Introduction
SARS-CoV-2 is a positive-sense, single stranded RNA in theCoronaviridae family of viruses1. While most
cases of infection present with mild to moderate symptoms consisting of
fever, fatigue, dry cough, headache, hypogeusia, anosmia, nausea and
diarrhea2; roughly 15% of patients develop a severe
disease phenotype requiring hospitalization, most commonly due to
dyspnea and hypoxia3,4. Laboratory findings of severe
infection include leukopenia, prolonged prothrombin time, and elevated
serum concentrations of D-dimer, lactate dehydrogenase (LDH), ferritin,
and c-reactive protein (CRP)5. Chest computed
tomography classically demonstrates bilateral ground glass
opacities1. Severe pathology associated with
SARS-CoV-2 infection involves a hyperactive immune response to the virus
resulting in a sudden, acute increase in pro-inflammatory cytokines,
termed “the cytokine storm”6. Key pro-inflammatory
cytokines upregulated in this process include interleukin 6 (IL-6) and
tumor necrosis factor-alpha (TNF-α)6. Elevated
cytokine levels prompt an influx of various immune cells into the site
of infection, leading to tissue destruction, acute respiratory distress
syndrome, septic shock and multiorgan failure7.
Several mRNA and adenovirus vaccines targeting the spike protein have
been approved8, but they appear to have reduced
efficacy against the multiple higher infectivity and immune evading
variants (e.g., spike protein mutations A222V, N501Y, or
E484K/N501Y/K417N) that have arisen9,10. Thus, general
SARS-CoV-2 therapies are needed. Early administration of monoclonal
antibodies to the spike protein, RNA-dependent RNA polymerase inhibitor
remdesivir and dexamethasone and late administration of enoxaparin may
modify the natural history of the infection11-15, but
additional treatments are needed. We previously reported the activity of
a ruxolitinib plus interferon combination16. In this
case report, we examine another combination that may show utility for
SARS-CoV-2 infections.
Well differentiated small intestinal neuroendocrine tumors arise from
serotonin-producing enterochromaffin cells and show epigenetic
alterations frequently leading to PI3K/mTOR
activation17. Upon metastases to liver and other
sites, serotonin escapes liver metabolism, and the carcinoid syndrome
occurs with flushing, diarrhea, and abdominal pain18.
Treatments include sandostatin analogues, telotristat ethyl,177Lu-DOTATATE, everolimus, sunitinib, interferon-α,
and surgical resection or ablation of metastases19.
Metastatic small intestinal NET patients have a 70% 5-year
survival20.
PI3K/mTOR pathway inhibitors have been proposed as a therapy to target
viral protein synthesis and the hyperinflammation associated with
SARS-CoV-221. mTOR is the serine/threonine protein
kinase catalytic subunit of the mTORC1 complex with LST8, PRA540 and
raptor. Targets of mTOR include phosphorylation inactivation of 4E-BP-1
and LARP-122,23. The result is release of eIF-4E
translation initiation factor and stimulation of cap-dependent,
5’-terminal oligopyrimidine tract viral RNA translation. SARS-CoV-2
proteins N and nsp1 assist in this seminal virus infectivity
step24,25. Inhibitors of mTOR block viral RNA
synthesis23. SARS-CoV-2 hyper-inflammation is
associated with the NLRP3 inflammasome containing the tripartite NLRP3
sensor protein, ASC adapter protein, and caspase-126.
Infection produces a “priming” signal with viral RNA binding and
signaling through Toll-like receptors or NOD-like receptors leading to
NF-κB nuclear translocation, and NLRP3 and procaspase gene
expression27. Then SARS-CoV-2 viroporins E, Orf3a and
Orf8a cause cellular potassium efflux, NLRP3 oligomerization, ASC
recruitment, and, finally, procaspase-1 recruitment and
cleavage27. Orf8b aids the steps by binding the
leucin-rich repeat domain of NLRP3 facilitating oligomerization.
Gasdermin D is cleaved by caspase 1 and pyroptosis occurs along with
inflammatory cytokine release. mTOR stimulates the NLRP3 inflammasome by
increased mitochondrial reactive oxygen species formation and inhibiting
autophagy28. As predicted, mTOR inhibitors inhibit
NLRP3 inflammasome induced hyper-inflammation in vitro andin vivo 29,30.
Interferons signal through cell surface interferon receptors to JAK and
STAT proteins and ultimately induce interferon-stimulated genes (ISGs)
that halt viral translation via protein kinase receptor (PKR) and block
viral NLRP3-induced inflammation via STAT131,32.
SARS-CoV-2 proteins block interferon activity via multiple pathways.
SARS-CoV-2 induced inflammasome caspases degrade interferon and
interferon signaling polypeptides33. Over a dozen SARS
CoV-2 proteins block early interferon induction or
activity31. Late in the natural history, infection is
associated with excessive inflammatory cytokinemia including interferons
with dysfunctional T and NK cell responses34.
We present the case of a 61-years-old male found to be SARS-CoV-2
positive who was relatively asymptomatic while taking everolimus for
co-existing metastatic neuroendocrine tumor but displayed a prolonged
period of nasal swab PCR positivity. Administration of pegylated
interferon was followed by prompt clearance of viral RNA by PCR. We
hypothesize that the combination of everolimus with interferon may be
useful in the acute COVID-19 setting to induce viral clearance with
reduced risk of cytokine storm.