Cryptococcus Strains with Different Pathogenic Potentials Have Diverse Protein Secretomes

Abstract

bSecreted proteins are the frontline between the host and pathogen. In mammalian hosts, secreted proteins enable invasive infection and can modulate the host immune response. Cryptococcosis, caused by pathogenic Cryptococcus species, begins when inhaled infectious propagules establish to produce pulmonary infection, which, if not resolved, can disseminate to the central nervous system to cause meningoencephalitis. Strains of Cryptococcus species differ in their capacity to cause disease, and the mechanisms underlying this are not well understood. To investigate the role of secreted proteins in disease, we determined the secretome for three genome strains of Cryptococcus species, including a hypovirulent and a hypervirulent strain of C. gattii and a virulent strain of C. neoformans. Sixty-seven unique proteins were identified, with different numbers and types of proteins secreted by each strain. The secretomes of the virulent strains were largely limited to proteolytic and hydrolytic enzymes, while the hypovirulent strain had a diverse secretome, including non-conventionally secreted canonical cytosolic and immunogenic proteins that have been implicated in virulence. The hypovirulent strain cannot establish pulmonary infection in a mouse model, but strains of this genotype have caused human meningitis. To directly test brain infection, we used intracranial inoculation and found that the hypovirulent strain was substantially more invasive than its hypervirulent counterpart. We suggest that immunogenic proteins secreted by this strain invoke a host response that limits pulmonary infection but that there can be invasive growth and damage if infection reaches the brain. Given their known role in virulence, it is possible that non-conventionally secreted proteins mediate this process. P rotein secretion is an essential process for all cells. Secretion has roles in various aspects of cell physiology and lifestyle, including nutrient acquisition, cell wall remodeling, signaling, quorum sensing, and defense against other organisms (1). For pathogenic organisms, the secretion of specific proteins can be key to disease progression, allowing the pathogen both to invade and obtain nutrients and to directly modulate the host organism's immune response.The ability to secrete proteins is of particular importance to fungal organisms. Fungi use exodigestion and absorptive nutrition to acquire nutrients and have evolved a complex suite of secreted proteins to degrade the diverse biopolymers encountered in the host or abiotic environment. Comparisons of characterized fungal secretomes suggest that their basal secretome consists of a core set of degradation enzymes. These include polysaccharideactive enzymes, including glycoside hydrolases, carbohydrate esterases, and polysaccharide lyases, which can degrade the major components of plant cell walls such as cellulose and pectin (2). Other degradative enzymes include proteases, for example, secreted aspartyl proteases (SAPs), which have been associated with pathogenicity in the human ...

Integrated Activity and Genetic Profiling of Secreted Peptidases in Cryptococcus neoformans Reveals an Aspartyl Peptidase Required for Low pH Survival and Virulence

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Immunoproteomic Approach of Extracellular Antigens From Paracoccidioides Species Reveals Exclusive B-Cell Epitopes

“…The secretion of these molecules seems to be related to virulence and/or host-pathogen interaction of Paracoccidioides spp. once it has been demonstrated that secretion of immunogenic molecules in other pathogens is implicated in virulence during hostpathogen interaction (Oliveira et al, 2010;Campbell et al, 2015;de Oliveira et al, 2018).…”

Virulence-Associated Enzymes of Cryptococcus neoformans

“…These enzymes are required for many important biological processes, including growth and infection. The importance of the secretome in cryptococcal pathogenesis is apparent from the fact that strain differences in secreted enzymes correlate with their virulence (134). Nonetheless, important questions remain.…”