Parasitic helminths are still a major health problem worldwide, affecting more than 2 billion people (approximately one-third of mankind) where most helminth infections are observed among the resource-limited countries.33 According to the World Health Organization (WHO) report, sub-Saharan Africa accounts 85% of the neglected tropical disease burden resulting from helminth infections.34

Helminth infections are known to induce immune regulatory responses in the host that can be helpful to control inflammation.35 In paradox, helminth infections do have a significant public health burden, particularly in low and middle-income countries,36-38 associated with high rates of morbidity, with chronic infection typically resulting in anemia and malnourishment and even severe manifestations like elephantiasis and blindness.39, 40 Helminth-induced immunomodulation reduces the host immune response by permitting parasite survival and minimizes tissue damages. As a result, most peoples with helminths are unaware of their infection.

2.1 Modulation of the innate immune response by helminth

Innate immunity is the first line response and typically identifies pathogens based on germline-encoded receptors that detect the conserved components of pathogens.

Helminths and productions of excretory/secretory product are recognized by receptors of phagocytes and other cells types, which participate in an intricate cytokine network to generate innate Th2 responses which in turn drives the polarization of AAM, and the activation of eosinophils, basophils, innate lymphocyte T cells 2 (ILC2s), and mast cells.41, 42 The fact that helminth parasites negatively regulate TLRs to a much larger degree suggests that the immune response to helminths could also influence subsequent activation of B and T lymphocytes.43 Besides TLR signaling modulation, helminth-derived immunomodulatory molecules such as cytokine & innate defense homologs and growth factors, enzymes and inhibitors, lipids, and lipid-binding mediators have been largely revealed in modulation of the innate immune response.44

2.2 Modulation of the adaptive immune response by helminth

It is clear that adaptive immunity is initiated when an innate immune response fails to eliminate a pathogen. The infection with helminth modulates CD4+ T cell differentiation, induces the activity of regulatory T cell (Treg) responses, regulates immunoglobulin class switching, and induces a regulatory B cell (Breg) response, and thereby dampening the host immune responses.44 These complex interactions result in the skewness of host immunity towards the type 2 immune response.45 This is typically characterized by the induction of cytokines such as IL-4, IL-5, IL-9, IL-13, and IL-21, and usually the absence of IFN-γ and IL-17 production.39 Besides, the Th2 responses support the initiation of Treg response that dampens the host Type 1 immune response pathway45, 46 (Table 2). Many helminth species secrete a plethora of immunomodulatory proteins that bind to cellular receptors and induce the production of IL-10 from cellular sources. These proteins may also block chemokine release, and Treg development, or inhibit B cell regulatory signaling and transendothelial migration.44

Table 2. An overview of studies focusing on the immune response profiles of helminth infections Author Helminth species Year, study subjects, and country of study Methodology Major findings Refs. Figueiredo et al. T. trichiura and A. lumbricoides 2010, Brazil children aged to 4–11 (N = 1060) Cytokine measurement using unstimulated and stimulated with mitogen or A. lumbricoides antigens Th2 immune response (increased production IL-10, IL-5, and IL-13) 47 Shalaby and Shalab Ascarislumbricoides 2016, Egypt (N = 60) 7−15 years children Serum cytokine profile using ELISA

High levels of

IL-4 and IL-5

48 Ferreira et al. Ancylostoma caninum excretory/secretory products (AcES) 2013, Australia AcES suppress intestinal pathology pro-inflammatory cytokine expression in mice model of colitis Type 2 cytokine response (increased IL-4, IL-10, AAM, and eosinophils, downregulation of pro-inflammatory cytokines) 49 Doyen et al. Hookworm 2021, Belgium N = 20 cases and 14 controls Evaluation of serum cytokine before and after Hookworm treatment A decrease in Treg which exhibited a decrease parallel to Th2 response 50 Kron et al. Brugia malayi 2013, USA Asparaginyl-tRNA synthetase E/S protein in mice model of colitis Resolves intestinal inflammation, induced regulatory responses and IL-10 in mice with T-Cell transfer colitis 51 Ferreira et al. Hookworm 2017, Australia Hookworm recombinant AIP-1 in mice model of colitis Increased IL-10, TGF-β, and TSLP resulted in the suppression of TNF-α, IL-13, and IL-17 A and GM-CSF, CXCL-11, and COX-2 mRNA transcripts 52 Sanin and Mountford S. mansoni 2015UK S. mansoni cercarial Sm16 E/S in murine model Blocks classical activation of macrophages to LPS or IFN-γ. Induces IL-10, Inhibit IL-12p40 and macrophage activation in response to TLR4 and TLR3 TLR ligands. production 53 Abbreviations: (COX)-2, cyclooxygenase; GM-CSF, granulocyte-macrophage colony-stimulating factor; (TNF)-α, tumor necrosis factor; AAM, alternatively activated macrophage; AIP-1, anti-inflammatory protein-1; CXCL, CX motif chemokine; E/S, excretory/secretory; ELISA, enzyme-linked immunosorbent assay; IL-10, interleukin- 10; LPS, Lipopolysaccharide; TGF-β, transforming growth factor; TLR, toll-like receptor; TSLP, thymic stromal lymphopoietin. 2.3 Immunomodulation of helminth during co-infections

Helminth infections are notable to modulate systemic pro-inflammatory cytokines and chemokines, which show a significant implication in a wide range of comorbidities. For example, a study done in India among type 2 diabetes mellitus patients shows that Strongyloides stercoralis alleviated the pro-inflammatory milieu while anthelmintic therapy partially restores the plasma pro-inflammatory cytokine and chemokine levels.54 Helminth immunomodulatory effects have been also observed in many other conditions such as Mycobacterium tuberculosis infection,55, 56 atopy, asthma,57 and Autoimmune disease.58 Besides this, helminth secretome has recently been shown as a novel therapeutic avenue for inflammatory disorder.59 Helminth or its derived product treatment induces Treg and/or alternatively activated macrophages (AAMs) which could directly slow down allergen-specific Th2 responses through a cell contact-dependent mechanism, synthesis of common immunomodulatory mediators such as IL-10 and TGF-ß inhibiting IFN-γ secreting cell (Th1), and inhibition of binding allergen-specific IgE via helminth-specific, and nonspecific polyclonal IgE production called IgE blocking hypothesis.60

The hypothesis that helminths infection modulates the immune response to viral infection is evident and corroborated by an experimental study by Rolot et al. The study uses the inoculation of eggs and adults of Schistosoma mansoni to murid herpesvirus 4 (MuHV-4) infected mice. They explored the helminths induced IL-4 dependent (possibly Th2 source) control of virus.61 Similar study has also shown that the helminth-derived immunomodulator AvCystatin, derived from filarial nematode reduced respiratory syncytial virus (RSV) associated inflammations by inducing CD4+ T cells producing IL-10 cytokine.62 In addition, helminths such as Heligmosomoides polygyrus can induce a protective antiviral response to respiratory syncytial virus. This is primarily mediated through the interaction between microbiota and upregulation of type-I IFN signaling.63 On the other hand, a study by Osborne et al.64 showed co-infection of helminth in viral infection resulted in diminished antiviral immunity, which is highly dependent on Ym1, a chitinase-like molecule that was associated with AAM without changes in the microbiota. However, the antiviral immunity was partly restored by the neutralization of Ym1.64 Such scenarios could have a similar impact on immunity to COVID-19 aforementioned and which in turn affect the response to the COVID-19 vaccine.

After the emergence of SARS-COV-2, several reports on the severity of COVID-19 variations among different countries with the possible factors have been raised from researchers all over the world. The observation that the low number of severe cases and deaths due to COVID-19 in resource-limited nations has been a puzzle for scientists.

The situation was similar in settings where there is a high Bacillus Calmette–Guérin (BCG) vaccine coverage and helminth infections, which has attention. This was the concept of trained immunity that defines the innate immune response to induce memory more specifically BCG could result in protection against SARS-CoV-2 infection and might reduce the severity of COVID-19.65-67 Moreover, based on the recent data reviewed, the high reactivity of BCG-derived antigen to its corresponding SARS-COV-2 substantially increased type II IFN production and its effect on CD4+ T-cells and nonspecific immune responses could harness cross-protection against severe COVID-19.66

Despite, studies not explored and compared with low-middle-income countries and developed countries yet, a review by Yildirim et al. also indicated that the genetic variants of the SARS-CoV-2 entry human angiotensin-converting enzymes ACE2 receptor and related, IFNs, interleukins, TLRs gene, MHC, and ABO gene locus, are critical factors to determine severe COVID-19.68, 69

Interestingly, based on global helminth endemic countries, the comparatively low impact of the COVID-19 disease in tropical and subtropical areas of the world coincides with areas of highly prevalent helminth infections.68 Moreover, it is not well known why the severity of COVID-19 remains lower in most of the resource-limited nations. Hence, we have attempted to summarize a few studies with hypotheses raised from several researchers as follows.

Bradbury et al.71 commentary first described and drew attention to the possible reduction of COVID-19 severity by helminth co-infection due to helminth immunomodulation in helminth-endemic regions. Helminth co-infection in SARS-COV-2 infected patients could derive a parasite-specific Th2 innate and adaptive immune response with CD4+ T cells, eosinophils, IL-4, IL-5, and IL-10 thereby reduce hyperinflammation in patients with severe COVID-19.72 On the contrary, Hays et al.73 put their alternative hypothesis stated that helminths may indeed have a mitigating effect based on a theoretical and empirical evidence of the negative impact of helminth infections suggests. Fonte et al.74 indicated that helminth coinfection, in conjunction with other factors such as low testing system, age, and genetic background, SARS-CoV-2 variant, BCG vaccination, environmental conditions, and endemicity of other infections, could be the possible reasons for low lethality in sub-Saharan Africa.

Hillyer75 has indicated to dedicate towards combating both SARS-COV-2 and helminth infections but with an ongoing understanding of their interaction and effects. Here also, other authors have highlighted, not to forget the negative effect of helminths in regions where undernutrition is a dominating concern where it might present a greater hazard in persons at risk for SARS-CoV-2 infection.76 A recent review also suggested the negative and positive effects of helminth which looks complex and requires exploring the disadvantages and the possible immunomodulatory effects in COVID-19 together.77

Following several hypotheses, a recent study conducted in Ethiopia on COVID-19 confirmed patients showed that parasite coinfected patients were associated with reduced COVID-19 severity which suggests that parasite-driven immunomodulatory response might mute hyperinflammation associated with severe COVID-19.78 In this context, parasite endemicity could be the possible reason for answering why COVID-19 severity remains lower in those endemic countries. However, not all parasites including protozoa will have immunomodulatory properties.79 Besides this, the diversity of helminth species co-infection resulting in human hosts is such not easily to make conclusions.72 While certain helminth infections could reduce the severity of COVID-19, other helminths at different life cycles can also exacerbate immunopathology. The immune response in acute stage of schistosomiasis is mostly associated with a Th1 type immune response which is dramatically shifted to a Th2 type cytokine expression when the females start to lay eggs.80

Research data analyzed from Uganda showed that an inverse correlation between helminth endemic countries and COVID-19 cases or deaths in the world.81 In addition, the direct and indirect effect of helminth in reducing other respiratory viruses could be taken as a lesson, which could potentially reduce pulmonary inflammation induced by COVID-19. In this context, helminth co-infections showed reduced COVID-19 severity. However, there is an urgent need to explore immunological profiles and elucidate the effect of species-specific parasite immunomodulatory effects on the severity of the SARS-CoV-2 infection. To the best of the author's knowledge, no study investigated the implication of helminth infection on the immune response to COVID-19. Thus, here we tried to show insight based on previous lessons and existing data on the immune response of COVID-19 related to helminth infection.