-2 with the CEO vaccine reduced the clinical signs of the CEO vaccine while enhancing natural killer cells and cytotoxic T lymphocyte response to decrease viral loads in their tissues, particularly in the trachea and conjunctiva. Importantly, we demonstrated that the chIL-2 treatment can ameliorate the replication of the CEO vaccine without compromising its effectiveness. This study provides new insights into further applications of chIL-2 and a promising strategy for alleviating the adverse reaction of vaccines.

Immune responses to inactivated COVID-19 vaccine were decreased in Chinese patients with chronic respiratory diseases.

Purpose: The effectiveness of inactivated vaccines against acute respiratory syndrome coronavirus 2 (SARS­CoV­2), the causative agent of coronavirus disease 2019 (COVID-19), has become a global concern. Hence, the aim of this study was to evaluate vaccine safety and to assess immune responses in individuals with chronic respiratory disease (CRD) following a two-dose vaccination. Methods: The study cohort included 191 participants (112 adult CRD patients and 79 healthy controls [HCs]) at least 21 (range, 21-159) days after a second vaccination. Frequencies of memory B cells (MBCs) subsets and titers of SARS-CoV-2 neutralizing antibodies (NAbs) and anti-receptor binding domain (RBD) IgG antibodies (Abs) were analyzed. Results: As compared to the HCs, CRD patients had lower seropositivity rates and titers of both anti-RBD IgG Abs and NAbs, in addition to lower frequencies of RBD-specific MBCs (all, p < 0.05). At 3 months, CRD patients had lower seropositivity rates and titers of anti-RBD IgG Abs than the HCs (p < 0.05). For CoronaVac, the seropositivity rates of both Abs were lower in patients with old pulmonary tuberculosis than HCs. For BBIBP-CorV, the seropositivity rates of CoV-2 NAbs were lower in patients with chronic obstructive pulmonary disease than HCs (all, p < 0.05). Meanwhile, there was no significant difference in overall adverse events between the CRD patients and HCs. Univariate and multivariate analyses identified the time interval following a second vaccination as a risk factor for the production of anti-RBD IgG Abs and CoV-2 NAbs, while the CoronaVac had a positive effect on the titers of both Abs. Female was identified as a protective factor for CoV-2 NAb levels. Conclusion: Inactivated COVID-19 vaccines were safe and well tolerated by CRD patients but resulted in lower Ab responses and the frequencies of RBD-specific MBCs. Therefore, CRD patients should be prioritized for booster vaccinations.

New Insights into the Role of the Complement System in Human Viral Diseases.

The complement system (CS) is part of the human immune system, consisting of more than 30 proteins that play a vital role in the protection against various pathogens and diseases, including viral diseases. Activated via three pathways, the classical pathway (CP), the lectin pathway (LP), and the alternative pathway (AP), the complement system leads to the formation of a membrane attack complex (MAC) that disrupts the membrane of target cells, leading to cell lysis and death. Due to the increasing number of reports on its role in viral diseases, which may have implications for research on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), this review aims to highlight significant progress in understanding and defining the role of the complement system in four groups of diseases of viral etiology: (1) respiratory diseases; (2) acute liver failure (ALF); (3) disseminated intravascular coagulation (DIC); and (4) vector-borne diseases (VBDs). Some of these diseases already present a serious global health problem, while others are a matter of concern and require the collaboration of relevant national services and scientists with the World Health Organization (WHO) to avoid their spread.

Vaccine-Associated Enhanced Respiratory Disease following Influenza Virus Infection in Ferrets Recapitulates the Model in Pigs.

Influenza A virus (IAV) causes respiratory disease in swine and humans. Vaccines are used to prevent influenza illness in both populations but must be frequently updated due to rapidly evolving strains. Mismatch between the circulating strains and the strains contained in vaccines may cause loss of efficacy. Whole inactivated virus (WIV) vaccines with adjuvant, utilized by the swine industry, are effective against antigenically similar viruses; however, vaccine-associated enhanced respiratory disease (VAERD) may happen when the WIV is antigenically mismatched with the infecting virus. VAERD is a repeatable model in pigs, but had yet to be experimentally demonstrated in other mammalian species. We recapitulated VAERD in ferrets, a standard benchmark animal model for studying human influenza infection, in a direct comparison to VAERD in pigs. Both species were vaccinated with WIV with oil-in-water adjuvant containing a δ-1 H1N2 (1B.2.2) derived from the pre-2009 human seasonal lineage, then challenged with a 2009 pandemic H1N1 (H1N1pdm09, 1A.3.3.2) 5 weeks after vaccination. Nonvaccinated and challenged groups showed typical signs of influenza disease, but the mismatched vaccinated and challenged pigs and ferrets showed elevated clinical signs, despite similar viral loads. VAERD-affected pigs exhibited a 2-fold increase in lung lesions, while VAERD-affected ferrets showed a 4-fold increase. Similar to pigs, antibodies from VAERD-affected ferrets preferentially bound to the HA2 domain of the H1N1pdm09 challenge strain. These results indicate that VAERD is not limited to pigs, as demonstrated here in ferrets, and the need to consider VAERD when evaluating new vaccine platforms and strategies. IMPORTANCE We demonstrated the susceptibility of ferrets, a laboratory model species for human influenza A virus research, to vaccine-associated enhanced respiratory disease (VAERD) using an experimental model previously demonstrated in pigs. Ferrets developed clinical characteristics of VAERD very similar to that in pigs. The hemagglutinin (HA) stalk is a potential vaccine target to develop more efficacious, broadly reactive influenza vaccine platforms and strategies. However, non-neutralizing antibodies directed toward a conserved epitope on the HA stalk induced by an oil-in-water, adjuvanted, whole influenza virus vaccine were previously shown in VAERD-affected pigs and were also identified here in VAERD-affected ferrets. The induction of VAERD in ferrets highlights the potential risk of mismatched influenza vaccines for humans and the need to consider VAERD when designing and evaluating vaccine strategies.

Microarray-Based Detection of Antibodies against SARS-CoV-2 Proteins, Common Respiratory Viruses and Type I Interferons.

A microarray-based assay to detect IgG and IgM antibodies against betacoronaviruses (SARS-CoV-2, SARS, MERS, OC43, and HKU1), other respiratory viruses and type I interferons (IFN-Is) was developed. This multiplex assay was applied to track antibody cross-reactivity due to previous contact with similar viruses and to identify antibodies against IFN-Is as the markers for severe COVID-19. In total, 278 serum samples from convalescent plasma donors, COVID-19 patients in the intensive care unit (ICU) and patients who recovered from mild/moderate COVID-19, vaccine recipients, prepandemic and pandemic patients with autoimmune endocrine disorders, and a heterogeneous prepandemic cohort including healthy individuals and chronically ill patients were analyzed. The anti-SARS-CoV-2 microarray results agreed well with the ELISA results. Regarding ICU patients, autoantibodies against IFN-Is were detected in 10.5% of samples, and 10.5% of samples were found to simultaneously contain IgM antibodies against more than two different viruses. Cross-reactivity between IgG against the SARS-CoV-2 nucleocapsid and IgG against the OC43 and HKU1 spike proteins was observed, resulting in positive signals for the SARS-CoV-2 nucleocapsid in prepandemic samples from patients with autoimmune endocrine disorders. The presence of IgG against the SARS-CoV-2 nucleocapsid in the absence of IgG against the SARS-CoV-2 spike RBD should be interpreted with caution.

The Role of Innate Lymphoid Cells in Chronic Respiratory Diseases.

The lung is a vital mucosal organ that is constantly exposed to the external environment, and as such, its defenses are continuously under threat. The pulmonary immune system has evolved to sense and respond to these danger signals while remaining silent to innocuous aeroantigens. The origin of the defense system is the respiratory epithelium, which responds rapidly to insults by the production of an array of mediators that initiate protection by directly killing microbes, activating tissue-resident immune cells and recruiting leukocytes from the blood. At the steady-state, the lung comprises a large collection of leukocytes, amongst which are specialized cells of lymphoid origin known as innate lymphoid cells (ILCs). ILCs are divided into three major helper-like subsets, ILC1, ILC2 and ILC3, which are considered the innate counterparts of type 1, 2 and 17 T helper cells, respectively, in addition to natural killer cells and lymphoid tissue inducer cells. Although ILCs represent a small fraction of the pulmonary immune system, they play an important role in early responses to pathogens and facilitate the acquisition of adaptive immunity. However, it is now also emerging that these cells are active participants in the development of chronic lung diseases. In this mini-review, we provide an update on our current understanding of the role of ILCs and their regulation in the lung. We summarise how these cells and their mediators initiate, sustain and potentially control pulmonary inflammation, and their contribution to the respiratory diseases chronic obstructive pulmonary disease (COPD) and asthma.

Staphylococcus aureus Arsenal To Conquer the Lower Respiratory Tract.

Staphylococcus aureus is both a commensal and a pathogenic bacterium for humans. Its ability to induce severe infections is based on a wide range of virulence factors. S. aureus community-acquired pneumonia (SA-CAP) is rare and severe, and the contribution of certain virulence factors in this disease has been recognized over the past 2 decades. First, the factors involved in metabolism adaptation are crucial for S. aureus survival in the lower respiratory tract, and toxins and enzymes are required for it to cross the pulmonary epithelial barrier. S. aureus subsequently faces host defense mechanisms, including the epithelial barrier, but most importantly the immune system. Here, again, S. aureus uses myriad virulence factors to successfully escape from the host's defenses and takes advantage of them. The impact of S. aureus virulence, combined with the collateral damage caused by an overwhelming immune response, leads to severe tissue damage and adverse clinical outcomes. In this review, we summarize step by step all of the S. aureus factors implicated in CAP and described to date, and we provide an outlook for future research.

NLRP3-Inflammasome Inhibition during Respiratory Virus Infection Abrogates Lung Immunopathology and Long-Term Airway Disease Development.

Respiratory syncytial virus (RSV) infects most infants by two years of age. It can cause severe disease leading to an increased risk of developing asthma later in life. Previously, our group has shown that RSV infection in mice and infants promotes IL-1ß production. Here, we characterized the role of NLRP3-Inflammasome activation during RSV infection in adult mice and neonates. We observed that the inhibition of NLRP3 activation using the small molecule inhibitor, MCC950, or in genetically modified NLRP3 knockout (Nlrp3-/-) mice during in vivo RSV infection led to decreased lung immunopathology along with a reduced expression of the mucus-associated genes and reduced production of innate cytokines (IL-1ß, IL-33 and CCL2) linked to severe RSV disease while leading to significant increases in IFN-ß. NLRP3-inflammasome inhibition or deletion diminished Th2 cytokines and inflammatory cell infiltration into the lungs. Furthermore, NLRP3 inhibition or deletion during early-life RSV infection led to reducing viral-exacerbated allergic response in a mouse model of RSV-induced allergy exacerbation. Here, we demonstrated the critical role of NLRP3-inflammasome activation in RSV immunopathology and the related long-term airway alteration. Moreover, these findings suggest the NLRP3-inflammasome as a potential therapeutic target to attenuate severe RSV disease and limit childhood asthma development.

Identification of Host Factors Associated with the Development of Equine Herpesvirus Myeloencephalopathy by Transcriptomic Analysis of Peripheral Blood Mononuclear Cells from Horses.

Equine herpesvirus-1 is the cause of respiratory disease, abortion, and equine herpesvirus myeloencephalopathy (EHM) in horses worldwide. EHM affects as many as 14% of infected horses and a cell-associated viremia is thought to be central for EHM pathogenesis. While EHM is infrequent in younger horses, up to 70% of aged horses develop EHM. The aging immune system likely contributes to EHM pathogenesis; however, little is known about the host factors associated with clinical EHM. Here, we used the "old mare model" to induce EHM following EHV-1 infection. Peripheral blood mononuclear cells (PBMCs) of horses prior to infection and during viremia were collected and RNA sequencing with differential gene expression was used to compare the transcriptome of horses that did (EHM group) and did not (non-EHM group) develop clinical EHM. Interestingly, horses exhibiting EHM did not show respiratory disease, while non-EHM horses showed significant respiratory disease starting on day 2 post infection. Multiple immune pathways differed in EHM horses in response to EHV-1. These included an upregulation of IL-6 gene expression, a dysregulation of T-cell activation through AP-1 and responses skewed towards a T-helper 2 phenotype. Further, a dysregulation of coagulation and an upregulation of elements in the progesterone response were observed in EHM horses.

The role of dectin-1 in health and disease.

Dendritic cell-associated C-type lectin-1 (Dectin-1), also known as ß-glucan receptor is an emerging pattern recognition receptor (PRR) which belongs to the family of C-type lectin receptor (CLR). This CLR identifies ligands independently of Ca2+ and is majorly involved in coupling of innate with adaptive immunity. Formerly, Dectin-1 was best known for its role in anti-fungal defense only. However, recent explorations suggested its wider role in defense against variety of infectious diseases caused by pathogens including bacteria, parasites and viruses. In fact, Dectin-1 signaling axis has been suggested to be targeted as an effective therapeutic strategy for cancers. Dectin-1 has also been elucidated ascetically in the heart, respiratory, intestinal, neurological and developmental disorders. Being a defensive PRR, Dectin-1 results in optimal immune responses in collaboration with other PRRs, but the overall evaluation reinforces the hypothesis of disease development on dis-regulation of Dectin-1 activity. This underscores the impact of Dectin-1 polymorphisms in modulating protein expression and generation of non-optimal immune responses through defective collaborations, further underlining their therapeutic potential. To add on, Dectin-1 influence autoimmunity and severe inflammation accredited to recognition of self T cells and apoptotic cells through unknown ligands. Few reports have also testified its redundant role in infections, which makes it a complicated molecule to be fully resolved. Thus, Dectin-1 is a hub that runs a complex collaborative network, whose interactive wire connections to different PRRs are still pending to be revealed. Alternatively, so far focus of almost all the researchers was the two major cell surface isoforms of Dectin-1, despite the fact that its soluble functional intracellular isoform (Dectin-1E) has already been dissected but is indefinable. Therefore, this review intensely recommends the need of future research to resolve the un-resolved and treasure the comprehensive role of Dectin-1 in different clinical outcomes, before determining its therapeutic prospective.

Characterizing T cell subsets in the nasal mucosa of children with acute respiratory symptoms.

BACKGROUND: In infants admitted to an ICU with respiratory failure, there is an association between the ratio of CD8+ to CD4+ T cells within the upper respiratory tract and disease severity. Whether this ratio is associated with respiratory disease severity within children presenting to a pediatric emergency department is not known. METHODS: We studied a convenience sample of 63 children presenting to a pediatric emergency department with respiratory symptoms. T cell subsets in the nasal mucosa were analyzed by flow cytometry. We compared CD4+ and CD8+ T cells subsets in these samples and analyzed the proportion of these subsets that expressed markers associated with tissue residency. RESULTS: We were able to identify major subsets of CD8 and CD4 T cells within the nasal mucosa using flocked swabs. We found no difference in the ratio CD8+ to CD4+ T cells in children with upper or lower respiratory illness. A positive association between tissue-resident memory T cell frequency and patient age was identified. CONCLUSIONS: In our patient populations, the CD8+:CD4+ ratio was not associated with disease severity. The majority of T cells collected on nasal swabs are antigen experienced, and there is an association between the frequency of tissue-resident T cells and age. IMPACT: Immune cell populations from the nasal mucosa can be captured using flocked nasal swabs and analyzed by flow cytometry. Nasal CD8+:CD4+ ratio does not predict respiratory illness severity in children presenting to the emergency department. The frequency of CD8+ and CD4+ resident memory T cells within the nasal mucosa increases with age.

Targeting eosinophils in respiratory diseases: Biological axis, emerging therapeutics and treatment modalities.

Eosinophils are bi-lobed, multi-functional innate immune cells with diverse cell surface receptors that regulate local immune and inflammatory responses. Several inflammatory and infectious diseases are triggered with their build up in the blood and tissues. The mobilization of eosinophils into the lungs is regulated by a cascade of processes guided by Th2 cytokine generating T-cells. Recruitment of eosinophils essentially leads to a characteristic immune response followed by airway hyperresponsiveness and remodeling, which are hallmarks of chronic respiratory diseases. By analysing the dynamic interactions of eosinophils with their extracellular environment, which also involve signaling molecules and tissues, various therapies have been invented and developed to target respiratory diseases. Having entered clinical testing, several eosinophil targeting therapeutic agents have shown much promise and have further bridged the gap between theory and practice. Moreover, researchers now have a clearer understanding of the roles and mechanisms of eosinophils. These factors have successfully assisted molecular biologists to block specific pathways in the growth, migration and activation of eosinophils. The primary purpose of this review is to provide an overview of the eosinophil biology with a special emphasis on potential pharmacotherapeutic targets. The review also summarizes promising eosinophil-targeting agents, along with their mechanisms and rationale for use, including those in developmental pipeline, in clinical trials, or approved for other respiratory disorders.

Obesity, malnutrition, and trace element deficiency in the coronavirus disease (COVID-19) pandemic: An overview.

The world is currently facing the coronavirus disease (COVID-19) pandemic which places great pressure on health care systems and workers, often presents with severe clinical features, and sometimes requires admission into intensive care units. Derangements in nutritional status, both for obesity and malnutrition, are relevant for the clinical outcome in acute illness. Systemic inflammation, immune system impairment, sarcopenia, and preexisting associated conditions, such as respiratory, cardiovascular, and metabolic diseases related to obesity, could act as crucial factors linking nutritional status and the course and outcome of COVID-19. Nevertheless, vitamins and trace elements play an essential role in modulating immune response and inflammatory status. Overall, evaluation of the patient's nutritional status is not negligible for its implications on susceptibility, course, severity, and responsiveness to therapies, in order to perform a tailored nutritional intervention as an integral part of the treatment of patients with COVID-19. The aim of this study was to review the current data on the relevance of nutritional status, including trace elements and vitamin status, in influencing the course and outcome of the disease 3 mo after the World Health Organization's declaration of COVID-19 as a pandemic.

Amelioration of airway inflammation and pulmonary edema by Teucrium stocksianum via attenuation of pro-inflammatory cytokines and up-regulation of AQP1 and AQP5.

Current study investigates the immunomodulatory effects of T. stocksianum using mouse model of ovalbumin (OVA)-induced allergic asthma. The mice were treated with methanolic extract, n-hexane, and ethyl acetate fractions for consecutive 7 days along with intranasal challenge. The mRNA expression levels of interleukin-4 (IL-4), IL-5, Aquaporin-1 (AQP1) and Aquaporin-5 (AQP5) were evaluated using reverse transcription polymerase chain reaction. The data showed that T. stocksianum significantly reduced airway inflammation as indicated by reduced inflammatory cell infiltration in lungs, and attenuated total and differential leukocyte counts both in blood and BALF. Expression levels of pro-inflammatory IL-4 and IL-5 in lungs were also found significantly reduced. T. stocksianum significantly reduced pulmonary edema as indicated by reduced lung wet/dry ratio and goblet cell hyperplasia. AQP1 and AQP5 expression levels were also found elevated in treatment groups. In conclusion, T. stocksianum possesses anti-asthmatic activity which may be attributed to reduction in IL-4 and IL-5 expression levels, and elevation in AQP1 and AQP5 expression levels.

Carvone Enantiomers Differentially Modulate IgE-Mediated Airway Inflammation in Mice.

Carvone is a monoterpene found in nature in the form of enantiomers (S- and R-). While previous research has demonstrated the anti-inflammatory and anti-allergic effects of carvone, the influence of carvone enantiomeric composition on its anti-allergic activity remains to be investigated. This study aimed to evaluate the anti-allergic activity of carvone enantiomers in a murine model of airway allergic inflammation induced by sensitization and challenge with ovalbumin (OVA). The oral treatment with R-carvone or S-carvone 1 h before each challenge inhibited the number of leukocytes and eosinophils in the bronchoalveolar lavage (BAL). R-carvone inhibited leukocyte infiltration and mucus production in the lung, which was correlated with decreased production of OVA-specific IgE in the serum and increased concentrations of IL-10 in the BAL. On the other hand, the administration of S-carvone had little inhibitory effect on inflammatory infiltration and mucus production in the lung, which might be associated with increased production of IFN-γ in the BAL. When administered 1 h before each sensitization, both enantiomers inhibited eosinophil recruitment to the BAL but failed in decreasing the titers of IgE in the serum of allergic mice. Our data indicate that carvone enantiomers differentially modulated IgE-mediated airway inflammation in mice. In conclusion, unlike S-carvone, R-carvone has the potential to be used in anti-allergic drug development.