Fig. 3

Mechanisms implicated in neurological complications after infection. In COVID-19, SARS-CoV-2 can access the brain by a trans-synaptic route and also through endothelial and lymphocyte invasion, resulting in neuroinflammation. Lower thrombin, higher D-dimer, fibrin/fibrinogen degradation products, and fibrinogen levels are frequent in COVID-19, and activation of the coagulation cascade may contribute to the development of stroke and cerebrovascular accidents. Brain-lung crosstalk is an axis involved in brain hypoxia due to systemic oxygenation reduction and, subsequently, secondary brain oxygenation damage. In sepsis-associated encephalopathy, the cytokine storm leads to endothelial activation and increased eNOS activity, which results in nitric oxide (NO) production, leading to hypotension and ischemic lesions. Cytokines trigger glial reactivity, reactive oxygen species (ROS) production, mitochondrial dysfunction, and neurotransmitter imbalances, with consequent glutamate excitotoxicity. In malaria infection, there is an exacerbated inflammatory response to the parasite and activation of multiple cell death pathways leading to microcirculatory damage. Endothelial dysfunction, platelet activation, cytoadherence, and a downregulation of normal endogenous anticoagulant pathways are hallmarks. Dysregulation of the coagulation pathway leads to microvascular lesions; thrombin may be implicated. In the process of hemoglobin digestion, the malaria parasite releases heme and aggregates it into hemozoin, a highly toxic and proinflammatory signaling molecule. Hemozoin and free heme released into the bloodstream lead to exacerbated inflammation, tissue damage, apoptosis of microvascular brain endothelial cells through activation of STAT3, and loss of BBB integrity through binding to the metalloproteinase MMP3. The proinflammatory milieu leads to microglial M1 phenotype activation, release of proinflammatory cytokines, astrogliosis, axonal injury, and increase in synapsin I. In influenza infection, there is a peripheral inflammatory response and release of several proinflammatory mediators, including interferons (IFs), interleukins (ILs), tumor necrosis factor (TNF), and chemokines. Both neurotropic and non-neurotropic strains of influenza are able to induce neuroinflammation, with microglial activation, decrease in neurotrophin levels, and increase in IFN-α and other proinflammatory cytokines