Helminth Immune Modulation and Invasive Fungal Infections in Sub-Saharan Africa

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

In this short review entitled “Helminth Immune Modulation and Invasive Fungal Infections in Sub-Saharan Africa”, the authors discuss the hypothesis that the high prevalence of helminth infections in Sub-Saharan Africa (SSA) may contribute to an increased burden of invasive fungal infections. This association is proposed to occur through helminth-induced Th2 immune polarization, which subsequently enhances Treg/IL-10 responses while suppressing Th1/Th17-mediated antifungal immunity.

The authors highlight four fungal infections that appear syndemic with helminth infections and may reflect this immune modulation: cryptococcal meningitis (with over 50% of global cases occurring in SSA), histoplasmosis in children with low HIV prevalence, Pneumocystis pneumonia (PcP) with trends that appear inconsistent with reduced AIDS-related infections following cotrimoxazole prophylaxis, and the high prevalence of allergic responses to Aspergillus antigens in SSA.

The topic is timely and of interest, particularly in the context of immune modulation during coinfections involving helminths, HIV, tuberculosis, and fungal pathogens that require Th1/Th17-mediated immunity for effective host defense. The authors attempt to use epidemiological observations to support their hypothesis, which may stimulate further investigation and experimental validation.

Major Concerns

1. Language and clarity
   The manuscript requires substantial revision by a native or proficient English speaker. It contains numerous grammatical errors, fragmented or unclear sentences. There are also many informal expressions and confusing sentence structures that significantly impair readability and scientific clarity.

2. Nomenclature and formatting
   Scientific names of organisms are used inconsistently throughout the manuscript and are frequently not italicized. All organism names should follow standard taxonomic conventions consistently across the text.

Comments on the Quality of English Language

The manuscript requires substantial revision by a native or proficient English speaker. It contains numerous grammatical errors, fragmented or unclear sentences. There are also many informal expressions and confusing sentence structures that significantly impair readability and scientific clarity.

Author Response

General Comment: In this short review entitled “Helminth Immune Modulation and Invasive Fungal Infections in Sub-Saharan Africa”, the authors discuss the hypothesis that the high prevalence of helminth infections in Sub-Saharan Africa (SSA) may contribute to an increased burden of invasive fungal infections. This association is proposed to occur through helminth-induced Th2 immune polarization, which subsequently enhances Treg/IL-10 responses while suppressing Th1/Th17-mediated antifungal immunity.

The authors highlight four fungal infections that appear syndemic with helminth infections and may reflect this immune modulation: cryptococcal meningitis (with over 50% of global cases occurring in SSA), histoplasmosis in children with low HIV prevalence, Pneumocystis pneumonia (PcP) with trends that appear inconsistent with reduced AIDS-related infections following cotrimoxazole prophylaxis, and the high prevalence of allergic responses to Aspergillus antigens in SSA.

The topic is timely and of interest, particularly in the context of immune modulation during coinfections involving helminths, HIV, tuberculosis, and fungal pathogens that require Th1/Th17-mediated immunity for effective host defense. The authors attempt to use epidemiological observations to support their hypothesis, which may stimulate further investigation and experimental validation.

Response:  Thank you very much for the overall evaluation of our manuscript.

Comments 1: The manuscript requires substantial revision by a native or proficient English speaker. It contains numerous grammatical errors, fragmented or unclear sentences. There are also many informal expressions and confusing sentence structures that significantly impair readability and scientific clarity.

Response 1:  As much as we appreciate your content evaluation, which we have already mentioned above, we also appreciate your thorough assessment of the use of English in the texts of our first version of the manuscript. In addition to thanking you, we would like to make some comments:

- Since we are not native English speakers, the four of us always send our manuscripts for review by a proficient English speaker. This time was no exception.

- When writing a scientific article, regardless of the language, the texts should be clear and direct. However, differences in style are inevitable and must be taken into account. Evidence of this is that the other two reviewers of this manuscript considered that “The English is fine and does not require any improvement.”

-Taking into account the content suggestions made by the other two reviewers and the comments on our English provided by you, we have prepared a new version of our manuscript that contains a few grammatical changes. This new version has also been reviewed by a proficient English speaker.

Comments 2:  Scientific names of organisms are used inconsistently throughout the manuscript and are frequently not italicized. All organism names should follow standard taxonomic conventions consistently across the text.

Response 2: You are right, we apologize. What happened is that when we uploaded our manuscript to the journal platform, we did not check that the names of the organisms were italicized. Those errors were corrected in the new version of the manuscript.

Reviewer 2 Report

Comments and Suggestions for Authors

Comment to the author

The article by Luis Fonte et al. provides an overview of the immune response to helminth infection. The text discusses the interpretation of immune responses in the context of co-infections with common fungal infections that are problematic in sub-Saharan Africa. This focus has not been widely considered until now, and I believe it is an important paper because it prompts readers to reconsider the pathophysiology and research on immune responses from a new perspective.

Major comment:

• The perspective of this paper is novel, and, as the authors note in their manuscript, a syndemic approach that considers interactions among social environments and individual infecting microorganisms is necessary when considering responses to invasive fungal infections in sub-Saharan Africa. However, from a critical perspective, it is difficult to treat helminth infections—which involve multiple species and diverse modes of infection—as a single disease model, especially when compared with more predictable and influential infectious diseases such as HIV and tuberculosis. Therefore, would it be possible for the authors to prioritize and present the types and disease states of helminth infections that should be addressed when considering their interactions in sub-Saharan Africa? While it is challenging to cover everything comprehensively, providing specific examples of representative helminth infections of concern could enhance the value of this review for readers interested in this approach but lacking extensive knowledge.
• While I understand there are a few reports in the literature, including case reports, I would appreciate it if, where possible, you could deepen the discussion of the immune response to cryptococcosis, a fungal infection that is particularly problematic in Africa, similar to how histoplasmosis and pneumocystis are discussed.

Minor comments:

Line 34

Please remove the period.

Line 235, 239

Corrected to italics (M. tuberculosis).

Author Response

General Comment: The article by Luis Fonte et al. provides an overview of the immune response to helminth infection. The text discusses the interpretation of immune responses in the context of co-infections with common fungal infections that are problematic in sub-Saharan Africa. This focus has not been widely considered until now, and I believe it is an important paper because it prompts readers to reconsider the pathophysiology and research on immune responses from a new perspective.

Response: Thank you very much for the overall evaluation of our manuscript. The suggestions contained in the two helpful commentaries of your revision helped us to prepare a more accurate version of our manuscript. Below some comments:

Comments 1: The perspective of this paper is novel, and, as the authors note in their manuscript, a syndemic approach that considers interactions among social environments and individual infecting microorganisms is necessary when considering responses to invasive fungal infections in sub-Saharan Africa. However, from a critical perspective, it is difficult to treat helminth infections—which involve multiple species and diverse modes of infection—as a single disease model, especially when compared with more predictable and influential infectious diseases such as HIV and tuberculosis. Therefore, would it be possible for the authors to prioritize and present the types and disease states of helminth infections that should be addressed when considering their interactions in sub-Saharan Africa? While it is challenging to cover everything comprehensively, providing specific examples of representative helminth infections of concern could enhance the value of this review for readers interested in this approach but lacking extensive knowledge.

Response 1: You write “The perspective of this paper is novel, and, as the authors note in their manuscript, a syndemic approach that considers interactions among social environments and individual infecting microorganisms is necessary when considering responses to invasive fungal infections in sub-Saharan Africa”.

Thank again for the overall evaluation of our manuscript.

You write, “However, from a critical perspective, it is difficult to treat helminth infections—which involve multiple species and diverse modes of infection—as a single disease model, especially when compared with more predictable and influential infectious diseases such as HIV and tuberculosis.”

Here, we completely agree with you. The uniqueness of helminths in terms of life cycles, pathogenicity mechanisms, clinical manifestations, epidemiology, among other aspects, is such that they cannot be treated “as a single disease model, especially when compared with more predictable and influential infectious diseases such as HIV and tuberculosis”

You write “Therefore, would it be possible for the authors to prioritize and present the types and disease states of helminth infections that should be addressed when considering their interactions in sub-Saharan Africa? While it is challenging to cover everything comprehensively, providing specific examples of representative helminth infections of concern could enhance the value of this review for readers interested in this approach but lacking extensive knowledge”

Here, we, as well as other authors (see references below), consider that the mechanisms by which helminths modulate the immune responses of their hosts, especially by soil-transmitted helminths and schistosomes, are generally more homogeneous and, therefore, in this particular aspect, more approachable as a general model of immunomodulation”.

In endemic areas, the prolonged coevolution of humans and helminths has led to the development of defensive responses by the former and to the achievement of complex immune modulatory means by the latter. To control helminth infections, adaptive immunity of the host usually develops type 2 immune responses. This host-helminth interaction has, at least, two additional outcomes: i) the classical and best-known down-regulation of type Th1 and type Th17 responses by the Th2 cytokines and ii) the relatively less-known down-regulation of immune responses by enhancing FOXP3+ T regulatory cells, B regulatory cells and M2 macrophages activities, which together cause the release of regulatory cytokines such as IL-10 and transforming growth factor and additionally down-regulate type Th1 and type Th17 inflammatory responses. 

• Turner JD, Jackson JA, Faulkner H, et al. Intensity of intestinal infection with multiple worm species is related to regulatory cytokine output and immune hyporesponsiveness. J Infect Dis. (2008) 197:1204–12
• Mc Sorley, H.J.; Maizels, R.M. Helminth Infections and Host Immune Regulation. Clin. Microbiol. Rev. 2012, 25, 585-608.
• Salgame, P.; Yap. G.S.; Gause, W.C. Effect of helminth-induced immunity on infections with microbial pathogens. Nat. immunol. 2013. 14, 1118-26.
• Nutman, T. Looking beyond the induction of Th2 responses to explain immunomodulation by helminths. Parasite. Immunol. 2015, 6, 303-13.
• Harris, N.; Loke, P. Recent advances in type-2-cell-mediated immunity: Insights from helminth infection. Immunity 2017, 47, 1024–1036
• Maizels, R.M. Regulation of immunity and allergy by helminth parasites. Allergy. 2020, 75, 524-34.

Comments 2: While I understand there are a few reports in the literature, including case reports, I would appreciate it if, where possible, you could deepen the discussion of the immune response to cryptococcosis, a fungal infection that is particularly problematic in Africa, similar to how histoplasmosis and pneumocystis are discussed.

Response 2:  Certainly, the literature regarding the immune response to Cryptococcus spp. is not abundant. However, the papers that address the topic agree that "Resistance to Cryptococcus spp. infection is clearly dependent upon T-cell-mediated immunity, particularly CD4+ Th1 and Th17 T cells, secretors of IFNγ and other inflammatory mediators, and to a lesser extent CD8+ T cells" as we described in the first version of our manuscript. Taking into account your well-founded comment, which we greatly appreciate, in the new version of our Opinion we delve deeper into the topic, just as you suggest (between lines 174 and 191).

Minor comments:

Line 34

Please remove the period.

Line 235, 239

Corrected to italics (M. tuberculosis).

Response: The observations contained in Minor comments were corrected in the new version of the manuscript (please, see new version)

Reviewer 3 Report

Comments and Suggestions for Authors

Overall, the authors provide an interesting and timely overview of coinfection dynamics from a syndemic perspective. The manuscript is, in principle, suitable for publication as a novel scholarly perspective. However, several substantive issues must be addressed and clarified before it can be considered further.

1. The parasitic infections, particularly helminth infections, are highly prevalent across equatorial regions and are not confined to SSA. The current emphasis on SSA is therefore overly narrow. The authors should provide a comparative discussion of similar epidemiological patterns in other equatorial regions outside SSA, or clearly justify the geographic focus of the manuscript.
2. The invasive fungal infections highlighted in the manuscript—aspergillosis, cryptococcosis, histoplasmosis, and Pneumocystis pneumonia—are globally distributed diseases. To strengthen the regional relevance and conceptual rigor of the discussion, the authors should also address African endemic mycoses, such as emergomycosis, and incorporate them into a comparative framework.
3. This opinion presented aligns closely with the Pirofski–Casadevall damage–response framework (DRF). This conceptual model has been previously applied to dimorphic fungi, including Talaromyces (Penicillium) marneffei, in which host defense is critically mediated by M1 and Th1 responses (https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1448729/full and https://journals.asm.org/doi/10.1128/mbio.02945-24). The authors should explicitly acknowledge this framework and expand their discussion to clarify how their arguments extend, refine, or differ from existing damage–response framework.

   Technical corrections: 

   – A. fumigatus in line 229 should be italicized.
   – M. tuberculosis in line 67, 137, 235, 239 should be italicized.

   - In lines 49–51, please verify the accuracy of the reported number (6,5 million and 2,55 million??), if I understand correctly, it should be "6.5 million and 2.55 million".

Author Response

General Comment: Overall, the authors provide an interesting and timely overview of coinfection dynamics from a syndemic perspective. The manuscript is, in principle, suitable for publication as a novel scholarly perspective. However, several substantive issues must be addressed and clarified before it can be considered further.

Response: Thank you very much for the overall evaluation of our manuscript. The suggestions contained in the three helpful commentaries of your revision helped us to prepare a more accurate version of our manuscript.

Comments 1: The parasitic infections, particularly helminth infections, are highly prevalent across equatorial regions and are not confined to SSA. The current emphasis on SSA is therefore overly narrow. The authors should provide a comparative discussion of similar epidemiological patterns in other equatorial regions outside SSA, or clearly justify the geographic focus of the manuscript.

Response 1: SSA has the largest population infected with HIV and M. tuberculosis, which are considered the main risk factors for fungal infections.  At the same time, SSA is the region of the world with the highest rates of helminth infections (for example, of the world’s 207 million estimated cases of schistosomiasis, 192 million occur in SSA*), whose immunomodulatory effects impair the host's immune responses to other microorganisms, included HIV and M. tuberculosis.  Recent advances in knowledge of immunity to HIV, M. tuberculosis, fungi, and parasites, including a better understanding of the mechanisms by which helminths modulate immune responses, are allowing a better comprehension of some peculiarities of IFIs in SSA. These peculiarities, which are related to the four fungal infections we refer to in our manuscript, allow us to hypothesize that helminth infections, mainly by schistosomes and STH, impact the clinical course of IFIs in SSA. In SSA, and not in other areas of the equatorial belt of the planet, because in this region converge the syndemic interactions (common sociodemographic conditions, high prevalences, interactions between microorganisms) that make these peculiarities possible. In response to your interesting comment, in the new version of our manuscript (which is an Opinion piece, not a Review), we are adding a new sentence that briefly provides data that further justify the geographic focus of the manuscript (lines 134 and 142).

*Hotez PJ, Kamath A. Neglected tropical diseases in Sub-Saharan Africa: review of their prevalence, distribution, and disease burden. PLoS Negl Trop Dis. (2009) 3:e412.

Comments 2: The invasive fungal infections highlighted in the manuscript—aspergillosis, cryptococcosis, histoplasmosis, and Pneumocystis pneumonia—are globally distributed diseases. To strengthen the regional relevance and conceptual rigor of the discussion, the authors should also address African endemic mycoses, such as emergomycosis, and incorporate them into a comparative framework.

Response 2: SSA is the region of the world with the most intense transmission of helminth infections, mainly by schistosomes and Soil Transmitted Helminths. Numerous articles over the past three decades have shown that helminths modulate the host's immune responses to other microorganisms, including HIV and M. tuberculosis. Epidemiological particularities of four of the most cosmopolitan fungal infections (cryptococcosis, histoplasmosis, Pneumocystis pneumonia and aspergillosis) suggest that helminth infections could be influencing the clinical course of these mycotic entities where these helminth infections are most prevalent and intense, in SSA. That is the conceptual core of our Opinion. However, and we appreciate your comment, African endemic mycoses, such as emergomycosis, due to the immune mechanisms that control them, could also be related to the immunomodulatory effects of helminths, which are more prevalent there. Taking your comment into account, which we greatly appreciate, we have included a fifth section (two paragraphs) addressing this topic in the new version of our manuscript (between lines 263 and 289).

Comments 3: This opinion presented aligns closely with the Pirofski–Casadevall damage–response framework (DRF). This conceptual model has been previously applied to dimorphic fungi, including Talaromyces (Penicillium) marneffei, in which host defense is critically mediated by M1 and Th1 responses (https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1448729/full and https://journals.asm.org/doi/10.1128/mbio.02945-24). The authors should explicitly acknowledge this framework and expand their discussion to clarify how their arguments extend, refine, or differ from existing damage–response framework

Response 3: Your third commentary is very useful too. From our perspective, it has led us to increase the academic value of our Opinion. Certainly, our work aligns closely with the Damage Response Framework for Microbial Pathogenesis of Pirofski and Casadevall. At the same time, and in a complementary way, we use the Syndemic Framework for a better understanding of the influences of social and biological interactions on the co-occurrence and clustering of infectious diseases. Implicitly, both theoretical frameworks are used throughout the first version of our manuscript to analyze a possible influence of helminth immune modulation on some epidemiological peculiarities of IFIs in Africa, particularly in the sub-Saharan region. In the new version of our manuscript, we include a new paragraph to explicitly refer to those models (between lines 90 and 96).

Technical corrections:

– A. fumigatus in line 229 should be italicized.

– M. tuberculosis in line 67, 137, 235, 239 should be italicized.

- In lines 49–51, please verify the accuracy of the reported number (6,5 million and 2,55 million??), if I understand correctly, it should be "6.5 million and 2.55 million".

Response: The observations contained in Technical corrections were corrected in the new version of the manuscript. (Please, see new version)

Round 2

Reviewer 3 Report

Comments and Suggestions for Authors

The manuscript is broadly suitable for publication as a novel academic perspective.

Author Response

Comments 1: The manuscript is broadly suitable for publication as a novel academic perspective.

Answer: Thank you