Impaired Innate Immune Responses Research Articles

Metapopulation model of phage therapy of an acute Pseudomonas aeruginosa lung infection.

Phage therapy is increasingly employed as a compassionate treatment for severe infections caused by multidrug-resistant (MDR) bacteria. However, the mixed outcomes observed in larger clinical studies highlight a gap in understanding when phage therapy succeeds or fails. Previous research from our team, using in vivo experiments and single-compartment mathematical models, demonstrated the synergistic clearance of acute P. aeruginosa pneumonia by phage and neutrophils despite the emergence of phage-resistant bacteria. In fact, the lung environment is highly structured, prompting the question of whether immunophage synergy explains the curative treatment of P. aeruginosa when incorporating realistic physical connectivity. To address this, we developed a metapopulation network model mimicking the lung branching structure to assess phage therapy efficacy for MDR P. aeruginosa pneumonia. The model predicts the synergistic elimination of P. aeruginosa by phage and neutrophils but emphasizes potential challenges in spatially structured environments, suggesting that higher innate immune levels may be required for successful bacterial clearance. Model simulations reveal a spatial pattern in pathogen clearance where P. aeruginosa are cleared faster at distal nodes of the bronchial tree than in primary nodes. Interestingly, image analysis of infected mice reveals a concordant and statistically significant pattern: infection intensity clears in the bottom before the top of the lungs. The combined use of modeling and image analysis supports the application of phage therapy for acute P. aeruginosa pneumonia while emphasizing potential challenges to curative success in spatially structured in vivo environments, including impaired innate immune responses and reduced phage efficacy.

Immunopathogenesis of Lung in Fatal COVID-19 Cases in Erbil, Iraq

Coronavirus disease 2019 (COVID-19) infection is caused by severe acute respiratory syndrome coronavirus-2 (SARS-Cov-2). It is characterized by respiratory distress, multiorgan dysfunction and death in some cases. The host immune response to SARS-CoV-2 appears to play a critical role in disease pathogenesis and clinical manifestation. However the pathological mechanism underling the disease has not been fully defined. Lung autopsy samples from 3 patients with fatal COVID-19 were evaluated using hematoxylin and eosin stain to analyze the histopathological changes. While immunohistochemical (IHC) staining was performed for detecting CD4 in helper T-cells, CD8 in cytotoxic T-cells, CD56 in NK-cells and CD45RO in memory T-cells. Histopathological examination revealed features of diffuse alveolar damage (DAD) with exudate in alveolar space and infiltration of inflammatory cells. Immunohistochemistry staining for CD4 showed weak to positive staining, CD8 showed weak positive staining, CD56 showed negative staining, while CD45RO showed a positive staining. It can be concluded that SARS-CoV-2 virus impaired innate immune response through a decrease in NK cells and adaptive immune response through a decrease in CD8 T cells which is one of the explanations of the destructive nature of SARS-CoV-2 virus.

Age-related dysregulation of CXCL9/10 in monocytes is linked to impaired innate immune responses in a mouse model of Staphylococcus aureus osteomyelitis

BackgroundAge-associated impairments in innate immunity are believed to be a causative factor responsible for severe pathogenesis of Staphylococcus aureus (S. aureus) infection in the bone tissue. However, the basis for age-associated decline in innate immune response upon S. aureus infection remains poorly understood.ResultsOur transcriptional data (GEO: GSE166522) from a mouse model of S. aureus osteomyelitis show up-regulated CXCL9 and CXCL10 (CXCL9/10), which is further confirmed in vitro and in vivo by the present study. Notably, monocytes are a main source for CXCL9/10 production in bone marrow upon S. aureus challenge, but this response declines in middle-aged mice. Interestingly, conditional medium of bone marrow monocytes from middle-aged mice has a strikingly decreased effect on bactericidal functions of neutrophils and macrophages compares with that from young mice. We further show that activation of CXCL9/10-CXCR3 axis between monocytes and macrophages/neutrophils promotes the bactericidal function of the cells, whereas blocking the axis impairs such function. Importantly, treatment with either exogenous CXCL9 or CXCL10 in a middle-aged mice model enhances, while pharmacological inhibition of CXCR3 in young mice model impairs, bacterial clearance and bone marrow structure.ConclusionsThese findings demonstrate that bone marrow monocytes act as a critical promotor of innate immune response via the CXLCL9/10-CXCR3 axis upon S. aureus infection, and that the increased susceptibility to S. aureus infection in skeleton in an aged host may be largely attributable to the declined induction of CXCR9/10 in monocytes.

Diabetes and Infectious Diseases with a Focus on Melioidosis.

Diabetes mellitus (DM) leads to impaired innate and adaptive immune responses. This renders individuals with DM highly susceptible to microbial infections such as COVID-19, tuberculosis and melioidosis. Melioidosis is a tropical disease caused by the bacterial pathogen Burkholderia pseudomallei, where diabetes is consistently reported as the most significant risk factor associated with the disease. Type-2 diabetes is observed in 39% of melioidosis patients where the risk of infection is 13-fold higher than non-diabetic individuals. B. pseudomallei is found in the environment and is an opportunistic pathogen in humans, often exhibiting severe clinical manifestations in immunocompromised patients. The pathophysiology of diabetes significantly affects the host immune responses that play a critical role in fighting the infection, such as leukocyte and neutrophil impairment, macrophage and monocyte inhibition and natural killer cell dysfunction. These defects result in delayed recruitment as well as activation of immune cells to target the invading B. pseudomallei. This provides an advantage for the pathogen to survive and adapt within the immunocompromised diabetic patients. Nevertheless, knowledge gaps on diabetes-infectious disease comorbidity, in particular, melioidosis-diabetes comorbidity, need to be filled to fully understand the dysfunctional host immune responses and adaptation of the pathogen under diabetic conditions to guide therapeutic options.

Whole-blood transcriptome analysis reveals distinct gene expression signatures in paediatric patients with sickle cell anaemia before and after exercise.

Sickle cell anaemia (SCA) patients display elevated levels of circulating pro-inflammatory cytokines and endothelial activation markers compared to healthy peers. The impact of exercise on the pro-inflammatory state in SCA remains unclear. This study aimed to characterize the whole-blood transcriptome profile in response to an acute bout of exercise in paediatric SCA patients. Twenty-three SCA participants (13 ± 3 years, 52% girls) and 17 healthy controls (14 ± 3 years, 29% girls) performed eight 2-min bouts of cycle ergometry interspersed with 1-min rest intervals. Whole-blood transcriptome profile (RNA-seq) was performed before and after exercise. At baseline, gene pathways associated with gas transport in erythrocytes were up-regulated in SCA patients compared to controls. Following exercise, gene pathways associated with innate immunity were altered in both groups. Interaction analyses revealed 160 annotated genes (101 up- and 59 down-regulated) that differentially altered by exercise in SCA patients. Moreover, genes that exhibited a blunted response to exercise in SCA patients were enriched in the IL-17 signalling pathway, suggesting an impaired innate immune response to exercise. This data will contribute to the development of evidence-based exercise prescription guidelines for this patient population.

Brain hypothyroidism silences the immune response of microglia in Alzheimer's disease animal model.

Thyroid hormone (TH) imbalance is linked to the pathophysiology of reversible dementia and Alzheimer's disease (AD). It is unclear whether tissue hypothyroidism occurs in the AD brain and how it affects on AD pathology. We find that decreased iodothyronine deiodinase 2 is correlated with hippocampal hypothyroidism in early AD model mice before TH alterations in the blood. TH deficiency leads to spontaneous activation of microglia in wild-type mice under nonstimulated conditions, resulting in lowered innate immune responses of microglia in response to inflammatory stimuli or amyloid-β. In AD model mice, TH deficiency aggravates AD pathology by reducing the disease-associated microglia population and microglial phagocytosis. We find that TH deficiency reduces microglial ecto-5'-nucleotidase (CD73) and inhibition of CD73 leads to impaired innate immune responses in microglia. Our findings reveal that TH shapes microglial responses to inflammatory stimuli including amyloid-β, and brain hypothyroidism in early AD model mice aggravates AD pathology by microglial dysfunction.

Impaired innate and adaptive immune responses to BNT162b2 SARS-CoV-2 vaccination in systemic lupus erythematosus.

Understanding the immune responses to SARS-CoV-2 vaccination is critical to optimizing vaccination strategies for individuals with autoimmune diseases, such as systemic lupus erythematosus (SLE). Here, we comprehensively analyzed innate and adaptive immune responses in 19 patients with SLE receiving a complete 2-dose Pfizer-BioNTech mRNA vaccine (BNT162b2) regimen compared with a control cohort of 56 healthy control (HC) volunteers. Patients with SLE exhibited impaired neutralizing antibody production and antigen-specific CD4+ and CD8+ T cell responses relative to HC. Interestingly, antibody responses were only altered in patients with SLE treated with immunosuppressive therapies, whereas impairment of antigen-specific CD4+ and CD8+ T cell numbers was independent of medication. Patients with SLE also displayed reduced levels of circulating CXC motif chemokine ligands, CXCL9, CXCL10, CXCL11, and IFN-γ after secondary vaccination as well as downregulation of gene expression pathways indicative of compromised innate immune responses. Single-cell RNA-Seq analysis reveals that patients with SLE showed reduced levels of a vaccine-inducible monocyte population characterized by overexpression of IFN-response transcription factors. Thus, although 2 doses of BNT162b2 induced relatively robust immune responses in patients with SLE, our data demonstrate impairment of both innate and adaptive immune responses relative to HC, highlighting a need for population-specific vaccination studies.

Lipoprotein signal peptidase-deficient Streptococcus pneumoniae exhibits impaired Toll-like receptor 2-stimulatory activity.

Streptococcus pneumoniae is a causative agent of community-acquired pneumonia. Upon pneumococcal infection, innate immune cells recognize pneumococcal lipoproteins via Toll-like receptor 2and induce inflammation. Here, we generated a strain of S. pneumoniae deficient in lipoprotein signal peptidase (LspA), a transmembrane type II signal peptidase required for lipoprotein maturation, to investigate the host immune response against this strain. Triton X-114 phase separation revealed that lipoprotein expression was lower in the LspA-deficient strain than in the wild-type strain. Additionally, the LspA-deficient strain decreased nuclear factor-κB activation and cytokine production in THP-1 cells, indicating impaired innate immune response against the strain.

Инфекционные заболевания у пациентов с сахарным диабетом: обзор литературы

Diabetes mellitus is associated with increased susceptibility to infectious diseases. This is due to the fact that uncontrolled hyperglycemia is accompanied by impaired innate and adaptive immune response, micro- and macroangiopathies, neuropathy, and decreased urine antibacterial activity. Furthermore, complications of diabetes mellitus such as neuropathy and peripheral vascular disease can lead to skin ulceration with secondary bacterial infections. Bacteria can invade any organ of the human body, with the most common foci of infection in diabetes mellitus being the urinary tract, respiratory tract, skin, and soft tissues. Some infectious diseases are specific to patients with diabetes mellitus, such as malignant external otitis media, foot infections, and nasopharyngeal mucormycosis. Infectious processes may be the first manifestations of diabetes mellitus or provoking factors for inherent complications such as diabetic ketoacidosis and hypoglycemia. Glucose control can be an alternative tool in infection control not only in patients with diabetes mellitus. In addition, controlling hyperglycemia offers the potential to improve the outcome of some infectious diseases.

Cellular iron governs the host response to malaria.

Malaria and iron deficiency are major global health problems with extensive epidemiological overlap. Iron deficiency-induced anaemia can protect the host from malaria by limiting parasite growth. On the other hand, iron deficiency can significantly disrupt immune cell function. However, the impact of host cell iron scarcity beyond anaemia remains elusive in malaria. To address this, we employed a transgenic mouse model carrying a mutation in the transferrin receptor (TfrcY20H/Y20H), which limits the ability of cells to internalise iron from plasma. At homeostasis TfrcY20H/Y20H mice appear healthy and are not anaemic. However, TfrcY20H/Y20H mice infected with Plasmodium chabaudi chabaudi AS showed significantly higher peak parasitaemia and body weight loss. We found that TfrcY20H/Y20H mice displayed a similar trajectory of malaria-induced anaemia as wild-type mice, and elevated circulating iron did not increase peak parasitaemia. Instead, P. chabaudi infected TfrcY20H/Y20H mice had an impaired innate and adaptive immune response, marked by decreased cell proliferation and cytokine production. Moreover, we demonstrated that these immune cell impairments were cell-intrinsic, as ex vivo iron supplementation fully recovered CD4+ T cell and B cell function. Despite the inhibited immune response and increased parasitaemia, TfrcY20H/Y20H mice displayed mitigated liver damage, characterised by decreased parasite sequestration in the liver and an attenuated hepatic immune response. Together, these results show that host cell iron scarcity inhibits the immune response but prevents excessive hepatic tissue damage during malaria infection. These divergent effects shed light on the role of iron in the complex balance between protection and pathology in malaria.

MicroRNA 205-5p and COVID-19 adverse outcomes: Potential molecular biomarker and regulator of the immune response.

Coronavirus disease 2019 (COVID-19) is an acute respiratory infection caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The uncontrolled systemic inflammatory response, resulting from the release of large amounts of pro-inflammatory cytokines, is the main mechanism behind severe acute respiratory syndrome and multiple organ failure, the two main causes of death in COVID-19. Epigenetic mechanisms, such as gene expression regulation by microRNAs (miRs), may be at the basis of the immunological changes associated with COVID-19. Therefore, the main objective of the study was to evaluate whether the expression of miRNAs upon hospital admission could predict the risk of fatal COVID-19. To evaluate the level of circulating miRNAs, we used serum samples of COVID-19 patients collected upon hospital admission. Screening of differentially expressed miRNAs in fatal COVID-19 was performed by miRNA-Seq and the validation of miRNAs by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The Mann-Whitney test and receiver operating characteristic (ROC) curve were used to validate the miRNAs, whose potential signaling pathways and biological processes were identified through an in silico approach. A cohort of 100 COVID-19 patients was included in this study. By comparing the circulating levels of miRs between survivors and patients who died due to complications of the infection, we found that the expression of miR-205-5p was increased in those who died during hospitalization, and the expression of both miR-205-5p (area under the curve [AUC] = 0.62, 95% confidence interval [CI] = 0.5-0.7, P = 0.03) and miR-206 (AUC = 0.62, 95% CI = 0.5-0.7, P = 0.03) was increased in those who lately evolved to severe forms of the disease (AUC = 0.70, 95% CI = 0.6-0.8, P = 0.002)."In silico" analysis revealed that miR-205-5p has the potential to enhance the activation of NLPR3 inflammasome and to inhibit vascular endothelial growth factor (VEGF) pathways. Impaired innate immune response against SARS-CoV-2 may be explained by epigenetic mechanisms, which could form early biomarkers of adverse outcomes.

Memory Th17 cell-mediated protection against lethal secondary pneumococcal pneumonia following influenza infection.

Streptococcus pneumoniae (Sp) frequently causes secondary pneumonia after influenza A virus (IAV) infection, leading to high morbidity and mortality worldwide. Concomitant pneumococcal and influenza vaccination improves protection against coinfection but does not always yield complete protection. Impaired innate and adaptive immune responses have been associated with attenuated bacterial clearance in influenza virus-infected hosts. In this study, we showed that preceding low-dose IAV infection caused persistent Sp infection and suppression of bacteria-specific T-helper type 17 (Th17) responses in mice. Prior Sp infection protected against subsequent IAV/Sp coinfection by improving bacterial clearance and rescuing bacteria-specific Th17 responses in the lungs. Furthermore, blockade of IL-17A by anti-IL-17A antibodies abrogated the protective effect of Sp preinfection. Importantly, memory Th17 responses induced by Sp preinfection overcame viral-driven Th17 inhibition and provided cross-protection against different Sp serotypes following coinfection with IAV. These results indicate that bacteria-specific Th17 memory cells play a key role in providing protection against IAV/Sp coinfection in a serotype-independent manner and suggest that a Th17-based vaccine would have excellent potential to mitigate disease caused by coinfection. IMPORTANCE Streptococcus pneumoniae (Sp) frequently causes secondary bacterial pneumonia after influenza A virus (IAV) infection, leading to increased morbidity and mortality worldwide. Current pneumococcal vaccines induce highly strain-specific antibody responses and provide limited protection against IAV/Sp coinfection. Th17 responses are broadly protective against Sp single infection, but whether the Th17 response, which is dramatically impaired by IAV infection in naïve mice, might be effective in immunization-induced protection against pneumonia caused by coinfection is not known. In this study, we have revealed that Sp-specific memory Th17 cells rescue IAV-driven inhibition and provide cross-protection against subsequent lethal coinfection with IAV and different Sp serotypes. These results indicate that a Th17-based vaccine would have excellent potential to mitigate disease caused by IAV/Sp coinfection.

Genotype 4 Hepatitis E virus replicates in the placenta, causes severe histopathological damage, and vertically transmits to fetuses

Hepatitis E virus (HEV) infection in pregnant women causes adverse pregnancy outcomes, including maternal death, premature delivery, stillbirth, and fetal infection. However, the pathogenesis of maternal and fetal HEV infection is unclear. Placenta and placental appendixes were collected from HEV-4 infected pregnant women to explore the vertical transmission of HEV from mothers to fetuses. HEV-4 replicated in the placenta, placental membrane, and umbilical cord and was vertically transmitted from mothers to fetuses. HEV-4 placental infection resulted in serious histopathological damage, such as fibrosis and calcification, and severe inflammatory responses. Adverse maternal outcomes were observed in 38.5% of HEV-4 infected pregnant women. The distinct cytokine/chemokine expression patterns of HEV-infected pregnant women and nonpregnant women may contribute to the adverse pregnancy outcomes. Furthermore, the impaired maternal and fetal innate immune responses against HEV-4 facilitated viral replication during pregnancy. HEV-4 replicates in the placenta and is vertically transmitted from mothers to fetuses, causing severe histopathological damage.

Effects of Atherogenic Factors on Endothelial Cells: Bioinformatics Analysis of Differentially Expressed Genes and Signaling Pathways.

(1) Background: Atherosclerosis is a serious medical condition associated with high morbidity and mortality rates. It develops over many years as a complex chain of events in the vascular wall involving various cells and is influenced by many factors of clinical interest. (2) Methods: In this study, we performed a bioinformatic analysis of Gene Expression Omnibus (GEO) datasets to investigate the gene ontology of differentially expressed genes (DEGs) in endothelial cells exposed to atherogenic factors such as tobacco smoking, oscillatory shear, and oxidized low-density lipoproteins (oxLDL). DEGs were identified using the limma R package, and gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, and protein-protein interaction (PPI) network analysis were performed. (3) Results: We studied biological processes and signaling pathways involving DEGs in endothelial cells under the influence of atherogenic factors. GO enrichment analysis demonstrated that the DEGs were mainly involved in cytokine-mediated signaling pathway, innate immune response, lipid biosynthetic process, 5-lipoxygenase activity, and nitric-oxide synthase activity. KEGG pathway enrichment analysis showed that common pathways included tumor necrosis factor signaling pathway, NF-κB signaling pathway, NOD-like receptor signaling pathway, lipid and atherosclerosis, lipoprotein particle binding, and apoptosis. (4) Conclusions: Atherogenic factors such as smoking, impaired flow, and oxLDL contribute to impaired innate immune response, metabolism, and apoptosis in endothelial cells, potentially leading to the development of atherosclerosis.

THE ROLE OF AUTOPHAGY IN THE REGULATION OF NEUROINFLAMMATION IN ACUTE ISCHEMIC STROKE (REVIEW OF LITERATURE)

Postischemic neuroinflammation is a critical pathophysiological process within the entire scheme of cerebral ischemia, covering early damage and the period of tissue repair. It is characterized by microglial and astroglial activation with increased expression of inflammatory mediators and is accompanied by impaired innate and adaptive immune responses. In acute ischemic stroke (IS), neuroinflammation is caused by the response of resident immune cells of microglia and peripheral immunocompetent cells infiltrating the brain tissue, which penetrate the blood-brain barrier (BBB) into the lesion. Recent studies have shown the important role of the NLRP3-mediated inflammation in the death of neurons and glial cells in acute IS. The review presents the main mechanisms of activation of NLRP3-mediated inflammation in acute IS, leading to the caspase-1 formation and the IL-1β and IL-18 release, which are involved in the initiation and progression of inflammation in the brain parenchyma. The literature data on the role of autophagy in the inhibition of postischemic neuroinflammation are summarized. Autophagy can suppress neuroinflammation through a wide range of the autophagy - related proteins. The role of autophagy as a negative regulator of NLRP3-mediated inflammation in acute IS is analyzed. Data on the participation of autophagic proteins Beclin-1, LC3, and p62 in the suppression of NLRP3 inflammation due to the induction of basic mitophagy are presented. Prospects for modulating autophagy aimed at suppressing postischemic neuroinflammation, including the inhibition of NLRP3-inflammasome, have been noted. The review was based on sources from international and national data bases: Scopus, Web of Science, Springer, RINC.

Risk Factors for Respiratory Viral Infections: A Spotlight on Climate Change and Air Pollution.

Climate change has both direct and indirect effects on human health, and some populations are more vulnerable to these effects than others. Viral respiratory infections are most common illnesses in humans, with estimated 17 billion incident infections globally in 2019. Anthropogenic drivers of climate change, chiefly the emission of greenhouse gases and toxic pollutants from burning of fossil fuels, and the consequential changes in temperature, precipitation, and frequency of extreme weather events have been linked with increased susceptibility to viral respiratory infections. Air pollutants like nitrogen dioxide, particulate matter, diesel exhaust particles, and ozone have been shown to impact susceptibility and immune responses to viral infections through various mechanisms, including exaggerated or impaired innate and adaptive immune responses, disruption of the airway epithelial barrier, altered cell surface receptor expression, and impaired cytotoxic function. An estimated 90% of the world's population is exposed to air pollution, making this a topic with high relevance to human health. This review summarizes the available epidemiologic and experimental evidence for an association between climate change, air pollution, and viral respiratory infection.

2160. Mucosal Antiviral Cytokine Responses Are Impaired in Children and Adolescents with Severe COVID-19

Abstract Background The factors associated with severe COVID-19 in pediatric patients remain poorly understood. We sought to determine whether mucosal innate immunity cytokines were associated with disease severity in children and adolescents with acute COVID-19. Methods Single-center, prospective study including children and adolescents < 21 years of age hospitalized because of symptomatic COVID-19 from 3/2020 to 1/2021, and age, sex and race matched pre-pandemic (2016-2019) healthy controls. Nasopharyngeal (NP) samples were obtained at enrollment for measurement of SARS-CoV-2 viral loads by rt-PCR and cytokine concentrations using a 92-plex inflammation/antiviral panel (Olink). Disease severity was assessed by the need for supplemental oxygen or PICU admission, and patients classified as severe and non-severe based on these two parameters. Statistical analyses were performed in R studio and Benjamini-Hochberg applied to adjust for multiple comparisons. Results Of the 75 children with acute COVID-19 (median IQR age: 3.4 [0.2-15.3] years), 28 (37%) were classified as severe COVID-19 (19 PICU; 25 supplemental oxygen) and 47 (63%) were non-severe. Children with severe COVID-19 were predominantly male and had an underlying condition more frequently than those with non-severe disease (79% vs 49% respectively; p< 0.01, Table 1). SARS-CoV-2 viral loads were comparable between groups, yet patients with severe COVID-19 had significantly higher concentrations of C-reactive protein (p=0.04), more frequent lymphopenia (p=0.03) and cardiac involvement (p=0.04), and received COVID-19 directed therapies more commonly (p< 0.001). Comparative analyses identified 24 cytokines that were significantly different between children with acute COVID-19 versus 45 healthy controls. Of those, concentrations of IFN-γ (p=0.004), CXCL10 (p=0.01), CXCL11 (p=0.02) and CCL19 (p=0.02) were significantly lower in children with severe versus those with non-severe COVID-19 (Fig 1). Table 1.Demographic and clinical characteristics in children with symptomatic COVID-19*Bolded p-values indicates statistical significance. Abbreviations: N, number. CRP, C-Reactive protein; PICU, pediatric intensive care unit.**Other including the following underlying conditions: prematurity, endocrine conditions, immunocompromising conditions, prematurity, trisomy 21 and complex care. Ł Lymphopenia defined as an ALC of <4,500 cells/μl in infants, and <1,500 cells /μl in children >12 months of age Continuous variables displayed as medians and 25%-75% interquartile ranges (IQR), Mann-Whitney test was used to determine differences between two groups; Kruskal-Wallis & Dunn’s multiple test correction was used to determine differences between three groups (p-values*). Categorical data expressed as numbers and proportions (in parenthesis) and analyzed by Fisher’s exact test or Chi square test. Figure 1.Nasal mucosal concentrations of antiviral/regulatory cytokines in children with symptomatic COVID-19 according to disease severity Conclusion Mucosal concentrations of antiviral/regulatory cytokines were decreased in children with severe COVID-19. These findings suggest that impaired mucosal innate immune responses might favor SARS-CoV-2 disease progression and severity in children. Disclosures Amy Leber, PhD, BioFire: Advisor/Consultant|BioFire: Grant/Research Support|Biorad: Advisor/Consultant|Cepheid: Grant/Research Support Octavio Ramilo, MD, Adagio: Advisor/Consultant|Bill & Melinda Gates Foundation: Grant/Research Support|Janssen: Advisor/Consultant|Janssen: Grant/Research Support|Lilly: Advisor/Consultant|Merck: Advisor/Consultant|Merck: Grant/Research Support|NIH: Grant/Research Support|Pfizer: Advisor/Consultant|Pfizer: Honoraria|Sanofi: Advisor/Consultant|Sanofi: Honoraria Asuncion Mejias, MD, PhD, MsCS, AstraZeneca: Honoraria|Janssen: Advisor/Consultant|Janssen: Grant/Research Support|Merck: Advisor/Consultant|Merck: Grant/Research Support|Roche: Advisor/Consultant|Sanofi-Pasteur: Advisor/Consultant|Sanofi-Pasteur: Honoraria.

Diminished antiviral innate immune gene expression in the placenta following a maternal SARS-CoV-2 infection

BackgroundCoronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and is associated with critical illness requiring hospitalization, maternal mortality, stillbirth, and preterm birth. SARS-CoV-2 has been shown to induce placental pathology, however, substantial gaps exist in our understanding of the pathophysiology of COVID-19 disease in pregnancy and the long-term impact of SARS-CoV-2 on the placenta and fetus. To what extent a SARS-CoV-2 infection of the placenta alters the placental antiviral innate immune response is not well understood. A dysregulated innate immune response in the setting of maternal COVID-19 disease may increase risk for inflammatory tissue injury or placental compromise and contribute to deleterious pregnancy outcomes.ObjectiveWe sought to determine the impact of a maternal SARS-CoV-2 infection on placental immune response by evaluating gene expression of a panel of six antiviral innate immune mediators that act as biomarkers of the antiviral and interferon cytokine response. Our hypothesis was that a SARS-CoV-2 infection during pregnancy would result in an upregulated placental antiviral innate immune response.Study DesignWe performed a case control study on placental tissues [chorionic villous (CV) tissues and chorioamniotic membrane (CAM)] collected from pregnant patients with (N=140) and without (N=24) COVID-19 disease. We performed real-time quantitative polymerase chain reaction (qPCR) and immunohistochemistry. Placental histopathology was evaluated. Clinical data was abstracted. Fisher’s exact test, Pearson correlations, and linear regression models were used to examine proportions and continuous data between patients with active (<10 days since diagnosis) versus recovered COVID-19 (>10 days since diagnosis) at time of delivery. Secondary regression models adjusted for labor status as a covariate and evaluated potential correlation between placental innate immune gene expression and other variables.ResultsSARS-CoV-2 vRNA was detected in placental tissues from 5 women with COVID-19 and from no controls (0/24, 0%). Only 1 of 5 cases with detectable SARS-CoV-2 vRNA in placental tissues was confirmed to express SARS-CoV-2 nucleocapsid and spike proteins in syncytiotrophoblast cells. We detected a significantly lower gene expression of five critical innate immune mediators (IFNB, IFIT1, MXA, IL6, IL1B) in CV and CAM from women with active or recovered COVID-19 compared to controls, which remained significant after adjustment for labor status. There were minimal correlations between placental gene expression and other studied variables including: gestational age at diagnosis, time interval from COVID-19 diagnosis and delivery, pre-pregnancy body mass index, COVID-19 disease severity or placental pathology.ConclusionA maternal SARS-CoV-2 infection was associated with an impaired placental innate immune response in chorionic villous tissues and chorioamniotic membranes that was not correlated with gestational age at COVID-19 diagnosis, timer interval from COVID-19 diagnosis to delivery, maternal obesity, disease severity or placental pathology.

Cigarette Smoke Extract Disturbs Mitochondria-Regulated Airway Epithelial Cell Responses to Pneumococci.

Mitochondrial functionality is crucial for the execution of physiologic functions of metabolically active cells in the respiratory tract including airway epithelial cells (AECs). Cigarette smoke is known to impair mitochondrial function in AECs. However, the potential contribution of mitochondrial dysfunction in AECs to airway infection and airway epithelial barrier dysfunction is unknown. In this study, we used an in vitro model based on AECs exposed to cigarette smoke extract (CSE) followed by an infection with Streptococcus pneumoniae (Sp). The levels of oxidative stress as an indicator of mitochondrial stress were quantified upon CSE and Sp treatment. In addition, expression of proteins associated with mitophagy, mitochondrial content, and biogenesis as well as mitochondrial fission and fusion was quantified. Transcriptional AEC profiling was performed to identify the potential changes in innate immune pathways and correlate them with indices of mitochondrial function. We observed that CSE exposure substantially altered mitochondrial function in AECs by suppressing mitochondrial complex protein levels, reducing mitochondrial membrane potential and increasing mitochondrial stress and mitophagy. Moreover, CSE-induced mitochondrial dysfunction correlated with reduced enrichment of genes involved in apical junctions and innate immune responses to Sp, particularly type I interferon responses. Together, our results demonstrated that CSE-induced mitochondrial dysfunction may contribute to impaired innate immune responses to Sp.

Myeloid-Derived Suppressor Cells in COVID-19: The Paradox of Good.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the ongoing coronavirus disease 2019 (COVID-19) pandemic. Viral replication in the respiratory tract induces the death of infected cells and the release of pathogen- associated molecular patterns (PAMPs). PAMPs give rise to local inflammation, increasing the secretion of pro- inflammatory cytokines and chemokines, which attract immune cells from the blood into the infected lung. In most individuals, lung-recruited cells clear the infection, and the immune response retreats. However, in some cases, a dysfunctional immune response occurs, which triggers a cytokine storm in the lung, leading to acute respiratory distress syndrome (ARDS). Severe COVID-19 is characterized by an impaired innate and adaptive immune response and by a massive expansion of myeloid-derived suppressor cells (MDSCs). MDSCs function as protective regulators of the immune response, protecting the host from over-immunoreactivity and hyper-inflammation. However, under certain conditions, such as chronic inflammation and cancer, MDSCs could exert a detrimental role. Accordingly, the early expansion of MDSCs in COVID-19 is able to predict the fatal outcome of the infection. Here, we review recent data on MDSCs during COVID-19, discussing how they can influence the course of the disease and whether they could be considered as biomarker and possible targets for new therapeutic approaches.