Glial alterations in tuberculous and cryptococcal meningitis and their relation to HIV co-infection – A study on human brains

Abstract

Introduction: Tuberculosis and cryptococcal infection of the central nervous system are common AIDS-associated opportunistic infections in tropical underdeveloped and developing countries. To date, research on these infections has focused on clinical, imaging, laboratory diagnosis, and animal models to elucidate the pathogenesis. There is paucity of information on astroglial and microglial alterations in the human nervous system following these infections. Methodology: The pathomorphologic and morphometric alterations of astroglia and microglia in the prefrontal cortex and hippocampus in cases of tuberculous meningitis (TBM) and cryptococcal meningitis (CM) with and without associated HIV were described and compared with cases of HIV encephalitis without opportunistic infections (OI) and HIV-negative human brain tissue. Results: In TBM, the microglia and astrocytes were activated with hypertrophy and hyperplasia, aggregating in the subpial zone and around granulomas in meningeal exudate. In cases of cryptococcal meningitis, reactive changes were less prominent, though activation of both cellular elements was found. Association of HIV with these OIs resulted in muted glial and microglial response. In HIV encephalitis without OI, the level of activation of was low. Both astroglial and microglial cells expressed caspase-3, a pro-apoptotic marker, following HIV and opportunistic infections. Neuronal apoptosis, a mechanism to ensure neuronal survival, was less evident. The reactive astrocytes and microglia following opportunistic infection developed dystrophic changes heralding senescence. Conclusions: Further studies on neuronal-astroglial-microglial interaction will offer deeper insight into the pathogenetic and immune mechanisms in the cellular and pathomorphological evolution of tuberculous and cryptococcal infections.

Microglia in the Physiology and Pathology of Brain

“…Microglial nodules close to blood vessels and even flanking around the neurons were also evident. However, microglia were comparatively in low densities in the white matter [153]. Microglial phagocytosis was directly involved in the synaptic damage and neuronal death following human immunodeficiency virus-1 (HIV-1) associated neurocognitive disorders (HANDs) as described in the rodent model of HAND.…”

Neuroglia in Infectious Brain Diseases

“…Tuberculosis infects nearly one-third of the world's population, causing CNS infections in many of those patients (Tripathi et al, 2014). Tuberculous meningitis is thought to occur due to reactivation of latent infection in the choroid plexus and leptomeninges, particularly in the young or the immunocompromised (Peterson et al, 1995;Tripathi et al, 2014).…”

“…For example, MMP production, key in BBB dysfunction, and IL-1β production have both been shown to be greater in microglia exposed to supernatants of monocytes/macrophages infected with tuberculosis (Green et al, 2010;Harris et al, 2007;Lee et al, 2013). Human autopsy specimens have demonstrated robust astrocyte and microglial activation in response to tuberculosis in the CNS, with astrogliosis suggesting that the immune response was attempting to limit spread of infection and inflammation (Tripathi et al, 2014). Human autopsy specimens have demonstrated robust astrocyte and microglial activation in response to tuberculosis in the CNS, with astrogliosis suggesting that the immune response was attempting to limit spread of infection and inflammation (Tripathi et al, 2014).…”

“…In the case of IL-1β production, this effect is dependent on activation of the NLRP3 inflammasome and can be modulated by dexamethasone, which may explain the improved survival and reduced morbidity seen in human patients treated with steroids for CNS tuberculosis (Figure 8.1) (Lee et al, 2013). Importantly, this reactivity is decreased in patients with HIV infection, suggesting that the diminished inflammatory response may play a role in this population's increased risk of infection (Tripathi et al, 2014). Importantly, this reactivity is decreased in patients with HIV infection, suggesting that the diminished inflammatory response may play a role in this population's increased risk of infection (Tripathi et al, 2014).…”

“…Immunosuppressed or otherwise immunocompromised individuals can develop CNS infection with the encapsulated yeast Cryptococcus neoformans, typically manifesting as meningoencephalitis and associated with a high mortality rate (Casadevall, 2010;Lee et al, 1994;Lipovsky et al, 1997;Tripathi et al, 2014;Zuger et al, 1986). Infection is very common following inhalation of spores or organisms from the soil, but disease is rare in immunocompetent hosts (Casadevall, 2010;Tripathi et al, 2014).…”