See CDC
Introduction:
Cryptococcus neoformans is a fungus that lives in the environment throughout the world. C. neoformans is an encapsulated yeast fungus found globally in soil and avian excrement. Infectious propagules in the form of desiccated yeast or spores are inhaled into the respiratory tract on a daily basis. Due to their small size, these organisms are able to avoid cough and mucociliary clearance and penetrate deep into alveolar spaces. Here, C. neoformans encounters lung resident immune cells. In healthy, or immunocompetent, individuals, these fungi are either successfully cleared or establish long-term, latent infections. Alternatively, in the case of immunocompromised individuals, including AIDS patients, organ transplant recipients and patients treated with immunosuppressive therapies, C. neoformans can establish symptomatic pulmonary infections resulting in pneumonia, acute respiratory distress syndrome, and subsequent extrapulmonary dissemination. (Shi, “Mechanisms of fungal dissemination” Cellular and Molecular Life Sciences (2021) 78:3219–3238)
C Neoformans is monomorphic unlike other dimorphic pathogens. It can be identified with India Ink (has a wide capsule) and is the leading cause of meningitis in AIDS patients.
Pathology:
Following pulmonary infection, one of the first immune cells C. neoformans encounters are lung resident alveolar macrophages. These professional phagocytes rapidly ingest cryptococcal cells for degradation. However, C. neoformans is a facultative intracellular pathogen and is equipped to survive and replicate within these cells. This enables viable yeast to be transported out of the lungs within migrating phagocytes, a process known as the Trojan horse mechanism of dissemination. (Shi, “Mechanisms of fungal dissemination” Cellular and Molecular Life Sciences (2021) 78:3219–3238)
Once phagocytosed, C. neoformans can exit macrophages following intracellular replication. Cryptococcal replication within phagocytes is accompanied by the formation of a leaky phagosome and the accumulation of polysaccharide containing vesicles in the cytoplasm and eventually culminates in the lysis of host cells. Once outside of the lungs, cryptococcal cells can enter into the bloodstream resulting in blood infections known as fungemia (Shi, “Mechanisms of fungal dissemination” Cellular and Molecular Life Sciences (2021) 78:3219–3238)
Capsule: The capsule is the most important virulence factor of C. neoformans, contributing approximately 25% of the total virulence composite. See Wear
Metabolism:
A key factor influencing the virulence of C. neoformans is adenosine triphosphate (ATP), which serves as the primary energy currency for cells. ATP is crucial not only for cellular metabolism but also for various processes that enable C. neoformans to thrive and cause disease within the host. Research has shown that disruption of ATP biosynthesis results in a complete loss of virulence in C. neoformans. The loss of adenylosuccinate synthetase (AdSS) leads to adenine auxotrophy and a consequent reduction in virulence in murine models. This distinct structural differences between fungal AdSS and its human counterpart, positions AdSS as a promising target for antifungal drug development.
Cryptococcal meningitis (CM)
Cryptococcal meningitis is a life-threatening fungal infection caused principally by Cryptococcus neoformans and Cryptococcus gattii. Generally, C. gattii is the most common cause of CM in immunocompetent patients, while C. neoformans is primarily responsible for disease in immunocompromised patients. See Day
Risk Populations/Symptoms/Transmission:
Despite CM being more common in immunocompromised patients, CM can also arise in apparently immunocompetent patients. Recent figures estimate an annual global CM incidence of 223,100 cases in patients infected with human immunodeficiency virus (HIV), resulting in 181,100 deaths.
Immune Response:
In addition to neutrophils, liver-resident macrophages, known as Kupffer cells (KCs), have been shown to play a role in clearing intravascular C. neoformans. The liver is the largest internal organ, receiving 30% of the total volume of blood in the body each minute, and contains
approximately 90% of the total tissue macrophages in the body.
Treatment:
Treatment is with amphotericin B or flucytosine.