Intraocular inflammation is a rag bag of conditions, described often by their clinical presentation but also by the causative agent. Etiologically, IOI is described as infectious when an infectious agent can be detected, isolated, and/or cultured from the intraocular compartment/tissues and is seen to be the cause of tissue damage. Molecular diagnostics are increasingly helpful in detecting microbes (30). “Infectious” in general terms implies transmissibility but this does not occur in IOI unless the ocular surface and the surrounding adnexae are involved as in herpes zoster ophthalmicus (31) and SARS-CoV-2 conjunctivitis (32). For instance, cataract surgery in survivors of the highly infectious Ebola virus (33) did not lead to transmission of disease even though they had recent signs of IOI (34). Rarely, infectious agents can be transmitted via corneal allografts in unsuspected donor infection [e.g. Chikungunya (35), herpes simplex (36), and prion disease (37)] but this does not come under the typical classification of “infectious” IOI. In contrast, non-infectious IOI is the label for conditions in which no infectious agent can be detected.

The Standardisation of Uveitis Nomenclature (SUN) working group has sought to bring order to the descriptors for the range of syndromes collected under the umbrella of IOI, and defined sets of clinical criteria have been proposed for each condition mainly to facilitate a bioinformatic approach to clinical studies (38). The initial SUN criteria are based on anatomical descriptions relating to the location of the primary site of inflammation in the eye (39). The more recent subset classification has necessarily been more restrictive, and some cases of IOI will not fit the criteria for any specific clinical entity. However, the overarching concept retains the possibility that some individual conditions can present in a variety of ways such as tuberculous or syphilitic IOI and that pathogenetic tissue-damaging processes are common to many of the conditions. This is important to realise since the level of inflammation and damage varies with the tissue involved and its intrinsic degree of tissue tolerance (IP) (5).

We, and others (40–42), have argued that IP is relative: some tissues exert greater control over immune responses compared to others and that this applies particularly to CNS tissues. Thus, the retina and the brain parenchyma have a range of physical, chemical and immunological barriers which provide a high level of IP while border tissues such as the uveal tract and the meninges, with their rich complement of immune cells and ready access to draining lymph nodes have low levels of IP. The brain parenchyma (and presumably retina) in fact, have connections with the secondary lymphoid tissues (cervical lymph nodes) through drainage of interstitial fluids and cerebrospinal fluid (CSF) via the recently recognised brain glymphatic system and meningeal lymphatics (5, 10, 41). Tissues such as the cornea and sclera have intermediate levels of IP, mainly due to their low vascularity and limited expression of MHC molecules (43) as well as their content of immunomodulatory mediators (21). Indeed, corneal IP is readily rescinded by infection (44).

Several species of fungi can cause damaging inflammation in the eye and brain including Cryptococcus neoformans, Aspergillus spp., Histoplasma capsulatum, and Fusarium sp. Fungi are typically not dependent for replication on a mammalian host and usually survive and replicate environmentally. While many infections are exogenous, some are endogenous and occur only when the host is immunosuppressed, suggesting that the microbe is reactivated from a “dormant” state after subclinical invasion. Fungi require two conditions to establish overt tissue-damaging infection: dormancy and immunosuppression (46). Cryptococcus neoformans infection is contracted early in life and persists in myeloid cells in granulomas in the lung and draining lymph nodes asymptomatically. How they are released from infected lymph nodes to enter the circulation is poorly understood but they invade the CNS when they have passed from the circulation into the CNS border regions (uveal tract and meninges). Access to the retina and brain is usually via direct passage across the BBB/BRB (transcytosis) or more commonly, inside migratory leukocytes (Trojan Horse mechanism) (47).

How fungi achieve a state of dormancy (a state of greatly slowed but still functioning metabolism) varies somewhat with each organism. For instance, C. neoformans may be inhaled either as yeast or a spore, but while yeasts are killed after phagocytosis by lung macrophages, spores only weakly stimulate PRRs and so can persist for long periods of time in macrophages and dendritic cells within granulomas (48). Granuloma formation is an important mechanism in controlling C. neoformans and involves IFNγ− producing Th1 cells within the lesion. Yeast glucuronoxylomannan (GXM, 80%) and galactoxylomannan (GalXM, 10%) are the major capsular polysaccharides which influence the immune responses (49). As for the lung, it is likely that C. neoformans-containing uveal and meningeal granulomas persist for long periods undetected (latent infections) until protective immunity (~CD4/CD8/NK cell) declines to a point where it fails to prevent extrusion of replicating fungi from macrophages and entry into the CNS parenchyma. The fungus may also contribute to this process since GXM, shed from yeast has immunosuppressive properties, reducing immune cell entry into the CNS (50). In addition, fungal urease seems to be required for invasion of the CNS [reviewed in ref (51)].

Other fungi which cause endogenous CNS infections, such as Aspergillus, may follow a similar pattern of pathogenicity of latency/dormancy and disease when immune control declines (52). They may even invade the CNS locally along nerve endings from the paranasal sinuses through cribriform plate (53–56) a route also taken by some viruses such as Ebola and SARS-CoV-2 COVID -19 (see below). Pneumocystis carinii occurs in normal lung tissue and does not usually cause pneumonia unless the patient is severely immunocompromised (57, 58). Spread to the choroid can then occur to cause disease. Whether it can reside latently in choroidal macrophages is not known. However, fungi generally such as Candida (the most common fungal infection), Fusarium and Mucorales probably do not fall into the category of latent infections, unless they have progressed through a barrier-breaching invasive phase of infection e.g. in the lungs or gut, and have reached a second stage of immune evasion by persistence as dormant microbes within myeloid cells, controlled by an adaptive immune response. In the absence of this process, they are better considered to be commensals, symbionts or parasitic-but-potentially-infectious agents as defined by the DRF (18).

Toxoplasma gondii (Tg) is the most common parasitic infection of the eye and in some regions such as Brazil is the commonest cause of IOI (59). Infection is acquired at any age mostly through ingestion of infected meat. Serological evidence of exposure to Tg increases with age and in some countries can reach levels of 80-90% of the population. However, most individuals are asymptomatic, or experience only a mild GI disturbance (60, 61).

Ingestion of Tg cysts (bradyzoites/oocysts) leads to the release of large numbers of tachyzoites on contact with digestive enzymes which rapidly invade the blood and lymphatic circulations. Tachyzoites disseminate freely or inside infected dendritic cells induced by the Tg 14-3-3 protein (62), and generate a marked IFNγ Th1 response in draining lymph nodes. Both free or leukocyte-internalised tachyzoites invade muscle tissue and cross the BRB/BBB to infect neurons where they are induced to transform to bradyzoites via formation of a parasitophorous vesicle. In this state they are considered to have entered a prolonged phase of latency, but in fact there is a low level of Tg replication within bradyzoites (63). Replication is inhibited by the continuous production of antigen-specific CD8 T cells which require CD4 T cells to “help” their generation (64). Reactivation of latent CNS Tg thus depends on failure of both CD4 and CD8 T cell responses (65). In addition, recent studies in Balb/c mice have shown that a specific peptide from Tg, Gra6, binds an unusual MHC Class I molecule, MHC-1 L(d), to enhance CD8 T cell protection against Tg reactivation (66, 67). Other cells are also involved in this CNS protective response: astrocytes and oligodendrocytes release IL33 in Tg infected brains (66) and probably also in Tg infected eyes (68), and is required for control of infection via chemokine-induced recruitment of immune cells, while microglial production of gasdermin adds a further layer of immune protection (69). Thus, the complexity of the immunological machinery required to keep Tg bradyzoites in latency is critically dependent on the CNS microenvironment.

Other latent parasitic infections affecting the eye are unusual. Malaria, giardiasis, leishmaniasis, and trypanosomiasis have all been reported, and ocular disease occurs often long after the initial infection, raising the possibility of an initial asymptomatic infection and sequestration of parasites in the eye. For instance, it is estimated that up to 33% of patients with giardiasis develop late extraintestinal manifestations including ocular disease (often in the form of retinal vascular occlusion and/or uveitis) and arthritis [reviewed in ref (70).]. The pigmentary degeneration which is characteristic of late ocular disease suggests that the parasite may reside latently in the retinal pigment epithelium (RPE) (71, 72).

Numerous other parasites, nematodes, cestodes and trematodes, as well as helminths are known to cause ocular infections [reviewed in ref (73)], but most would not be classified as latent infections. However, they often induce minimal inflammation as in the case of intraocular loiasis (74) or in cases of DUSN (75) prior to onset of symptoms, and the invading parasites (e.g. Loa loa) might be regarded as having a symbiotic, mutualistic or even a commensal relationship with the intraocular compartment. In another tissue, such parasites would likely induce a vigorous immune response and be rapidly cleared by the immune system.

A large number of viruses, both DNA and RNA, are recognised to establish latent CNS infections and cause CNS inflammation and IOI when reactivated. Top of the list are herpes viruses including HSV-1 and HSV-2, VZV, CMV and EBV. Herpes viruses have tropism for particular cells (neurons: HSV, VZV; myeloid cells: CMV; B cells: EBV; T cells: HIV) and reside in CNS cells or in leukocytes populating the CNS border regions (uvea, meninges). They infect neighbouring cells by shedding virus-containing exosomes (76). CMV establishes latency in haemopoietic cells and renders them inactive/anergic (77) thereby promoting latency (78). Reactivation of most DNA viruses occurs in immunosuppressed or immunodeficient patients indicating that latency and control of reactivation is actively mediated by the immune system. Interestingly, as for parasites, control is achieved through CD8 T cell activity (79).

EBV has been implicated in the pathogenesis of multiple sclerosis (MS) for many years. Despite evidence of EBV in the brains of MS patients (80), resistance to this concept has been long standing (81, 82) in part because EBV infection is so ubiquitous [EBV seropositivity is present in over ~85% of the population (83)]. However, a recent extensive study in US military personnel of the relationship between EBV antibody seroconversion and newly onset MS strongly suggests that EBV is required as a trigger for MS disease (84), and that certain specific proteins (EBER, EBNA-1) act as molecular mimics of CNS proteins such as glial CAM (85) and anoctamin 2 (86). As indicated above, EBV latently infects B cells, which account for ~20% of immune cells in the immune cell rich meninges. MS patients consistently develop B cell granulomas in the meninges which extend into the subarachnoid space and pial meninges lining the cortex where the inflammatory damage and virus spreads to glial cells and oligodendrocytes, eventually affecting axonal transport and neuronal function (87–89). Reactivation of EBV in situ would thus cause extensive damage at the cortical level.

RNA viruses such as Ebola, Chikungunya (90), Rubella (91), Dengue (92), Measles (93), Zika (94) and more recently SARS-CoV-2 are known to persist in the CNS and are recognised causes of IOI in survivors from the primary infection (95). Here, the definition of latency is less clear. Current thinking is that such viruses develop persistence (i.e. low-level replication) rather than latency, as in the case of Ebola which persists as a slowly replicating virus in the RPE (96). Even with vaccination, Ebola can persist and reactivate with dire consequences (97).

Latent HIV persists in CNS microglial reservoirs (98) and can cause retinopathy. CNS HIV persistence can impinge negatively on efficacy of treatment (99). The retrovirus HTLV-1, a world-wide cause of IOI (100, 101), reactivates when the immunoregulatory aryl hydrocarbon receptor (Ahr) (102) IDO system is functional: reactivation is controlled by the level of Ahr ligands and balanced by persistent activation of NF-кB (103). Thus, this immunoregulatory system, which is active within the immune-privileged eye (104, 105), may determine whether HTLV-1 induces uveitis. Like Ebola and RNA viruses generally, HTLV-1 persistence is maintained by low level replication and in the CNS microenvironment is at risk of reactivation. As for most viral infections, HTLV-1 is a “life-long infection which is never truly silent” (106).

Interestingly, “subclinical” virus reactivation in the form of viral shedding (for instance in the urine) is a common phenomenon and is exacerbated by many forms of stress (107).

Mycobacterium tuberculosis (Mtb) is the paradigmatic cause of latent bacterial infection involving the CNS. The disease is contracted as an airborne lung infection and produces two forms: caseating tuberculosis when the organism is replicating and causing tissue necrosis, and immunoreactive TB where replicating Mtb is held in check by a prominent immune response. The latter takes the form of a granuloma, either in the lung or in the draining lymph node (108) and, as for many microbes, the organism evades direct attack by the immune system by residing in myeloid cells (macrophages and DC) where it disables the lysosomal killing machine (109). Viral co-infection promotes survival of Mtb in macrophages by co-opting TNFα to reduce T cell priming (110). However, intracellular Mtb proliferation is controlled by a CD4 T cell response but this is a complex interaction between the host and the pathogen and this immune response may be either protective or pathogenic (tissue damaging) (111). Infected myeloid cells, or, in the absence of CD169, their shed extracellular vesicles (112), escape the granuloma and disseminate to cause extrapulmonary TB (miliary TB) with a predilection for CNS border tissues. This presents as TB meningitis and choroiditis and is typically contained as a granulomatous immunoreactive inflammation. However, when immune dysregulation looms, caseation and tissue necrosis within a “tuberculoma” can occur ( Figure 1 ). Ocular TB is a classic example of latent infection safely sequestered in macrophages: latent TB IOI disease in its miliary form does not contain replicating bacilli while the choroidal tuberculoma may contain replicating microbes and be “infectious” in the true sense.

TB is widespread: one third of the world’s population have been infected with TB, most of whom survive the disease and present with latent TB, demonstrated by a positive skin test (TST, Mantoux) and/or interferon gamma release assay positivity (Quantiferon test). These tests indicate that the patient has been prior infected by Mtb and probably that the tubercle Bacillus is resident in the host with the capability to induce pathology even though the lung may have cleared the infection (113). Latent TB is long-lasting and clearance of Mtb is probably never complete (113, 114). Disease reactivation involving the CNS parenchyma occurs particularly in states of relative immunosuppression but is more commonly restricted to the CNS border regions. Despite large numbers of latently infected people, <10% develop overt disease: this suggests that persistence of latent Mtb is the norm in immunocompetent individuals and that the site of latency is frequently the CNS border regions (meninges and uveal tract).

Other latent bacterial infections in the eye are uncommon. Treponema pallidum becomes “latent” (i.e. clinically silent) after resolution of the primary and secondary stages and manifests itself in the tertiary stage in the CNS and eye. During latency, control of spirochete replication is maintained by a robust immune response such that progression from the latent stage to the tertiary stage is not inevitable, occurring in around 15-40% of cases (115). Patients in the latent stage who do not progress may have cleared the infection (with the help of antibiotic therapy) but may also harbour non-replicating spirochetes. Interestingly, the spirochete traverses the blood-CSF barrier without causing neurological disease in the early stages (116), resides in the CNS border regions during the latent period (117) and can be detected by CSF PCR technology (118, 119).The same occurs with Borrelia Burgdorferi, the tick-borne etiologic agent of Lyme disease and a rare cause of IOI (120). Another tick-borne disease, Rickettsia, has been reported to cause “epidemic rickettsia retinitis”. Such cases develop as a later event after the primary infection and are diagnosed by the serological Felix-Weil test (121). However, such cases probably do not fit the diagnosis of latent infection. Bartonella ssp., a further vector borne pathogen can cause IOI in rare cases, and can present in various forms including serpiginous choroiditis (122). Lastly, certain cell wall deficient and mycoplasma-like organisms have been reported in chronic intermediate uveitis, but their nature is obscure (123, 124).

Intermediate uveitis includes the subgroups pars planitis, vitritis, and the peripheral retinal vasculitis of MS. The retinal parenchyma is not generally involved. All of the above classes of microbes have been associated with intermediate uveitis (90, 128–132). Latent tuberculosis has been implicated in peripheral occlusive retinal vasculitis (previously known as Eales’ disease) (133–135), while latent EBV infection is a strong candidate for the same pathology in MS (84, 136). Pars planitis with or without snowbanking has been linked to parasitic infections such as toxocariasis (137) while vitritis has long been associated with low level infections with mycoplasma and other cell wall deficient bacteria (138, 139).

Increasingly, viral aetiologies have been identified for many cases of chronic, recurrent uveitis including rubella, VZV, CMV and HSV-1 and HSV-2. Patients recovering from Ebola and Zika virus infection develop recurrent/chronic anterior uveitis (see above section on viruses). M. tuberculosis and sarcoidosis are known causes of granulomatous uveitis; while Mtb has not be definitively identified as the cause of sarcoidosis, the disease has been linked to atypical mycobacterial infection (140). On a different note, HLA B27-associated acute anterior uveitis is associated with a disturbed microbiome in which translocating gut commensals have been incriminated (141, 142).

Retinitis can be caused by all classes of microorganism described above. However, the AIDS epidemic brought viral infections as a cause of retinitis to attention particularly CMV, HSV-1 and HSV-2 and VZV. Exposure to these viruses is widespread in the population (see above section on viruses). Initial infection occurs early in life and latent infection is controlled by the immune system for the lifetime of the host. CMV resides in myeloid cells in the uveal tract and can pass to RPE cells by direct spread. CD8+ T cells control latent virus which replicates slowly and spreads contiguously in a brush-fire or patchy fashion when CD4/CD8 T cell immunity is impaired (143).

Choroiditis as a discrete entity is uncommon and takes several clinical forms including multifocal choroiditis and serpiginous choroiditis. Tuberculosis is strongly implicated in serpiginous disease (144) while several infectious aetiologies have been linked to cases of acute posterior multifocal placoid pigment epitheliopathy (APMPPE) (145–153).