5. Type I IFNs and COVID-19
Type I IFNs play an essential role in fighting viral infections, and
deficiencies in type I IFN signaling have been associated with poor
outcomes from COVID-19 in multiple studies. These cases are often
associated with autoantibodies to type I IFNs. As reviewed below, type I
IFNs have been used with some success in treating severe COVID-19,
particularly if administered very early in the disease process. If, as
argued above, the mRNA vaccines interfere with type I signaling, this
could lead to increased susceptibility to COVID-19 in the two weeks
following the first vaccine, before an antibody response has been
initiated.
Cells infected with a virus detect the presence of virus replication
through a number of pattern recognition receptors (PPRs), which serve as
sentinels sensing aberrant RNA structures that often form during viral
replication. These receptors respond by oligomerizing and subsequently
inducing type I IFNs, ultimately upregulating a large number of proteins
involved in suppressing viral proliferation [100].
A multi-author study by researchers in Paris, France, involving a cohort
of 50 COVID-19 patients with varying degrees of disease severity,
revealed that patients with severe disease were characterized by a
highly impaired type I IFN response [101]. These patients had
essentially no IFN-β and low IFN-α production and activity. This was
associated with a persistent blood viral load and an exacerbated
inflammatory response, characterized by high levels of tumor necrosis
factor α (TNF-α) and Il-6. The authors proposed type I IFN therapy as a
potential treatment option. A paper by several researchers in the United
States also identified a unique and inappropriate inflammatory response
in severe COVID-19 patients, characterized by low levels of both type I
and type III IFNs along with elevated chemokines and elevated expression
of Il-6 [102].
Type I IFNs have even been proposed as a treatment option for severe
COVID-19. In a hamster model, researchers exposed hamsters to SARS-CoV-2
and induced an inflammatory response in the lungs and systemic
inflammation in distal tissues. They found that intranasal
administration of recombinant IFN-α resulted in a reduced viral load and
alleviation of symptoms [103]. A retrospective cohort study of 446
COVID-19 patients determined that early administration of IFN-α2b was
associated with reduced in-hospital mortality. However, late IFN therapy
increased mortality and delayed recovery, revealing that early
administration of interferon therapy is essential for a favorable
response [104].
A surprising number of people have neutralizing autoantibodies against
type I IFNs, although the underlying etiology of this phenomenon is not
understood. A study using longitudinal profiling of over 600,000
peripheral blood mononuclear cells and transcriptome sequencing from 54
patients with COVID-19 and 26 controls found a notable lack of type I
IFN-stimulated gene responses in myeloid cells from patients with
critical disease [105]. Neutralizing autoantibodies against type I
IFNs were found in 19% of patients with critical disease, 6% of
patients with severe disease, and 0% of patients with moderate disease.
Another study based in Madrid, Spain revealed that 10% of patients with
severe COVID-19 disease had autoimmune antibodies to type I IFNs
[106]. Finally, Stertz and Hale (2021) note that, whether due to
autoantibodies or perhaps loss-of-function polymorphisms associated with
interferon system genes, deficiencies in interferon production are
associated with as many as 15% of all life-threatening COVID-19 cases
[107].