Cryptococcus: History, Epidemiology and Immune Evasion

Round 1

Reviewer 1 Report

This paper reviews the history of C. gattii, what’s known about its virulence factors and how they influence pathogenesis, disease development, and the host immune response. Overall, I like the format of the manuscript, and I think a review of what has been published recently is informative. However, I have a few comments.

Comments:

1. The manuscript needs major English grammar and language corrections. I would suggest have it read by a native English speaker or using a professional editing service.
2. I suggest adding a summary figure that ties together all of the main points you discuss in the review.

Author Response

Please see the attached letter

Author Response File: Author Response.pdf

Reviewer 2 Report

In this manuscript, Diniz-Lima et al. summarized recent research on cryptococcal disease including cryptococcal structures, cell wall, polysaccharide capsule, virulence factors, disease development, cryptococcosis resistance, and host immunity to the fungus. Although the manuscript was focused on Cryptococcus gattii, the authors also compared C. gattii with C. neoformans in virulence and immunity. It is an intensive review and contains abundant information regarding cryptococcosis. It was well written. As this manuscript does not include any figures and tables, I would suggest the authors include a table to compare the major difference between C. gattii and C. neoformans. A minor thing is that “Cryptococcus” is not italic in parts of the manuscript such as lines 176, 318, 536, and 714…..

Author Response

Please see the attached letter

Author Response File: Author Response.pdf

Reviewer 3 Report

In this review by Diniz-Lima et al, the authors review a variety of topics relating to cryptococcal pathogenesis and host responses to the organisms. The manuscript is well-written and could serve as a useful reference in the cryptococcal field. There are a few minor suggestions for the authors:

Minor issues:

1.      The title may not be quite appropriate for the content. The review covers history, virulence factors, pathogenesis, etc substantially more than immunology. It would be helpful to update the title to reflect the actual content of the review. Maybe something like: “Cryptococcus – history, epidemiology, and immune evasion”

2.      Some specifics in the “immune responses” section are missing. Make sure to specify whether the statements refer to neoformans or gattii in order to not confuse the reader.

3.      It would be helpful to include a figure in the review – perhaps something comparing/contrasting neoformans to gattii (in terms of virulence factors or immune response/suppression).

4.      Line 367 – TLR4 and CD14 are pattern recognition receptors (PRRs), not cytokines. It is not clear which cytokines the authors meant to include here?

5.      Line 369-370 – what are “alveolar cells”? Was this meant to say “alveolar macrophages”?

6.      In the GXM section (Section 7.1) – it would also help to include that GXM non-specifically prevents T cell proliferation. This was published in Yauch et al 2006, and was also covered in Vechhiarelli et al (your current reference #163). This should be included in this section (maybe just after the statement in line 382?).

7.      Line 435 – the RAW macrophage is a “cell line” not a lineage.

8.      Line 504 – reference 187 refers to C. neoformans, not C. gattii. This section (section 10) should be relabeled to say “Cryptococcus dissemination”, since the papers referenced in this section go back & forth between C. gattii and C. neoformans.

9.      Section 10 – two additional points – titan cells have been observed in both species, so please clarify this. Also, C. gattii is less likely to disseminate to the CNS as compared to C. neoformans. C. gattii is more likely to present as pneumonia (at least during the Vancouver outbreak this was the case).

Author Response

Please see the attached letter

Author Response File: Author Response.pdf