Immunological interactions in helminths-SARS CoV-2 coinfection: Could old enemy be a friend today?

Helminths are metazoan parasites affecting about one third of the worldwide population. Chronic helminth infections (CHIs) confer immunological tolerance to harmless and self-antigens mediated by regulatory T cells (Treg) that are up-regulated. In coronavirus disease 2019 (COVID-19), abnormal adaptive immune response and unrestrained innate immune response could result in local and systemic immune-mediated tissue damage. COVID-19 and CHIs establish complicated immune interactions due to SARS-CoV-2-induced immunological stimulation and CHIs-induced immunological tolerance. However, COVID-19 severity in patients with CHIs is mild, as immunosuppressive anti-inflammatory cytokines counterbalance the risk of cytokine storm. Here, an overview of the interplay between helminths and COVID-19 severity is given. CHIs through helminth-derived molecules may suppress SARS-CoV-2 entry and associated hyperinflammation through attenuation of the TLR4/NF-kB signalling pathway. In addition, CHIs may reduce the COVID-19 severity by reducing the SARS-CoV-2 entry points at ACE2/DPP4/CD147 axis in the initial phase and immunomodulation in the late phase of the disease by suppressing TLR4/NF-kB signalling pathway


| Helminths and immune modulation
Helminths are metazoan parasites that affect about one third of the world's population, evading and regulating the host immune response. 1 Associated with resetting of human immune reactivity through regulation of host immune response, helminths are regarded as human body xenotransplants, whose interaction with the host immune system leads to damping of the host immune response to auto-antigens and allergens by modulating the host immune response to specific antigens. [1][2][3] Epidemiologically, helminths do not multiply or reproduce within the human host, but can survive for many years in tissues and intestinal niches. This long stay of helminths has been related to immunological tolerance, hypo-responsiveness and modulation of immune response. 4,5 Therefore, clearance of helminths through the use of anthelminthic drugs in immune tolerant carriers may trigger specific antigen responses and immune stimulation, hindering the role of helminths in immune responses. 6,7 Likewise, T cells from asymptomatic subjects with helminthic infection illustrate the favourable antiinflammatory cytokine profile, while in symptomatic patients the immunological tolerance is reduced, leading to tissue damage due to activation of the immune response to helminth antigens. 8 Indeed, it has been reported that the immunological tolerance to harmless and self-antigens is mediated by regulatory T cells (Treg), which are upregulated in chronic helminth infections (CHIs). Briefly, the Treg cells in helminth infected patients express a forkhead box protein 3 (Foxp3), which reduce the anthelmintics activity, since Foxp3 serum level is correlated with Treg cells level and decreased allergic response. 9 For this reason, the immunological response to vaccines is attenuated in children infected with helminths. 10 As well, an exaggerated human immune system response against malaria and pulmonary tuberculosis is reduced in CHIs patients. 11,12 Therefore, helminth infection attenuates immune-mediated tissue injury by modulating immune and inflammatory responses, mostly by up-regulating anti-inflammatory interleukin (IL)-10 levels. 8,9,11 It has been proposed that CHIs-mediated immune-modulating effects involve: (1) modulation of cytokine production towards antiinflammatory axis with reduction of pro-inflammatory cytokines 13 ; (2) regulation of cell-surface interactions through activation of cytotoxic T cells and programmed cell death 4 ; (3) driving of human immunoglobulin G (IgG) to be non-inflammatory IgG4 by Treg dependent-Foxp3 production 14 ; (4) activation of host cells to produce tumour growth factor, which provokes Treg cell function; (5) up-regulation of regulatory B (Breg) cells, triggering immunological tolerance to helminth infections 15 ; (6) alteration in macrophage response from classically activated macrophage (M1) to alternatively ones (M2), where helminth-stimulated M2 leads to activation of Treg and induction of immune tolerance. 16 Moreover, helminth-derived molecules (HDMs) are also capable of preventing and attenuating metabolic disorders such as obesity, glucose intolerance and insulin resistance (IR) through activation of M2 macrophages 17 ( Figure 1). The immunomodulatory effects of CHIs may affect the immune response and pathogenesis of coronavirus disease 2019 . Therefore, this mini-review aimed to clarify the interactions between CHIs and COVID-19.

| COVID-19 AND IMMUNE STIMULATION
COVID-19 is a worldwide pandemic disease caused by the severe acute respiratory syndrome-coronavirus type 2 (SARS-CoV-2). 18 As broadly recognized, the SARS-CoV-2 spike protein binds to the angiotensin converting enzyme 2 (ACE2), which acts as a receptor for the SARS-CoV-2entry inside cells. ACE2 is highly expressed in different tissues, including lung pneumocytes, enterocytes, endothelial cells and cardiomyocytes, 19 and the interaction between SARS-CoV-2 and F I G U R E 1 Immunomodulation during chronic helminth infections (CHIs): CHIs enhance anti-inflammatory cytokines while suppressing pro-inflammatory cytokines, slowing the development of inflammatory reactions. Moreover, CHIs encourage the proliferation of regulatory T cells (Treg) and B cells (Breg), which results in the establishment of immunological tolerance. Furthermore, CHIs cause the transition of classical (M1) to alternative (M2) macrophages, which trigger type 2 immune response (Th2) and suppress type 1 immune response (Th1) and enhance protective immune responses.
ACE2 results in the down-regulation of the protective ACE2 with the initiation of hyper-inflammation and oxidative stress, that cause acute lung injury (ALI), acute respiratory distress syndrome (ARDS) and multi-organ failure (MOF). [20][21][22] In addition, the SARS-CoV-2 infection can simultaneously provoke both adaptive and innate host immunity. 23,24 However, an impaired adaptive immune response and an unrestrained innate immune response could result in extensive local and systemic immune-mediated tissue damage. 25 31 Therefore, high IgG levels, besides its antiviral activity, may lead to secondary organ damage through recruitment of monocytes, macrophages and production of pro-inflammatory cytokines. 30 On the other hand, Gan et al. conducted a meta-analysis lately to investigate the relationship between post-immune infection and disease severity from a population perspective and concluded that SARS-CoV-2 may not trigger ADE at the population level. 32 Also, high pro-inflammatory cytokine levels, such as IL-2, IL-6, TNF-α, IL-17 and IL-18 can lead to cytokine storm (CS) induceddiffuse organ damage, shock, ALI and ARDS. 33 Therefore, modulation of exaggerated immune responses and pro-inflammatory cytokines by IL-6 receptor monoclonal antibody (tocilizumab), complement activation inhibitors, anti-inflammatory and immunosuppressive agents may reduce the likelihood of ALI in COVID-19 patients. [34][35][36]

| IMMUNOLOGICAL INTERACTIONS BETWEEN SARS-CoV-2 AND HELMINTHS
The lethality rate of COVID-19 significantly varied worldwide with higher rates observed in economically developed regions in comparison to nations with weak economies and insufficient health services. 37 The lack of diagnostic tests, population age and genetic makeup, SARS-CoV-2 mutational variations in relation to geographic settings, environmental temperature and humidity that are unfavourable for viral replication, BCG vaccination policies, and the endemicity of other infections are some of the factors, or combinations of them, that have been cited to explain the unexpected evolution. 38 Here, we speculate on the potential role of helminth infection.

The immunological interactions between SARS-CoV-2 infection
and CHIs are complicated and not simply defined by SARS-CoV-2-inducedimmunological stimulation and associated helminth F I G U R E 2 Immune system responses against COVID-19 infection: SARS-CoV-2 triggers type 1 immunological response (Th1) and type 2 immune response by activating antigen presentation cells (APCs) and T cells (Th2). When cytokine storm (CS) develops, Th1 stimulates the release of pro-inflammatory cytokines, whereas Th2 stimulates the release of anti-inflammatory cytokines, which prevents CS and the emergence of ALI and ARDS.
immunological changes. 39 In brief, helminth infections can decrease the risk of metabolic disorders like metabolic syndrome, diabetes mellitus and obesity that are commonly associated with higher COVID-19 severity. Indeed, lymphopenia and CS are more common among COVID-19 patients with underlying metabolic disorders. As well, eosinopenia and reduction of Treg are closely linked to COVID-19 severity. [39][40][41] Different epidemiological studies have confirmed that CHIs reduce the risk of type 2 diabetes mellitus (T2DM) and IR through modulation of pro-inflammatory cytokines. 42 For example, the low frequency rates of COVID-19 in Africa are an extraordinary concern for scientists, and it has been theorized that this could be an effect of the augmented exposure to parasites in less developed countries (e.g., African and Latin American populations are much more likely to suffer from parasitic diseases than those living in more developed countries). 53

| HELMINTH INFECTIONS AND PATHOGENESIS OF SARS-CoV-2 INFECTION
It has been shown that there is a mutual relationship between SARS-CoV-2 infection and parasite co-infection. 54  Likewise, eosinophilia has been correlated with SARS-CoV-2 clearance in COVID-19. 77 Nonetheless, IL-5-dependent eosinophilia in CHIs can reduce COVID-19 severity through the antiviral and antiinflammatory effects of high eosinophil counts. 39 In contrast, CHIs may increase the risk of secondary bacterial infections in COVID-19 patients, as well as attenuate the vaccine efficacy and inhibit the longterm immunity against SARS-CoV-2 due to suppression of the immune response against intracellular microorganisms causing diseases like tuberculosis, malaria, human immune deficiency virus (HIV) and opportunistic respiratory bacterial infections. 38,78,79 Hence, CHIs and SARS-CoV-2 co-infection can lead to more critical outcomes, particularly in patients with underlying HIV, tuberculosis, and malaria. [80][81][82] However, secondary bacterial infections are uncommon in COVID-19, unlike those that occur in influenza pneumonia, which has a high rate of severe secondary bacterial infections. 83,84 In addition, CHIs can weaken the preliminary immune response during the initiation of SARS-CoV-2 infection, leading to a high viral load, decreased viral clearance and prolongation of the infection length. 85,86 CHIs are among the most common infectious diseases, despite the negative interactions between helminth infection and COVID-19 severity in helminth-endemic regions, and the alterations in the gut microbiome associated with helminth infection appear to have systemic immunomodulatory properties. 87,88 It has also been planned that helminth coinfection may increase COVID-19 morbidity and mortality, because the immune system cannot professionally respond to the virus. 86,89,90 As a result, vaccines will also be less effective for these patients, but treatment and prevention of helminth infections may reduce the negative effect of COVID-19. 78  to the progression of ALI and ARDS. 23 Thus, immunosuppressive agents may be effective in the late phase of COVID-19 by dampening the CS. However, these agents may reduce the initial immune response that is required to control viral replication. 75 Nonetheless, both cyclosporine and tacrolimus are effective against viral replication in the early phase and prevent CS in the late stage of infection. 94,95 On the other hand, HDMs modulate helminth-host immune interactions by inhibiting TNF-α and IL-1β, as well as TLR4. 96,97 In addition, HDMs suppress the signal transducer and activator of transcription 3 (STAT3) and nuclear factor kappa-B (NF-κB) signalling pathways, leading to a marked inhibition of inflammatory and pro-inflammatory release. 98 Soltillo et al. illustrated that the protein fraction of helminth secretory and excretory products (HSEPs) and extracellular vesicles, such as the miRNA cargo protein, can inhibit the host metalloproteinase activity. 64 Also, it has been reported that HDMs reduce viral pneumonia-induced lung inflammation. 99 Recently, Choudhury et al. showed that SARS-CoV-2 binds to TLR4 as an entry-point for pneumocyte cells, with this binding being able to activate the expression of ACE2. 100 Therefore, activation of TLR4 leads to more viral binding and entry through ACE2 in type II pneumocyte cells, causing a significant reduction in surfactant with the development of ARDS. 101 Furthermore, activated TLR4 induces hyperinflammation and CS through the MyD88-dependent pathway, leading to multi-organ damage. 101 In addition, activation of platelet TLR4 by SARS-CoV-2 may lead to activation of pro-thrombotic cascades, and therefore TLR4 antagonists can attenuate COVID-19 complications, 102 with prolonged TLR4 activations leading to a marked activation of STAT3 and NF-κB signalling pathway and induction of pro-inflammatory activations. 103 In short, CHIs counteract COVID-19 severity along different lines, from local to systemic immune modulating effects, as summarized in Figure 3.  F I G U R E 3 SARS-CoV-2 viral infection and chronic helminth infections interact immunologically; NLRP3 and TL4 activation is inhibited, and type 2 immune response (Th2), anti-inflammatory cytokines, regulatory T cells (Treg), and eosinophilia are activated. These actions reduce the immunological issues related to COVID-19.

CONFLICT OF INTEREST STATEMENT
The authors have no relevant financial or non-financial interests to disclose.

PEER REVIEW
The peer review history for this article is available at https://www. webofscience.com/api/gateway/wos/peer-review/10.1111/pim.

DATA AVAILABILITY STATEMENT
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ETHICS STATEMENT
This article does not contain any studies with human participants or animals performed by any of the authors.

CONSENT FOR PUBLICATION
This article does not contain any studies with human or animal subjects.