The immune cytokine granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) is an effective treatment for both Alzheimer’s disease and the viral diseases caused by West Nile Virus and SARS‐CoV‐2 infection, indicating that inflammation and viral infection may be partners and therapeutic co‐targets in many brain disorders

Abstract

AbstractBackgroundGM‐CSF has been considered a potential therapeutic target in many disorders associated with inflammation because it is upregulated and upregulates other inflammatory molecules such as IL‐1, IL‐6, and TNF‐a. However, its ability to increase the number and activation of phagocytic cells in the periphery and brain suggested to us that its upregulation in rheumatoid arthritis (RA) might underlie the finding that RA protects against another inflammatory disorder, Alzheimer’s disease (AD) by aiding phagocytosis of amyloid deposits. Treatment of mouse models of AD with GM‐CSF reverses amyloid deposition and normalizes cognition. A double‐blind placebo‐controlled phase II trial showed that three weeks of treatment with human recombinant GM‐CSF (sargramostim) in mild‐to‐moderate AD participants led to improved cognition (MMSE) and blood biomarkers of amyloid, Tau, and neurodegeneration (A+T+N). GM‐CSF/sargramostim treatment is also efficacious in humans and/or animal models with other inflammation‐associated diseases/disorders (Parkinson’s disease, Down syndrome, chemo‐brain, and normal aging).MethodBased on findings that innate immunity and microglia underlie viral control, we investigated GM‐CSF in a mouse model of West Nile Virus encephalopathy and a mouse model of SARS‐CoV‐2/COVID‐19. C57BL/6 mice were infected by footpad injection of 1,000 pfu of WNV (TX2002‐HC strain). ACE2 receptor Tg mice were infected with 4,000 pfu of SARS‐CoV‐2 by nasal instillation. Mice were treated IP daily with 5 mg of recombinant GM‐CSF starting the day after infection and analyzed for pathology, morbidity, and mortality at death or at sacrifice at 2 weeks. The SARS‐CoV2‐infected mice were also analyzed for viral titers in brain and lung.ResultGM‐CSF treatment improved survival in both the WNV and SARS‐CoV‐2 models. SARS‐CoV‐2 viral titers in affected tissues, including brain, were greatly reduced by GM‐CSF treatment.ConclusionBy activating both the innate and adaptive immune systems, GM‐CSF may be an effective therapy for viral diseases and may protect against viral re‐infection more effectively than antiviral drugs or monoclonal antibodies, a serious concern during the COVID‐19 pandemic. These results also challenge the belief that inflammation in these disorders contributes essentially to the disease. It is possible that the anti‐viral activity of GM‐CSF may also underlie some of its efficacy in AD.