The emerging links between immunosenescence in innate immune system and neurocryptococcosis

Abstract

Immunosenescence refers to the age-related progressive decline of immune function contributing to the increased susceptibility to infectious diseases in older people. Neurocryptococcosis, an infectious disease of central nervous system (CNS) caused by Cryptococcus neoformans (C. Neoformans) and C. gattii, has been observed with increased frequency in aged people, as result of the reactivation of a latent infection or community acquisition. These opportunistic microorganisms belonging to kingdom of fungi are capable of surviving and replicating within macrophages. Typically, cryptococcus is expelled by vomocytosis, a non-lytic expulsive mechanism also promoted by interferon (IFN)-I, or by cell lysis. However, whereas in a first phase cryptococcal vomocytosis leads to a latent asymptomatic infection confined to the lung, an enhancement in vomocytosis, promoted by IFN-I overproduction, can be deleterious, leading the fungus to reach the blood stream and invade the CNS. Cryptococcus may not be easy to diagnose in older individuals and, if not timely treated, could be potentially lethal. Therefore, this review aims to elucidate the putative causes of the increased incidence of cryptococcal CNS infection in older people discussing in depth the mechanisms of immunosenscence potentially able to predispose to neurocryptococcosis, laying the foundations for future research. A deepest understanding of this relationship could provide new ways to improve the prevention and recognition of neurocryptococcosis in aged frail people, in order to quickly manage pharmacological interventions and to adopt further preventive measures able to reduce the main risk factors.

Keywords: IFN-I dysregulation; aging; cryptococcal meningitis; inflammaging; vomocytosis.

Figure 1

Current model of the immune response to Cryptococcus in older and young health host. (1) Primary cryptococcosis stars when dehydrated spores are inhaled into the lungs of both immunocompetent and immunocompromised older hosts. This is followed by the phagocytosis of the spores by the alveolar macrophages. (2)This activation triggers three different immune-responses of macrophage: (3a) successful killing and clearance, resulting in no disease; (3b) evasion of phagocytosis, leading to either an asymptomatic state or localized infection, such as pneumonia; and (3c) survival within the macrophages through evasion mechanisms, often likened to “Trojan horses” (3d). During the latency stages, survival within macrophages and granuloma formation tends to be the predominant response. (4) In older hosts, reactivation occurs more frequently due to immune dysregulation. The spread of the pathogen beyond the respiratory system via vomocytosis leads to secondary cryptococcosis. (5) Cryptococcal cells, ejected through vomocytosis, enter the bloodstream and disseminate, resulting in a blood infection called cryptococcaemia. (6) After crossing the blood brain barrier, Cryptococcus migrates to the brain parenchyma and starts to proliferate, leading to fatal meningoencephalitis.

Figure 2

Immunological characteristics of the normal and the aging lung. (A). Normal lung. Surface barriers: their integrity contributes to protect against inhaled CC. Neutrophils: activated neutrophils produce ROS and contribute to recruitment and activation of macrophages and dendritic cells. Macrophages: M1 macrophages show a proinflammatory profile and express chemotactic activity and phagocytosis ability with free radical production. (B). Aging lung. Surface barriers: the decreased cilia motility is associated to higher risk of CC infection. Neutrophils, DC, and NK cells: reduced chemotactic activity, phagocytosis and ROS production. Macrophages: accumulation of M2 macrophages with anti-inflammatory profile. PC, proinflammatory cytokines; AC, anti-inflammatory cytokines; CC, Cryptococcal cells.

Figure 3

Age-related neurovascular changes in the brain parenchima and BBB. Progressive aging-related neurovascular changes in the BBB include mechanisms of inflammation mediated by the complement pathway (C3a/C3aR), with alterations to various components of the BBB structure as tight junctions, transporters, microglia, astrocytes and pericytes. (1). An increase in C3a/C3aR signaling promotes the over expression of VCAM1, and a dysregulation of CRTC1/cyclooxygenase-2. (2). The resulting inflammation promotes the recruitment of leukocytes across the BBB, and their interaction with endothelial cells. (3). The leukocyte-endothelial cell interaction increases the BBB permeability and induces the production of proinflammatory mediators, such as reactive oxygen species and cytokines. (4). Proinflammatory response leads to decreased tight junction proteins expression and conducts to peripheral immune cell infiltration. (5). Proinflammatory cytokines spread outside the vessels, induce the recruitment and activation of glial cells. (6). The accumulation of senescent astrocytes contributes to microglia activation, neuroinflammation and secretion of SASP factors, which communicate cellular damage to neighboring cells via autocrine/paracrine pathway. BBB, blood brain barrier; VCAM1, vascular cell adhesion molecule-1; CRTC1, CREB-regulated transcription coactivator 1.

Figure 4

Enhancement of vomocytosis via IFN-I mediated pathway. The different effects of IFN-I signaling, depending on ligand, dose, and duration of exposure. (1). The TLR-PAMP/DAMP interactions induce the selective recruitment of TRIF, which binds to the TLRs and then recruits a series of downstream signaling molecules, leading to IFN-I production. (2). TLR-PAMP/DAMP interactions induce TRIF to form a signaling complex with TRAF and this leads to phosphorylation of IRF3. (3). This phosphorylation event causes IRF3 to dimerize, translocating into the nucleus, and inducing the expression of IFNα and IFNβ. (4). Both secreted IFN-Is can bind IFNAR1/2 in an autocrine or paracrine manner and activate a signaling cascade leading to expression of ISGs. (5). In particular, the c-termini of IFNAR1 and IFNAR2 are associated with TYK2 and JAK1, respectively, and activation of the receptor transduces the phosphorylation of JAK1 and TYK2 by tyrosine phosphorylation. (6). This initiates a signaling cascade composed of proteins of the STAT family. (7). STAT1 and STAT2 proteins, activated upon JAK1 phosphorylation, dimerize and rapidly translocate to the nucleus, where they, together with IRF9, form a trimolecular complex called IFN-stimulated gene factor 3 (ISGF3). ISGF3 is a critical transcription factor complex involved in the cellular response to IFN-Is, particularly IFN-α and IFN-β. (8). This complex activates the transcription of ISGs. (9). However, IFN-I responses may also induce innate immune cells to act as “vomocytes”, giving rise to an ineffective fungal clearance which leads to a latent asymptomatic lung infection. In any case, this ISGF3 engagement by IFN-I production leads to activation of the inflammatory gene expression program, responsible for activation and/or exacerbation of inflammatory responses. Altogether, ISGs may produce, via JAK-STAT/IRF signaling network, distinct biological responses and sustained IFN-I signaling leads to chronic immune activation, inflammation and, consequently, immune exhaustion and dysfunction. Consequently, during infections, the effects of IFN-I signaling can be protective or detrimental, depending on the context, including pathogen species, infection route, and tissue specific features. DAMP, damage-associated molecular patterns; IFNAR1/2, IFN-α/β receptor; IFN-I, interferon; IRF, interferon regulatory factor; ISGs, IFN-stimulated genes; ISGF3, interferon stimulated gene factor 3; ISGF9, interferon stimulated gene factor 9; JAK1, Janus kinase; PAMP, pathogen-associated molecular patterns; STAT, signal transducer and activator of transcription; TRAF, TNF receptor-associated factor; TRIF, Toll/IL-1R domain-containing adaptor-inducing IFN-β; TYK2, tyrosine kinase 2.