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Abstract Background Cryptococcus neoformans (C. neoformans) is a globally distributed fungal pathogen with the potential to cause serious disease, particularly among immune compromised hosts. Exposure to this organism is believed to occur by inhalation and may result in pneumonia and/or disseminated infection of the brain as well as other organs. Little is known about the role of airway epithelial cells in cryptococcal recognition or their ability to induce an inflammatory response. Methods Immortalized BEAS-2B bronchial epithelial cells and primary normal human bronchial epithelium (NHBE) were stimulated in vitro with encapsulated or acapsular C. neoformans cultivated at room temperature or 37°C. Activation of bronchial epithelial cells was characterized by analysis of inflammatory cytokine and chemokine expression, transcription factor activation, fungal-host cell association, and host cell damage. Results Viable C. neoformans is a strong activator of BEAS-2B cells, resulting in the production of the neutrophil chemokine Interleukin (IL)-8 in a time- and dose-dependent manner. IL-8 production was observed only in response to acapsular C. neoformans that was grown at 37°C. C. neoformans was also able to induce the expression of the chemokine CXCL1 and the transcription factor CAAT/enhancer-binding protein beta (CEBP/β) in BEAS-2B cells. NHBE was highly responsive to stimulation with C. neoformans; in addition to transcriptional up regulation of CXCL1, these primary cells exhibited the greatest IL-8 secretion and cell damage in response to stimulation with an acapsular strain of C. neoformans. Conclusion This study demonstrates that human bronchial epithelial cells mediate an acute inflammatory response to C. neoformans and are susceptible to damage by this fungal pathogen. The presence of capsular polysaccharide and in vitro fungal culture conditions modulate the host inflammatory response to C. neoformans. Human bronchial epithelial cells are likely to contribute to the initial stages of pulmonary host defense in vivo.

Lumacaftor/ivacaftor (LUMA-IVA) therapy is prescribed to people with cystic fibrosis (pwCF) homozygous for the Phe508del-CFTR variant to restore CFTR protein function. There is, however, large inter-individual variability in treatment response. Here, we seek to identify clinical and/or genetic factors that may modulate the response to this CFTR modulator therapy. A total of 765 pwCF older than 12 years under LUMA-IVA therapy and with lung function and nutritional measurements available before and after treatment initiation were included. Response to treatment was determined by the change in lung function and nutritional status, from baseline and over the first two years after initiation, and it was assessed by weighted generalized estimating equation models. Gains in lung function and nutritional status were observed after 6 months of treatment (on average 2.11 ± 7.81% for percent predicted FEV1 and 0.44 ± 0.77 kg/m2 for BMI) and sustained over the 2 years. We observed that the more severe patients gained the most in lung function and nutritional status. While females started with a nutritional status more impaired than males, they had a larger response and regained BMI Z-score values similar to men after 2 years of treatment. We observed no association between variants in solute carrier (SLC) genes and the respiratory function response to LUMA-IVA, but the SLC6A14 rs12839137 variant was associated with the nutritional response. Further investigations, including other genomic regions, will be needed to fully explore the inter-individual variability of the response to LUMA-IVA. [ABSTRACT FROM AUTHOR]

Secretory phospholipase A2 (sPLA2) regulates the first step of inflammatory cascade and is involved in several pathological processes. sPLA2 also plays a role in preterm labor and parturition, since they are triggered by inflammatory mediators such as prostaglandins. Interestingly, chorioamnionitis (i.e., the presence of intrauterine inflammation) is also often associated with preterm birth. We aimed to verify if chorioamnionitis with fetal involvement modifies sPLA2 activity and expression profile in mothers and neonates delivered prematurely. We collected maternal plasma and amniotic fluid, as well as bronchoalveolar lavage fluid from preterm neonates born to mothers with or without clinical chorioamnionitis with fetal involvement. We measured concentrations of sPLA2 subtype-IIA and -IB, total enzyme activity, and proteins. Urea ratio was used to obtain epithelial lining fluid concentrations. Enzyme activity measured in maternal plasma ( P < 0.001) and amniotic fluid ( P < 0.001) was higher in chorioamnionitis cases than in controls. This was mainly due to the increased production of sPLA2-IIA, as the subtype -IB was present in a smaller amount and was similar between the two groups; sPLA2-IIA was increased in epithelial lining fluid ( P = 0.045) or increased, although without statistical significance, in maternal plasma ( P = 0.06) and amniotic fluid ( P = 0.08) of chorioamnionitis cases. Cytokines that are known to increase sPLA2-IIA expression (TNF-α and IL-1β) or whose expression was increased by sPLA2-IIA (IL-8) were higher in histologically confirmed chorioamnionitis [TNF-α ( P = 0.028), IL-1β ( P < 0.001), and IL-8 ( P = 0.038)]. These data represent the basis for future studies on sPLA2-IIA inhibition to prevent deleterious consequences of chorioamnionitis and preterm birth.

COVID-19 is caused by the Severe Acute Respiratory Syndrome (SARS) coronavirus (Cov)-2, an enveloped virus with a positive-polarity, single-stranded RNA genome. The initial outbreak of the pandemic began in December 2019, and it is affecting the human health of the global community. In common with previous pandemics (Influenza H1N1 and SARS-CoV) and the epidemics of Middle east respiratory syndrome (MERS)-CoV, CoVs target bronchial and alveolar epithelial cells. Virus protein ligands (e.g., haemagglutinin or trimeric spike glycoprotein for Influenza and CoV, respectively) interact with cellular receptors, such as (depending on the virus) either sialic acids, Dipeptidyl peptidase 4 (DPP4), or angiotensin-converting enzyme 2 (ACE2). Host proteases, e.g., cathepsins, furin, or members of the type II transmembrane serine proteases (TTSP) family, such as Transmembrane protease serine 2 (TMPRSS2), are involved in virus entry by proteolytically activating virus ligands. Also involved are Toll Like Receptor (TLR) family members, which upregulate anti-viral and pro-inflammatory mediators [interleukin (IL)-6 and IL-8 and type I and type III Interferons among others], through the activation of Nuclear Factor (NF)-kB. When these events (virus cellular entry and innate immune responses) are uncontrolled, a deleterious systemic response is sometimes encountered in infected patients, leading to the well-described "cytokine storm" and an ensuing multiple organ failure promoted by a downregulation of dendritic cell, macrophage, and T-cell function. We aim to describe how the lung and systemic host innate immune responses affect survival either positively, through downregulating initial viral load, or negatively, by triggering uncontrolled inflammation. An emphasis will be put on host cellular signaling pathways and proteases involved with a view on tackling these therapeutically., (Copyright © 2020 Sallenave and Guillot.)

The rising incidence of serious fungal diseases represents a growing threat to human health. Cryptococcus neoformans, an encapsulated yeast saprophyte with global distribution, has been recognized as an important emerging pathogen. Humans frequently develop asymptomatic or mild infection with C. neoformans, but individuals with impaired host defense systems may develop severe pneumonia and potentially fatal meningoencephalitis. Insight into the biology and virulence of C. neoformans is advancing rapidly and will be propelled even further by the recently completed and published genome sequences for two related strains of C. neoformans serotype D. Several mammalian model hosts including the guinea pig, rabbit, rat, and mouse have been developed for the study of cryptococcosis. The combination of microbial genomics with well-characterized model hosts that are amenable to immunologic and genetic manipulation represents a powerful resource for comprehensive study of cryptococcal disease pathogenesis as well as vaccine and antifungal drug therapy. This review provides an introduction to each mammalian model host and briefly highlights the advantages, limitations, and potential of each system for future research involving cryptococci.