# Impact of Cryptococcus titan cells on pathogenesis

> **NIH NIH R01** · VIRGINIA POLYTECHNIC INST AND ST UNIV · 2024 · $685,902

## Abstract

Project Summary
Cryptococcus neoformans (Cn) infections cause almost half of deaths due to fungal infection and are
responsible for 20% of HIV-related mortality. Even with access to the best available antifungals, cryptococcosis
mortality rates of 30% remain unacceptably high. Although natural immunity to fungal infection is quite efficient
in healthy individuals, disease in advanced HIV/AIDS patients is a complex interaction between 1) failure to
control fungal replication and 2) a qualitative shift towards a deleterious immune response.
The high mortality observed clinically suggests current antifungal drug treatments are inadequate in
immunocompromised individuals. This paradox suggests we are missing critical components of the Cn-host
interaction. Characterization of cryptococcal cells during infection has revealed that Cn produces a unique cell
type - referred to as “titan cells” - during infection that alter the host-pathogen interaction. These titan cells are
produced in response to the host pulmonary environment and are 5-10x larger than typical-sized Cn cells. We
demonstrated previously that titan cell production is critical for virulence and impacts dissemination to the CNS.
We further showed titan cell formation alters the host response by reducing phagocytosis and stimulating a
detrimental Th2-mediated response. The interaction between pathogens and their human hosts can be very
complex, and the outcome depends on both host and pathogen responses. The host must sense pathogen
associated molecular patterns (PAMPs), and then produce an appropriate immune response to kill the
pathogen. Conversely, the pathogen must sense and respond to the host environment to promote its own
survival. This proposal aims to identify critical alterations involved in the genesis of titan cells and their
progeny, as well as define how their unique cellular structure impacts the host immune response and thereby,
pathogenesis.
Titan cells have a number of unique characteristics, thus the focus of our proposed investigations is to
determine how these traits influence: 1) pathogen adaptation/survival in the host, and 2) the host immune
response. Our previous studies showed titan cells undergo ploidy changes associated with their formation and
replication, and lead us to hypothesize these changes are critical for adaptation and survival in the host
environment. Therefore, our first aim is to define the genetic changes in titan cell progeny cells that lead to
enhanced adaptation and survival in the host. In our second aim, we will determine how titan cells undergo
reductive division, testing the hypothesis that titan progeny contain only the newly synthesized copy of DNA.
The third aim will determine how titan cell formation alters the immune response to promote latent infection
establishment and reactivation upon immune dysfunction.
These studies will ultimately coalesce into multi-faceted antimicrobial therapies that combine targeting patho-
gen-specific process...

## Key facts

- **NIH application ID:** 11009355
- **Project number:** 2R01AI134636-06
- **Recipient organization:** VIRGINIA POLYTECHNIC INST AND ST UNIV
- **Principal Investigator:** Kirsten Nielsen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $685,902
- **Award type:** 2
- **Project period:** 2018-04-25 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11009355

## Citation

> US National Institutes of Health, RePORTER application 11009355, Impact of Cryptococcus titan cells on pathogenesis (2R01AI134636-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/11009355. Licensed CC0.

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