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Hemorrhagic Fever with Renal Syndrome in Asia: History, Pathogenesis, Diagnosis, Treatment, and Prevention

Viruses 2023, 15(2), 561; https://doi.org/10.3390/v15020561

by Ayushi Sehgal¹, Sanya Mehta¹, Kritika Sahay¹, Ekaterina Martynova², Albert Rizvanov²

, Manoj Baranwal¹

, Sara Chandy³, Svetlana Khaiboullina², Emmanuel Kabwe^2,4

and Yuriy Davidyuk^2,*

Reviewer 1: Anonymous

Reviewer 2: Anonymous

Reviewer 3:

Lourdes Lledó

Reviewer 4:

Michel Pépin

Viruses 2023, 15(2), 561; https://doi.org/10.3390/v15020561

Submission received: 23 December 2022 / Revised: 30 January 2023 / Accepted: 16 February 2023 / Published: 18 February 2023

(This article belongs to the Special Issue Hantavirus 2022)

Round 1

Reviewer 1 Report (Previous Reviewer 2)

Thanks for the opportunity to review this article.

The authors entitle their work “Hemorrhagic fever with Renal Syndrome in Asia: history, pathogenesis, diagnosis, treatment, and prevention” and they do an extensive review.

The extension of the paper makes difficult to follow the different topics included in the paper. Probably would be better to focalize strictly in what the title announces and do not cover all the hantaviruses. For example, during the description of pathogeneses the authors attribute to all orthohantaviruses some characteristics of de New World hantavirus, and the idea is that after reading the paper the reader gets a concrete idea of Eurasian hantaviruses.

I would suggest reviewing the old references to add some new information when changes have occurred in the clinical description, the epidemiology or pathogenesis of HFRS. In addition, to check if the references are correctly assigned.

In general, I think the authors have done a good effort to obtain this paper and need to be reviewed again if they agree with the suggestions.

Specific observations:

-In the paper, incubation period is mentioned a 2 to 4 weeks, however the reference 50 says 10 days to 6 weeks. 50.- Jonsson, C.B.; Figueiredo, L.T.M.; Vapalahti, O. A Global Perspective on Hantavirus Ecology, Epidemiology, 751 and Disease. Clin Microbiol Rev 2010, 23, 412–441, doi:10.1128/CMR.00062-09. 752

-The same paragraph ends describing the HFRS phases, the reference is wrong, recheck.

51.- Oreopoulos, A.; Ezekowitz, J.A.; McAlister, F.A.; Kalantar-Zadeh, K.; Fonarow, G.C.; Norris, C.M.; Johnson, 753 J.A.; Padwal, R.S. Association Between Direct Measures of Body Composition and Prognostic Factors in 754 Chronic Heart Failure. Mayo Clin Proc 2010, 85, 609–617, doi:10.4065/mcp.2010.0103.

-“For the first time after the detection of hantaviruses, the prevailing opinion was that 118 their carriers were rodents; however, later studies have identified hantavirus antigen 119 (virus) or/and specific antibodies in domestic animals, such as cats, rabbits, and dogs 120 [Ref 31]”. Song G. Epidemiological Progresses of Hemorrhagic Fever with Renal Syndrome in China. Chin Med J (Engl). 698 1999, 112, 472–477. I suggest updating the reference.

-Reference 53 was used to describe the proportion of patients who develop shock o hypotension in HFRS. However, the main goal of reference 53 was “The objective of this study was to explore the role of laboratory parameters as early indicators of severity and as effective predictors of prognosis in patients with hemorrhagic fever with renal syndrome (HFRS)”, please review.

-Paragraph included between line 183-197 refers to orthohantaviruses pathogenesis, however in particular the given information has to do with ANDV which is, for example, one of the hantavirus with prolonged viremia which is not described for all the hantavirus. Please precise or complement with information referent to Euroasian viruses.

-Line 369-370 reference 157 is related to COVID-19, NPS viral load and lymphocytes count and severity, please precise the idea.

-Paragraph about inactivated vaccines, please extend the comments to available information about effectiveness

-Line 411, 479, 482, says SEOL instead of SEOV

-Figure 1: Improve resolution and increase the size of letter, especially ones that describes the components of the viral particle (Fig. 1A). In addition, the horizontal arrow indicating the diameter of the viral particle is not aligned, please correct.

-Figure 1B: The ends of the boxes representing the coding regions of each segment should be called 5' and 3' UTR (Untranslated regions) and not NCR. This nomenclature is detailed in a work of Andes Orhtohantavirus 3’UTR: J Virol 2010 Oct;84(19):10420-4. doi: 10.1128/JVI.01270-10. Epub 2010 Jul 21.

In figure 1B it would be correct to shorten the 3'UTR ends since the mRNA does not have the same length as the vRNA.

-Figure 5: It is suggested to indicate the name of the most important components of the figure, such as endothelial cells, monocytes, among others.

Author Response

Agree: Information on New World hantaviruses in pathogenesis section of this review was removed.

I would suggest reviewing the old references to add some new information when changes have occurred in the clinical description, the epidemiology or pathogenesis of HFRS.

Agree: The references were revised and more information about the clinical outcome have been added: Lines 185-188.

In addition, to check if the references are correctly assigned.

Agree: The references were checked and updated.

In general, I think the authors have done a good effort to obtain this paper and need to be reviewed again if they agree with the suggestions.

Agree: We have revised the paper according to the reviewers’ comments and suggestions.

Specific observations:

Agree: We made changes in the text addressing this comment: Lines138-139: "The incubation period of HFRS generally ranges between 2 and 4 weeks; however, in some cases it could be as long as 6 weeks".

-The same paragraph ends describing the HFRS phases, the reference is wrong, recheck.

Agree: The reference was updated: Line 142 , reference 53.

Agree: The reference was updated: Lines 121-122.

Agree: Changes were made. The more appropriate reference was added (reference 52).

Agree: we removed all information and references including New World orthohantaviruses. We kept only references on Old World orthohantaviruses. The text was also modified (lines 177-188): "Infection of respiratory epithelial cells and dissemination of orthohantavirus happens early before clinical symptoms can be identified (Figure 2). Several studies have demonstrated orthohantavirus RNA in the serum of patients up to three weeks before the onset of the disease [64–66]. These data indicate that the virus replicates in the respiratory tissue; however, the body's reaction to infection is delayed. The non-cytopathic nature of orthohantavirus replication could explain this delay in clinical symptoms. The lack of infected cell death was demonstrated in vitro [67,68]. Also, virus replication-explained damage was not found in tissues collected from orthohantavirus-infected patients [69–71]. In contrast, HNTV RNA was detected in the plasma of patients at an early stage of HFRS and the high viral load led to the correlation with the severity of the disease[72]. Also, DOBV RNA level in HFRS patients serum correlated with disease severity[73]".

-Line 369-370 reference 157 is related to COVID-19, NPS viral load and lymphocytes count and severity, please precise the idea.

Agree: The reference was removed.

-Paragraph about inactivated vaccines, please extend the comments to available information about effectiveness.

Agree: We updated the text to include the information about the effectiveness of inactivated vaccines: Lines 433-438 and 443-445.

-Line 411, 479, 482, says SEOL instead of SEOV.

Agree: The typographical mistakes were corrected.

Agree: Figure 1 was updated.

Agree: Figure 1B was updated.

In figure 1B it would be correct to shorten the 3'UTR ends since the mRNA does not have the same length as the vRNA.

Agree: Figure 1B was updated.

-Figure 5: It is suggested to indicate the name of the most important components of the figure, such as endothelial cells, monocytes, among others.

Agree: Figure 5 was updated.

Reviewer 2 Report (New Reviewer)

Very well written review

Please re read for minor typos and the reference list

but overall solid manuscript

Author Response

Very well written review. Please reread for minor typos and the reference list but overall solid manuscript.

Agree: The authors thank the reviewer for his positive review of our manuscript. The manuscript was revised again, the references were checked and the typos were fixed.

Reviewer 3 Report (New Reviewer)

The work is an extensive review of Hantavirus infections in a geographical area endemic for these infections. The greatest interest is the updating of the review of the pathogenesis of these infections, as well as prevention and the different lines of research in vaccines and their treatment.

--Remarks: The authors have to review the bibliographic references cited in lines 83, and 86 because they are not correct

Author Response

--Remarks: The authors have to review the bibliographic references cited in lines 83, and 86 because they are not correct

Agree: The authors thank the reviewer for his positive review. The references were checked and updated.

Reviewer 4 Report (New Reviewer)

The bibliographic review submitted for my evaluation aims to provide an update on Orthohantavirus infections present in Asia, particularly targeting India and Asian Russia. The chapters devoted to the history of the identification of hantaviruses (HNTV, SEOV, PUUV and DOBV to name only the most important) and their reservoirs are correctly written. The part on the pathogenesis of Hantavirus infections is also very informative. Finally, the proposed figures are clear and well drawn. In conclusion, I recommend the publication of this synthesis which will allow specialists and non-specialists to have the state of the art at this t time on the subject of hantaviruses.

Author Response

The authors thank the reviewer for the positive comment on our manuscript and for his recommendation of the manuscript to be published.

This manuscript is a resubmission of an earlier submission. The following is a list of the peer review reports and author responses from that submission.

Round 1

Reviewer 1 Report

Sehgal et al. have written a very ambitious review on “Orthohantaviruses in Asia”. It surely required an enormous effort to put together this review. It not only catalogues and discusses the evidence for hantavirus species present in Asia and their incidence in humans, it also goes into acute detail about peripheral topics such as the pathogenesis of orthohantavirus infection (complete with subsections on vascular permeability, coagulation pathways, cytokine release, and immune activation) and the availabilities of vaccines and post-exposure treatments. The review is 22 pages, and nearly 1000 lines long. The reason I agreed to review the manuscript, based on the abstract, was that I thought/think the topic (Orthohantaviruses in Asia) is very important and would benefit from a synthesis. A review on what is known/presumed unknown about the distribution and incidence of hantaviruses in Asia would be very interesting, and I believe there are certainly specific fields of virology (epidemiology, clinical virology, ecology, etc) that would appreciate such a review.

Unfortunately, the authors attempted to include several other topics that (in my opinion) are not immediately germane to the topic of hantaviruses in Asia. This is my major criticism of this manuscript. There is simply no focus to it. Who is the intended target? A review on the presence and diversity of orthohantaviruses in Asia would certainly benefit scientists. Perhaps the addition of information (briefly) on incidence in humans, clinical presentation, vaccines, treatments, and control might also appeal to clinicians and epidemiologists. The authors’ discussions of pathogenesis and immune response are excellent, and could form the basis of an entirely different review, as these topics are not specific to “Orthohantaviruses in Asia.” However, including all of these into one review creates a very unfocused manuscript that provides very little overall benefit to any given audience. Surely this manuscript would be better served as a book chapter.

The most unfortunate consequence of trying to write an all-inclusive review on any complex topic, such as hantaviruses, is that the authors will invariably be forced to write about very specialized topics about which they have little expertise. I feel that is the case with this review, particularly the sections on the genetic diversity and ecology of hantaviruses, as well as the sections on epidemiology and control of hantaviruses. These sections offer very little to the field, as the authors did not fully synthesize what is known (i.e., the objective of a review), and made some misstatements when interpreting literature about which they are likely unfamiliar.

Major Point 1. Therefore, I suggest the authors reformulate and refocus their review. Should they wish to write about “Orthohantaviruses in Asia,” they should absolutely expand their knowledge about the diversity and ecology of hantaviruses in Asia (and elsewhere for comparison) and provide a synthesis. This would require that they eliminate, for example, lines 358-674: nearly 4000 words on the cellular and systemic response to hantavirus infection! However, it seems clear to me that the authors’ main expertise are in the immune responses to hantavirus infection, and perhaps this should be the focus of a review, provided they reduce (or eliminate) the discussion of diversity, phylogenetics, ecology, and epidemiology.

Major Point 2. The references are in a very bad state. For example References 3 and 4 are the same; 21 and 22; 33 and 34; 38 and 44; 40 and 45; 41 and 46; 58 and 63; 59 and 62; 60 and 61; 70 and 71; 89 and 102; 90 and 92; 94 and 96; 97 and 116; 113 and 385; 120 and 134; 132 and 133; 152 and 153; 155 and 162; 167 and 168; 349 and 350; 384 & 387; 389 and 391; I am confident in saying that there are many many many other duplicated references. And some references are simply strange, incomplete or formatted incorrectly: 9, 39, 42, 53, 54, 55, 56, 74, 75, 77, 121, 325, 326&327 (same reference), 386, 393, 399, 401, 404, 405, 408, 410, etc. It was very difficult to provide a critical peer review of this manuscript, as I was completely uncertain whether the authors were providing citations reliably (e.g., the references appear to be incorrect for the entire section on “Genetic Diversity amongst Asian Orthohantaviruses”). I have tried to go through as many as possible – both within my areas of expertise and outside my areas of expertise – and have made comments below (included as minor comments) where the cited reference seems completely inappropriate. I am sure there are others. In addition to fixing the references formatting an duplication of references, the authors must carefully examine whether the references are appropriate and/or essential.

3. Although the manuscript was readable throughout, with few very ambiguous sentences, the English writing must be improved. Nearly every sentence had problems with subject-verb agreement, dropped articles, and very awkward phrasings. I have tried to make minor comments below of the egregious errors (where meaning was ambiguous or indecipherable), however the authors must perform an extensive language editing of the manuscript.

4. Below is a non-exhaustive list of minor (but important) issues that could be corrected. I have tried to include suggestions where appropriate.

Line 29 the genus is Orthohantavirus.

Table 1 for Soochong virus “Korean field mouse” (not “filed mouse”)

Table 1, it is important to be consistent with naming, not all of these are official species (as noted in the footnotes). I like that that authors mostly used “orthohantavirus” when it is considered a species, and otherwise used “virus”. However, “Amur” should probably be “Amur virus” and “Hokkaido” should be “Hokkaido virus”, for example.

Table 1, please check the hosts of Hokkaido virus and Muju virus (e.g., doi’s: 10.1016/j.meegid.2015.05.021, 10.1099/vir.0.045377-0, 10.1111/j.1348-0421.2007.tb04003.x)

Table 1, please modify the text referring to Table 1, wherein non-rodent hantaviruses are included. E.g., lines 38-39 “The small mammal host, orthohantaviruses, and their distrubtion…” Strictly speaking, rodents are in the order Rodentia, as the authors mention later on line 87. However, again in the paragraph beginning on line 105, the authors state “rodents” when actually “small mammals” were included in this study (in fairness, Chin et al. 2000 also make the mistake of stating “rodent” when referring to shrews).

Table 1, curious as to why some species orthohantaviruses endemic to Asia are excluded (e.g., Khabarovsk orthohantavirus).

Line 89, italicize genus Orthohantavirus

Lines 91 and 92, correct the spelling of genus Thottimvirus

Lines 92-96 – please clarify the source of the serum samples (from which species)

Line 94 – this should be “cross-reactivity” with SEOV and PUUV

Line 97 – it is probably prudent to clarify that Far East, Russia, is the name of the federal district, to avoid confusion with the geographic region commonly referred to in English as the “Far East” (i.e., East Asia or the Asia-Pacific Region”.

Lines 103-104 – perhaps it is better to state “genus Apodemus”

Line 110 – “Rattus…were also commonly habitat in some rural parts…”. I think there is a verb missing.

Line 115 – Fix orthography of virus names: Thailand orthohantavirus (italicized) or Thailand virus (not italicized). Probably the former is better as this is a recognized species of orthohantavirus.

Line 121-123 – the part beginning at “such as…” can be deleted from the end of this sentence.

Line 125 – route is missing an “e”

Line 131 – “droppings” and also line 132 “droplet” is ambiguous here when referring to rodent excreta.

Line 137-138 – The meaning of this sentence is not clear, and seems to contradict the previous paragraph where virus-contaminated aerosol transmission is established as the main mode of transmission to humans. Perhaps this refers to enzootic transmission, as the last sentence of the paragraph explains, but it is not clear what is meant by this sentence, that “Each hantavirus may have a different strategy for transmission.” Eliminate it or explain with substantiation from the literature. If it were true (that each hantavirus species has a different strategy for transmission), this would be a significant and quite a novel contribution to the field.

Line 147-148 – obviously not “respectively” as the Cricetidae are distributed throughout the New World and Old World.

Line 154 – Crocidurinae, but I think it is sufficient to say “Soricidae” here. It would be better to then list Suncus murinus here (instead of “white-toothed shrew”), as this is the natural host of TPMV and is the species “mainly found in India” (also note that these are not rodents!)

Line 159 – please use the international numeral system and not 1,5 lakh to 2 lakh (150,000 to 200,000).

The paragraph beginning at line 159 is out of place and mostly repeats what was previously established in the “Historical overview” section. Anyway, this should not be in the section discussing “Geographical distribution amongst natural rodent hosts in Asia”. Line 163 is repeating this same fact for the third time, each time with a different set of references (e.g., line 891 [365]? A reference on SARS-CoV-2?).

Figures 2 and 3 – what do the dots mean? In Figure 2, does each dot indicate a distinct “virus” or virus species? In figure 3, there are multiple dots per virus – what does each dot mean?

Is Figure 4 reproduced from somewhere? If so, then cite that publication. If not, then explain how this phylogeny was constructed. Clearly the S segment cds (for the nucleocapsid protein?) was used, and apparently, judging by the numbered nodes, there was some sort of test of the phylogeny. How were the sequences aligned, how was the phylogeny constructed (i.e., substitution matrix) and how was the phylogeny tested?

Line 190 – these are not appropriate references, line 192 – this is not the appropriate reference,

Line 193-194 – this statement is not supported by the reference (from the abstract of Garanina et al. 2009, “DOBV strains might have 8–9% of nucleotide difference although they were collected at places separated by 30–100km.”

Lines 200-201 – since references 70 and 71 are the same reference perhaps this sentence should begin with “A study has demonstrated the…” Secondly, this reference provides data to support exactly the opposite of what the authors propose: from the abstract, “Notably, the phylogenetic histories of the viruses are not always congruent with those of their hosts, suggesting that cross-species transmission has played a major role during hantavirus evolution and at all taxonomic levels, although we also noted some evidence for virus-host co-divergence.”

Line 204 – there is no “Souza, et al.” in the references section, and the cited reference is not appropriate for this statement.

Lines 206 and 208 – this dating is absolutely false and I would challenge the authors to provide substantive evidence of this. The manuscript they cite explicitly says, “Hantaviruses have traditionally been considered to have co-diverged (including co-speciation) with their rodent hosts on time-scales of millions of years.” It is widely recognized that there remain serious problems to resolving the precise timing of the evolution of orthohantaviruses, but I would challenge the authors to find a reference that supports the emergence on the order of 1000s of years (that does not also include in the discussion how such a short time for MRCA is highly unlikely).

Line 217 and 223 – the authors state that “the genome orthohantaviruses appears to have higher variability.” And then contradict this later with stating that the rate of diversity “appears similar to values calculated for other RNA viruses.”

Line 304 – no need to italicize orthohantavirus

Line 229 –References [81,82] have nothing to do with reassortment.

Lines 309-310, I assume the authors intended to write, “These data provide the basis …” but I do not understand what an “adapted susceptibility” means. Perhaps the authors are suggesting “donor-specific” susceptibility?

Line 329, “peak” not “pick” (it’s the title of the manuscript they cite), and in the paper it took up to 15 days for peak virus replication in the lung cell model.

Line 338 – could probably add the Hägele et al. 2021 reference here and in the next sentence

Line 338-339: this is not the “best” reference to demonstrate that hantaviruses use integrins as cellular receptors (the other Gavrilovskaya et al. references are more appropriate).

Line 367 –VE-cadherin was already defined to mean “vascular endothelial (VE)-cadherin “in lines 363-364. Write “VE-cadherin” (no brackets) just as it is also used in the next sentence.

Line 388 – remove commas, and they are spelled “adherens” junctions.

Line 692-694 – The authors write that studies have demonstrated the direct relationship between rodent density and hantavirus prevalence. From the abstract of the review the authors cite (Khalil et al. 2014), “The relationship between density and prevalence merits more investigation”. Therefore I would challenge this statement, and the authors should reformulate it if they wish to include it in a review of the topic. Also – yet again – this publication is cited twice as [315] and [319]

Lines 785-786, I see no reason to provide citations for this well-known and well-established fact, particularly when the citations are for SARS-CoV-2. Also this sentence must be rewritten, I suggest “The ability to elicit neutralizing antibodies is an established benchmark for assessing the efficacy of a vaccine” Or something like that.

Line 871 - Surely, [257] is not the correct reference

Line 890 – SEOV

Line 891 – Does this really need to be restated?

Line 894 – serotype? Is there evidence of this?

Line 899 – I disagree completely, as these were shown to be novel genotypes and not evidence of spreading to nonendemic territories.

Line 903 – must be re-written, as it seems the authors are suggesting that small rodents be tasked with testing for “orthohantavirus antigens”. Are there antigen-based tests for hantaviruses? Or do the authors mean that rodents or small mammals be screened for hantaviruses (via virus isolation, RT-PCR, or seroconversion).

Line 905 – this is a sentence fragment. “Serological testing [of] febrile patients for orthohantavirus-reactive IgM…” in non-endemic countries? Is this really a great suggestion?

Author Response

Comments and Suggestions for Authors

Agree: we added the paragraph describing the role of ecology on orthohantavirus more of transmission Lines 130-144

The objective to reduce the spillover of viruses from natural hosts to humans requires a better understanding of the ecology and epizootiology of zoonotic pathogens. Studies have shown that the prevalence and transmission rates of viruses within host populations depend on the ecosystem affecting the incidence of orthohantavirus diseases [33,34]. The changes in the environment, such as global warming, habitat reduction, and changes in the landscape, could affect the behavior, host density, and diversity of small mammals car-rying orthohantaviruses [33]. Supporting the role of the environment was the study by Dearing and Dizney demonstrating that natural climate cycles such as El Ni˜no and an-thropogenic climate changes could enhance orthohantavirus prevalence [35]. Territories highly affected by human activity are often associated with a high rate of zoonotic disease emergence [34,36]. Five regulators of zoonotic virus prevalence and transmission have been suggested, such as (i) environmental regulators; (ii) anthropogenic factors; (iii) genetic factors; (iv) behavioral factors; and (v) physiological factors [36]. Therefore, the disease in-cidence rate control could be improved by investigating how environmental changes affect the transmission of the viruses among the hosts.

This would require that they eliminate, for example, lines 358-674: nearly 4000 words on the cellular and systemic response to hantavirus infection!

Agree: We agree that the sections within lines 358-674 could be modified to reduce the word counts. After modification, the updated section was reduced to 1,575 words, lines 376-527.

We believe removing these sections entirely would reduce the comprehensiveness and inclusiveness of this review. We believe that this review, in addition to have information on orthohantavirus diversity, phylogenetic, ecology and epidemiology, it also should contain information on pathogenesis.

However, it seems clear to me that the authors’ main expertise are in the immune responses to hantavirus infection, and perhaps this should be the focus of a review, provided they reduce (or eliminate) the discussion of diversity, phylogenetics, ecology, and epidemiology.

Answer: it is correct that some authors have expertise in studying immune response to orthohantavirus infection. To ensure the comprehensiveness of this review, we included several authors with substantial expertise in studying orthohantavirus genetics, diversity, phylogenetic and epidemiology. Here are some publications where data on orthohantavirus genetics, diversity and phylogenetic was presented (https://www.frontiersin.org/articles/10.3389/fphar.2019.00970/full; https://www.sciencedirect.com/science/article/pii/S1201971221010584; DOI:10.3390/pathogens10091169; https://pubmed.ncbi.nlm.nih.gov/32971887/).

Agree: all references were checked to make sure that references are not duplicated and formatted correctly.

Although the manuscript was readable throughout, with few very ambiguous sentences, the English writing must be improved. Nearly every sentence had problems with subject-verb agreement, dropped articles, and very awkward phrasings. I have tried to make minor comments below of the egregious errors (where meaning was ambiguous or indecipherable), however the authors must perform an extensive language editing of the manuscript.

Agree: English was edited by an Editor with expertise writing research manuscripts.

Below is a non-exhaustive list of minor (but important) issues that could be corrected. I have tried to include suggestions where appropriate.

Line 29 the genus is Orthohantavirus.

Agree: Changes were made to correct Hantavirus to Orthohantavirus Line 29

Table 1 for Soochong virus “Korean field mouse” (not “filed mouse”)

Agree: Changes were made to “Korean field mouse”

Agree: changes were made: we have changes “Amur” to “Amur virus” and “Hokkaido” to “Hokkaido virus”.

Table 1, please check the hosts of Hokkaido virus and Muju virus (e.g., doi’s: 10.1016/j.meegid.2015.05.021, 10.1099/vir.0.045377-0, 10.1111/j.1348-0421.2007.tb04003.x)

Agree: Changes were made

Table 1, please modify the text referring to Table 1, wherein non-rodent hantaviruses are included. E.g., lines 38-39 “The small mammal host, orthohantaviruses, and their distrubtion…”

Agree: changes were made Line 38-39: “The small mammal host, orthohantaviruses, and their distribution…..”

Strictly speaking, rodents are in the order Rodentia, as the authors mention later on line 87. However, again in the paragraph beginning on line 105, the authors state “rodents” when actually “small mammals” were included in this study (in fairness, Chin et al. 2000 also make the mistake of stating “rodent” when referring to shrews).

Agree: changes were made in lines 105 and 106.

Table 1, curious as to why some species orthohantaviruses endemic to Asia are excluded (e.g., Khabarovsk orthohantavirus).

Line 89, italicize genus Orthohantavirus

Agree: changes were made in line 89

Lines 91 and 92, correct the spelling of genus Thottimvirus

Agree: changes were made in lines 90 and 91

Lines 92-96 – please clarify the source of the serum samples (from which species)

Agree: the source of serum samples was identified, line 92

Later, studies demonstrated a high rate of orthohantavirus seropositivity in serum samples collected from healthy individuals in the Cochin and Chennai regions of India [25].

Line 94 – this should be “cross-reactivity” with SEOV and PUUV

Agree: changes were made in line 94

Agree: Sentence was changed to “HFRS is also endemic in the Far Eastern Federal District of Russia, where about 84,687 cases were reported between 1978 and 1995 ….” In line 96

Lines 103-104 – perhaps it is better to state “genus Apodemus”

Agree: changes were made in line 103

Line 110 – “Rattus…were also commonly habitat in some rural parts…”. I think there is a verb missing.

Agree: changes were made line 110

“Rattus rattus and Suncus murinus, small rodents, were also commonly found to habitat in some rural parts of the region.”

Agree: changes were made to Thailand virus to comply with abbreviation (THAIV).in line 114

Line 121-123 – the part beginning at “such as…” can be deleted from the end of this sentence.

Agree: part of this sentence was deleted

Line 125 – route is missing an “e”

Agree: changes were made in line 122

Line 131 – “droppings” and also line 132 “droplet” is ambiguous here when referring to rodent excreta.

Agree: changes were made “droppings” and “droplet” to “feces”. In line 128-129

Agree; this section was removed

Line 147-148 – obviously not “respectively” as the Cricetidae are distributed throughout the New World and Old World.

Agree: the word “respectively” is removed

Agree: changes were made: line 155-157

A notable exception is the TPMV, which is carried by Suncus murinus (Asian house shrew), an insectivore of the Soricidae family. This shrew is mainly found in India [23].

Line 159 – please use the international numeral system and not 1,5 lakh to 2 lakh (150,000 to 200,000).

Agree: Changes were made. Lines 164-165

Around 150,000 to 200,000 cases of orthohantavirus infection are reported annually worldwide.

Agree; this paragraph is repetitive and therefore it was removed

Line 163 is repeating this same fact for the third time, each time with a different set of references (e.g., line 891 [365]? A reference on SARS-CoV-2?).

Agree: reference was removed.

Figures 2 and 3 – what do the dots mean? In Figure 2, does each dot indicate a distinct “virus” or virus species?

Agree: changes were made in Figure legend 2 to clarify that dots indicate the distribution of the small mammals natural hosts for orthohantaviruses.

Figure 2. Map of rodent hosts carrying orthohantaviruses causing HFRS in the Old World.

Habitat areas for orthohantavirus natural hosts are indicated as colored circles. Green circles – family Muridae, subfamily Murinae; Blue circles – family Cricetidae, subfamily Arvicolinae.

In figure 3, there are multiple dots per virus – what does each dot mean?

Agree; clarifications were made in Figure legend 3.

Figure 3. Map of HFRS endemic regions and orthohantaviruses isolates.

The colored dots indicate the distribution regions of orthohantavirus species in the Old World: DOBV – Dobrava-Belgrade orhtohantavirus; PUUV – Puuma-la orhtohantavirus; TULV – Tula orhtohantavirus; LUXV – Luxi orhtohanta-virus; CBNV – Cao Bang orhtohantavirus; THAIV – Thailand orhtohantavirus; HNTV – Hantaan orhtohantavirus; ASAV – Asama orhtohantavirus; YKSV – Yakeshi orhtohantavirus; JJUV – Jeju orhtohantavirus.

Grey: regions endemic for HFRS. Line 179-186

Is Figure 4 reproduced from somewhere? If so, then cite that publication.

Answer: This figure was made by authors specifically for this review

If not, then explain how this phylogeny was constructed. Clearly the S segment cds (for the nucleocapsid protein?) was used, and apparently, judging by the numbered nodes, there was some sort of test of the phylogeny. How were the sequences aligned, how was the phylogeny constructed (i.e., substitution matrix) and how was the phylogeny tested?

Agree: information on phylogenetic tree construction, sequence alignment and phylogeny testing was added to the figure legend 2.

The phylogenetic analysis was done using the complete coding region of the S segment. Multiple nucleotide sequence alignments of the orthohantaviruses were performed using the MegAlign program (Clustal W algorithm) located in the DNASTAR software package Lasergene (DNASTAR, Madison, WI, USA; https://www.dnastar.com/, accessed on 06 August 2022) and MEGA v6.0 [68]. Phylogenetic trees were inferred using the Maximum Likelihood (ML) method incorporated in Mega v6.0. [68]. The Tamura–Nei model was used. The bootstrap values of less than 70% are not shown on the trees. In line 222-228

Line 190 – these are not appropriate references, line 192 – this is not the appropriate reference,

Agree: correct reference was added. Line 199 and line 201

Agree; reference which is supporting this statement in included line 203

Lines 200-201 – since references 70 and 71 are the same reference perhaps this sentence should begin with “A study has demonstrated the…”

Agree: duplicate reference was removed. Line 210

Secondly, this reference provides data to support exactly the opposite of what the authors propose: from the abstract, “Notably, the phylogenetic histories of the viruses are not always congruent with those of their hosts, suggesting that cross-species transmission has played a major role during hantavirus evolution and at all taxonomic levels, although we also noted some evidence for virus-host co-divergence.”

Agree: we made changes in the text to include other hypothesis, stating that phylogenetic histories of the viruses are not always congruent with those of their hosts. Line 210-212

Line 204 – there is no “Souza, et al.” in the references section, and the cited reference is not appropriate for this statement.

Agree: references were corrected. Line 213

Answer: We agree, orthohantaviruses co-evolved with rodent hosts for millennia. We corrected our statement, to indicate that the virus co-speciation could be recent event. Changes were made in the text; line 213-215

Orthohantaviruses' phylogeny and host relationships analysis demonstrated a host-virus phylogenetic congruence which supports the hypothesis of their co-evolution and co-divergence from a common ancestor [65]. However, there are hypotheses challenging this assumption [66] . Souza, et al., data suggests that co-speciation of orthohantaviruses was the result of the host switch from Murinae to Arvicorinae and it happened about 500-700 years ago [67].

Agree: we rewrote this section to remove the contradicting statement: lines 233-242. We included two papers analyzing the in substitution/site/year calculations rate in different orthohantaviruses (Ramsden et al (ref 70) and Sironen et al (ref73)).

Within the co-evolution theory, calculating the evolution rate of PUUV, HNTV, TULV, and Japanese PUUV-like viruses demonstrated values in interval 0.7×10-7–2.2×10-6 syn-onymous nucleotide substitutions/site/year. [69]. In another study by Ramsden et al lower rate, is ~3×10-4 and ~5.5×10-4 substitutions/site/year, was calculated for DOBV and PUUV, respectively [66]. These variations could be explained by the use of different methods for substitution/site/year calculations calculation. Other authors noted that genetic drift due to the accumulation of deletions and point mutations contributes more to orthohantavirus genome variations [70,71]. The main cause of genetic drift is the limited proofreading ac-tivity of viral RdRp, which leads to an incorporation of many mismatched nucleotides during genome replication [72].

Line 304 – no need to italicize orthohantavirus

Agree; changes were made line 320

Line 229 –References [81,82] have nothing to do with reassortment.

Agree: appropriate references were included. Line 247

Agree: changes were (line 326) made to “These data provide the basis……”

The “adapted susceptibility” was replaced with “individual specific susceptibility”

Line 329, “peak” not “pick” (it’s the title of the manuscript they cite), and in the paper it took up to 15 days for peak virus replication in the lung cell model.

Agree: changes were made line 364

Line 338 – could probably add the Hägele et al. 2021 reference here and in the next sentence

Agree: Hägele et al. 2021 reference was added in two places as suggested line 324

Line 338-339: this is not the “best” reference to demonstrate that hantaviruses use integrins as cellular receptors (the other Gavrilovskaya et al. references are more appropriate).

Agreed: the appropriate reference was added. Line 356

Line 367 –VE-cadherin was already defined to mean “vascular endothelial (VE)-cadherin “in lines 363-364. Write “VE-cadherin” (no brackets) just as it is also used in the next sentence.

Agree: brackets were removed

Line 388 – remove commas, and they are spelled “adherens” junctions.

Agree: comma is removed

Agree, that the rodent population density not always leads to increased human infection. In our statement, we said that increased rodent population could lead to increase of rodent exposure to hantavirus (Line 545-547): “Studies have shown that the density of the population could affect the horizontal transmission of the orthohantavirus, increasing the number of infected rodents. “

Next we stated that increased number of infected rodents could increase the chance of people contact with infected small mammals. Line 548-551:” A higher number of infected small rodents could potentially increase the chance of human contact and exposure to orthohantavirus.”

We are not challenging the statement that there is no link between rodent population and human infection. We merely state hat increased rodent population could increase number of infected small mammals and, as the result, it could increase chances of human exposure to orthohantaviruses.

Answer in the text (line 545): Studies have shown that the density of the population could affect the horizontal transmission of the orthohantavirus, increasing the number of infected rodents [34,210]. It was also shown that the threshold density of the rodent population is required to maintain orthohantavirus [33,211,212]. A higher number of infected small rodents could potentially increase the chance of human contact and exposure to orthohantavirus. Therefore, the efficacy of rodent control remains an important measure to prevent orthohantavirus infection.

Also – yet again – this publication is cited twice as [315] and [319]

Agree: references were corrected,.

Agree: Sentence was replaced with suggested: The ability to elicit neutralizing antibodies is an established benchmark for assessing the efficacy of a vaccine.

We believe that the reference on SARS-Cov-2 is relevant as this statement is referring to value of neutralizing antibodies in general, not only for orthohantaviruses. However, this is not a fundamental point, so the reference was removed.

Line 871 - Surely, [257] is not the correct reference

Agree: reference was removed

Line 890 – SEOV

Agree: Changes were made

Line 891 – Does this really need to be restated?

Agree: the sentence was removed

Line 894 – serotype? Is there evidence of this?

Agree: we replaced “species” for “serotype”. Line 740

Yes, serological evidence for circulation of these orthohantaviruses in Asia are present.

Line 899 – I disagree completely, as these were shown to be novel genotypes and not evidence of spreading to nonendemic territories.

Agree: we made substantial changes in this section. Line 746-748

Recently, novel orthohantavirus serotypes have been isolated from small animals having natural habitats in Asian countries, such as India and Thailand. These data provide evidence for the emergence of new genotypes of orthohantaviruses in these territories.

Answer: we made substantial changes in this section of conclusion (lines 752-754). Testing could be done using ELISA (for antibodies) and PCR (for virus RNA) methods.

One approach could be integrating small screening rodents for orthohantavirus antibodies and antigens using ELISA and PCR, respectively [293,294] into epidemiological surveys in territories, believed to be non-endemic.

Line 905 – this is a sentence fragment. “Serological testing [of] febrile patients for orthohantavirus-reactive IgM…” in non-endemic countries? Is this really a great suggestion?

Agree: the sentence was completed Line 755-756

Also, serological testing of febrile patients for anti-orthohantavirus IgM could facilitate early diagnosis of orthohantavirus infection in non-endemic countries [25].

Author Response File: Author Response.pdf

Reviewer 2 Report

I have read a very nice and extensive review about hantavirus in "old world."

The organization of the writing is good, although I would suggest checking what paragraphs could be reduced, making it easier for the reader to complete the article within a reasonable time.

Check the references, number 94 and 96 are repeated.

Author Response

I have read a very nice and extensive review about hantavirus in "old world."

The organization of the writing is good, although I would suggest checking what paragraphs could be reduced, making it easier for the reader to complete the article within a reasonable time.

Agree: substantial reduction of the manuscript size was made to make it easier to read

Check the references, number 94 and 96 are repeated.

Agree: all references were checked

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

Previously, my main criticism was that the review was too broad and did not focus on the expressly stated scope. The authors responded that "removing these sections entirely would reduce the comprehensiveness and inclusiveness of this review. We believe that this review, in addition to have information on orthohantavirus diversity, phylogenetic, ecology and epidemiology, it also should contain information on pathogenesis."

The section “Genetic Diversity Amongst Asian Orthohantaviruses” is simply poorly written. In their responses to my comments, wherein I previously questioned the expertise by the authors on the topic of hantavirus genetic diversity, the authors provided links to published manuscripts. However, I restate my previous critique that there is an overall lack of understanding demonstrated in the writing of these paragraphs. It does not nearly approach a synthesis of the topic, includes rather trivial factoids, and seems to misunderstand some rather large concepts in hantavirus genetic diversity. I am sorry to say that I stopped providing a critical review of the mansucript at this point, as this alone is not adequate to publish.

Therefore, I suggest that the authors mostly remove the sections "Modes of transmission and ecology", "Geographical distribution", and "Genetic diversity". These can be dealt with quite succinctly, perhaps in the introduction, and the review can then focus on Clinical presentation, pathogenesis, vaccines and treatment, and diagnostics. These areas are well-written, and seem to provide a synthesis of the topics. These topics are out of my areas of expertise, so I cannot expressly comment in detail about whether the topics are dealt with "comprehensively" and/or "inclusively".

In reducing these sections, the authors can refocus the title and introduction of the manuscript to plainly describe what they intend to review. The authors entitled the review “Orthohantaviruses in Asia: epidemiology, clinical manifestation, protection and treatment”. Where in that list is “Pathogenesis of orthohantavirus infections”? A topic that the authors spend nearly 3000 words, 200-lines, over 6-pages with 4 figures. Furthermore, they state in their introduction (lines 58-61) that the review (paraphrasing) will provide an historical overview of infections in Asia, with particular emphasis on the "epidemic" in India (which they never mention again), and address diagnosis and treatment. Again, genetic diversity, ecology, pathogenesis and immune response are not mentioned! Presumably, because they seem out of scope to the authors as well.

Minor comments:

1. Line 62: the authors claim that this is an “Historical overview” and begin with a detailed chronology of hantavirus in China, but then abandon the “historical” context and list the evidence for the presence of hantaviruses in India, Russia, Taiwan, and Thailand.

2. Line 67: this manuscript puts the number of cases between 1931 and 1949 at 10,378; not 30,000 (Chen and Qui, 1993).

3. Line 68: this number (1557622) comes from reference [21] (Zhang et al. 2010). The next four sentences are essentially describing figure 1 from that manuscript.

4. Line 83: Hantaan virus is the prototype Orthohantavirus. Thottapalayam virus is the prototype shrew-borne hantavirus (Thottimvirus). Please correct the use of the word “prototype”.

5. Line 87: cite the evidence that dogs, rabbits, and cats “carry this virus” (and clarify what “carrying” a virus actually means)

6. Line 109: again, Suncus murinus is not a rodent

7. Line 136 – 138, (Dearing and Dizney, 2010) is not a study, it is a review. From the abstract “natural climate cycles such as El Niño as well as anthropogenic climate change enhance hantavirus prevalence”, seems very similar to what the authors wrote here “natural climate cycles such as El Niño and anthropogenic climate changes could enhance orthohantavirus prevalence.”

8. Line 168: Reference 37 is inappropriate here

Figures and Tables

Table 1: I am still curious as to why the authors assembled this particular list of hantaviruses, including some strains of established species but excluding other species that are endemic to Asia. E.g., why is Fusong virus not included? No Fugong virus? No mention of Topografov virus (even though it is not classified)? Why not include all that are listed in Figure 4?

Figure 2. Previously I asked the authors to clarify what the circles mean. I suppose I should have written that circles are inappropriate here. Does a blue circle in northwestern France mean that a murine host is found there, but not in southern France? Puumala virus is documented from many regions of France (so it should be a blue circle), but to my knowledge DOBV has never been reported in France (even though Apodemus is endemic). Perhaps the authors are acknowledging SEOV in France, but they have left this off of the map for Figure 3, which again uses circles for some reason. So again, I ask the authors to change this map or just eliminate it. For that matter, why include Africa and Europe on a map in a review on “Orthohantaviruses in Asia”?

Figure 3 – what does a circle represent? Is it an isolate? Evidence from a host? evidence in humans? A sequence in GenBank? Are all circles shown? Just a few? Why use circles? And, again, why include Africa and Europe on a map in a review on “Orthohantaviruses in Asia”?

English writing

Previously I strongly recommended that the authors improve the writing of the manuscript. They claimed they used an editor. I have a hard time believing that, as the English writing is still very bad. I am not (only) criticizing the writing style, there are numerous grammatical errors and (worse) the meaning of the sentence is ambiguous. This is just the first 200 lines :

Line 12: aerosols

Line 12: aerosols are not produced by urine and feces, excreta may become aerosolized.

Line14-16: rewrite this sentence, “Orthohantavirus infection may cause hemorrhagic fever with renal syndrome (HRFS), a disease that is characterized by acute kidney injury and increased vascular permeability”.

Line 16: “Orthohantaviruses are endemic to several Asian countries”, countries are not endemic to a disease.

Line 17: Why “Also”? Is Far East, Russia not in Asia?

Line 18: rewrite “Recently, orthohantavirus circulation was demonstrated in small mammals in Thailand and India, where orthohantavirus was not believed to be endemic.”

Line 28 and 29, remove commas after genus and family

Line 35: strange wording. have been confined? Are they not presently confined?

Line 37: remove commas, “The group of orthohantaviruses which cause HFRS circulate primarily…”

Line 38: rewrite “The geographic distribution of orthohantaviruses endemic to Asia and their small mammal hosts are summarized in Table 1.”

Table 1: define SEOV, THAI and PUUV

Line 49, Figure1 legend: “Schematic representation of an orthohantavirus virion”

Line 51: “Inside the virion are three segments of single-stranded RNA: small (S), medium (M) and large (L). (B) The S, M, and L genomic segments encode for the nucleocapsid protein (433 aa), glycoprotein precursor (1138 aa) and the RNA-dependent RNA polymerase (2155 aa), respectively.”

Line 55: comma after envelope

Line 57: “…to many continents,…”

Line 58: South Korea? North Korea? or just "Korea"? Maybe "Korean peninsula"?

Line 58: “…an historical…”

Line 66: Ambiguous. Are the authors implying that hantavirus was not endemic to China prior to 1931?

Line 84: why is India in brackets?

Line 94-95 begins “In another study” but cites the same study [26] from the previous line.

Line 97: which orthohantavirus? Hantaan virus?

Line 104: “Hantavirus-reactive antibodies were found…”

Line 110: “Habitat” is not a verb. Perhaps the rodents were found to inhabit some rural parts of the region.

Line 120, 124, 127: “aerosols”, “aerosol” is an adjective (correctly used, e.g., on line 122)

Line 126: aerosols are not the same as droplets

Line 129: Ambiguous. Rodent bites, contact with rodent excreta, but ingestion of food contaminated by excreta from rats? Just rats? Or any rodents? Or just reservoir rodents?

Lines 180-185, “orthohantavirus” is misspelled each time.

And finally, I previously commented that the references were completely disorganized. The authors apparently corrected some, but not all, of the errors. I still see references that are inappropriate, as mentioned above. The following references are incomplete, and I am sure there are many many many others, just as before:

4, 5, 17, 18, 20, 31, 33, 44, 45, 48,

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