Neuro-Immune Interactions in Severe COVID-19 Infection

Abstract

SARS-CoV-2 is a new coronavirus that has affected the world since 2019. Interstitial pneumonia is the most common clinical presentation, but additional symptoms have been reported, including neurological manifestations. Severe forms of infection, especially in elderly patients, present as an excessive inflammatory response called "cytokine storm", which can lead to acute respiratory distress syndrome (ARDS), multiorgan failure and death. Little is known about the relationship between symptoms and clinical outcomes or the characteristics of virus-host interactions. The aim of this narrative review is to highlight possible links between neurological involvement and respiratory damage mediated by pathological inflammatory pathways in SARS-CoV-2 infection. We will focus on neuro-immune interactions and age-related immunity decline and discuss some pathological mechanisms that contribute to negative outcomes in COVID-19 patients. Furthermore, we will describe available therapeutic strategies and their effects on COVID-19 neurological symptoms.

Keywords: aging; inflammatory responses; lymphopenia; neurologic symptoms; neuro–immune interactions; renin-angiotensin system; severe COVID-19.

Figure 1

COVID-19 and potential routes to the CNS. (A) Olfactory route. SARS-CoV-2 may reach the cribriform plate and olfactory bulb through olfactory nerve projections and gain access to the brain [53,54]. This hypothesis is supported by the presence of SARS-CoV-2 RNA in olfactory mucosa and the neuroanatomical area receiving olfactory tract projections [55]. (B) Vascular endothelium route and blood–brain barrier disruption. Another possible viral route to the nervous system starts from the interaction between SARS-CoV-2 and the vascular endothelium expressing ACE2. The binding of SARS-CoV-2 to ACE2 can induce an increase in vascular permeability and blood–brain barrier disruption [62]. In addition, cytokine and inflammatory mediators transported through the circulatory system might affect the integrity of the blood–brain barrier [63,64]. (C) Transneuronal route from the lungs involves a potential SARS-CoV-2 neuronal retrograde dissemination from the lungs. Because the vagal nerve innervates lungs, the virus may use it to gain access into the brain [70,71], as SARS-CoV-2 has been detected in the vagal nerve fibres [72].

Figure 2

Aging and severe COVID-19: possible roles of immune system effects, brain environment and other age-related dysfunctions. Age is one of the most important risk factors for severe forms of infection [170,171]. Each of age-related immune system changes [175,176,181] reported in yellow on the left side of the figure could contribute to the dysregulation of immune responses against the virus. In addition, comorbidities [184] and other age-related dysfunction can contribute to the risk of developing severe forms of SARS-CoV-2 infection, as shown in blue at the top of the figure. The effects of aging on the brain environment are reported in red on the right side of Figure 2, including alterations in neuronal and microglial activities and dysfunction of the blood–brain barrier [179,193]. Thus, age-related immunity dysregulations and brain environment alterations might play a role in the pathogenicity of disease, supporting neurological involvement in severe COVID-19 infection.