Peer Review History

Original SubmissionMarch 25, 2022
Decision Letter - Dario Ummarino, PhD, Editor

Dear Dr Hale,

Thank you for submitting your manuscript entitled "Herpesvirus Reactivations in Critically-Ill COVID-19 Patients with Autoantibodies Neutralizing Type I Interferons" for consideration as a Research Article by PLOS Biology.

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PLOS Biology

Revision 1
Decision Letter - Dario Ummarino, PhD, Editor

Dear Dr Hale,

Thank you for your patience while your manuscript "Herpesvirus Reactivations in Critically-Ill COVID-19 Patients with Autoantibodies Neutralizing Type I Interferons" was peer-reviewed at PLOS Biology. It has now been evaluated by the PLOS Biology editors, an Academic Editor with relevant expertise, and by several independent reviewers.

As you will see in the reviews pasted below, two reviewers found your study interesting and important, and raised minor points around methodology, reporting and presentation/interpretation of the results. However, reviewer 3 raised concerns about the strength of the evidence supporting your main findings. Having discussed the reviews with the Academic Editor, we feel that it would not be necessary to address the comments from reviewer 3 regarding ex-vivo models. We appreciate that these additional experiments would strengthen your clinical findings; however, given that we are considering your paper as a Discovery Report, these additional mechanistic details would be beyond the scope of the current submission and may be the subject of future work (to be reported, for instance, in a follow-up Update Article:

In light of the reviews, we are pleased to offer you the opportunity to address the comments from the reviewers in a revised version that we anticipate should not take you very long. Please also make sure to address the following data and other policy-related requests:

1) Title: We would like to suggest a minor modification: "Critically-ill COVID-19 patients with neutralizing autoantibodies against Type I interferons have increased risk of herpesvirus reactivations."

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Dario Ummarino, PhD

Senior Editor

PLOS Biology


Reviewer #1: This paper is excellent. Novel, important, and timely. Suggestions to improve it include:

1/ It is not clear if the entire cohort was tested for neutralization of IFN-alpha and -omega at low and high concentrations (as should be) or only the ELISA-positive patients. It is also not clear either if IFN-beta neutralization was tested.

2/ They should quote all recent studies of auto-Abs to IFN in COVID patients, including Moscow, Japan, Bogota, and Leuven.

3/ They could cite the seminal 1984 paper Ion Gresser, especially because the viral disease was shingles.

4/ Describing the age of AAB+ patients in the COVID cohort in the text would be reader-friendly (it's in the table).

5/ For the HSV/CMV reactivation, a missing info is if the infection had any clinical impact. Was it CMV disease (GI involvement, eye, neuro etc.) or just positive PCR in blood? And if only PCR, which viral load?

6/ About the reactivation of CMV and HSV, it is not entirely clear if those tests were performed only in patients who had positive serologies for those viruses. The term reactivation is used, implying that these patients were infected before.

7/ The authors might tone down a little bit the conclusion, because many parameters were compared between patients with or without AAB. I doubt the association between AAB and viral reactivation (which makes a lot of sense anyway) would remain statistically significant after accounting for multiple testing. The immunological evidence, paradoxically, may be stronger.

Reviewer #2: Busnadiego et al. investigated the interplay between autoantibodies against antiviral type I IFNs, COVID-19, and reactivation of persistent Herpesvirus infections. In about 10% of their over 100 ICU patients with COVID they detected antibodies neutralizing IFN-a2 and/or IFN-o, mostly of the IgG type. The antibodies were present in the plasma as well as in tracheobronchial secretions, indicating they could positively influence SARS-CoV-2 replication in situ. No particular pattern of antibody increase or decrease could be discerned over the observation period. While the association of such anti-IFN antibodies with COVID-19 has already been described, the authors went on to demonstrate that the anti-IFN autoantibodies were also a predictor of Herpes virus (HSV, CMV) reactivation in the COVID patients.

This important and interesting study shows that the association of anti-IFN autoimmunity with severe COVID-19 may not only (or not necessarily) be based on an elevated SARS-CoV-2 replication, but perhaps because IFN neutralization can reactivate latent Herpes virus infections, a known other COVID risk factor. Moreover, the authors have established a convenient and sensitive neutralizing assay for type I IFNs that will facilitate similar screening efforts in the future.

The results are therefore advancing our knowledge, will inspire further studies, and may help to improve diagnosis and treatment of COVID-19. I have only minor remarks.

Minor points:

- Apart from the mention that the bead-based assay for autoantibody screening was based on methods from a previous study, the rationale for choosing these three specific IFN subtypes remains unclear.

- Patients were also tested for anti-IFN-b autoantibodies (line 202), but the result of the screen is neither shown nor mentioned. Only the lack of a correlation with IFN-a2 antibodies is described later on (line 236). Similar plots as the ones in Fig.1A and B would be helpful to understand the role (or non-role) anti-IFN-b autoimmunity.

- Why are the detection thresholds for IFN-a2 and IFN-o antibodies set differently? Please provide an explanation.

- Is it known whether the anti-IFN-a2 antisera would also be neutralizing other IFN-a subtypes? Please add at least a short discussion.

- Description of figure 1 in the main text: Please do always provide the number of samples and not only of patients in the text, as it was done in line 219 for the IFN-a2 IgG positives. Otherwise it looks like a discrepancy between the numbers in text and the dots in the figure.

Reviewer #3: Busnadiegoa et al assessed the presence of anti IFN-I ab in severe covid.

They confirmed previous reports and highlight the high prevalence of these AAB in critical COVID-19 partients (around 10%).

They found an association between herpes reactivation and the presence of AAB.

i regret that only a part of patients have been investigated for these analysis.

Moreover, I am not convinced by the direct link between latent virus reactivation and presence of AAB anti IFN-I.

Ex vivo models are requested to deeper investigate the relationship between herpes virus and IFN impairment.

this would greatly improve the quality of the manuscript.

Revision 2

Submitted filename: 2_IFNautoAbs_ResponsetoReviewers_revision.docx
Decision Letter - Paula Jauregui, PhD, Editor

Dear Dr. %LMEAST_NA%,

Thank you for the submission of your revised Discovery Report "Critically-Ill COVID-19 Patients with Neutralizing Autoantibodies against Type I Interferons have Increased Risk of Herpesvirus Disease" for publication in PLOS Biology. On behalf of my colleagues and the Academic Editor, Bill Sugden, I am pleased to say that we can in principle accept your manuscript for publication, provided you address any remaining formatting and reporting issues. These will be detailed in an email you should receive within 2-3 business days from our colleagues in the journal operations team; no action is required from you until then. Please note that we will not be able to formally accept your manuscript and schedule it for publication until you have completed any requested changes.

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