Dangerous Liaisons: Interactions of Cryptococcus neoformans with Host Phagocytes

Gaylord, Elizabeth A; Choy, Hau Lam; Doering, Tamara L.

doi:10.3390/pathogens9110891

Cited by 33 publications

(30 citation statements)

References 124 publications

(174 reference statements)

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“…Also, all strains showed a reduction in phagocytosis after capsule induction in DMEM ( Fig. 7 , DMEM versus YPD), which is not surprising, because the capsule is antiphagocytic ( 31 , 73 ). Notably, the reduction in uptake was greatest for the pdr802 mutant under both of these conditions, even though it showed normal engulfment when all strains were grown under control conditions (YPD).…”

Section: Resultsmentioning

confidence: 72%

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The Transcription Factor Pdr802 Regulates Titan Cell Formation and Pathogenicity of Cryptococcus neoformans

Reuwsaat

Agustinho

Motta

et al. 2021

mBio

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Cryptococcus neoformans is a ubiquitous, opportunistic fungal pathogen that kills almost 200,000 people worldwide each year. It is acquired when mammalian hosts inhale the infectious propagules; these are deposited in the lung and, in the context of immunocompromise, may disseminate to the brain and cause lethal meningoencephalitis. Once inside the host, C. neoformans undergoes a variety of adaptive processes, including secretion of virulence factors, expansion of a polysaccharide capsule that impedes phagocytosis, and the production of giant (Titan) cells. The transcription factor Pdr802 is one regulator of these responses to the host environment. Expression of the corresponding gene is highly induced under host-like conditions in vitro and is critical for C. neoformans dissemination and virulence in a mouse model of infection. Direct targets of Pdr802 include the quorum sensing proteins Pqp1, Opt1, and Liv3; the transcription factors Stb4, Zfc3, and Bzp4, which regulate cryptococcal brain infectivity and capsule thickness; the calcineurin targets Had1 and Crz1, important for cell wall remodeling and C. neoformans virulence; and additional genes related to resistance to host temperature and oxidative stress, and to urease activity. Notably, cryptococci engineered to lack Pdr802 showed a dramatic increase in Titan cells, which are not phagocytosed and have diminished ability to directly cross biological barriers. This explains the limited dissemination of pdr802 mutant cells to the central nervous system and the consequently reduced virulence of this strain. The role of Pdr802 as a negative regulator of Titan cell formation is thus critical for cryptococcal pathogenicity. IMPORTANCE The pathogenic yeast Cryptococcus neoformans presents a worldwide threat to human health, especially in the context of immunocompromise, and current antifungal therapy is hindered by cost, limited availability, and inadequate efficacy. After the infectious particle is inhaled, C. neoformans initiates a complex transcriptional program that integrates cellular responses and enables adaptation to the host lung environment. Here, we describe the role of the transcription factor Pdr802 in the response to host conditions and its impact on C. neoformans virulence. We identified direct targets of Pdr802 and also discovered that it regulates cellular features that influence movement of this pathogen from the lung to the brain, where it causes fatal disease. These findings significantly advance our understanding of a serious disease.

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Section: Resultsmentioning

confidence: 72%

“…Titan cells are poorly engulfed by host phagocytes ( 19 , 45 , 73 ), which may reflect their increased size as well as alterations in capsule and cell wall ( 51 ). We observed this reduced uptake for all strains after growth in conditions that favor Titan cell formation ( Fig.…”

Section: Resultsmentioning

confidence: 99%

The Transcription Factor Pdr802 Regulates Titan Cell Formation and Pathogenicity of Cryptococcus neoformans

Reuwsaat

Agustinho

Motta

et al. 2021

mBio

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“…However, cells have a particular predilection for the brain. For cryptococcal cells to reach the brain, they have to cross the blood-brain barrier (BBB) to cause a fatal infection called meningitis [74,75]. To achieve this, cells can traverse between the damaged tight junctions of the BBB via a paracellular passage [76].…”

Section: Possible Role Of Cryptococcal Proteases In Promoting Brain Invasion In the Context Of Co-infection With Sars-cov-2mentioning

confidence: 99%

The Possible Role of Microbial Proteases in Facilitating SARS-CoV-2 Brain Invasion

Mjokane

Folorunso

Ogundeji

et al. 2021

Biology

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SARS-CoV-2 has been shown to display proclivity towards organs bearing angiotensin-converting enzyme (ACE2) expression cells. Of interest herein is the ability of the virus to exhibit neurotropism. However, there is limited information on how this virus invades the brain. With this contribution, we explore how, in the context of a microbial co-infection using a cryptococcal co-infection as a model, SARS-CoV-2 could reach the brain. We theorise that the secretion of proteases by disseminated fungal cells might also activate the S2 domain of the viral spike glycoprotein for membrane fusion with brain endothelial cells leading to endocytosis. Understanding this potential invasion mechanism could lead to better SARS-CoV-2 intervention measures, which may also be applicable in instances of co-infection, especially with protease-secreting pathogens.

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“…This yeast, which is responsible for roughly 200,000 deaths from meningitis each year, elaborates an extracellular capsule that is composed of large (up to millions of daltons) polysaccharides and can comprise >75% of the pathogen volume. The capsule, made primarily of mannose or galactose chains with appendant glucuronic acid and xylose residues, is required for infection and inhibits host cell phagocytosis ( Gaylord et al, 2020 ). Shed capsule components also perturb host immune responses; this material is also the basis for rapid tests that are valuable for diagnosis of this frequently lethal infection.…”

Section: Glycans In Host-pathogen Recognition and Diseasementioning

confidence: 99%

The Crossroads of Glycoscience, Infection, and Immunology

et al. 2021

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Advances in experimental capabilities in the glycosciences offer expanding opportunities for discovery in the broad areas of immunology and microbiology. These two disciplines overlap when microbial infection stimulates host immune responses and glycan structures are central in the processes that occur during all such encounters. Microbial glycans mediate host-pathogen interactions by acting as surface receptors or ligands, functioning as virulence factors, impeding host immune responses, or playing other roles in the struggle between host and microbe. In the context of the host, glycosylation drives cell–cell interactions that initiate and regulate the host response and modulates the effects of antibodies and soluble immune mediators. This perspective reports on a workshop organized jointly by the National Institute of Allergy and Infectious Diseases and the National Institute of Dental and Craniofacial Research in May 2020. The conference addressed the use of emerging glycoscience tools and resources to advance investigation of glycans and their roles in microbe-host interactions, immune-mediated diseases, and immune cell recognition and function. Future discoveries in these areas will increase fundamental scientific understanding and have the potential to improve diagnosis and treatment of infections and immune dysregulation.

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Dangerous Liaisons: Interactions of Cryptococcus neoformans with Host Phagocytes

Cited by 33 publications

References 124 publications

The Transcription Factor Pdr802 Regulates Titan Cell Formation and Pathogenicity of Cryptococcus neoformans

The Transcription Factor Pdr802 Regulates Titan Cell Formation and Pathogenicity of Cryptococcus neoformans

The Possible Role of Microbial Proteases in Facilitating SARS-CoV-2 Brain Invasion

The Crossroads of Glycoscience, Infection, and Immunology

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