Abstract
The fungal pathogen Cryptococcus neoformans can infect the central nervous system (CNS) and cause fatal meningoencephalitis, which accounts for an estimated 180,000 deaths per year. Cryptococcal meningoencephalitis (CM) occurs mainly in the individuals with compromised immune systems. Thus, cryptococcal disease in the CNS has been predominantly attributed to insufficient immune responses and subsequent uncontrolled fungal growth. However, evidence has emerged that an inappropriate immune response, as much as an insufficient response, may promote clinical deterioration and pathogenesis. In this chapter, we will review the different types of immune responses to C. neoformans and their contribution to tissue damage and diseases.
Keywords
- Cryptococcus neoformans
- pathogenesis
- immune pathology
1. Introduction
The human fungal pathogen
Cryptococcal infections usually manifest in patients who are immunocompromised secondary to HIV infection, cancer therapies, or organ transplantation [3]. This has led to the characterization of
This evidence challenges the view that cryptococcal disease is a consequence of a compromised immune system. Instead, the outcomes of cryptococcal disease can be better understood as a balance of
2. Cryptococcal immune reconstitution inflammatory syndrome
Antiretroviral therapy (ART) in AIDS patients rapidly restores host T cell responses. However, in a portion of patients it leads to a highly lethal complication, cIRIS, which is defined as a paradoxical clinical deterioration after initiation of ART, despite efficient control of fungal infection [28]. cIRIS occurs in 15–30% of HIV-infected individuals with cryptococcosis [28, 47]. Similarly, patients who undergo immune suppressive regiments during bone marrow transplantation or autoimmune diseases can develop cIRIS like syndromes once the host immune response is restored when immunosuppressive therapy is tapered [48]. Previous studies have found that paucity of initial CSF inflammation, low IFN-γ levels, and high fungal loads are risk factors for the development of IRIS [27, 45]. During cIRIS, the immune response in the brain is characterized by excessive activation of Th1 CD4+ subsets with elevated production of cytokines including IFN-γ and TNF-α [27, 33, 49].
While the exact pathogenic mechanisms of IRIS have not been unraveled, the lymphopenic environment during HIV infection may result in abnormal function of residual CD4 T cells, rendering them more pathogenic as the population expands after ART [50]. Furthermore, it has also been proposed that there exists a decoupling of innate and adaptive immune responses in AIDS patients prior to ART due to deficient T cell responses, which sets the stage for excessive inflammation after T cell reconstitution. Indeed, several lines of evidence show that mononuclear immune cells are implicated in cIRIS. Predisposition to cIRIS has been shown to be associated with higher CCL2/MCP-1, CCL3/MIP-1α, and GMCSF production in the CSF, which promotes trafficking and activation of macrophages in the infection sites [45]. Patients with cIRIS had increased numbers of proinflammatory intermediate monocytes (CD14highCD16+) which produce reactive oxygen species [51, 52]. Although macrophages can be primed by fungal pathogens in AIDS patients prior to ART, they never become fully activated in the absence of T cell help to exert their effector functions in fungal clearance. This results in high levels of pathogen replication as the disease progresses. Nevertheless, increasing numbers of primed macrophages accumulate and create a state of immunological hyperresponsiveness to the subsequently CD4+ T cell help. ART rapidly restores Th1 type response in the host with high level of IFN-γ production. Large numbers of primed macrophages then become fully activated to produce an acute spike in proinflammatory mediators, which may drive immunopathology during cIRIS. Thus, macrophage activation in cIRIS may act in concert with T-cell responses resulting in tissue-destructive inflammatory responses.
The mechanisms of tissue damage by host inflammation during fungal infections are still under active research. Macrophage or T cell production of TNF-α, IL-1β, reactive oxygen species (ROS) and nitrogen species (RNS), may contribute to irreversible tissue damage and/or lead to neuronal apoptosis [53, 54, 55].
3. Postinfectious inflammatory response syndrome
Another example showing that strong host immune responses during
4. Animal models of IRIS and PIIRS
Detrimental roles for immune responses in the pathogenesis of cryptococcus-associated IRIS or PIIRS have also been recently demonstrated in experimental mouse models. A recent study in our lab established a reproducible mouse model of CM using C57BL/6 mice infected intravenously with 106 CFU of
Brain cellular inflammation, marked by leukocyte accumulation after 21 dpi and dominated by CD4+ T cell infiltration, plays an important role in the pathology of the CNS in cryptococcal-infected mice. Similar to human patients with IRIS and PIIRS, infiltrating CD4+ T cells in brains of cryptococcal-infected mice exhibit a Th1-type bias and produce high levels of IFN-γ. Critically, the influx of immune cells into the CNS after 21 dpi was synchronized with the onset of fungal clearance, development of neurological symptoms, and mortality. The depletion of CD4 + T cells leads to a reduction in mortality and inflammatory pathology, providing conceptual evidence that CD4 + T cells are a principal mediator of inflammation and pathology in this model. Notably, over the course of the study, the survival of CD4+ T cell depleted mice significantly improved despite having higher fungal loads in the CNS compared to mice with sufficient CD4+ T cells (Figure 1). Depletion of CD4+ T cells during CM also broadly inhibited all other aspects of the CNS inflammatory response, including accumulation of CD8+ T cells and CD11b + Ly6C+ myeloid effector cells. Taken together, these data strongly support the idea that CD4+ T cells exert dual but opposing roles during CM: promoting the elimination of the fungal pathogen in the CNS but simultaneously driving tissue damage, neurological deterioration, and death.
Another animal model has also demonstrated the pathological role of CD4+ T cells in cIRIS. Eschke and colleagues reconstituted RAG−/− mice, which are deficient in T and B cells, with WT CD4+ T cells after infection with
5. Host immunity to C. neoformans infection: protective or non-protective, the yin and yang
Protective immunity is conferred by a fine balance between immune responses that eliminate the pathogen and those that limit host damages. However, an immune response induced by the pathogen may be non-protective for any one or combination of the following reasons: (1) it could occur in the wrong location or timeframe, promoting inflammatory injury without effective clearance of pathogens; (2) it could be too strong and cause immunopathology despite control of pathogen burden; 3) regulatory mechanisms meant to maintain host tissue integrity may lead to microbial survival and persistence and thus result in chronic inflammation. Below, we describe cellular and molecular mechanisms by which dysregulation of immune responses contribute to host disease during infection with
5.1 Host immune responses contribute to fungal clearance but also tissue damage
Upon infection,
Although generation of the Th1/Th17 response and subsequent M1 activation play a critical role in controlling fungal growth, excessive immune responses can become destructive and cause lung immunopathology following fungal infection. Recent studies demonstrated that FADD and RIPK3 proteins, which are mediators of death receptor-triggered extrinsic apoptosis, play a crucial immune regulatory role in preventing excessive inflammation during
DCs play a critical role in modulating host antifungal responses. Distinct PRRs and intracellular signaling pathways in DCs help to define the immune response to fungal pathogens [95]. Studies from Bonifazi
5.2 Host immune responses normally associated with homeostasis can contribute to fungal persistence
Cryptococcal virulence includes evasion of immune recognition, interference with phagocytosis, and modulation of host immune responses [56, 99]. Many fungal factors have been shown to promote allergic Th2 or Treg responses. These types of responses are characterized by alternatively activated macrophages and may promote uncontrolled fungal growth [56]. However, the regulatory immune response is also crucial for maintaining host tissue homeostasis and limiting the inflammatory responses that can cause tissue damage.
IL-4 and IL-13 provide the most potent proximal signals for Th2 cell polarization [13, 17, 103]. The epithelial-derived cytokines thymic stromal lymphopoietin (TSLP), IL-25, and IL-33 have been shown to regulate the development of Th2 response during asthma [104, 105]. A time-dependent increase in IL-33 expression in the lungs has been found during
While Treg may lead to pathogen persistence, they can actually be beneficial in protecting against immune-mediated damage to the host. This has been demonstrated in diseases caused by
IL-10 is a critical effector molecule involved in the immunoregulatory functions of Treg cells [125]. IL-10 has been reported to inhibit production of cytokines such as IL-1, IL-6, IL-23, IFN-γ, TNF-α and chemokines including CCL2(MCP-1), CCL12(MCP-5), CCL5(RANTES), IL-8, CXCL10(IP-10), and CXCL2(MIP-2) [126]. During
The roles of Tregs in the CNS during fungal infection, however, remain less studied. One report shows an increase in the abundance of Treg cells within cIRIS patients [134]. Further clinical and animal studies are needed to investigate the functions of Tregs during fungal CNS infections.
6. Conclusions and future directions
A tightly-regulated balance between inflammatory and regulatory mechanisms is required to control fungal infection, maintain host homeostasis, and ultimately develop protective immunity (Figure 3). Recent studies have demonstrated that disease and mortality in cryptococcal infection can result from either uncontrolled fungal growth due to defective host immunity, or excessive host inflammation. As the spectrum of hosts with cryptococcal disease expands, it is critical to understand and distinguish pathology caused by the pathogen or host responses. For example, additional suppression of weak immunity by steroid therapy in patients with uncontrolled fungal growth may lead to enhanced fungus-mediated damage and mortality in HIV-associated cryptococcal patients [135]. Instead, adjunctive IFN-γ therapy to bolstering immunity in these patients has the potential to ameliorate fungus-mediated damage and mortality [136]. However, in cIRIS patients, who experience inflammation-mediated tissue damage and mortality, corticosteroids can be effective to control disease-related deterioration [30]. Furthermore, mounting evidence implies that the top priority for cIRIS and PIIRS is to control the devastating immunopathology. Thus, comprehensive therapeutic strategies that take fungus- and host mediated damage into account could have the potential to significantly improve therapeutic outcomes.
Recent studies have identified the involvement of a number of immunopathogenic mechanisms including CD4+ T cells. However, the function of CD4 T cells overlaps with the mechanisms required for fungal clearance. Little is known about whether it is possible to uncouple the anti-fungal host defense mechanisms from the host immune responses that mediate deleterious immunopathology. One of the future directions in this research field is to identify mechanisms that are not required for fungal clearance but are major culprits in immunopathology which could be promising targets for future immunotherapies.
Acknowledgments
The authors thank Mr. Mack Reynolds for thoughtful edit of the manuscript.
This work was supported in part by the Intramural Research Program of the NIH, NIAID, AI001123-01 and AI001124-01 to PRW and Veterans Administration Merit Review Awards to M.A.O. (1I01BX000656) and VA RCS Award M.A.O. (1IK6BX003615).
Conflict of interest
The authors declare that there is no conflict of interest regarding the publication of this article.
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