Fungal Pathogens: Survival and Replication within Macrophages

Abstract

The innate immune system is a critical line of defense against pathogenic fungi. Macrophages act at an early stage of infection, detecting and phagocytizing infectious propagules. To avoid killing at this stage, fungal pathogens use diverse strategies ranging from evasion of uptake to intracellular parasitism. This article will discuss five of the most important human fungal pathogens (Candida albicans, Aspergillus fumigatus, Cryptococcus neoformans, Coccidiodes immitis, and Histoplasma capsulatum) and consider the strategies and virulence factors adopted by each to survive and replicate within macrophages. Macrophages are phagocytic immune cells, derived from monocyte differentiation, and are involved in the first line of defense during microbial invasion. They recognize, engulf, and destroy foreign bodies, such as pathogenic organisms before then presenting antigen to coordinate subsequent adaptive immunity (Fig. 1). Macrophages are found in almost all tissues and are particularly abundant at mucosal surfaces in which pathogen exposure is naturally higher, such as the alveoli. They are able to engulf particles ranging from 0.5 mm (such as bacteria) to .5 mm (such as yeast), although an upper size limit does exist (Chen et al. 1997;Krombach et al. 1997;Kinchen and Ravichandran 2008).Macrophages express a wide range of different receptors able to detect nonself particles. These receptors can be split into two groups: opsonic and nonopsonic. Opsonic receptors, such as the Fc receptor or complement receptor families (Flannagan et al. 2012), are able to recognize particles coated (opsonized) in antibody or complement (Johnston and May 2013). In contrast, nonopsonic receptors are pathogen recognition receptors (PRRs) that directly detect pathogen-associated molecular patterns (PAMPs) on the surface of microorganisms. Macrophages are heterogeneous in the receptors they express, and can change this repertoire when differentiating into different subtypes. For instance, the nonopsonic Dectin-1 receptor Once engulfment has been achieved, the macrophage must then digest the pathogen, now segregated into a phagosome (digesting vesicle). To complete the digestion, the phagosome must mature via the fusion of early and late stage endosomes and ultimately fuse with the lysosome, generating a phagolysosome (Kinchen and Ravichandran 2008). The phagolysosome uses vacuolar ATPases to pump H þ ions into the phagolysosome, reducing the pH. Once the pH is reduced sufficiently, acid-dependent proteases, such as cathepsin D, are activated to degrade the pathogen (Fig. 1) (Kinchen and Ravichandran 2008).Many human fungal pathogens have developed strategies to resist phagocytic attack, thus facilitating pathogenicity. The field of fungal research has exploded over the last three decades because of the increase in fungal-related illnesses that appears to correlate with the AIDS pandemic and more effective immunosuppressive medicines . Macrophages have been shown to play a role in resistance to disseminated candidiasis, although they are ...

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