scholarly journals The novel Dbl homology/BAR domain protein, MsgA, of Talaromyces marneffei regulates yeast morphogenesis during growth inside host cells

2018 ◽  
Author(s):  
Harshini Weerasinghe ◽  
Hayley E. Bugeja ◽  
Alex Andrianopoulos
Keyword(s):  
Pathogenic Fungi ◽  
Host Cells ◽  
Microbial Pathogens ◽  
Mammalian Host ◽  
Host Immune System ◽  
Nucleotide Exchange ◽  
Phagocytic Cells ◽  
Macrophage Infection ◽  
Bar Domain ◽  
Talaromyces Marneffei

AbstractMicrobial pathogens have evolved many strategies to evade recognition by the host immune system, including the use of phagocytic cells as a niche within which to proliferate. Dimorphic pathogenic fungi employ an induced morphogenetic transition, switching from multicellular hyphae to unicellular yeast that are more compatible with intracellular growth. A switch to mammalian host body temperature (37°C) is a key trigger for the dimorphic switch. This study describes a novel gene, msgA, from the dimorphic fungal pathogen Talaromyces marneffei that controls cell morphology in response to host cues rather than temperature. The msgA gene is upregulated during murine macrophage infection, and deletion results in aberrant yeast morphology solely during growth inside macrophages. MsgA contains a Dbl homology domain, and a Bin, Amphiphysin, Rvs (BAR) domain instead of a Plekstrin homology domain typically associated with guanine nucleotide exchange factors (GEFs). The BAR domain is crucial in maintaining yeast morphology and cellular localisation during infection. The data suggests that MsgA does not act as a canonical GEF during macrophage infection and identifies a temperature independent pathway in T. marneffei that controls intracellular yeast morphogenesis.

scholarly journals The novel Dbl homology/BAR domain protein, MsgA, of Talaromyces marneffei regulates yeast morphogenesis during growth inside host cells

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Harshini Weerasinghe ◽  
Hayley E. Bugeja ◽  
Alex Andrianopoulos
Keyword(s):  
Pathogenic Fungi ◽  
Host Cells ◽  
Microbial Pathogens ◽  
Mammalian Host ◽  
Host Immune System ◽  
Nucleotide Exchange ◽  
Phagocytic Cells ◽  
Macrophage Infection ◽  
Bar Domain ◽  
Talaromyces Marneffei

AbstractMicrobial pathogens have evolved many strategies to evade recognition by the host immune system, including the use of phagocytic cells as a niche within which to proliferate. Dimorphic pathogenic fungi employ an induced morphogenetic transition, switching from multicellular hyphae to unicellular yeast that are more compatible with intracellular growth. A switch to mammalian host body temperature (37 °C) is a key trigger for the dimorphic switch. This study describes a novel gene, msgA, from the dimorphic fungal pathogen Talaromyces marneffei that controls cell morphology in response to host cues rather than temperature. The msgA gene is upregulated during murine macrophage infection, and deletion results in aberrant yeast morphology solely during growth inside macrophages. MsgA contains a Dbl homology domain, and a Bin, Amphiphysin, Rvs (BAR) domain instead of a Plekstrin homology domain typically associated with guanine nucleotide exchange factors (GEFs). The BAR domain is crucial in maintaining yeast morphology and cellular localisation during infection. The data suggests that MsgA does not act as a canonical GEF during macrophage infection and identifies a temperature independent pathway in T. marneffei that controls intracellular yeast morphogenesis.

scholarly journals Identification of Metabolically Quiescent Leishmania mexicana Parasites in Peripheral and Cured Dermal Granulomas Using Stable Isotope Tracing Imaging Mass Spectrometry

mBio ◽  
2021 ◽  
Vol 12 (2) ◽  
Author(s):  
Joachim Kloehn ◽  
Berin A. Boughton ◽  
Eleanor C. Saunders ◽  
Sean O’Callaghan ◽  
Katrina J. Binger ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Heavy Water ◽  
Large Population ◽  
Imaging Mass Spectrometry ◽  
Host Cells ◽  
Microbial Pathogens ◽  
Mammalian Host ◽  
Leishmania Mexicana ◽  
First Line

ABSTRACT Leishmania are sandfly-transmitted protists that induce granulomatous lesions in their mammalian host. Although infected host cells in these tissues can exist in different activation states, the extent to which intracellular parasites stages also exist in different growth or physiological states remains poorly defined. Here, we have mapped the spatial distribution of metabolically quiescent and active subpopulations of Leishmania mexicana in dermal granulomas in susceptible BALB/c mice, using in vivo heavy water labeling and ultra high-resolution imaging mass spectrometry. Quantitation of the rate of turnover of parasite and host-specific lipids at high spatial resolution, suggested that the granuloma core comprised mixed populations of metabolically active and quiescent parasites. Unexpectedly, a significant population of metabolically quiescent parasites was also identified in the surrounding collagen-rich, dermal mesothelium. Mesothelium-like tissues harboring quiescent parasites progressively replaced macrophage-rich granuloma tissues following treatment with the first-line drug, miltefosine. In contrast to the granulomatous tissue, neither the mesothelium nor newly deposited tissue sequestered miltefosine. These studies suggest that the presence of quiescent parasites in acute granulomatous tissues, together with the lack of miltefosine accumulation in cured lesion tissue, may contribute to drug failure and nonsterile cure. IMPORTANCE Many microbial pathogens switch between different growth and physiological states in vivo in order to adapt to local nutrient levels and host microbicidal responses. Heterogeneity in microbial growth and metabolism may also contribute to nongenetic mechanisms of drug resistance and drug failure. In this study, we have developed a new approach for measuring spatial heterogeneity in microbial metabolism in vivo using a combination of heavy water (2H2O) labeling and imaging mass spectrometry. Using this approach, we show that lesions contain a patchwork of metabolically distinct parasite populations, while the underlying dermal tissues contain a large population of metabolically quiescent parasites. Quiescent parasites also dominate drug-depleted tissues in healed animals, providing an explanation for failure of some first line drugs to completely eradicate parasites. This approach is broadly applicable to study the metabolic and growth dynamics in other host-pathogen interactions.

scholarly journals Temporal Kinetics and Quantitative Analysis of Cryptococcus neoformans Nonlytic Exocytosis

2014 ◽  
Vol 82 (5) ◽  
pp. 2059-2067 ◽  
Author(s):  
Sabriya A. Stukes ◽  
Hillel W. Cohen ◽  
Arturo Casadevall
Keyword(s):  
Cryptococcus Neoformans ◽  
Time Lapse ◽  
Host Cells ◽  
Type I ◽  
Phagocytic Cells ◽  
Macrophage Infection ◽  
Content Type ◽  
Type Iii ◽  
Cell To Cell Transfer ◽  
Extracellular Environment

ABSTRACTCryptococcus neoformansis a facultative intracellular pathogen and the causative agent of cryptococcosis, a disease that is often fatal to those with compromised immune systems.C. neoformanshas the capacity to escape phagocytic cells through a process known as nonlytic exocytosis whereby the cryptococcal cell is released from the macrophage into the extracellular environment, leaving both the host and pathogen alive. Little is known about the mechanism behind nonlytic exocytosis, but there is evidence that both the fungal and host cells contribute to the process. In this study, we used time-lapse movies ofC. neoformans-infected macrophages to delineate the kinetics and quantitative aspects of nonlytic exocytosis. We analyzed approximately 800 macrophages containing intracellularC. neoformansand identified 163 nonlytic exocytosis events that were further characterized into three subcategories: type I (complete emptying of macrophage), type II (partial emptying of macrophage), and type III (cell-to-cell transfer). The majority of type I and II events occurred after several hours of intracellular residence, whereas type III events occurred significantly (P< 0.001) earlier in the course of macrophage infection. Our results show that nonlytic exocytosis is a morphologically and temporally diverse process that occurs relatively rapidly in the course of macrophage infection.

scholarly journals Molecular crypsis by pathogenic fungi using human factor H. A numerical model

2018 ◽  
Author(s):  
Stefan Lang ◽  
Sebastian Germerodt ◽  
Christina Glock ◽  
Christine Skerka ◽  
Peter F. Zipfel ◽  
...  
Keyword(s):  
Immune System ◽  
Molecular Mimicry ◽  
Pathogenic Fungi ◽  
Blood Stream ◽  
Factor H ◽  
Host Cells ◽  
Microbial Pathogens ◽  
Complement Factor ◽  
Interaction Modelling ◽  
Predominant Factor

AbstractMolecular mimicry is the formation of specific molecules by microbial pathogens to avoid recognition and attack by the immune system of the host. Several pathogenic Ascomycota and Zygomycota show such a behaviour by utilizing human complement factor H to hide in the blood stream. We call this type of mimicry molecular crypsis. Such a crypsis can reach a point where the immune system can no longer clearly distinguish between self and non-self cells. Thus, a trade-off between attacking disguised pathogens and erroneously attacking host cells has to be made, which can lead to autoreactivity. Based on signalling theory and protein-interaction modelling, we here present a mathematical model of molecular crypsis of pathogenic fungi using the example of Candida albicans. We tackle the question whether perfect crypsis is feasible, which would imply that protection of human cells by complement factors would be useless. The model identifies pathogen abundance relative to host cell abundance as the predominant factor influencing successful or unsuccessful molecular crypsis. If pathogen cells gain a (locally) quantitative advantage over host cells, even autoreactivity may occur. Our new model enables insights into the mechanisms of candidiasis-induced sepsis and complement associated autoimmune diseases.

scholarly journals The Glycan-Rich Outer Layer of the Cell Wall of Mycobacterium tuberculosis Acts as an Antiphagocytic Capsule Limiting the Association of the Bacterium with Macrophages

2004 ◽  
Vol 72 (10) ◽  
pp. 5676-5686 ◽  
Author(s):  
Richard W. Stokes ◽  
Raymond Norris-Jones ◽  
Donald E. Brooks ◽  
Terry J. Beveridge ◽  
Dan Doxsee ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Surface Hydrophobicity ◽  
Host Cells ◽  
Microbial Pathogens ◽  
Mammalian Host ◽  
Human Macrophage ◽  
Bacterial Surface ◽  
Important Virulence Factor ◽  
Complement Receptor 3 ◽  
Macrophage Populations

ABSTRACT Mycobacterium tuberculosis, the causative agent of tuberculosis, is a facultative intracellular pathogen that infects macrophages and other host cells. We show that sonication of M. tuberculosis results in the removal of material from the surface capsule-like layer of the bacteria, resulting in an enhanced propensity of the bacteria to bind to macrophages. This effect is observed with disparate murine and human macrophage populations though, interestingly, not with freshly explanted alveolar macrophages. Enhanced binding to macrophages following sonication is significantly greater within members of the M. tuberculosis family (pathogens) than within the Mycobacterium avium complex (opportunistic pathogens) or for Mycobacterium smegmatis (saprophyte). Sonication does not affect the viability or the surface hydrophobicity of M. tuberculosis but does result in changes in surface charge and in the binding of mannose-specific lectins to the bacterial surface. The increased binding of sonicated M. tuberculosis was not mediated through complement receptor 3. These results provide evidence that the surface capsule on members of the M. tuberculosis family may be an important virulence factor involved in the survival of M. tuberculosis in the mammalian host. They also question the view that M. tuberculosis is readily ingested by any macrophage it encounters and support the contention that M. tuberculosis, like many other microbial pathogens, has an antiphagocytic capsule that limits and controls the interaction of the bacterium with macrophages.

scholarly journals Pilus Adhesin RrgA Interacts with Complement Receptor 3, Thereby Affecting Macrophage Function and Systemic Pneumococcal Disease

mBio ◽  
2012 ◽  
Vol 4 (1) ◽  
Author(s):  
Sofia Orrskog ◽  
Samuli Rounioja ◽  
Tiziana Spadafina ◽  
Marilena Gallotta ◽  
Martin Norman ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Immune Cells ◽  
Host Cells ◽  
Complement Receptor ◽  
Disease Development ◽  
Phagocytic Cells ◽  
Macrophage Infection ◽  
Upper Airways ◽  
Human Macrophages ◽  
Complement Receptor 3

ABSTRACTPneumococcal pili have been shown to influence pneumococcal colonization, disease development, and the inflammatory response in mice. The role of the pilus-associated RrgA adhesin in pneumococcal interactions with murine and human macrophages was investigated. Expression of pili with RrgA enhanced the uptake of pneumococci by murine and human macrophages that was abolished by antibodies to complement receptor 3 (CR3) and not seen in CR3-deficient macrophages. Recombinant RrgA, but not pilus subunit RrgC, promoted CR3-mediated phagocytosis of coated beads by murine and human macrophages. Flow cytometry showed that purified CR3 binds pneumococcal cells expressing RrgA, and purified RrgA was shown to interact with CR3 and its I domain.In vivo, RrgA facilitated spread of pneumococci from the upper airways and peritoneal cavity to the bloodstream. Earlier onset of septicemia and more rapidly progressing disease was observed in wild-type mice compared to CR3-deficient mice challenged intranasally or intraperitoneally with pneumococci. Motility assays and time-lapse video microscopy showed that pneumococcal stimulation of macrophage motility required RrgA and CR3. These findings, together with the observed RrgA-dependent increase of intracellular survivors up to 10 h following macrophage infection, suggest that RrgA-CR3-mediated phagocytosis promotes systemic pneumococcal spread from local sites.IMPORTANCEStreptococcus pneumoniaeis a major contributor to morbidity and mortality in infectious diseases globally. Symptomatology is mainly due to pneumococcal interactions with host cells leading to an inflammatory response. However, we still need more knowledge on how pneumococci talk to immune cells and the importance of this interaction. Recently, a novel structure was identified on the pneumococcal surface, an adhesive pilus found in about 30% of clinical pneumococcal isolates. The pilus has been suggested to be important for successful spread of antibiotic-resistant pneumococcal clones globally. Here we sought to identify mechanisms for how the pneumococcal pilin subunit RrgA contributes to disease development by interacting with host immune cells. Our data suggest a new way for how pneumococci may cross talk with phagocytic cells and affect disease progression. An increased understanding of these processes may lead to better strategies for how to treat these common infections.

scholarly journals Actin-Based Motility of Intracellular Microbial Pathogens

2001 ◽  
Vol 65 (4) ◽  
pp. 595-626 ◽  
Author(s):  
Marcia B. Goldberg
Keyword(s):  
Molecular Mechanisms ◽  
Host Cells ◽  
Microbial Pathogens ◽  
Mammalian Host ◽  
Cell Periphery ◽  
Actin Assembly ◽  
Cell Cytoplasm ◽  
Shigella Spp ◽  
The Subject ◽  
Actin Rearrangement

SUMMARY A diverse group of intracellular microorganisms, including Listeria monocytogenes, Shigella spp., Rickettsia spp., and vaccinia virus, utilize actin-based motility to move within and spread between mammalian host cells. These organisms have in common a pathogenic life cycle that involves a stage within the cytoplasm of mammalian host cells. Within the cytoplasm of host cells, these organisms activate components of the cellular actin assembly machinery to induce the formation of actin tails on the microbial surface. The assembly of these actin tails provides force that propels the organisms through the cell cytoplasm to the cell periphery or into adjacent cells. Each of these organisms utilizes preexisting mammalian pathways of actin rearrangement to induce its own actin-based motility. Particularly remarkable is that while all of these microbes use the same or overlapping pathways, each intercepts the pathway at a different step. In addition, the microbial molecules involved are each distinctly different from the others. Taken together, these observations suggest that each of these microbes separately and convergently evolved a mechanism to utilize the cellular actin assembly machinery. The current understanding of the molecular mechanisms of microbial actin-based motility is the subject of this review.

scholarly journals Modulation of the Host Immune Response by Schistosome Egg-Secreted Proteins Is a Critical Avenue of Host–Parasite Communication

Pathogens ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 863
Author(s):  
Jack P. Carson ◽  
Geoffrey N. Gobert
Keyword(s):  
Immune Response ◽  
Current Knowledge ◽  
Host Immune Response ◽  
Egg Laying ◽  
Host Cells ◽  
Future Application ◽  
Mammalian Host ◽  
Immunomodulatory Activity ◽  
Host Immune System

During a schistosome infection, the interactions that occur between the mammalian host and the parasite change rapidly once egg laying begins. Both juvenile and adult schistosomes adapt to indefinitely avoid the host immune system. In contrast, the survival of eggs relies on quickly traversing from the host. Following the commencement of egg laying, the host immune response undergoes a shift from a type 1 helper (Th1) inflammatory response to a type 2 helper (Th2) granulomatous response. This change is driven by immunomodulatory proteins within the egg excretory/secretory products (ESPs), which interact with host cells and alter their behaviour to promote egg translocation. However, in parallel, these ESPs also provoke the development of chronic schistosomiasis pathology. Recent studies using high-throughput proteomics have begun to characterise the components of schistosome egg ESPs, particularly those of Schistosoma mansoni, S. japonicum and S. haematobium. Future application of this knowledge may lead to the identification of proteins with novel immunomodulatory activity or pathological importance. However, efforts in this area are limited by a lack of in situ or in vivo functional characterisation of these proteins. This review will highlight the current knowledge of the content and demonstrated functions of schistosome egg ESPs.

scholarly journals Interactions of Burkholderia cenocepacia and other Burkholderia cepacia complex bacteria with epithelial and phagocytic cells

Microbiology ◽  
2009 ◽  
Vol 155 (9) ◽  
pp. 2809-2817 ◽  
Author(s):  
M. Soledad Saldías ◽  
Miguel A. Valvano
Keyword(s):  
Burkholderia Cepacia ◽  
Host Cells ◽  
Burkholderia Cenocepacia ◽  
Burkholderia Cepacia Complex ◽  
Mammalian Host ◽  
Rapid Decline ◽  
Phagocytic Cells ◽  
Opportunistic Bacteria ◽  
Persistent Inflammation ◽  
Almost All

Burkholderia cenocepacia is a member of the B. cepacia complex (Bcc), a group of opportunistic bacteria that infect the airways of patients with cystic fibrosis (CF) and are extraordinarily resistant to almost all clinically useful antibiotics. Infections in CF patients with Bcc bacteria generally lead to a more rapid decline in lung function, and in some cases to the ‘cepacia syndrome’, a virtually deadly exacerbation of the lung infection with systemic manifestations. These characteristics of Bcc bacteria contribute to higher morbidity and mortality in infected CF patients. In the last 10 years considerable progress has been made in understanding the interactions between Bcc bacteria and mammalian host cells. Bcc isolates can survive either intracellularly within eukaryotic cells or extracellularly in host tissues. They survive within phagocytes and respiratory epithelial cells, and they have the ability to breach the respiratory epithelium layer. Survival and persistence of Bcc bacteria within host cells and tissues are believed to play a key role in pulmonary infection and to contribute to the persistent inflammation observed in patients with CF. This review summarizes recent findings concerning the interaction between Bcc bacteria and epithelial and phagocytic cells.

scholarly journals Cu Homeostasis in Bacteria: The Ins and Outs

Membranes ◽  
2020 ◽  
Vol 10 (9) ◽  
pp. 242
Author(s):  
Andreea Andrei ◽  
Yavuz Öztürk ◽  
Bahia Khalfaoui-Hassani ◽  
Juna Rauch ◽  
Dorian Marckmann ◽  
...  
Keyword(s):  
Current Knowledge ◽  
Host Cells ◽  
Microbial Pathogens ◽  
Host Immune System ◽  
Biological Processes ◽  
Multiple Strategies ◽  
Relay Systems ◽  
Bacterial Response ◽  
Cu Homeostasis ◽  
Living Organisms

Copper (Cu) is an essential trace element for all living organisms and used as cofactor in key enzymes of important biological processes, such as aerobic respiration or superoxide dismutation. However, due to its toxicity, cells have developed elaborate mechanisms for Cu homeostasis, which balance Cu supply for cuproprotein biogenesis with the need to remove excess Cu. This review summarizes our current knowledge on bacterial Cu homeostasis with a focus on Gram-negative bacteria and describes the multiple strategies that bacteria use for uptake, storage and export of Cu. We furthermore describe general mechanistic principles that aid the bacterial response to toxic Cu concentrations and illustrate dedicated Cu relay systems that facilitate Cu delivery for cuproenzyme biogenesis. Progress in understanding how bacteria avoid Cu poisoning while maintaining a certain Cu quota for cell proliferation is of particular importance for microbial pathogens because Cu is utilized by the host immune system for attenuating pathogen survival in host cells.

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