-
Frontiers in Immunology 2021Neutrophil extracellular traps (NETs) have been identified as one pathogenetic trigger in severe COVID-19 cases and therefore well-described animal models to understand...
Neutrophil extracellular traps (NETs) have been identified as one pathogenetic trigger in severe COVID-19 cases and therefore well-described animal models to understand the influence of NETs in COVID-19 pathogenesis are needed. SARS-CoV-2 infection causes infection and interstitial pneumonia of varying severity in humans and COVID-19 models. Pulmonary as well as peripheral vascular lesions represent a severe, sometimes fatal, disease complication of unknown pathogenesis in COVID-19 patients. Furthermore, neutrophil extracellular traps (NETs), which are known to contribute to vessel inflammation or endothelial damage, have also been shown as potential driver of COVID-19 in humans. Though most studies in animal models describe the pulmonary lesions characterized by interstitial inflammation, type II pneumocyte hyperplasia, edema, fibrin formation and infiltration of macrophages and neutrophils, detailed pathological description of vascular lesions or NETs in COVID-19 animal models are lacking so far. Here we report different types of pulmonary vascular lesions in the golden Syrian hamster model of COVID-19. Vascular lesions included endothelialitis and vasculitis at 3 and 6 days post infection (dpi), and were almost nearly resolved at 14 dpi. Importantly, virus antigen was present in pulmonary lesions, but lacking in vascular alterations. In good correlation to these data, NETs were detected in the lungs of infected animals at 3 and 6 dpi. Hence, the Syrian hamster seems to represent a useful model to further investigate the role of vascular lesions and NETs in COVID-19 pathogenesis.
Topics: Animals; COVID-19; Cricetinae; Disease Models, Animal; Extracellular Traps; Lung; Mesocricetus; SARS-CoV-2; Vasculitis; Viral Proteins
PubMed: 33912167
DOI: 10.3389/fimmu.2021.640842 -
Antimicrobial Agents and Chemotherapy May 1994The pulmonary residence time of free and liposome-encapsulated tobramycin was studied with uninfected rats and rats infected with Pseudomonas aeruginosa. Chronic...
The pulmonary residence time of free and liposome-encapsulated tobramycin was studied with uninfected rats and rats infected with Pseudomonas aeruginosa. Chronic infection in lungs was established by intratracheal administration of 10(8) CFU of P. aeruginosa PA 508 prepared in agar beads. After 3 days, a single dose (300 micrograms) of free or liposome-encapsulated tobramycin was given intratracheally to both infected and uninfected rats. At various time intervals (0.25 to 16 h) after drug instillations, the remaining tobramycin was evaluated in blood, lungs, and kidneys by a microbiological assay. Intratracheal instillation of liposome-encapsulated tobramycin resulted in high and sustained levels of tobramycin in lungs of uninfected and infected rats over the 16-h period studied; however, the tobramycin levels were two times higher in uninfected rats. There was no tobramycin detected in the blood or kidneys from these animals. In contrast, the intratracheally instilled free tobramycin was cleared within 3 and 1 h from the lungs of uninfected and infected animals, respectively. These data suggest that the encapsulation of tobramycin in liposomes can result in a significant increase of its residence time within lungs. This study also shows that pulmonary infection was associated with a lowering of tobramycin levels in lungs.
Topics: Animals; Drug Carriers; Intubation, Intratracheal; Liposomes; Lung; Male; Pseudomonas Infections; Rats; Rats, Sprague-Dawley; Tobramycin
PubMed: 8067743
DOI: 10.1128/AAC.38.5.1090 -
Acta Pharmacologica Sinica Oct 2021Respiratory syncytial virus (RSV) is leading cause of respiratory tract infections in early childhood. Gut microbiota is closely related with the pulmonary antiviral...
Respiratory syncytial virus (RSV) is leading cause of respiratory tract infections in early childhood. Gut microbiota is closely related with the pulmonary antiviral immunity. Recent evidence shows that gut dysbiosis is involved in the pathogenesis of RSV infection. Therefore; pharmacological and therapeutic strategies aiming to readjust the gut dysbiosis are increasingly important for the treatment of RSV infection. In this study, we evaluated the therapeutic effects of a probiotic mixture on RSV-infected mice. This probiotic mixture consisted of Lactobacillus rhamnosus GG, Escherichia coli Nissle 1917 and VSL#3 was orally administered to neonatal mice on a daily basis either for 1 week in advance or for 3 days starting from the day of RSV infection. We showed that administration of the probiotics protected against RSV-induced lung pathology by suppressing RSV infection and exerting an antiviral response via alveolar macrophage (AM)-derived IFN-β. Furthermore, administration of the probiotics reversed gut dysbiosis and significantly increased the abundance of short-chain fatty acid (SCFA)-producing bacteria in RSV-infected mice, which consequently led to elevated serum SCFA levels. Moreover, administration of the probiotics restored lung microbiota in RSV-infected mice. We demonstrated that the increased production of IFN-β in AMs was attributed to the increased acetate in circulation and the levels of Corynebacterium and Lactobacillus in lungs. In conclusion, we reveal that probiotics protect against RSV infection in neonatal mice through a microbiota-AM axis, suggesting that the probiotics may be a promising candidate to prevent and treat RSV infection, and deserve more research and development in future.
Topics: Animals; Antiviral Agents; Dysbiosis; Fatty Acids, Volatile; Female; Gastrointestinal Microbiome; Interferon-beta; Lung; Macrophages, Alveolar; Mice, Inbred BALB C; Probiotics; Respiratory Syncytial Virus Infections; Respiratory Syncytial Viruses; Mice
PubMed: 33495515
DOI: 10.1038/s41401-020-00573-5 -
Expert Opinion on Drug Safety Jul 2009The lungs are the most common site of serious infection owing to their large surface area exposed to the external environment and minimum barrier defense. However, this... (Review)
Review
The lungs are the most common site of serious infection owing to their large surface area exposed to the external environment and minimum barrier defense. However, this architecture makes the lungs readily available for topical therapy. Therapeutic aerosols include those directed towards improving mucociliary clearance of pathogens, stimulation of innate resistance to microbial infection, cytokine stimulation of immune function and delivery of antibiotics. In our opinion inhaled antimicrobials are underused, especially in patients with difficult-to-treat lung infections. The use of inhaled antimicrobial therapy has become an important part of the treatment of airway infection with Pseudomonas aeruginosa in cystic fibrosis and the prevention of invasive fungal infection in patients undergoing heart and lung transplantation. Cytokine inhaled therapy has also been explored in the treatment of neoplastic and infectious disease. The choice of pulmonary drug delivery systems remains critical as air-jet and ultrasonic nebulizer may deliver sub-optimum drug concentration if not used properly. In future development of this field, we recommend an emphasis on the study of the use of aerosolized hypertonic saline solution to reduce pathogen burden in the airways of subjects infected with microbes of low virulence, stimulation of innate resistance to prevent pneumonia in immunocompromised subjects using cytokines or synthetic pathogen-associated molecular pattern analogues and more opportunities for the use of inhaled antimicrobials. These therapeutics are still in their infancy but show great promise.
Topics: Administration, Inhalation; Animals; Anti-Infective Agents; Cytokines; Drug Delivery Systems; Humans; Immunity, Innate; Lung; Models, Biological; Nebulizers and Vaporizers; Pneumonia; Saline Solution, Hypertonic
PubMed: 19538104
DOI: 10.1517/14740330903036083 -
Infection and Immunity Apr 2022Klebsiella pneumoniae is a Gram-negative, opportunistic pathogen that commonly causes nosocomial pneumonia, urinary tract infection, and septicemia. Our recent work...
Klebsiella pneumoniae is a Gram-negative, opportunistic pathogen that commonly causes nosocomial pneumonia, urinary tract infection, and septicemia. Our recent work utilizing a murine model of respiratory tract infection with classical K. pneumoniae demonstrated leukocyte aggregates in the lungs of mice at 28 days postinfection. Here, we sought to characterize the composition and development of these structures. Histopathological analyses of murine lungs revealed immune cell clusters surrounding the pulmonary vasculature and airways by 14 days postinfection, resembling inducible bronchus-associated lymphoid tissue (iBALT). Further investigation of these structures demonstrated central B cell aggregates with concomitant dispersed T cells. At day 28 postinfection, these lymphoid clusters expressed germinal center markers and CXCL12, qualifying these structures as iBALT with nonclassical B cell follicles. Investigations in mutant mice revealed that those lacking B and/or T cells were not able to form fully defined iBALT structures, although some rudimentary B cell clusters were identified in mice lacking T cells. The longevity of K. pneumoniae-induced BALT was assessed for up to 120 days postinfection. Lymphoid aggregates significantly decreased in size and quantity by 90 days after K. pneumoniae infection; however, aggregates persisted in mice that were restimulated with K. pneumoniae every 30 days. Finally, infections of mice with an array of classical K. pneumoniae clinical isolates demonstrated that the development of these structures is a common feature of K. pneumoniae lung infection. Together, these data confirm that murine lungs infected with K. pneumoniae develop iBALT, which may play a role in pulmonary immunity to this troublesome pathogen.
Topics: Animals; Bronchi; Klebsiella Infections; Klebsiella pneumoniae; Lung; Lymphoid Tissue; Mice; Respiratory Tract Infections
PubMed: 35311545
DOI: 10.1128/iai.00596-21 -
Nano Letters Jul 2020We report cellular nanosponges as an effective medical countermeasure to the SARS-CoV-2 virus. Two types of cellular nanosponges are made of the plasma membranes derived...
We report cellular nanosponges as an effective medical countermeasure to the SARS-CoV-2 virus. Two types of cellular nanosponges are made of the plasma membranes derived from human lung epithelial type II cells or human macrophages. These nanosponges display the same protein receptors, both identified and unidentified, required by SARS-CoV-2 for cellular entry. It is shown that, following incubation with the nanosponges, SARS-CoV-2 is neutralized and unable to infect cells. Crucially, the nanosponge platform is agnostic to viral mutations and potentially viral species, as well. As long as the target of the virus remains the identified host cell, the nanosponges will be able to neutralize the virus.
Topics: Betacoronavirus; COVID-19; Cell Membrane; Coronavirus Infections; Epithelial Cells; Host Microbial Interactions; Humans; Lung; Macrophages; Nanostructures; Nanotechnology; Pandemics; Pneumonia, Viral; Receptors, Virus; SARS-CoV-2; Virus Internalization
PubMed: 32551679
DOI: 10.1021/acs.nanolett.0c02278 -
American Journal of Physiology. Lung... Oct 2018Pregnancy is associated with significant anatomic and functional changes to the cardiopulmonary system. Using pregnant C57BL/6 mice, we characterized changes in...
Pregnancy is associated with significant anatomic and functional changes to the cardiopulmonary system. Using pregnant C57BL/6 mice, we characterized changes in pulmonary structure and function during pregnancy in healthy animals and following infection with influenza A virus (IAV). We hypothesized that pregnancy-associated alterations in pulmonary physiology would contribute to the more severe outcome of IAV infection. Nonpregnant and pregnant females (at embryonic day 10.5) were either mock-infected or infected with 2009 H1N1 IAV for assessment of pulmonary function, structure, and inflammation at 8 days postinoculation. There were baseline differences in pulmonary function, with pregnant females having greater lung compliance, total lung capacity, and fixed lung volume than nonpregnant females. Following IAV infection, both pregnant and nonpregnant females exhibited reduced circulating progesterone, which in nonpregnant females was associated with increased pulmonary resistance and decreased lung compliance, minute ventilation, and oxygen diffusing capacity compared with uninfected nonpregnant females. In pregnant females, reduced concentrations of progesterone were associated with adverse pregnancy outcomes, but measures of pulmonary function were preserved following IAV infection and were not significantly different from uninfected pregnant mice. Following IAV infection, infectious virus titers and total numbers of pulmonary leukocytes were similar between pregnant and nonpregnant females, but the histological density of pulmonary inflammation was reduced in pregnant animals. These data suggest that pregnancy in mice is associated with significant alterations in pulmonary physiology but that these changes served to preserve lung function during IAV infection. Pregnancy-associated alterations in pulmonary physiology may serve to protect females during severe influenza.
Topics: Animals; Female; Influenza A Virus, H1N1 Subtype; Lung; Male; Mice; Mice, Inbred C57BL; Orthomyxoviridae Infections; Pneumonia; Pregnancy; Pregnancy Complications; Respiratory Physiological Phenomena; Viral Load
PubMed: 29847990
DOI: 10.1152/ajplung.00066.2018 -
Proceedings of the American Thoracic... Jun 2011Community-acquired pneumonia affects approximately 4 million people in the United States, with 40,000 deaths per year. The incidence is increased about 35-fold in... (Review)
Review
Community-acquired pneumonia affects approximately 4 million people in the United States, with 40,000 deaths per year. The incidence is increased about 35-fold in HIV-infected individuals, and this rate has decreased since the antiretroviral era has begun. Bacterial pneumonia has decreased from 5 to 20 cases per 100 person-years to less than 1 to 5 cases per 100 person-years in the era of antiretroviral therapy. HIV-1 infection impairs the function of neutrophils in the lung and infects CD4⁺ cells and alveolar macrophages. Opportunistic infections dramatically increase local HIV replication in the lung cells, especially alveolar macrophages and CD4⁺ cells. This enhanced replication increases viral mutations and provides opportunities for viral escape from latent reservoirs. Mortality is increased with more comorbidities in this highly susceptible population. Immunization with vaccines is recommended, especially pneumococcal vaccines, although the vaccine itself may stimulate viral replication. Recent studies show that the lower respiratory tract is a microbial reservoir in HIV-infected individuals rather than being a sterile environment, as originally thought. This may provide new opportunities for preventing opportunistic infections in HIV-infected subjects. Bacterial pneumonia presents an ongoing challenge in these high-risk individuals, particularly in studying the functions of the innate and acquired immune response.
Topics: AIDS-Related Opportunistic Infections; Anti-Retroviral Agents; Bacteria; Bronchoalveolar Lavage Fluid; CD4 Lymphocyte Count; Community-Acquired Infections; DNA, Ribosomal; HIV Infections; HIV-1; Humans; Lung; Neutrophils; Pneumonia, Bacterial; Risk Factors; Severity of Illness Index
PubMed: 21653529
DOI: 10.1513/pats.201006-044WR -
Infection and Immunity Aug 2021Short-chain fatty acids (SCFAs) are the main metabolites produced by the gut microbiota via the fermentation of complex carbohydrates and fibers. Evidence suggests that... (Review)
Review
Short-chain fatty acids (SCFAs) are the main metabolites produced by the gut microbiota via the fermentation of complex carbohydrates and fibers. Evidence suggests that SCFAs play a role in the control of infections through direct action both on microorganisms and on host signaling. This review summarizes the main microbicidal effects of SCFAs and discusses studies highlighting the effect of SCFAs in the virulence and viability of microorganisms. We also describe the diverse and complex modes of action of the SCFAs on the immune system in the face of infections with a specific focus on bacterial and viral respiratory infections. A growing body of evidence suggests that SCFAs protect against lung infections. Finally, we present potential strategies that may be leveraged to exploit the biological properties of SCFAs for increasing effectiveness and optimizing patient benefits.
Topics: Animals; Anti-Infective Agents; Fatty Acids, Volatile; Humans; Infections; Lung; Microbial Viability; Respiratory Tract Infections; Signal Transduction; Virulence
PubMed: 34097474
DOI: 10.1128/IAI.00188-21 -
American Journal of Physiology. Lung... Jul 2020COVID-19 can be divided into three clinical stages, and one can speculate that these stages correlate with where the infection resides. For the asymptomatic phase, the...
COVID-19 can be divided into three clinical stages, and one can speculate that these stages correlate with where the infection resides. For the asymptomatic phase, the infection mostly resides in the nose, where it elicits a minimal innate immune response. For the mildly symptomatic phase, the infection is mostly in the pseudostratified epithelium of the larger airways and is accompanied by a more vigorous innate immune response. In the conducting airways, the epithelium can recover from the infection, because the keratin 5 basal cells are spared and they are the progenitor cells for the bronchial epithelium. There may be more severe disease in the bronchioles, where the club cells are likely infected. The devastating third phase is in the gas exchange units of the lung, where ACE2-expressing alveolar type II cells and perhaps type I cells are infected. The loss of type II cells results in respiratory insufficiency due to the loss of pulmonary surfactant, alveolar flooding, and possible loss of normal repair, since type II cells are the progenitors of type I cells. The loss of type I and type II cells will also block normal active resorption of alveolar fluid. Subsequent endothelial damage leads to transudation of plasma proteins, formation of hyaline membranes, and an inflammatory exudate, characteristic of ARDS. Repair might be normal, but if the type II cells are severely damaged alternative pathways for epithelial repair may be activated, which would result in some residual lung disease.
Topics: Alveolar Epithelial Cells; Betacoronavirus; COVID-19; Coronavirus Infections; Epithelial Cells; Epithelium; Humans; Lung; Pandemics; Pneumonia, Viral; Respiratory Mucosa; SARS-CoV-2
PubMed: 32493030
DOI: 10.1152/ajplung.00126.2020