Fine Tuning the Cytokine Storm by IFN and IL-10 Following Neurotropic Coronavirus Encephalomyelitis

Abstract

The central nervous system (CNS) is vulnerable to several viral infections including herpes viruses, arboviruses and HIV to name a few. While a rapid and effective immune response is essential to limit viral spread and mortality, this anti-viral response needs to be tightly regulated in order to limit immune mediated tissue damage. This balance between effective virus control with limited pathology is especially important due to the highly specialized functions and limited regenerative capacity of neurons, which can be targets of direct virus cytolysis or bystander damage. CNS infection with the neurotropic strain of mouse hepatitis virus (MHV) induces an acute encephalomyelitis associated with focal areas of demyelination, which is sustained during viral persistence. Both innate and adaptive immune cells work in coordination to control virus replication. While type I interferons are essential to limit virus spread associated with early mortality, perforin, and interferon-γ promote further virus clearance in astrocytes/microglia and oligodendrocytes, respectively. Effective control of virus replication is nonetheless associated with tissue damage, characterized by demyelinating lesions. Interestingly, the anti-inflammatory cytokine IL-10 limits expansion of tissue lesions during chronic infection without affecting viral persistence. Thus, effective coordination of pro- and anti-inflammatory cytokines is essential during MHV induced encephalomyelitis in order to protect the host against viral infection at a limited cost.

Existing bitter medicines for fighting 2019‐nCoV‐associated infectious diseases

“…A cytokine storm is also a key event causing death in patients infected with coronavirus 2,47 . Thus, inhibiting overactive immune responses is very important for preventing cytokine storms 48 . Indeed, we found that TAS2R10 may help prevent a cytokine storm because it can regulate natural killer cell‐mediated cytotoxicity, chemokine signaling pathways, T cell receptor signaling pathways, TNF signaling pathways, and others (Figure 3).…”

Systemic sterile induced-co-expression of IL-12 and IL-18 drives IFN-γ-dependent activation of microglia and recruitment of MHC-II-expressing inflammatory monocytes into the brain

“…Our results show that peripheral inflammation is mediated by a cytokine storm including persistent high levels of IL-12, TNF-α and IFN-, along with a pronounced splenomegaly, which thereof became a distinctive trait, and more important, a control of an efficient treatment. Accordingly, it has been previously shown that an increase in IL-10 correlates with a protective role mediated by this cytokine, limiting an exacerbated inflammation induced by pro-inflammatory cytokines such as IL-12 (26) and IFN- (39). Besides, TNF-α was associated with hepatic toxicity and diminished mice survival when IL-12 cDNA was injected alone (32).…”

Neuropathogenic human coronaviruses: A review

“…Reports of neuromusculoskeletal disorders, complicating HCoV infections and COVID‐19, postulate that myopathies and neuropathies are a result of the significantly elevated inflammatory cytokines in patients' sera leading to virus‐induced immune damage 19,31,34 . This is further supported by evidence of immune‐mediated neurological conditions due to cytokine and chemokine release after HCoV infection as the disease progresses 21,24,44,45 . Another explanation could be the development of chronic illness myopathy (CIM), particularly in patients requiring mechanical ventilation for long periods 31 .…”

“…Old age, underlying comorbidities, and critical illness are identified as risk factors that are capable of producing serious neurological manifestations in COVID‐19 patients 19 . HCoV infections, in more vulnerable patients, can induce an exacerbation of underlying neurological conditions via virus‐induced neuro‐immunopathology 14‐16,44,45 . It has been recognised that patients with pre‐existing neurological diseases, such as myasthenia gravis, 18 cerebrovascular stroke, 17,19,20 Parkinson's disease, 17,40,41 multiple sclerosis, 17,40,42 and other demyelinating disorders, 17,40,41 may be at a higher risk of contracting infection with SARS‐CoV‐2 or experiencing severe manifestations of COVID‐19.…”