Contribution of sMAdCAM and IL-6 to COVID-19 associated
lymphopenia
To assess the contribution of known soluble inflammatory cytokines and
mucosal migration markers to the observed cellular immune signatures we
undertook the evaluation of circulating IL-6 and
sMAdCAM levels in our cohort. As
expected, we observed elevated IL-6 levels, with the highest being
observed in hypoxemic individuals, in plasma of all groups compared to
seronegative controls (Figure 2A). Additionally, extending our
previously reported results (12) obtained with sMAdCAM in mild
infection, we observed a progressive decline in these levels across mild
as well as hypoxemic patients that seemed converse to the pattern
observed for IL-6 (Figure 2B). Indeed, the levels of these 2 markers
were significantly negatively correlated (Figure 2C). Further, it was
interesting to note that neither in the case of IL-6 or sMAdCAM was it
possible to discriminate between AM and SM individuals. Next,
correlation analysis was undertaken to delineate putative relationships
between the aforementioned soluble markers and cellular subsets
described above (Supplementary Figure S4). Intriguingly and reflective
of their apparently divergent relationship, both IL-6 and sMAdCAM showed
significant opposing correlations with absolute counts of lymphocytes, T
cells (CD4+ and CD8+), B cells and NK cells supporting their clear,
albeit, opposing roles in COVID-19 associated lymphopenia (Figure 2
D-I). We also noted a unique negative correlation of IL-6 with Treg
counts together with a heretofore unreported positive correlation of
sMAdCAM levels with CD8+ effector memory T cell counts (Supplementary
Figure S5A-B). Elevated LPS levels, associated with microbial
translocation and severe COVID-19 disease were observed in hypoxemic
individuals (Supplementary Figure S5C). Furthermore, and possibly
related to altered monocyte frequencies observed ex vivo (Figure 1G), a
negative correlation of sMAdCAM levels occurred with frequencies of
intermediate monocytes (Supplementary Figure S5D). Gut pathology
associated markers LPS and sMAdCAM were poorly correlated with only the
latter exhibiting major correlations to lymphopenia.