Animal Models of Cryptococcus neoformans in Identifying Immune Parameters Associated With Primary Infection and Reactivation of Latent Infection

Abstract

Cryptococcus species are environmental fungal pathogens and the causative agents of cryptococcosis. Infection occurs upon inhalation of infectious particles, which proliferate in the lung causing a primary infection. From this primary lung infection, fungal cells can eventually disseminate to other organs, particularly the brain, causing lethal meningoencephalitis. However, in most cases, the primary infection resolves with the formation of a lung granuloma. Upon severe immunodeficiency, dormant cryptococcal cells will start proliferating in the lung granuloma and eventually will disseminate to the brain. Many investigators have sought to study the protective host immune response to this pathogen in search of host parameters that keep the proliferation of cryptococcal cells under control. The majority of the work assimilates research carried out using the primary infection animal model, mainly because a reactivation model has been available only very recently. This review will focus on anti-cryptococcal immunity in both the primary and reactivation models. An understanding of the differences in host immunity between the primary and reactivation models will help to define the key host parameters that control the infections and are important for the research and development of new therapeutic and vaccine strategies against cryptococcosis.

Cryptococcus neoformans Δsgl1 Vaccination Requires Either CD4+ or CD8+ T Cells for Complete Host Protection

“…These SGs were believed to cause the significantly increased levels of Th1 cytokines, including IL-1a, TNFa, IL-17, and IFNg, and decreased levels of Th2 cytokines, including IL-4 and IL-5 (Figure 2) since they occurred over the same timeline as the SGs were measurable in vivo (Figure 1C). It is widely accepted that host protection against C. neoformans requires a pro-inflammatory type 1 immune response mediated by IFNg (Mourad and Perfect, 2018;Li et al, 2019;Linyu et al, 2020;Hester et al, 2020;Normile et al, 2020a;Akhtar et al, 2020;Montoya et al, 2021). Interestingly, SGs have been shown to induce Th1 T cell polarization (Bouic et al, 1996;Lee and Han, 2006;Lee et al, 2007), but these studies have used plant-based SGs, not fungal-derived SGs.…”

Case Report: A Great Mimicker of Neoplasm: Pulmonary Cryptococcosis in an Immunocompetent Host After High-Altitude Descent

“…Upon primary exposure to Cryptococcus, the immunocompetent host will typically entrap fungal cells within granulomas. [6][7][8][9] Eventual cryptococcosis reactivation may represent one of the stages of the disease. 9 In the immunocompetent host, greater virulence may be dependent on alterations in environmental features.…”

“…[6][7][8][9] Eventual cryptococcosis reactivation may represent one of the stages of the disease. 9 In the immunocompetent host, greater virulence may be dependent on alterations in environmental features. Cryptococcus is an obligate aerobe with a preference for atmospheric oxygen levels of approximately 21%, suggesting that replication and virulence may be decreased at lower oxygen tensions.…”

A hyper-immunogenic and slow-growing fungal strain induces a murine granulomatous response to cryptococcal infection

“…The reactivation of fungal cells from granulomas is an understudied facet of cryptococcal disease, largely due to limited reactivation models. Although the mouse is the most well-characterized and commonly used animal model to study Cryptococcushost interactions, many murine models do not form sustained granulomas in response to clinically relevant isolates of C. neoformans (12). As a result, most murine experiments focus on primary cryptococcal infection and subsequent systemic dissemination.…”

“…As a result, most murine experiments focus on primary cryptococcal infection and subsequent systemic dissemination. To explore cryptococcal latency and reactivation, investigators have adopted models of cryptococcosis in rabbits (13) and rats (14,15) or employed less virulent C. neoformans strains in mice (12,16,17). Recently, a novel latent model was reported in which pulmonary granulomas form in mice in response to infection with the gcs1 mutant cryptococcal strain lacking the glucosylceramide synthase (18)(19)(20)(21).…”