ABSTRACT
Background COVID‐19 results in increased expression of inflammatory cytokines and Alzheimer's disease (AD) biomarkers of neuronal damage, but inflammation‐targeting clinical trials have yielded poor to mixed results. Our studies of other disorders with an inflammatory component, including AD, chemobrain, Down syndrome, normal aging, and West Nile Virus infection, showed that treatment with the ‘pro‐inflammatory' cytokine granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) in humans or mouse models alleviated clinical, behavioral, and pathological features. Most recently, we completed a Phase 2 clinical trial (NCT01409915) using sargramostim/Leukine (rhuGM‐CSF) in mild‐to‐moderate AD participants, which showed that three weeks of sargramostim treatment improved MMSE scores and improved ATN blood biomarkers of AD pathology (Potter et al., 2021). Therefore, we proposed that human GM‐CSF may be repurposed to promote both the innate and adaptive immune responses in COVID‐19 patients to reduce viral load and mortality. Method We investigated GM‐CSF's effects in eight‐week old male and female human ACE2 (hACE2) transgenic mice infected intranasally with 104 PFU of SARS‐CoV‐2 virus and followed them for 14 days. Mice received daily IP injections of either recombinant murine GM‐CSF or saline. Viral titers, anti‐spike protein antibody levels, and mortality were assessed. Results Intranasal inoculation of hACE2 transgenic mice with 104 PFU SARS‐CoV2 virus resulted in high viral titers in lungs and brains and over 85% mortality. GM‐CSF treatment beginning one day post‐infection increased anti‐spike protein antibody titers, lowered mean lung viral titers proportionately (p = 0.0020), and increased the odds of long‐term survival by up to 5.8‐fold (p = 0.0358), compared to saline. Conclusion GM‐CSF represents a new approach to the treatment of COVID‐19 by recruiting inflammation and the immune system to attack SARS‐CoV‐2 infection and promote survival. GM‐CSF is likely to have a significant advantage over current approaches to the treatment of COVID‐19, including anti‐virus monoclonal antibodies, drugs designed to inhibit viral replication, and immunosuppressants, because, unlike short‐term antivirals, it activates the endogenous immune system, with likely long‐term increases in immune memory required for protection against re‐infection, Based on its mode of action as a natural stimulator of the immune response, GM‐CSF should be effective against all current and future SARS‐CoV‐2 variants.
ABSTRACT
Reuse of disposable personal protective equipment is traditionally discouraged, yet in times of heightened medical applications such as the SARS CoV-2 pandemic, it can be difficult to obtain. In this article we examine the reuse of disposable gowns with respect to still providing personnel protection. XR7, a fluorescent powder, was used to track contamination of gowns after manipulation of rodent cages. Mouse cages were treated with XR7 prior to manipulations. Disposable gowns were labeled for single person use and hung in common procedure spaces within the vivarium between usages. A simulated rack change of 140 cages was completed using XR7-treated cages. One individual changed all cages with a break occurring after the first 70 cages, requiring the gown to be removed and reused once. To simulate research activities, 5 individuals accessed 3 XR7-treated cages daily for 5 d. Each mouse in the XR7-treated cages was manipulated at least once before returning cages to the housing room. Disposable gowns were reused 5 times per individual. Gowns, gloves, clothing, bare arms, and hands were scanned for fluorescence before and after removing PPE. Fluorescence was localized to gloves and gown sleeves in closest contact with animals and caging. No fluorescence was detected on underlying clothing, or bare arms and hands after removing PPE. Fluorescence was not detected in procedure spaces where gowns were hung. The lack of fluorescence on personnel or surfaces indicate that gowns can be reused 1 time for routine husbandry tasks and up to 5 times for research personnel. A method for decontamination of used gowns using Vaporized Hydrogen Peroxide (VHP) was also validated for use in areas where animals are considered high risk such as quarantine, or for fragile immunocompromised rodent colonies.