CSF1R inhibition by PLX5622 reduces pulmonary fungal infection by depleting MHCII^hi interstitial lung macrophages

PLX5622 is a small molecular inhibitor of the CSF1 receptor (CSF1R) and is widely used to deplete macrophages within the central nervous system (CNS). We investigated the impact of PLX5622 treatment in wild-type C57BL/6 mice and discovered that one-week treatment with PLX5622 was sufficient to deplete interstitial macrophages in the lung and brain-infiltrating Ly6Clow patrolling monocytes, in addition to CNS-resident macrophages. These cell types were previously indicated to act as infection reservoirs for the pathogenic fungus Cryptococcus neoformans. We found that PLX5622-treated mice had significantly reduced fungal lung infection and reduced extrapulmonary dissemination to the CNS but not to the spleen or liver. Fungal lung infection mapped to MHCIIhi interstitial lung macrophages, which underwent significant expansion during infection following monocyte replenishment and not local division. Although PLX5622 depleted CNS infiltrating patrolling monocytes, these cells did not accumulate in the fungal-infected CNS following pulmonary infection. In addition, Nr4a1-deficient mice, which lack patrolling monocytes, had similar control and dissemination of C. neoformans infection to wild-type controls. PLX5622 did not directly affect CD4 T-cell responses, or significantly affect production of antibody in the lung during infection. However, we found that mice lacking lymphocytes had reduced numbers of MHCIIhi interstitial macrophages in the lung, which correlated with reduced infection load. Accordingly, PLX5622 treatment did not alter fungal burdens in the lungs of lymphocyte-deficient mice. Our data demonstrate that PLX5622 may help reduce lung burden of pathogenic fungi that utilise CSF1R-dependent myeloid cells as infection reservoirs, an effect which is dependent on the presence of lymphocytes. </p

Genome-Wide Association Study of Lung Adenocarcinoma in East Asia and Comparison With a European Population

Lung adenocarcinoma is the most common type of lung cancer. Known risk variants explain only a small fraction of lung adenocarcinoma heritability. Here, we conducted a two-stage genome-wide association study of lung adenocarcinoma of East Asian ancestry (21,658 cases and 150,676 controls; 54.5% never-smokers) and identified 12 novel susceptibility variants, bringing the total number to 28 at 25 independent loci. Transcriptome-wide association analyses together with colocalization studies using a Taiwanese lung expression quantitative trait loci dataset (n = 115) identified novel candidate genes, including FADS1 at 11q12 and ELF5 at 11p13. In a multi-ancestry meta-analysis of East Asian and European studies, four loci were identified at 2p11, 4q32, 16q23, and 18q12. At the same time, most of our findings in East Asian populations showed no evidence of association in European populations. In our studies drawn from East Asian populations, a polygenic risk score based on the 25 loci had a stronger association in never-smokers vs. individuals with a history of smoking (Pinteraction = 0.0058). These findings provide new insights into the etiology of lung adenocarcinoma in individuals from East Asian populations, which could be important in developing translational applications

Genome-wide association study of lung adenocarcinoma in East Asia and comparison with a European population

Lung adenocarcinoma is the most common type of lung cancer. Known risk variants explain only a small fraction of lung adenocarcinoma heritability. Here, we conducted a two-stage genome-wide association study of lung adenocarcinoma of East Asian ancestry (21,658 cases and 150,676 controls; 54.5% never-smokers) and identified 12 novel susceptibility variants, bringing the total number to 28 at 25 independent loci. Transcriptome-wide association analyses together with colocalization studies using a Taiwanese lung expression quantitative trait loci dataset (n = 115) identified novel candidate genes, including FADS1 at 11q12 and ELF5 at 11p13. In a multi-ancestry meta-analysis of East Asian and European studies, four loci were identified at 2p11, 4q32, 16q23, and 18q12. At the same time, most of our findings in East Asian populations showed no evidence of association in European populations. In our studies drawn from East Asian populations, a polygenic risk score based on the 25 loci had a stronger association in never-smokers vs. individuals with a history of smoking (P interaction  = 0.0058). These findings provide new insights into the etiology of lung adenocarcinoma in individuals from East Asian populations, which could be important in developing translational applications

Genome-wide association study of lung adenocarcinoma in East Asia and comparison with a European population.

Lung adenocarcinoma is the most common type of lung cancer. Known risk variants explain only a small fraction of lung adenocarcinoma heritability. Here, we conducted a two-stage genome-wide association study of lung adenocarcinoma of East Asian ancestry (21,658 cases and 150,676 controls; 54.5% never-smokers) and identified 12 novel susceptibility variants, bringing the total number to 28 at 25 independent loci. Transcriptome-wide association analyses together with colocalization studies using a Taiwanese lung expression quantitative trait loci dataset (n = 115) identified novel candidate genes, including FADS1 at 11q12 and ELF5 at 11p13. In a multi-ancestry meta-analysis of East Asian and European studies, four loci were identified at 2p11, 4q32, 16q23, and 18q12. At the same time, most of our findings in East Asian populations showed no evidence of association in European populations. In our studies drawn from East Asian populations, a polygenic risk score based on the 25 loci had a stronger association in never-smokers vs. individuals with a history of smoking (Pinteraction = 0.0058). These findings provide new insights into the etiology of lung adenocarcinoma in individuals from East Asian populations, which could be important in developing translational applications

Functional Characterization of the Small Heat Shock Protein Hsp12p from Candida albicans

Hsp12p is considered to be a small heat shock protein and conserved among fungal species. To investigate the expression of this heat shock protein in the fungal pathogen Candida albicans we developed an anti-CaHsp12p antibody. We show that this protein is induced during stationary phase growth and under stress conditions including heat shock, osmotic, oxidative and heavy metal stress. Furthermore, we find that CaHsp12p expression is influenced by the quorum sensing molecule farnesol, the change of CO2 concentration and pH. Notably we show that the key transcription factor Efg1p acts as a positive regulator of CaHsp12p in response to heat shock and oxidative stress and demonstrate that CaHsp12p expression is additionally modulated by Hog1p and the cAMP-PKA signaling pathway. To study the function of Hsp12p in C. albicans we generated a null mutant, in which all four CaHSP12 genes have been deleted. Phenotypic analysis of the strain shows that CaHSP12 is not essential for stress resistance, morphogenesis or virulence when tested in a Drosophila model of infection. However, when overexpressed, CaHSP12 significantly enhanced cell-cell adhesion, germ tube formation and susceptibility to azole antifungal agents whilst desensitizing C. albicans to the quorum sensing molecule farnesol

Molecular and functional characterisation of HSP 12 in fungal pathogen Candida albicans

EThOS - Electronic Theses Online ServiceGBUnited Kingdo

The Diverse Roles of Monocytes in Cryptococcosis

Monocytes are considered to play a central role in the pathogenesis of Cryptococcus neoformans infection. Monocytes and monocyte-derived macrophages and dendritic cells are key components for the control of infection, but paradoxically they can also contribute to detrimental host responses and may even support fungal proliferation and dissemination. Simultaneously, the C. neoformans polysaccharide capsule can impair the functions of monocytes. Although monocytes are often seen as simple precursor cells, they also function as independent immune effector cells. In this review, we summarize these monocyte-specific functions during cryptococcal infection and the influence of C. neoformans on monocyte responses. We also cover the most recent findings on the functional and phenotypic heterogeneity of monocytes and discuss how new advanced technologies provide a platform to address outstanding questions in the field

The ‘Amoeboid Predator-Fungal Animal Virulence’ Hypothesis

The observation that some aspects of amoeba-fungal interactions resemble animal phagocytic cell-fungal interactions, together with the finding that amoeba passage can enhance the virulence of some pathogenic fungi, has stimulated interest in the amoeba as a model system for the study of fungal virulence. Amoeba provide a relatively easy and cheap model system where multiple variables can be controlled for the study of fungi-protozoal (amoeba) interactions. Consequently, there have been significant efforts to study fungal&#8315;amoeba interactions in the laboratory, which have already provided new insights into the origin of fungal virulence as well as suggested new avenues for experimentation. In this essay we review the available literature, which highlights the varied nature of amoeba-fungal interactions and suggests some unsolved questions that are potential areas for future investigation. Overall, results from multiple independent groups support the &#8216;amoeboid predator&#8315;fungal animal virulence hypothesis&#8217;, which posits that fungal cell predation by amoeba can select for traits that also function during animal infection to promote their survival and thus contribute to virulence