Vaccine-Induced Immunological Memory in Invasive Fungal Infections - A Dream so Close yet so Far

Abstract

The invasive fungal infections (IFIs) are a major cause of mortality due to infectious disease worldwide. Majority of the IFIs are caused by opportunistic fungi including Candida, Aspergillus and Cryptococcus species. Lack of approved antifungal vaccines and the emergence of antifungal drug-resistant strains pose major constraints in controlling IFIs. A comprehensive understanding of the host immune response is required to develop novel fungal vaccines to prevent death from IFIs. In this review, we have discussed the challenges associated with the development of antifungal vaccines. We mentioned how host-pathogen interactions shape immunological memory and development of long-term protective immunity to IFIs. Furthermore, we underscored the contribution of long-lived innate and adaptive memory cells in protection against IFIs and summarized the current vaccine strategies.

Keywords: fungus; immunity; invasive infections; memory response; vaccine.

Figure 1

Differentiation of T-helper cells: During fungal infections, DCs present antigens to naive CD4 T cells. During DCs:T cells interaction, DCs produce cytokines which drives the differentiation of various Th subsets. For example, naïve CD4 T cells in the presence of IL-12 upregulate transcription factor T-bet and become Th1 cells. Similarly, IL-6, IL-1 and IL-23 aid in the differentiation of Th17 cells, which produce IL-17 family of cytokines. These subsets (Th1, Th2, Th17 and Tregs) by virtue of their cytokine production exert various effector functions, which modulates the immune response against the fungus. In the context to antifungal immunity, activated Th1 and Th17 cells migrate to the site of infection from secondary lymphoid organs and help in the fungal clearance.

Figure 2

Generation of innate and adaptive antifungal memory response: Following fungal infections, innate cells like neutrophils, monocytes/macrophages and NK cells infiltrate the infected organs and clear the fungi. During this process the monocytes/macrophages and NK cells undergo epigenetic and metabolic reprogramming to form innate memory cells in a process known as Trained immunity. Following initial innate response, naïve CD4 and CD8 T cells recognize fungal antigens in context to APCs and form effector cells, which aid in the clearance of infection. Once the infection is cleared most of the effector cells die leaving few CD4 and CD8 T cells to become long lived memory cells. The memory CD4 and CD8 T cells either reside in the secondary lymphoid organs or tissues and confer rapid protection following secondary fungal infections. B cells recognize antigen by the B cell receptor and signals derived from the antigen specific CD4 T cells in the T/B zone of the secondary lymphoid organs. Some activated B cells form short-lived plasmablasts while others enter germinal center (GC). In the GC, the B cells undergo clonal expansion, somatic hypermutation and class-switch recombination. Antigen selected B cells eventually differentiate into memory B cells or antibody secreting long lived plasma cells, which migrate to the bone marrow.

Figure 3

Research strategies to develop successful antifungal vaccines.