Host chitinase 3-like-1 is a universal therapeutic target for SARS-CoV-2 viral variants in COVID-19

Essential revisions:

It would be helpful to know whether CHI3L1 expression is increased with SARS-CoV-2 infection. Is there a positive feedback mechanism at play in which early infection increases CHI3L1 expression, for which CHI3L1 then upregulates ACE2 and SPP, thus creating a positive feedback loop that amplifies disease pathogenesis?

To address this question we compared the levels of circulating CHI3L1 in patients presenting to the emergency department at Rhode Island Hospital in Providence, R.I. USA during the early pandemic. These studies demonstrated that SARS-CoV-2 infection was associated with impressive increases in the levels of circulating CHI3L1 and that the levels of CHI3L1 were higher in patients with more severe disease. These findings have recently been published in Bioarchives and JCI Insight (1, 2). Importantly, the induction of CHI3L1 in COVID 19 and its correlation with adverse outcomes has also just been confirmed in a recent publication from Italy (3). Both publications are compatible with and support the concept that the severe acute disease that is seen in these patients is due, at least in part, to SARS-CoV-2 stimulation of CHI3L1 which, in turn, stimulates ACE2 and SPP creating a positive feedback loop as envisioned by the reviewer. It is not clear, however, if CHI3L1 plays a role in long COVID. The degree to which CHI3L1 plays a role in the pathogenesis of long COVID will need to be addressed in separate studies.

Reviewer #1 (Recommendations for the authors):

It would be helpful to know whether CHI3L1 expression is increased with SARS-CoV-2 infection. Is there a positive feedback mechanism at play in which early infection increases CHI3L1 expression, for which CHI3L1 then upregulates ACE2 and SPP, thus creating a positive feedback loop that amplifies disease pathogenesis?

This issue has been addressed above and cited below in references 1-3 from our lab and investigators in Italy.

Reviewer #2 (Recommendations for the authors):

1. The work seems preliminary and the data would need to be confirmed with a live virus – preferably on human primary cells or organoids.

2. In vivo work would also increase the overall impact of the work.

The issues have been commented on above.

References Cited:

1. Kamle S, Ma B, He CH, Akosman B, Zhou Y, Lee CM, El-Deiry WS, Huntington K, Liang O, Machan J, Kang M-J, Shin HJ, Mizoguchi E, Lee CG, Elias JA. 2021. Chitinase 3-like-1 is a Therapeutic Target That Mediates the Effects of Aging in COVID-19. bioRxiv: 2021.01.05.425478

2. Kamle S, Ma B, He CH, Akosman B, Zhou Y, Lee C-M, El-Deiry WS, Huntington K, Liang O, Machan JT, Kang M-J, Shin HJ, Mizoguchi E, Lee CG, Elias JA. 2021. Chitinase 3-like-1 is a therapeutic target that mediates the effects of aging in COVID-19. JCI insight 6: e148749

3. De Lorenzo R, Sciorati C, Lorè NI, Capobianco A, Tresoldi C, Cirillo DM, Ciceri F, Rovere-Querini P, Manfredi AA. 2022. Chitinase-3-like protein-1 at hospital admission predicts COVID-19 outcome: a prospective cohort study. In Scientific reports, pp. 7606