Anthony Kicic

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Papers by Anthony Kicic

Real Time Monitoring of Respiratory Viral Infections in Cohort Studies Using a Smartphone App

medRxiv (Cold Spring Harbor Laboratory), Apr 5, 2024

A smartphone app can facilitate capturing symptomatic respiratory viral infections in longitudina... more A smartphone app can facilitate capturing symptomatic respiratory viral infections in longitudinal cohort studies, while supporting adherence and reducing participant burden. The app helped identify community variations in virus prevalence as well as the individual variability in viral responses necessary to understand the mechanism of chronic disease development.

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Influenza Infection Facilitates Allergic Sensitization

In Vitro Airway Epithelial Cell Models Differ in Their Functional Response to Neutrophil Elastase Exposure

Respirology, 2013

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Asthma and unified airways disease through epithelial cells

Progress in Model Systems of Cystic Fibrosis Mucosal Inflammation to Understand Aberrant Neutrophil Activity

Frontiers in Immunology, Apr 7, 2020

In response to recurrent infection in cystic fibrosis (CF), powerful innate immune signals trigge... more In response to recurrent infection in cystic fibrosis (CF), powerful innate immune signals trigger polymorphonuclear neutrophil recruitment into the airway lumen. Exaggerated neutrophil proteolytic activity results in sustained inflammation and scarring of the airways. Consequently, neutrophils and their secretions are reliable clinical biomarkers of lung disease progression. As neutrophils are required to clear infection and yet a direct cause of airway damage, modulating adverse neutrophil activity while preserving their pathogen fighting function remains a key area of CF research. The factors that drive their pathological behavior are still under investigation, especially in early disease when aberrant neutrophil behavior first becomes evident. Here we examine the latest findings of neutrophils in pediatric CF lung disease and proposed mechanisms of their pathogenicity. Highlighted in this review are current and emerging experimental methods for assessing CF mucosal immunity and human neutrophil function in the laboratory.

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Overcoming Biofilm Mediated Respiratory Infections Through Exploitation of Pathogen and Host-Directed Novel Peptides

Respirology, Nov 1, 2018

This was a retrospective observational study, which examined patient medical records with diagnos... more This was a retrospective observational study, which examined patient medical records with diagnosis of community acquired pneumonia (CAP) during hospitalization in the Pulmonary Ward Dr. Soetomo General Hospital from January to December 2016. Outcomes observed includes survival and mortality cases after therapy. Results: There were 569 cases of CAP. Three most common bacteria found were Streptococcus viridans (20.2%), Acinetobacter baumannii (19.4%), and Klebsiella pneumoniae (14.8%). Amikacin, Cefoperazone-Sulbactam, and Meropenem were the most sensitive antibiotic with sensitivity of 87.8%, 81.9%, and 76.3% respectively. There were 79 cases of MDR pathogen involvement. Appropriateness of empirical therapy was found in 162 (41.1%) patients and Fluoroquinolone monotherapy has the highest appropriateness cases with 59.3% (P < 0.001). Survival outcomes was 278 (56.3%), while mortality outcomes was 216 (43.7%) and Fluoroquinolone monotherapy has the highest survival cases in all CAP cases with 90.1% (P < 0.001). In severe CAP cases, initial combination therapy with Betalactam+Aminoglycoside has a better outcomes compared to Betalactam+Fluoroquinolone with survival cases 50.9% vs 27.6% (P = 0.001). There was a relationship between initial antibiotic therapy and therapy outcomes. Initial monotherapy with Fluoroquinolone has the highest survival cases in all patients with CAP. Initial combination therapy with Betalactam+Aminoglycoside has a better outcomes compared to Betalactam+Fluoroquinolone in patients with severe CAP.

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212 Direct Evidence of Chronic Epithelial Injury and Dysregulated Repair in the Lung Allograft

Journal of Heart and Lung Transplantation, Apr 1, 2012

the presentation of EMT with the onset of BOS and triggering clinical events such as acute reject... more the presentation of EMT with the onset of BOS and triggering clinical events such as acute rejection, infections, or GERD, highlighting the potential for inhibition of EMT as a therapeutic target. Methods and Materials: We analyzed over 300 post-transplant transbronchial biopsy specimens from patients at several time points between 3-60 months. Using confocal immunofluorescence imaging, we looked for the onset of co-staining of epithelial and mesenchymal markers such as Ecadherin and Vimentin, or ZO-1 and alpha-SMA in conjunction with clinical data from the same subject. We then assayed bronchial-alveolar lavage (BAL) fluid from the same subset of patients for the presence of pro-EMT cytokines including TGF, TNF, and IL-17. Finally, we cultured primary small airway cells with TGF, TNF, and N-acetylcysteine and assessed the inhibition of EMT markers by immunoblot. Results: We found significantly increased expression of EMT markers in correlation with progressed stage of BOS compared to that of samples taken at stable time points, with the presentation of EMT typically preceding clinically assessed decline in lung function. Pro-EMT cytokines were present in BAL fluid at time points prior to a significant drop in FEV1, which are to be correlated with aggravating clinical episodes. NAC inhibition of EMT resulted in the suppression of mesenchymal Vimentin and Fibronectin but failed to preserve epithelial E-cadherin expression. Conclusions: EMT seems to play a role in the development of BOS, presenting prior to declination of lung function. Myofibroblasts derived via EMT may be the primary source of excess scar tissue occluding the small airways as seen in BOS. Production of pro-EMT cytokines may be aggravated by acute rejection and infection and may further instigate EMT and the progression of BOS. Therapies aimed at inhibiting EMT have the potential to slow the progression of BOS and prolong the life of the transplanted lung.

Pediatric nasal epithelial cells are less permissive to SARS-CoV-2 replication compared to adult cells

bioRxiv (Cold Spring Harbor Laboratory), Mar 8, 2021

Children typically experience more mild symptoms of COVID-19 when compared to adults. There is a ... more Children typically experience more mild symptoms of COVID-19 when compared to adults. There is a strong body of evidence that children are also less susceptible to SARS-CoV-2 infection with the ancestral viral isolate. However, the emergence of SARS-CoV-2 variants of concern (VOCs) has been associated with an increased number of pediatric infections. Whether this is the result of widespread adult vaccination or fundamental changes in the biology of SARS-CoV-2 remains to be determined. Here, we use primary nasal epithelial cells from children and adults, differentiated at an air-liquid interface to show that the ancestral SARS-CoV-2 replicates to significantly lower titers in the nasal epithelial cells of children compared to those of adults. This was associated with a heightened antiviral response to SARS-CoV-2 in the nasal epithelial cells of children. Importantly, the Delta variant also replicated to significantly lower titres in the nasal epithelial cells of children. This trend was markedly less pronounced in the case of Omicron. It is also striking to note that, at least in terms of viral RNA, Omicron replicated better in pediatric NECs compared to both Delta and the ancestral virus. Taken together, these data show that the nasal epithelium of children supports lower infection and replication of ancestral SARS-CoV-2, although this may be changing as the virus evolves.

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Ancestral SARS-CoV-2, but not Omicron, replicates less efficiently in primary pediatric nasal epithelial cells

PLOS Biology, Aug 1, 2022

Children typically experience more mild symptoms of Coronavirus Disease 2019 (COVID-19) when comp... more Children typically experience more mild symptoms of Coronavirus Disease 2019 (COVID-19) when compared to adults. There is a strong body of evidence that children are also less susceptible to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection with the ancestral viral isolate. However, the emergence of SARS-CoV-2 variants of concern (VOCs) has been associated with an increased number of pediatric infections. Whether this is the result of widespread adult vaccination or fundamental changes in the biology of SARS-CoV-2 remain to be determined. Here, we use primary nasal epithelial cells (NECs) from children and adults, differentiated at an air-liquid interface to show that the ancestral SARS-CoV-2 replicates to significantly lower titers in the NECs of children compared to those of adults. This was associated with a heightened antiviral response to SARS-CoV-2 in the NECs of children. Importantly, the Delta variant also replicated to

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Stability Considerations for Bacteriophages in Liquid Formulations Designed for Nebulization

Cells

Pulmonary bacterial infections present a significant health risk to those with chronic respirator... more Pulmonary bacterial infections present a significant health risk to those with chronic respiratory diseases (CRDs) including cystic fibrosis (CF) and chronic-obstructive pulmonary disease (COPD). With the emergence of antimicrobial resistance (AMR), novel therapeutics are desperately needed to combat the emergence of resistant superbugs. Phage therapy is one possible alternative or adjunct to current antibiotics with activity against antimicrobial-resistant pathogens. How phages are administered will depend on the site of infection. For respiratory infections, a number of factors must be considered to deliver active phages to sites deep within the lung. The inhalation of phages via nebulization is a promising method of delivery to distal lung sites; however, it has been shown to result in a loss of phage viability. Although preliminary studies have assessed the use of nebulization for phage therapy both in vitro and in vivo, the factors that determine phage stability during nebulize...

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Ca-EDTA restores the activity of ceftazidime-avibactam or aztreonam against carbapenemase-producing Klebsiella pneumoniae infections

iScience

Multiple traces of monkeypox detected in non-sewered wastewater with sparse sampling from a densely populated metropolitan area in Asia

Science of The Total Environment

Influenza Infection Facilitates Allergen-Specific Responses in Pre-Sensitized Mice

Respirology, 2015

Aim: Respiratory viral infections have been shown to exacerbate asthma. We have previously shown,... more Aim: Respiratory viral infections have been shown to exacerbate asthma. We have previously shown, in mice, that influenza infection increases serum IgE to house dust mite (HDM) via disruption of the epithelial barrier in vivo. In this study, we aimed to assess the effects of influenza infection on allergic airways disease development in pre-sensitized individuals, and secondly to assess whether these responses were allergen specific. Methods: Adult female BALB/c mice were sensitized with OVA/alum on d0 and infected with 104.5pfu of influenza A/Mem/71 (or control) on d7. Mice received a second OVA/alum sensitization on d14 followed by challenge with 1% ovalbumin, 100 μg HDM protein or 1% saline. 24 hours later we assessed responsiveness to methacholine using the forced oscillation technique, serum antibodies and bronchoalveolar inflammation. Results: Inflammation due to influenza infection had completely resolved by the day of study. Mice previously infected with influenza and challe...

Blocking Notch3 Signaling Abolishes MUC5AC Production in Airway Epithelial Cells from Individuals with Asthma

American Journal of Respiratory Cell and Molecular Biology, 2020

In asthma, goblet cell numbers are increased within the airway epithelium, perpetuating the produ... more In asthma, goblet cell numbers are increased within the airway epithelium, perpetuating the production of mucus that is more difficult to clear and results in airway mucus plugging. Notch1, Notch2, or Notch3, or a combination of these has been shown to influence the differentiation of airway epithelial cells. How the expression of specific Notch isoforms differs in fully differentiated adult asthmatic epithelium and whether Notch influences mucin production after differentiation is currently unknown. We aimed to quantify different Notch isoforms in the airway epithelium of individuals with severe asthma and to examine the impact of Notch signaling on mucin MUC5AC. Human lung sections and primary bronchial epithelial cells from individuals with and without asthma were used in this study. Primary bronchial epithelial cells were differentiated at the air-liquid interface for 28 days. Notch isoform expression was analyzed by Taqman quantitative PCR. Immunohistochemistry was used to localize and quantify Notch isoforms in human airway sections. Notch signaling was inhibited in vitro using dibenzazepine or Notch3-specific siRNA, followed by analysis of MUC5AC. NOTCH3 was highly expressed in asthmatic airway epithelium compared with nonasthmatic epithelium. Dibenzazepine significantly reduced MUC5AC production in air-liquid interface cultures of primary bronchial epithelial cells concomitantly with suppression of NOTCH3 intracellular domain protein. Specific knockdown using NOTCH3 siRNA recapitulated the dibenzazepine-induced reduction in MUC5AC. We demonstrate that NOTCH3 is a regulator of MUC5AC production. Increased NOTCH3 signaling in the asthmatic airway epithelium may therefore be an underlying driver of excess MUC5AC production.

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Elastase Exocytosis by Airway Neutrophils Is Associated with Early Lung Damage in Children with Cystic Fibrosis

American Journal of Respiratory and Critical Care Medicine, 2018

Rationale: Neutrophils are recruited to the airways of individuals with cystic fibrosis (CF). In ... more Rationale: Neutrophils are recruited to the airways of individuals with cystic fibrosis (CF). In adolescents and adults with CF, airway neutrophils actively exocytose the primary granule protease elastase (NE), whose extracellular activity correlates with lung damage. During childhood, free extracellular NE activity is measurable only in a subset of patients, and the exocytic function of airway neutrophils is unknown. Objectives: To measure NE exocytosis by airway neutrophils in relation to free extracellular NE activity and lung damage in children with CF. Methods: We measured lung damage using chest computed tomography coupled with the Perth-Rotterdam Annotated Grid Morphometric Analysis for Cystic Fibrosis scoring system. Concomitantly, we phenotyped blood and BAL fluid leukocytes by flow and image cytometry, and measured free extracellular NE activity using spectrophotometric and Förster resonance energy transfer assays. Children with airway inflammation linked to aerodigestive disorder were enrolled as control subjects. Measurements and Main Results: Children with CF but not disease control children harbored BAL fluid neutrophils with high exocytosis of primary granules, before the detection of bronchiectasis. This measure of NE exocytosis correlated with lung damage (R = 0.55; P = 0.0008), whereas the molecular measure of free extracellular NE activity did not. This discrepancy may be caused by the inhibition of extracellular NE by BAL fluid antiproteases and its binding to leukocytes. Conclusions: NE exocytosis by airway neutrophils occurs in all children with CF, and its cellular measure correlates with early lung damage. These findings implicate live airway neutrophils in early CF pathogenesis, which should instruct biomarker development and antiinflammatory therapy in children with CF.

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Editorial: Emerging Therapeutic Approaches for Cystic Fibrosis

Frontiers in Pharmacology, Nov 29, 2019

Cystic fibrosis (CF) is the most common life-shortening inherited disease in Caucasian population... more Cystic fibrosis (CF) is the most common life-shortening inherited disease in Caucasian populations. It affects 90,000 to 100,000 individuals worldwide and results in multi-organ dysfunction, although the respiratory disorder represents the major cause of morbidity and mortality of these patients. Understanding of cellular and molecular defects of CF-causing mutations has substantially improved since the discovery of the CF transmembrane conductance regulator (CFTR) gene in 1989 , bringing perspectives for the development of novel therapies. Up to 2012, therapeutic regimens were exclusively focused on disease symptoms. These comprised of physical and inhaled therapies, and numerous daily medications to enhance airway clearance, mitigate inflammation, eradicate lung infections, and supplement absent pancreatic enzymes. Together with early diagnosis and multidisciplinary healthcare, patients' life expectancy has risen from early childhood in the 1960s to 40 to 50 years in several countries nowadays . From 2012 to date, four drugs targeting the root cause of CF have reached the market: ivacaftor (Kalydeco ™ ), the dual combinations lumacaftor/ivacaftor (Orkambi ™ ) and tezacaftor/ivacaftor (Symdeko ™ ), and the triple combination elexacaftor/tezacaftor/ivacaftor (Trikafta ™ ). In patients carrying specific CF genotypes, these pharmacotherapies have been demonstrating short-and longterm therapeutic outcomes, including improvements in lung function and body mass index, and reduction in detection of Pseudomonas aeruginosa and frequency of pulmonary exacerbations (Ramsey et al.

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Direct Evidence of Chronic Epithelial Injury and Dysregulated Repair in Small and Large Airways of Lung Transplant Patients

Respirology, 2012

Tracing the transmission of mpox through wastewater surveillance in Southeast Asia

Journal of Travel Medicine

High population density and tourism in Southeast Asia increase the risk of mpox due to frequent i... more High population density and tourism in Southeast Asia increase the risk of mpox due to frequent interpersonal contacts. Our wastewater surveillance in six Southeast Asian countries revealed positive signals for Monkeypox virus (MPXV) DNA, indicating local transmission. This alerts clinicians and helps allocate resources like testing, vaccines and therapeutics in resource-limited countries.

COVID-19 monitoring with sparse sampling of sewered and non-sewered wastewater in urban and rural communities

iScience

High prevalence of mgrB-mediated colistin resistance among carbapenem-resistant Klebsiella pneumoniae is associated with biofilm formation, and can be overcome by colistin-EDTA combination therapy

Scientific Reports

The global prevalence of colistin-resistant Klebsiella pneumoniae (ColRkp) facilitated by chromos... more The global prevalence of colistin-resistant Klebsiella pneumoniae (ColRkp) facilitated by chromosomal and plasmid-mediated Ara4N or PEtN-remodeled LPS alterations has steadily increased with increased colistin usage for treating carbapenem-resistant K. pneumoniae (CRkp). Our study demonstrated the rising trend of ColRkp showing extensively and pandrug-resistant characteristics among CRkp, with a prevalence of 28.5%, which was mediated by chromosomal mgrB, pmrB, or phoQ mutations (91.5%), and plasmid-mediated mcr-1.1, mcr-8.1, mcr-8.2 alone or in conjunction with R256G PmrB (8.5%). Several genetic alterations in mgrB (85.1%) with increased expressions of Ara4N-related phoPQ and pmrK were critical for establishing colistin resistance in our isolates. In this study, we discovered the significant associations between extensively drug-resistant bacteria (XDR) and pandrug-resistant bacteria (PDR) ColRkp in terms of moderate, weak or no biofilm-producing abilities, and altered expressions ...

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