Macrophage Mediated Immunomodulation During Cryptococcus Pulmonary Infection

Abstract

Macrophages are key cellular components of innate immunity, acting as the first line of defense against pathogens to modulate homeostatic and inflammatory responses. They help clear pathogens and shape the T-cell response through the production of cytokines and chemokines. The facultative intracellular fungal pathogen Cryptococcus neoformans has developed a unique ability to interact with and manipulate host macrophages. These interactions dictate how Cryptococcus infection can remain latent or how dissemination within the host is achieved. In addition, differences in the activities of macrophages have been correlated with differential susceptibilities of hosts to Cryptococcus infection, highlighting the importance of macrophages in determining disease outcomes. There is now abundant information on the interaction between Cryptococcus and macrophages. In this review we discuss recent advances regarding macrophage origin, polarization, activation, and effector functions during Cryptococcus infection. The importance of these strategies in pathogenesis and the potential of immunotherapy for cryptococcosis treatment is also discussed.

Keywords: C.neoformans-macrophage interaction; Cryptococcus neoformans; cryptococcal evasion strategies; host immune response; macrophage.

Figure 1

Development of tissue resident macrophages: Tissue resident macrophages are derived from either blood monocytes or fetal yolk sac. Depending upon the signals they receive, they form tissue specific macrophages. PU.1 and macrophage colony stimulating factor are required for the differentiation into tissue resident macrophages. These tissue resident macrophages can be polarized into either M1 or M2 macrophages. M1 macrophages are activated macrophages which result in a Th-1 response (killing intracellular pathogen) whereas M2 macrophage are alternatively activated macrophages which result in a Th-2 response (wound healing, and tissue repair).

Figure 2

Possible outcomes of C. neoformans-macrophage interaction: Engulfment of C. neoformans results in containment within the phagolysosome and C. neoformans killing (shown in pink arrows). C. neoformans has multiple methods of interacting with host immune responses which include: (i) Intra-cellular proliferation, (ii) Dormant/latent, (iv) Titanization or exiting the macrophage via (A) exocytosis or (B) lateral transfer. Lateral transfer can also contribute to the dissemination of C. neoformans to the brain via Trojan horse mechanism.