Caspase-1 up-regulation is not limited to the acute stage of
COVID-19 disease
Up to 87% of inpatients and 35% of outpatients who recover from
COVID-19 report persistence of at least 1 symptom, particularly fatigue
and dyspnea (32, 33). Although preliminary reports describe this new
feature as “post-COVID-19 syndrome”, its mechanisms and natural
history remains unknown. We assayed caspase-1 activity in
CD4+ T cells of health care workers (HCWs) with
persistent respiratory and/or neurological (fatigue) symptoms at least
90 days post-SARS-CoV-2 infection (Table 2 ). There was
statistically significant up-regulation of baseline as well as nigericin
stimulated T-helper cell caspase-1 levels only in symptomatic
“post-COVID-19” HCWs, also known as long haulers (Figure 3 ).
An asymptomatic group of patients with history of PCR+ virus infection
no flu like illness preceding the PCR test and absent seroconversion
showed elevated T-helper cell caspase-1 expression. Interestingly,
PCR-negative symptomatic HCWs with history of flu-like illness in early
2020 as well as those with positive IgG to SARS-CoV-2 also had increase
caspase-1 expression. The level of expression of nigericin stimulated
caspase-1 was comparable to those with active infection as seen in
Figure 2, although the baseline caspase-1 levels are lower in long
haulers. Non-exposed control subjects showed no T cell caspase-1
overexpression. The non-exposed subjects were identified from a
different geographical area (Fairfax, Virginia, USA), at a time when the
pandemic was at its lowest numbers (August-September 2020). These
subjects were also exercising strict self-isolation.
Pan-caspase inhibitor suppresses elevated caspase-1 activity in
CD4 + T cells derived from moderate-severe
COVID-19 patients
To assess whether CD4+ T cell caspase-1 activity can
be suppressed by small molecule caspase inhibitors, we incubated whole
blood samples with either the oral pan-caspase inhibitor emricasan (EMR)
(34) or the selective orally active ICE/caspase-1 inhibitor VX765 (35),
followed 24hrs later with or without nigericin stimulation. We found
that EMR suppressed CD4+ T cell caspase-1 activity in
COVID-19 samples or prevented its upregulation in healthy subjects
(Figure 4 ), while VX765 showed only minimal suppressive effect.