This study was designed to evaluate the clinical relevance of TB/Sch. m co-infection in the disease progression and active tuberculosis epidemiology dynamic. Therefore, published original research articles that reported the immunological interaction, and clinical frequencies of Mycobacterium tuberculosis and Schistosoma mansoni co-infections were searched and reviewed.

Relevant research articles were searched using two search terms from two different databases, (Google Scholar, Embase, Scopus, PubMed, and Web All of Science) detailed as follow:

“Mycobacterium tuberculosis” [MeSH Terms] OR (“mycobacterium” [All Fields] AND “tuberculosis” [All Fields]) OR “mycobacterium tuberculosis” [All Fields] OR (“tuberculosis” [All Fields] AND “mycobacterium” [All Fields]) OR “tuberculosis mycobacterium” [All Fields]) AND (“tuberculosis” [All Fields] OR “tuberculosis” [MeSH Terms] OR “tuberculosis” [All Fields] OR “tuberculoses” [All Fields] OR “tuberculosis” [All Fields]) AND (“Schistosoma mansoni” [MeSH Terms] OR (“schistosoma” [All Fields] AND “mansoni” [All Fields]) OR “Schistosoma mansoni” [All Fields]) AND (“co-infect” [All Fields] OR “co-infected” [All Fields] OR “co-infecting” [All Fields] OR “co-infection” [MeS Terms] OR “co-infection” [All Fields] OR “co-infections” [All Fields] OR “co-infects” [All Fields]).

All full-text articles found throughout this database search were assessed and all those eligible with an abstract in English were included in this study regardless of the language of the full article.

All full-text research articles from the search result of the study using the two search terms built from the words “Tuberculosis and Schistosoma mansoni” were included in the study. All studies that full text or abstract have not been found in the search and studies that do not include results of one of the two infections were excluded from the study.

Each included article was reviewed to retrieve information about TB and Schistosoma mansoni co-infections. Article on immune response interactions between the two-infection found in the literature was also described and analyzed in this literature review. Case reports, case series, case control, and cohort studies were summarized in different tables (Table 1 & Table 2).

Tanzania*: Schistosoma mansoni was 16.4% in the rural area vs. 4.13% in the Urban. Kenya ꝉ: HIV/TB co-infected patients.

The conduct of this systematic review was approved through a current project on the prevalence of Schistosoma mansoni among pulmonary TB patients in Mali by the Ethics committee of the Faculties of Medicine and Odonto-Stomatology, and Pharmacy of the University of Sciences, Techniques, and Technologies of Bamako (USTTB) in Point-G, Bamako, Postal Box: 1805; Mali.

In total five (5) search engines were explored using the same term, three thousand five hundred ninety-one (3591) articles were found in the databases, including Google Scholar (3530), Embase (23), Scopus (14), PubMed (12) and Web of Science (12) (Figure 2). After removing duplicates and those not fulfilling

TB and Schistosoma mansoni co-infection criteria, one hundred twenty-three (123) articles were eligible among those, fifty-three (53) were used for qualitative discussion and ten (10) for the quantitative analysis and data discussion.

The immunological disturbances occurring during M. tb and helminth co-infections have been reported in animal but also human studies. Since the beginning of the 20^th century, Kullberg et al. (1992) observed that Sch. m infection downregulates the host’s Th-1 immune response, and induces an exaggerated Th-2 response that alters existing protective immune response against other infectious agents; the findings were later supported by observations of Rafi et al. (2012), that helminth infection diminishes immune protection against LTBI [24] [25] [26] . In vaccinology, helminth chronic infection has also been found to affect immunization conferred by vaccines; Kondĕlková et al. (2010) & Méndez-Samperio et al. (2014), found in their investigation that Treg cells modulate immune reaction by suppressing cell’s multiplication and production of cytokines, implying that the presence of helminth infection confers a buffer medium that neutralizes the effect of ongoing immune responses [27] [28] . McArdle et al. (2018) reported that reactivation of latent TB infection (LTBI) in the presence of helminth infection comes from a switch from Th1 to Th2 cytokine production [29] . Abate et al. (2015) observed that the simple presence of helminth infection without any clinical manifestation in patients with active TB could downregulate host immune response similar to that seen in patients with immunodepression. The co-infection creates a coexistence of T-Regulatory Cells (Treg cells), and type-1 cytokines (IL-10) but also the secretion of type-2 expressing cytokines (IL-5) conferring an immunodeficiency status to the patient. Thereby, the low bacteria load in sputum observed in TB and Sch. m co-infected patients was already reported as a common finding in TB and HIV co-infection [30] [31] . Babu et al. (2016) also brought evidence from the animal model and human studies that helminth infections affect the host immune control of TB infection, thereby increasing the risk of TB bacteria reactivation in an organism with both infections [32] . Rajamanickam et al. (2019 & 2020) found that helminth and LTBI co-infection exposes LTBI control failure by inducing low-production chemokines and alteration of their function. They also observed an alteration of monocyte cells’ function through inadequate activation and polarization during the co-infection [33] [34] . Cadmus et al. (2020) reported in a literature review that helminth infection negatively impacts the strength of vaccination response, thereby immunization programs should consider helminth endemic areas regarding the protection level of vaccines [13] Kiflie et al. (2021) found that helminth co-infection in active TB patients had a positive correlation between TB disease severity and an increase of helminth-specific TGF-β+ Tregs that was restored after anti-helminth treatment [35] . Resende et al. observed that TB and helminth co-infection leads to a decrease in T-cells and natural killers number, cytokine production, and severe lung damage compared to TB mono-infected patients and healthy controls [36] [37] . A similar observation was reported by Bogdan et al. (1991); Gong et al. (1996); Abate et al. (2015) and Aira et al. showed that IL-10 production down-regulates Th1-driven immune response against TB infection [38] [39] [40] [41] . These observations demonstrate that in the presence of helminth infection, the expression of the Th2 immune profile involves Treg cell proliferation and certain types of cytokines that down-regulate existing Th1 immune inflammatory response against other types of infections and particularly in the case of LTBI.

In more than four past decades, Olds et al. (1981) reported that Sch. m co-infection impairs immune response in active TB patients, and a decrease in killer monocyte cell rate was observed in Sch. m co-infected and TB patients [42] . Several other studies supported the hypothesis that in the presence of Sch. m infection, the host immune response undergoes a modulation process leading to a poor immune response quality against a new or an existing infection. Elias et al. (2006) reported a low protective effect of the BCG vaccine in children infected with Sch. m [17] . The observation was further supported by Musaigwa et al. (2022) that Sch. m infection affects vaccine response again TB infection by inducing deaths of plasmablast and plasma cells in the bone marrow [43] . Among the diverse helminth, Sch. m one of the Schistosoma subspecies, has been identified to possess specific proteins that lead to failure of maintaining type1 granuloma formation by promoting a strong type 2 inflammatory immune response. Monin et al. (2015) were pioneers of that observation by describing that during M. tb and Sch. m co-infection, Sch. m increases susceptibility to TB reactivation but also the disease severity by increasing the level of inflammatory response with the accumulation of arginine-1 expressing macrophages [44] . Pearce et al. also demonstrated that the presence of soluble Sch. m egg antigen inhibits IL-12 cytokine production by dendritic cells and induces a Th2 inflammatory immune response profile promoting T-cell regulatory (Treg) responses that inhibits the establishment of type Th1 response [45] . Giera et al. have also identified lipids such as prostaglandins (rich in Sch. m eggs) to be specifically driving expression of type Th2 immune response profile during Sch. m infection [46] . Meurs et al. in Senegal investigated cytokine production during schistosomiasis infection and observed that Sch. m induces the production of Th2 profile cytokines but is not as stronger compared to Schistosoma haematobium (Sch. h). This implies that Sch. m can induce a switch of immune response profile from Th1 to Th2 but does not induce such a stronger response to limit damages from other infections [47] . Schramm et al. (2018) investigated the immune modulatory effect of Sch. m and observed that using Sch. m egg-specific antigens can significantly decrease the immune response against Salmonella infection [48] . Dinardo et al. (2016) observed that M. tb-specific CD4+ T-cell functions are altered in presence of soluble schistosome antigen and block the maturation of macrophage phagolysosome [49] . However, McLaughlin et al. (2020) reported a contradictory finding that Th1 immune functions are still maintained by TCD4 cells during TB and Sch. m co-infection [50] .

Lessons learned from this step are that Sch. m infection induces a buffered media in the immune response pattern and plays an important role in TB infection control. In the presence of Sch. m antigens, the host immune system fails to establish an appropriate defense against other infections. This immunological disaster happens when the host immune system is facing an acute infection and knocking it down to a latency phase or when Sch. m infection occurs in an individual with an immunologically well-controlled latent TB infection (Figure 3).

Schistosoma mansoni and Mycobacterium tuberculosis co-infections have gained increasing interest over the last two decades. Observations started with single case reports; Cristina et al. (2006), in Brazil reported a case of hepatic TB co-infected with Sch. m [51] . Basile et al. (2007) published one of the first cases of Sch. m and M. tb tuberculosis co-infection in a 32-year-old, male, living in France but of Sub-Saharan African origin [52] . Gobbi et al. (2014), further support a case of Schistosoma mansoni and Mycobacterium tuberculosis co-infection mimicking a single infection of Schistosoma mansoni in the lung [53] . Range et al. (2007) in Tanzania found more than one-third (35.5%) of Schistosoma mansoni co-infection among confirmed pulmonary TB patients and also HIV co-infection was 43.6% [54] Ten years later, structured case series started to report remarkable frequencies, and clinical characteristics of patients with the co-infection. Earlier in 2012, Abate et al. (2012) conducted another study in Ethiopia, the frequency of Sch. m co-infection among TB patients was 19% [55] . Li & Zhou (2013) conducted a systematic review on TB and parasite co-infections, they observed a prevalence of 5.4% of Sch. m among TB patients [56] . McLaughlin et al., in a recent study in Kenya, it has been observed a 4% increase in TB incidence in HIV-Negative people infected with Sch. m (19.7%) compared to Sch. m-uninfected cases (15.8%) whereas a 14% increase was observed in TB incidence in HIV-Positive patients co-infected with Sch. m (27.3%) compared to HIV-Positive Sch. m-uninfected patients (41.2%) [57] . Tegegne et al. (2018) conducted a study in Gondar (Ethiopia) that reported a prevalence of 0.4% of Sch. m in patients suspected of pulmonary tuberculosis [58] . Gashaw et al. (2019) reported a prevalence of 4.3% of Sch. m in active TB patients with under-nutritional status in Northeastern Ethiopia [59] . Mhimbira et al. (2017) found 5.7% of Sch. m co-infection in TB patients compared to their household control individuals. There was a 2.15-fold higher risk of Sch. m co-infection in TB patients compared to their household controls. Sch. m and M. tb co-infected patients had a

2.63-fold risk of being in the group of TB patients with lower sputum bacterial load, and also 0.41-fold less chance of having pulmonary cavitations [20] . Sikalengo et al. (2018) in Tanzania found 16.4% of Sch. m co-infection among active TB patients living in the rural area of Dar Salam [60] . From the findings of this review, there is evidence of an association between the two infections that Sch. m infection increases active TB incidence in individuals with LTBI regardless of their immunological status and there is a clear pathway explaining the mechanism of switching Th1 immune response to a predominant Th2 cytokines production creating a buffer media that drive out the immune control of TB latent bacteria.