Gut-dwelling STHs modify the microenvironment of the gastrointestinal tract, including the epithelial cell layer and immune cells located in the underlying stroma, but also the surrounding microbiota (Zaph et al., 2014; Harris and Loke, 2018; Loke et al., 2022). In addition, certain STHs, such as A. lumbricoides, A. duodenale, and N. americanus, undergo an extraintestinal phase in which larvae migrate through different tissues before developing into sexually mature adult worms in the intestine (Vacca and Le Gros, 2022).

Following host invasion, worm-induced barrier damage leads to the release of alarmins (TSLP, IL-25, IL-33) from epithelial, mesenchymal, and innate cells (Hepworth et al., 2012; Peng et al., 2022). These early events drive the activation and proliferation of innate immune cells, such as mast cells, dendritic cells, and type 2 innate lymphoid cells (ILC2s), promoting the induction of an adaptive type 2 (Th2) immune response (Peng et al., 2022). In parallel, epithelial tuft cells have recently been shown to be important regulators of the host response to various infections in the gut (Strine and Wilen, 2022). Tuft cells respond to helminth infection by releasing IL-25, which drives the release of IL-5, IL-13, and IL-4 by activated ILC2s (Colombo and Grencis, 2020; Hendel et al., 2022). Subsequently, Th2 cells and ILC2s amplify IL-4 and IL-13 signaling to activate host protective responses at the epithelial barrier, including tuft cell differentiation, hyperplasia of mucin-producing goblet cells, and increased epithelial cell turnover (Colombo and Grencis, 2020). IL-4/-13 and IL-5 produced by Th2 cells also promote the expansion of alternatively activated macrophages (AAM) and the recruitment of eosinophils into affected tissues (Peng et al., 2022). In the gut, IL-4 and IL-13 increase smooth muscle hypercontractility, embodying the “weep-and-sweep” response that eliminates luminal parasites (Sorobetea et al., 2018). Furthermore, IL-4 derived from follicular T-helper cells contributes to effective anti-parasitic immunity in promoting IgG and IgE production by B cells (Zaini et al., 2021). Immune mechanisms directed to STH infections are summarized in Figure 3 .

Worldwide, and thus also in helminth endemic areas, enteric viruses such as noroviruses and rotaviruses are the main cause of severe acute gastroenteritis in children under five years of age (Djeneba et al., 2007; Potgieter et al., 2023). Reinfection is common, with virus-specific IgA correlating with protection and increasing over time, whereas IFN-γ-dominated specific T cell responses are transient (Malm et al., 2019). However, the effects of STH coinfection with intestinal viruses in humans are not well understood. In mice, acute enteric helminth infections with Heligmosomoides polygyrus and Trichinella spiralis resulted in impaired virus-specific CD8+ T cell responses (Osborne et al., 2014). This defect was STAT6-dependent, associated with the nematode-triggered alternative activation of macrophages, and was partially restored by neutralization of Ym-1, a product released by AAM (Osborne et al., 2014). Another study reported the increased enteric replication of flaviviruses in H. polygyrus-infected mice which was associated with a tuft cell-IL-4 receptor signaling axis leading to dampening of antiviral adaptive immunity (Desai et al., 2021). Associated with goblet cell hyperplasia during murine H. polygyrus coinfection, murine astrovirus replication and shedding was also enhanced (Ingle et al., 2021).

HAV, HBV, and HCV are responsible for most cases of viral hepatitis, with HEV emerging and often being underdiagnosed (Shin et al., 2016; Kamar et al., 2017). Thus, a correlation between human infections with A. lumbricoides and HBV has been demonstrated (Xiao et al., 2015), but the effects on correlated immune responses and liver pathology are unknown. To date, studies addressing the potential impact of helminth infections on the controls of hepatotropic viruses focused on patients coinfected with schistosomes. Interestingly, HEV seroprevalence was very high among Egyptian workers and a Brazilian cohort infected with schistosomes (el-Esnawy and Al-Herrawy, 2000; Passos-Castilho et al., 2016). Here, previous HEV infection was associated with a higher frequency of liver enzyme abnormalities (Passos-Castilho et al., 2016), indicating long-lasting effects of HEV. Similarly, concurrent infections with HBV and HCV in trematode endemic areas are often observed (Abruzzi et al., 2016; Gao et al., 2020). Related to increased Th2 cytokines, patients with concurrent helminth and HBV or HCV infection showed increased viral replication and liver fibrosis (Abruzzi et al., 2016; Li et al., 2016; Dong et al., 2022). Hence, chronic inflammatory processes associated with hepatic viral replication next to Th2-mediated fibrotic responses to Schistosome eggs may result in more extensive liver damage caused mainly by immune-mediated mechanisms (Shin et al., 2016). Furthermore, the modulation of early intrahepatic antiviral immune pathways (e.g. type I IFN) in murine helminth-virus coinfection was shown to be associated with increased viral replication in the liver (Edwards et al., 2005). Whether recurrent tissue damage induced by migrating Ascaris larvae has a similar effect remains to be investigated. Furthermore, it is unclear whether tissue damage induced by blood-feeding hookworm species may affect the immune response to hepatic viruses. A. lumbricoides, A. duodenale and N. americanus, have an extraintestinal phase in which the larvae migrate through various tissues before developing into sexually mature adult worms in the gut. The liver, as an organ that preferentially induces tolerance to immunity, is passed by Ascaris during its life cycle before the larvae reach the lungs with liver larvae attrition occurring under certain circumstances (Midha et al., 2021). This function can be exploited by parasites to evade host immunity. Thus, hepatotropic viruses that exploit similar strategies preferentially infect hepatocytes.

Tissue-invasive STHs that migrate through the lungs evoke inflammatory changes and tissue damage that can negatively impact concurrent respiratory viral infections or even pave the way for secondary infections. Respiratory syncytial virus (RSV) is the most common cause of acute respiratory diseases in children worldwide (Gatt et al., 2023). An imbalance in the Th1/Th2 cytokine immune response has been associated with the RSV pathogenesis of bronchiolitis (Pinto et al., 2006). Thus, Th1/Th2 ratios, helminth-specific-IgE and TLR4-gene-polymorphisms are related to infant RSV disease severity in parasite-endemic areas (Caballero et al., 2015; Buendía et al., 2022). Research is also underway to determine how coinfection with STHs can influence inflammatory immune activity in SARS-CoV-2 infection and thus disease severity, but also the efficacy of vaccination against SARS-CoV-2 (Adjobimey et al., 2022; Akelew et al., 2022). Interestingly, the prevalence and mortality due to COVID-19 have remained moderate on the African continent (Cepon-Robins and Gildner, 2020). However, Ascaris antigens affected immune reactivity to SARS-CoV-2 peptides by reducing virus-reactive Th cells and type 1 cytokines in COVID-19 patients, suggesting a negative impact of concurrent helminth infestation on antiviral immunity (Adjobimey et al., 2022). In line, Ascaris-infected pigs were shown to be more susceptible to respiratory virus infection (Oba et al., 2023). Indicating a bidirectional interaction, pulmonary Ascaris and vaccinia virus coinfection in mice weakened virus-specific immunity and not only exacerbated virus-associated pathology, but also reduced lung larval loads (Gazzinelli-Guimarães et al., 2017). However, in addition to the detrimental effects in STH coinfections, strictly enteric helminth infection with H. polygyrus protected mice from severe pulmonary RSV infection by microbiota-dependent type I interferon production, with Th2 responses dispensable (McFarlane et al., 2017).

Herpesviruses have a marked tropism for immune cells and latently infected cells remain for life with virus reactivation occurring under certain circumstances (Lan and Luo, 2017). Because of their high prevalence, many people are coinfected with herpesviruses and STHs, and although both pathogens modulate the host’s immunity (Peacock et al., 2003; Barton et al., 2007; Lan and Luo, 2017), their interactions in humans remain largely unexplored. The local cytokine environment during acute helminth infection alters latent herpesvirus infection, whereby IL-4 reactivated human Kaposi’s sarcoma-associated herpesvirus from latency in cultured human cells (Reese et al., 2014). The extent of immunity to helminth infection may be relevant here, as no reactivation of latent Epstein-Barr virus infection was observed in multiple sclerosis patients who underwent low-dose therapeutic oral hookworm administration (Maple et al., 2020). A “two-signal” model for viral reactivation was postulated, as exogenous IL-4 and IFN-γ-blockade reactivated latent murine gammaherpesvirus-68 (MHV68) infection in vivo (Reese et al., 2014), which required macrophage IL-4-receptor-expression. Accordingly, Nippostrongylus brasiliensis infected mice developed type 2 immune-driven enhanced pathology upon genital herpesvirus infection (Chetty et al., 2021), a finding also translatable to humans, since hookworm-infected women in an African cohort were at high risk for viral infections in the genital tract (Holali Ameyapoh et al., 2021). However, IL-4 also has beneficial effects on IFN-γ-dependent antiviral effector responses, as helminth-mediated (N. brasiliensis, H. polygyrus) conditioning of virtual memory CD8+ T cells (TVMs) enhanced control of murine gammaherpesvirus 4 (MHV-4) infection (Hussain et al., 2023). Of note, this helminth-mediated increase in TVMs is transient and absent in aged mice (Hussain et al., 2023) which may be particularly relevant to herpesvirus reactivation in elderly worm-infected patients.

Human retroviruses such as HIV cause damage to lymphoid and mucosal tissues, leading to progressive immunodeficiency (Heron and Elahi, 2017). Sub-Saharan Africa is burdened by HIV/AIDS and helminthiasis, and there is considerable overlap between these infections, with poor sanitation and socioeconomic status influencing the occurrence of HIV and STH coinfections (Mpaka-Mbatha et al., 2023). Compared to HIV-infected patients in Africa, adults coinfected with HIV and intestinal helminths (e.g. hookworms) have been found to have increased susceptibility to micronutrient deficiencies and anaemia, as well as higher viral loads and lower CD4+ T cell counts (Mkhize-Kwitshana et al., 2011; Morawski et al., 2017; Amoo et al., 2018; Wondmieneh et al., 2020). According to two studies in South Africa, HIV- and A. lumbricoides-coinfected individuals with high Ascaris-specific-IgE levels and eosinophilia displayed the highest viral loads and reduced levels of type 1 cytokines, indicating a suppressive effect of helminth-mediated immunity on HIV control (Mkhize-Kwitshana et al., 2011; Mkhize-Kwitshana et al., 2014). However, findings are conflicting, as serum cytokine profiling of HIV- and STH-coinfected pregnant women in Nigeria revealed increased IFN-γ and IL-17 levels (Rabiu et al., 2022). In line, Peruvian patients coinfected with another retrovirus, HTLV-1, and Strongyloides stercoralis have higher parasite burdens and lower type 2 immune responses than patients with strongyloidiasis alone (Montes et al., 2009).

In conclusion, STH coinfections with viruses can have profound effects on the outcome of each infection through the following interactions ( Figure 4A ): i.) STHs facilitate viral replication by remodeling tissue morphology and counteracting classical IFN-γ/TNF-mediated type 1 inflammatory pathways due to initiated type 2 immune circuits; ii.) Depending on the timing and extent of virus-induced inflammation, an unfavorable environment for migrating STH larvae is created, which may compromise the development of patent worm infection; iii.) STHs may also exert direct type 2 cytokine-mediated and indirect microbiota-dependent remote effects in non-infested organs, resulting in enhanced antiviral immunity that protects against virus-related pathology. Thus, infections with STH can alter host immunity and tissue integrity both directly in parasitized organs and indirectly in uninfected organs, and therefore have systemic effects that are highly complex and appear to depend largely on the context and biology of viral coinfection in a bidirectional manner.

As with enteric viruses, coinfections with STHs and enteric bacteria, some of which share the fecal-oral route of transmission, are also widespread. Between human and animal studies of STH-bacterial coinfections as well as data from other helminths such as vector-borne filarial nematodes and trematodes such as Schistosoma, there is considerable evidence for helminth immunomodulation leading to increased bacterial burdens and pathology (Rocha et al., 1971; Gendrel et al., 1994; Bobat et al., 2014; Reynolds et al., 2017). The outcomes of coinfection can also be influenced by the pathogens in question as well as by timing. Mice coinfected with S. mansoni and Listeria monocytogenes displayed increased resistance to Listeria infection early in Schistosoma infection, and decreased resistance to bacterial infection later in the course of Schistosoma infection (Collins et al., 1972).

Infection with A. lumbricoides is negatively associated with IFN-γ and IL-7 production in response to LPS as demonstrated in Tsimane hunter-horticulturalists (Schneider-Crease et al., 2021). This negative association is also associated with impaired responses to bacterial vaccines. PBMCs from teenage Ecuadorian patients infected with A. lumbricoides had impaired cholera toxin B-specific IL-2 and IFN-γ responses following vaccination with CVD 103-HgR, a live attenuated Vibrio cholerae strain used for cholera vaccination (Cooper et al., 2001). Interestingly, anthelmintic treatment of the same ascariasis patients enhanced the vibriocidal antibody response (Cooper et al., 2000). In pigs, A. suum infection negatively affects the protective response of Mycoplasma hypopneumoniae vaccination, including impaired seroconversion and antibody titres, while increasing lung pathology (Steenhard et al., 2009).

Clinical observations indicate that coinfection with Schistosoma and Salmonella is quite common; helminth-infected Gabonese children and rural Congolese villagerss were more often found to carry Salmonella (Gendrel et al., 1994; Mbuyi-Kalonji et al., 2020) and schistosomiasis patients were found to suffer from prolonged bacteremia and salmonellosis (Rocha et al., 1971), a situation which can be improved by anthelmintic treatment (Hathout et al., 1966; Gendrel et al., 1984). These observations are well supported by coinfection studies in mice where Schistosoma-Salmonella coinfected mice have higher bacterial burdens and increased mortality compared to mice infected only with Salmonella (Njunda and Oyerinde, 1996). Importantly, similar outcomes are observed in STH-Salmonella coinfection, including with N. brasiliensis (Bobat et al., 2014) and H. polygyrus (Reynolds et al., 2017) wherein helminth-impaired host resistance to Salmonella is restored by deworming (Brosschot et al., 2021).

Protective responses against Salmonella are typically initiated by bacterial recognition via patterns-associated molecular patterns such as lipopolysaccharide (LPS), type-3 secretion system proteins, flagella, fimbriae, and bacterial DNA combined with endogenous danger-associated molecular patterns, leading to neutrophil and macrophage recruitment and pro-inflammatory cytokine secretion, including IL-1β, IL-6, IL-17, TNF-α, and IFN-γ (de Jong et al., 2012). Innate antibacterial responses by neutrophils and macrophages can be influenced by helminth infection. Su and colleagues demonstrated that H. polygyrus can worsen intestinal inflammation during S. Typhimurium infection by compromising neutrophil recruitment and control of bacterial replication (Su et al., 2014). Furthermore, helminth antigens trigger IL-4 and IL-13 release by basophils leading to alternative activation of macrophages, impaired IFN-γ and IL-17 production, and thus impaired anti-Salmonella protective Th1/Th17 responses (Knuhr et al., 2018; Schramm et al., 2018). Similar observations have been made in mice coinfected with H. polygyrus and Citrobacter rodentium, a gram-negative model to investigate enteropathogenic and enterohaemorrhagic E. coli (EPEC and EHEC, respectively) infections and colitis (Collins et al., 2014), where coinfected mice display considerable morbidity and mortality (Chen et al., 2005) and higher bacterial loads compared to single-infected mice (Weng et al., 2007). The Th2-driven alternative activation of macrophages resulted in downregulated protective IFN-γ and corresponding impaired bacterial killing alongside worsened colitis mediated by enhanced TNF-α responses (Chen et al., 2005; Weng et al., 2007). H. polygyrus infection can also promote S. Typhimurium infection independently of a modulated Th2 response. Reynolds and colleagues demonstrated the host intestinal metabolome was altered by H. polygyrus to enhance the expression of Salmonella pathogenicity island 1 genes, leading to increased bacterial invasion (Reynolds et al., 2017).

Interestingly, bacterial infection can also impact parasite burdens. Mice coinfected with S. japonicum and S. Typhimurium had reduced adult worm burdens and reduced mortality compared to S. japonicum infection alone (Zhu et al., 2017). In these mice, Schistosoma infection was associated with increased serum IFN-γ and IL-4 levels compared to uninfected controls while coinfection further increased IFN-γ, but reduced IL-4 to uninfected levels (Zhu et al., 2017). Another important consideration is the order of infection. In the case of N. brasiliensis-S. Typhimurium coinfection, an established helminth infection impairs control of subsequent bacterial infection while simultaneous coinfection impaired protective immunity to both pathogens despite robust antibody responses (Bobat et al., 2014). Interestingly, Salmonella infection restrained the regulatory response induced by N. brasiliensis as reflected by reduced IL-10 secretion by splenocytes (Bobat et al., 2014).

The lung is a major site of immunomodulation with an impact on coinfecting bacteria. Clinical outcomes of helminth-respiratory bacterial coinfection are mixed though there is ample evidence to suggest that as with intestinal infections, helminth immunomodulation alters responses to respiratory pathogens as well. Higher prevalence of helminth infections have been reported in Ethiopian and Brazilian patients with active tuberculosis (TB) compared to matched controls (Tristão-Sá et al., 2002; Elias et al., 2006) as well as eosinophilia, a prominent feature of helminth infections (Elliott et al., 2003). Urban Indian adults coinfected with Strongyloides stercoralis and M. tuberculosis have higher circulating levels of matrix metalloproteinases and tissue inhibitors of metalloproteinases compared to M. tuberculosis single infection, indicating that coinfection could result in greater degradation of the basement membrane thereby creating an immune privileged site for the growth of M. tuberculosis (Kathamuthu et al., 2021). In one study, STHs, namely Ascaris and Trichuris, were identified as a risk factor for increased pneumococcal carriage density in Ecuadorian children (Law et al., 2021) In the same report, T. muris-infected mice coinfected with Streptococcus pneumoniae had increased pneumococcal carriage density in the nasopharynx and enhanced bacterial dissemination into the lungs (Law et al., 2021). Another study found coinfection with H. polygyrus and Bordatella bronchiseptica led to higher bacterial loads in the lungs and higher mortality (Lass et al., 2013). Similarly, mice coinfected with A. suum (at day 8 post-infection during A. suum’s lung migration) and Pasteurella multocida developed more severe pneumonia and septicemia than did mice infected with bacteria alone (Tjørnehøj et al., 1992), suggesting that while STHs are actively migrating through the lungs, the host may be at an increased risk for bacterial coinfection.

As with Salmonella, resistance to mycobacterial infection is initiated with inflammatory responses by phagocytes triggered by pattern recognition receptors and control is mediated by Th1 and Th17 cells while the progression of tuberculosis is associated with the regulatory type-2 cytokines IL-4 and IL-10 (Babu and Nutman, 2016; Cadmus et al., 2020; Bustamante-Rengifo et al., 2021; Bhengu et al., 2022). Numerous studies have documented helminth-impaired reactivity to tuberculin antigens and compromised tuberculosis diagnostics (Babu and Nutman, 2016). Specifically, helminth infection appears to dampen the efficacy of Bacille Calmette-Guerin (BCG) vaccination, an attenuated strain of Mycobacterium bovis, and helminth infection can reduce mycobacterial-induced IFN-γ production in Bangladeshi children and pregnant Ethiopian mothers (Cadmus et al., 2020; Bhengu et al., 2022). S. stercoralis-M. tuberculosis coinfections in Indian adults are associated with lower circulating levels of inflammatory cytokines, including IFN-γ, TNF-α, IL-17A, and IL-17F alongside increased type 2 cytokines IL-4, IL-5, and IL-13 (George et al., 2015). Similarly, Indian TB patients coinfected with hookworms had fewer Mycobacterium-specific Th1 and Th17 cells and associated circulating cytokines (TNF-α, IFN-γ, IL-2, IL-17A) but increased Th2 cells and associated cytokines (IL-4, IL-13) as well as increased frequencies of regulatory T cells compared to patients infected with M. tuberculosis alone (George et al., 2013).

In conclusion, helminth coinfections can modulate antibacterial immune responses against bacterial pathogens in different organs. A general picture emerges whereby a helminth-induced regulatory type 2 response dampens cellular responses to bacteria and their antigens, polarizes macrophages away from an antibacterial proinflammatory state, and alters antibody responses against bacteria, thus establishing an environment better suited to the proliferation of bacterial pathogens ( Figure 4B ).

Malaria as well as STH infections remain highly endemic in sub-Saharan Africa. A number of studies investigated the potential impact of STH infection on malaria prevalence, infection intensity and the associated immunopathology in humans as well as in experimental animal models. Several studies reported that infection with A. lumbricoides, T. trichiura, and hookworms were associated with an increased risk for the development of clinical, non-severe malaria (Nacher et al., 2002; Spiegel et al., 2003; Degarege et al., 2012; Zeukeng et al., 2014; Babamale et al., 2018), which was further increased with the number of coinfecting intestinal helminth species (Nacher et al., 2002; Degarege et al., 2012). Similarly, studies performed in murine models reported higher peak parasitemia in mice coinfected with H. polygyrus or N. brasiliensis (Su et al., 2005; Noland et al., 2008; Helmby, 2009; Hoeve et al., 2009; Segura et al., 2009; Tetsutani et al., 2009), and, in some cases, accelerated mortality associated with uncontrolled liver pathology (Helmby, 2009; Craig and Scott, 2017). By contrast, studies in humans found a protective effect of Ascaris and hookworm infection against the development of severe malaria as well as malaria-related acute renal failure (Nacher et al., 2000; Nacher et al., 2001). Timing is important for the outcome of GI nematode/Plasmodium coinfection in mice. Nematode infection one to two weeks prior to infection with P. chabaudi had limited impact on the course of Plasmodium infection, whereas simultaneous coinfection led to a dramatic rise in mortality, associated with highly increased liver damage. The latter was dependent on the elevated expression of IL-12, IFN-γ and IL-23 in coinfected mice (Helmby, 2009). Increased mortality coincided with larval-driven intestinal barrier damage, suggesting that danger signals reaching the liver via the portal system promoted overt hepatic inflammation when mice were simultaneously coinfected with Plasmodium parasites (Helmby, 2009).

Several studies reported impaired IFN-γ responses in coinfected mice, arguing for a detrimental effect of type 2 responses driven by nematode coinfection (Su et al., 2005; Noland et al., 2008; Tetsutani et al., 2009). However, peak parasitemia was also increased in coinfected STAT-6^-/- mice incapable of inducing a Th2 response to H. polygyrus (Segura et al., 2009). Importantly, a placebo-controlled deworming trial in Indonesia reported increased immune responsiveness after anthelmintic treatment (Wammes et al., 2016). Regular deworming resulted in lower expression of the suppressive molecule CTLA-4 by T cells, coinciding with significantly increased Plasmodium-specific TNF-α/IFN-γ and elevated Ascaris-specific IL-2 production (Wammes et al., 2016).

While some studies determined a higher risk for anemia and low body weight in STH coinfected patients (Degarege et al., 2010; Zeukeng et al., 2014), others found no effect on P. falciparum-induced anemia (Abanyie et al., 2013; Babamale et al., 2018). Investigating experimental infections in mice, Griffith and colleagues reported suppressed immune responses, yet smaller Plasmodium populations in mice coinfected with N. brasiliensis (Griffiths et al., 2015). In this model, target cell availability exerted a stronger effect on the dynamics of malaria replication than suppression of IFN-γ and IgG2a responses, potentially linked to altered mean age and population size of red blood cells in mice afflicted with hemorrhage induced during migration of nematode larvae through the lung. Considering resource-mediated next to immune-mediated mechanisms may hence be essential in understanding the dynamics of helminth-Plasmodium coinfections (Griffiths et al., 2015).

Th1 responses associated with the production of cytophilic IgG antibodies (IgG1, IgG3) are important for the clearance of Plasmodium blood-stage infection (Torre et al., 2002; Courtin et al., 2009). By contrast, helminth infections predominantly cause the production of IgG4 and IgE in a Th2-dependent manner (Harris and Gause, 2011). Accordingly, several studies reported a negative effect of concurrent helminth infection on the humoral response to malaria, seen in the reduction of P. falciparum-specific IgG (Ateba-Ngoa et al., 2016), IgG1 and IgG3, and a rise in IgG4 (Roussilhon et al., 2010; Courtin et al., 2011). On the other hand, two studies found higher IgG1, IgG2 and IgG3 responses to P. falciparum antigens in schistosome coinfected individuals (Diallo et al., 2010; Tokplonou et al., 2020). Similarly, Amoani and colleagues reported a positive effect of hookworm coinfection on the levels of IgG3 directed against the malaria vaccine candidate GMZ2 at baseline and a decline in the antibody level after albendazole treatment (Amoani et al., 2021). Another recent study surveyed antibody responses directed against a broad array of Plasmodium as well as STH antigens in Mozambican children and found consistently higher IgG levels against Plasmodium and nematode antigens as well as higher total IgE levels in the coinfected group (Santano et al., 2021). In trend, the study confirmed earlier reports of higher Plasmodium density in coinfected children and found significantly higher Trichuris worm burdens in malaria-positive subjects. Finally, socioeconomic score and improved sanitary conditions clearly impacted overall IgE levels and IgG levels against some Plasmodium and helminth antigens (Santano et al., 2021). Hence, synergies may exist between the Th2-related support of antibody production in helminth infection and humoral responses directed against Plasmodium parasites. However, as the risk of being infected and Plasmodium density tend to increase with helminth coinfection, it seems that such synergistic effects reflect the increased exposure rather than protection of coinfected patients. Although the gut microbiota may play a role in Plasmodium infections and contribute to the complexity of coinfection with STH (Easton et al., 2020), further studies are needed to specify this interaction.

In conclusion, there are at least three potential interactions between helminths and Plasmodium coinfection ( Figure 4C ): i) By the induction of Th2 responses, STH coinfection may interfere with Th1/IFN-γ driven effector/cytophilic IgG1/IgG3 responses required for the control of Plasmodium infection. Conversely, a strong Th1-bias may hamper effective type-2 driven control of STH infections. However, coinfection was also reported to be associated with enhanced parasite-specific IgG and IgE responses compared to single infections; ii) Some animal models suggest that simultaneous tissue damage driven by malaria parasites and helminths may result in an adverse inflammatory response, worsening disease outcome. However, STH infection rather seems to protect from severe malaria in humans; iii) Coinfection with Ascaris/hookworms is associated with hemorrhage in the liver during lung stage infection. In addition, adult hookworms feed on host blood. This may alter the age profile of erythrocytes and thereby limit resources for Plasmodium species favoring matured blood cells for infection.

Giardia duodenalis colonizes the small intestinal tract where the trophozoite stage attaches to epithelial cells. The infection is often asymptomatic, but may also be associated with diarrheal disease, leading to malabsorption and, under chronic exposure, stunted growth (Klotz and Aebischer, 2015; Fekete et al., 2021). Experimental Giardia infections are controlled by Th17 and IgA responses and elevated Th17 activity was also linked with protective immunity against human giardiasis (Dann et al., 2015; Saghaug et al., 2016; Paerewijck et al., 2019). Despite the fact that Giardia shares the small intestinal habitat with Ascaris, hookworms and threadworms, relatively few studies tested for potential interactions between enteric nematode and Giardia infections. Furthermore, although the prevalence of Giardia infection is often high in areas where STH and/or schistosome infections are highly endemic (Fofana et al., 2019; Geus et al., 2019; Archer et al., 2020), data on potential interference of immune responses directed against the two types of parasites are largely lacking.

A survey of Plasmodium, Ascaris and Giardia infection in Rwandan schoolchildren showed that parasitic coinfections were common, but the clinical picture was mostly associated with Plasmodium infection and not modified by Ascaris or Giardia coinfection. However, malnutrition was more pronounced in children coinfected with Ascaris and Giardia compared to individuals with single infections (Geus et al., 2019). Similarly, a study in subtropical Argentina observed an association between stunting in older children and the presence of enteric parasites, multi-parasitism and giardiasis (Rivero et al., 2018). A long-term survey of over 80 villages in Bolivia revealed an antagonistic relationship between STH and Giardia infection (Blackwell et al., 2013). Both hookworm and Ascaris infection were negatively associated with Giardia infection in a cross-sectional as well as in a longitudinal survey. However, anthelminthic treatment only resulted in a marginal rise of the risk of being infected with Giardia on the next visits (Blackwell et al., 2013). Concerning modifications of the immune profile, one study reported reduced IL-2, IL-12 and TNF-α serum levels in 3-year old children coinfected with Ascaris and Giardia compared with Giardia mono-infected individuals, while Th2 cytokine levels were not different from the controls in any of the groups (Weatherhead et al., 2017). Finally, high Giardia-specific IgG and IgE levels were seen in a cohort affected by light, but not moderate Ascaris infection and high IL-10 levels in individuals with moderate Ascaris infection associated with poor inflammatory cytokine responses against Giardia antigens (Hagel et al., 2011).

Hence, evidence of the detrimental effects of STH on Giardia infection and the associated sequelae exists. However, more work in experimental models is needed addressing immunological cross-regulation, competition for resources and potential changes in barrier functions, mucus composition and gut microbial communities in the context of STH-Giardia coinfections.

The life cycles of STHs differ significantly between the major species. The larval stages of Ascaris and hookworm species undergo extensive migration through the body. Ascaris larvae hatch in the intestine followed by migration via the liver and lung before being coughed up and swallowed. Upon maturation, the worms reproduce in the small intestine ( Figure 1 ). Thus, in Ascaris infection the small intestine, the liver and the lungs are dominantly affected and inflammation as well as cellular remodeling and modulation are detectable (Midha et al., 2021). In contrast, hookworm larvae invade the host through the skin and reach the blood circulation which they leave in the lungs ( Figure 1 ). Like Ascaris larvae, hookworm larvae are then coughed up and swallowed, reaching finally the small intestine. Similar to Ascaris, hookworm larvae migrate through the body and thus affect the skin, blood circulation, the lungs and the small intestine of infected hosts. In comparison, whipworm infections in humans occur when the eggs are ingested, as is the case with Ascaris infections. The larvae hatch in the small intestine and adult worms establish and dwell in the large intestine ( Figure 1 ). Whipworms do not show a body migration, the organ primarily affected is the intestine. However, intriguingly, intestinal worms without body migration also do affect the entire mucosal system and anti-helminth effector and memory responses are clearly detectable in the lungs (Yordanova et al., 2022).

Although multiple helminths are detected in infected individuals (Donohue et al., 2019), data on host immunological consequences of helminth coinfections are sparse. Some studies in animal models with poly-helminth infections indicate significant immunological effects of the second worm infection. For instance, in pigs coinfected with T. suis and Oesophagostomum dentatum the O. dentatum-specific IgG1 and IgG2 levels in poly-infected pigs were two-fold higher than in O. dentatum mono-infected pigs (Andreasen et al., 2015). Thereby, the Trichuris infection enhanced the typically weak response induced by O. dendatum. These data were underpinned in addition by a stronger Th2 response, measured by parasite-specific IL-4 secreting cells in PBMCs and associated gene expression (IL-13, ARG1, CCL11) at the site of infection as well as by peripheral eosinophil counts. Thus, one helminth infection overrides the coinfecting second worm infection ( Figure 4D ). A prominent effect was also demonstrated in a coinfection with the nematode H. polygyrus and the trematode S. mansoni in mice. Here, a pre-infection with H. polygyrus resulted in a marked reduction of hepatic egg-induced granulomatous inflammation associated with dampened proinflammatory cytokines in mice coinfected with S. mansoni (Bazzone et al., 2008). Thereby a dominant Th2-polarized environment induced by one infection ameliorated the immunopathology induced by the second helminth infection ( Figure 4D ). Another study in mice using coinfections of T. muris and H. polygyrus showed that coinfections are capable of changing susceptibility to infection (Colombo et al., 2022). The authors observed a complete impairment of T. muris expulsion in immunocompetent mice when coinfected with H. polygyrus. Interestingly, this drastic effect was not coupled with a change in parasite-specific cytokine production in draining lymph nodes or mucosal barrier immune responses in coinfected mice. However, changed susceptibility did also not impair immunization-induced immunity ( Figure 4D ) which was attributed to helminth excretory-secretory products (ES products) (Colombo et al., 2022).

In conclusion, multiple helminth infections are common and have significant consequences on the outcome of each infection ( Figure 4D ): i) one helminth infection overrules the immune response to the second infection; ii) the temporal sequence of the respective infection is important for the immunopathological consequences; iii) host susceptibility or resistance can be changed by the coinfecting helminth but is independent of immunization-induced immunity.