Title : Treatment inefficacy for Salmonella during Schistosoma-Salmonella co-infections background , mechanisms and future exploration

Antibiotic inefficacy in treating bacterial infections is largely studied in the context of developing resistance mechanisms. However, little attention has been paid to combined diseases mechanisms, interspecies pathogenesis and the resulting impact on antimicrobial treatment. This review will consider the co-infections of Salmonella and Schistosoma mansoni. It summarises the protective mechanisms that the pathophysiology of the two infections confer, which leads to an antibiotic protection phenomenon. This review will elucidate the functional characteristics of the gut microbiota in the context of these co-infections, the pathogenicity of these infections in infected mice, and the efficacy of the antibiotics used in treatment of these co-infections over time. Salmonella-Schistosoma interactions and the mechanism for antibiotic protection are not well established. However, antimicrobial drug inefficacy is an existing phenomenon in these coinfections. The treatment of schistosomiasis to ensure the efficacy of antibiotic therapy for bacterial infections should be considered in co-infected patients.


Introduction
The severeity and treatment efficacy of schistosomiasis on bacterial, viral or other parasitic co-infections has a growing concern. Among the much studied are cases of Salmonella infection during schistosomiasis. Co-infections of Schistosoma and hepatitis B or C, malaria, leishmaniasis and HIV aslo are under study [1]. Moreover, Schistosoma as co-infection with other protozoa, with helminths and with bacteria other than Salmonella are also been studied [2]. Co-infections with Schistosoma and Salmonella confound the clinical picture of both diseases.
Evidence emerging from in vitro [3,4], animal model experiment [5] and clinical observations [6] regarding the symbiotic relationship existing between Schistosoma and Salmonella showed efficacy in the drug administered for treatment is only optimal when concurrent anti-Schistosomal therapy is administered. Although number of studies centred on the study of the concurrent Schistosoma-Salmonella infections, their complicated mechanisms where bacteria adhere to the adult Schistosomes present in the mesenteric vasculature require further research [3]. The pathogenicity of Schistosoma mansoni, alteration in host gut microbiota, and the evolution of drug resistance in concurrent Schistosoma-Salmonella infections in vitro and in vivo is yet to shed light on the pathogenicity of the two pathogens that might give rise to the evolution of antibacterial drug resistance [7]. To this end, the phenomena that give rise to persistent Salmonella enterica serovar Typhimurium bacteraemia or bacteriuria in the presences of Schistosoma mansoni will be explored in this review. The paper will investigate these synergistic effects of schistomiasis and salmonellosis as a co-infectoin.

Salmonellosis as a disease
The most common bacterial genus causing foodborne infections is Salmonella. They infect wide range of hosts including human and bird species [8]. Worldwide, the various serovars of Salmonella spp. are known as a water and food borne gastrointestinal pathogens, and a systemic diseases pathogen. Typhoid fever alone is estimated at 10.9 million cases annually, most in low-and middle-income countries [9]. In eah year, 129.5 million cases of non-typhoidal Salmonella (NTS) human cases give between 100,000 and 1 million deaths worldwide [10]. With more than 2600 serovars, Salmonella enterica subspecies enterica infections are a persistent public health burden, among animals and food industry [11]. The pathogen is transmitted through contamination of food, water and fomites. Some serovars are species-specific but the vast number are "hostadapted" (broad host spectrum) serovars [11].

Epidemiology
The genus Salmonella is divided into two species; S. enterica and S. bongori. S. enteric alone is further divided into 6 subspecies and more than 1500 serotypes. More than 99% of human salmonellosis is caused by S. enterica subspecies enterica [12]. Non-enterica subspecies of Salmonella have a reduced ability to invade host cells due to less essential virulence factors and thus are considered as opportunistic infections since they thrive well only in depressed host immunity [12].

Invasive and non-invasive
There are more than 2600 serovars of S. enterica subsp. enterica and these are divided into typhoidal and NTS serovars. The two groups elicit diverse diseases and very distinct immune response in human host [13]. The Salmonella enterica serovars Typhi, Sendai and Paratyphi serotype A, B or C is human-restricted. These are called typhoidal Salmonella serovars as they cause the systemic diseases typhoid fever or paratyphoid fever, depending on pathogenic serovar [14]. Due to their invasiveness, infection with these serovars often leads to focal systemic infections and bacteraemia rather than gastroenteritis. Extra-intestinal non-typhoidal Salmonella (NTS) such as serovars Typhimurium, Dublin, and Choleraesuis causing invasive infections are also prominent [10] and invasive NTS is particularly in SSA [15].
As a major cause of global morbidity and mortality, non-typhoidal salmonella (NTS) invasive diseases comes second to Typhoid in case fatality [16] NTS serovars are associated with a high burden of foodborne Salmonella outbreaks in humans. These include the Typhimurium, Heidelberg, Newport and Enteritidis serovars [11]. Invasive NTS infections caused by S.
Typhimurium and S. Enteritidis are the most prominent agents of invasive NTS disease. Naturally, these are generalist pathogens with broad host specificity. NTS induce gastroenteritis in 5% of options are required. The supplementation of probiotic-organisms seems promising. However, the strain and organism type used as probiotic might encourage the growth of opportunistic pathogens. Furthermore, antibiotic susceptibility and antibiotic-resistant carriers are other phenomenal issues associated with probiotic complementary therapy. To this end, a holistic study on probiotic mechanisms and their efficacy is needed [24].
The current state in the treatment of salmonella infections does not look promsing.
Although the burden of infectious disease lies in the least developed countries, routine surveillance for antimicrobial resistance is not robust. For instance, NTS is now taken to be 50 Due to the poor economic status and inadequate resource in sub-Saharan Africa, the prudent use of effective antimicrobials looks unrealistic [25]. What this review will recommend is the typhoid vaccines and hope that there will be acceleration of trials for novel iNTS vaccines [25].
Again, a radical and aggressive approach is the only way to establish rational use of antibiotics during treating infections [26].

Issues in sub-Saharan Africa (sSA)
Salmonella remains an important pathogen of humans and animals in low income countries globally [13]. The infections inflicted is serotype-specific [21]. Although not considered as a neglected tropical infection, Salmonella related deaths in 2010 were 129,000 out of the 11.9 million cases of typhoid fever across the globe. This is more than 100 cases per 100,000 personyears [28]. The more recent, 2 to 3 million cases of NTS gave a mortalitiy rate of up to 700,000 deaths per year in sub-Saharan Africa. People who are immunocompromised are the much affected [10].
In SSA, gastroenteritis is the most common form of disease. The inflammatory response and toxins induced by bacterial overgrowth in intestinal submucosa and diarrhoea respectively are the typical conditions [22]. As a leading cause of bacteriamia in sSA, iNTS is has been representing a major public health burden. The two common iNTS serovars devastating children and immunocompromised individuals are Salmonella Typhimurium clade ST313 and Salmonella Enteriditis [29]. Taking Kenya as a case for sSA, iNTS has a mortality rate between 20-25% without prompoted treatment strategy. Among the MDR isolates in one study conducted in Kenya, 8.5% are resistant to extended spectrum beta lactams. While asymyptomatic carriage is concern for transmission expcially among the vulnerable individuals, iNTS vaccine development could be seen as an emergency intervention [30].

Schistosomiasis epidemiology
After malaria, Schistosomiasis is the parasitic diseases with the greatest impact socioeconomic development more than 50 countries. These diseases are caused by trematodes of the genus Schistosoma [31]. Schistosomiasis is characterised as a neglected tropical disease by the World Health Organization (WHO) and poverty-related parasitic infection [32]. Schistosomes infect humans bathing fresh water and drinking untreated water in areas with inadequate sanitation facilities and the suitable watersnail intermediate hosts [33].

Schistosoma life cycle
In contaminated water, the parasitic helminths Schistosomes infect humans through dermo-invasion. After the migration of schistosomulae to the lung, the adult worms reside in blood vessels in a close proximity of intestinal mucosa [41]. Through asexual or sexually reproduction, the life of schistosome snails and mammals host. In sexual reproduction, it occurs in freshwater snails. This begins with the development of miracidia into a sporocyst and these sporocysts will then multiply and grow into cercariae. For the mammalian hosts like humans, mice, and dogs, the parasites grow ,mature, mate, and produce eggs [42].

Schistosomiasis disease
It is estimated that, 230 million people from the 74 developing tropical and subtropical countries are infected by schistosomiasis yearly. 200,000 deaths are recorded per year [43].
Furthermore, there are number of asymptomatic cases and those with the appearance of symptoms.
In human, the clinical manifestations of schistosomiasis are in three phase and these are; acute, sub acute and chronic stages. Once the matured parasite settled in the targeted organs, for example, in the lower urinary tract with Schistosoma haematobium and the other spieces in colon and rectum, it develop into secondary manifestations, which happens in liver, lungs, kidneys etc.
The healing of granulomata by fibrosis and calcification in the renal glomeruli by deposition of schistosomal antigen-antibody complexes, the development of secondary amyloidosis or at the sites of oval entrapment are attributed to chronic morbidity [1].
Based on the immune response, the clinical manifestations of schistosomiasis full under acute, sub-acute and chronic stages. The acute stage (Katayama fever) is species-specific is seen during the early invasion and migration [44]. During the log phase of parasite growth curve, granulomata around the eggs are formed.
Immunity is seen during the chronic stages of disease. During this stage, the pathogen will gain an upper hand against innate, TH1 and TH2 adaptive cells [1]. Complications are seen among some patients. Co-infections or associated pathogenic agents will persist and this condition avails salmonella diseases treatment inefficacy [2]. Inflammation, liver fibrosis, micro abscess formation, ulceration, polyposis and hyperplasia are abnormal physiological functions induce by Schistosoma ova [33].

Pathogenicity
Schistosome eggs will have to pass through the intestinal wall without inflicting enteric inflammation. Some eggs reach ectopic sites such as the kidney, liver, genitourinary tract and central nervous system. Immune response from the host due to Proteolytic enzymes produced by those retained eggs results in eosinophilic inflammation and granuloma formation [45]. The pathogenicity is proven difficult to control during the secondary manifestations. These manifestations occur in organs such as liver, kidneys, lungs and other ectopic sites [2].
Deposition of Schistosomal antigen-antibody complexes in the renal glomeruli are attributes of chronic morbidity. In addition, the development of secondary amyloidosis, the healing of granulomata by fibrosis, co-infection with hepatitis C [44] and calcification at the sites of oval entrapment are seen during chronic morbidity [2]. Pelvic venous plexus is virulence factor that can enable male and female worms to co-habit for several decades. This protects the worms from host immune invasion [44]. In the study of bladder cancer in Africa, the pathogenesis of squamous cell carcinoma (SCC) is S. haematobium-related [46].

Prevention and Treatment
The preventive measures for schistosomiasis will not be effective without effective education and periodic mass treatment. The implementation of chemical mollusciciding-based control of Bulinus and Biomphalaria spp., snails is proven effective. With the elimination of these intermediate hosts, local transmission is drastically reduced, albeit incomplete. S. mansoni and S.
haematobium transmission are minimized even in the in high risk areas [47].
Praziquantel as the drug of choice has 80% cure rate and can only be supplemented with effective vaccine for absolute eradication of schistosomiasis [2]. However, for fibrotic lesions, surgical treatment is the last resort. In effective reduction of infection intensity, Praziquantel 40 mg/kg is reccomended among preschool-and school-aged children [48].
To elicit a mucosal response, attenuated S. Typhimurium strain (YS1646) is produce as multi-modality vaccine. This intervention is targeting Cathepsin B (CatB) is a promising intervention for complete protection against S. mansoni [41]. Schistosoma vaccine development is promised on oral delivery of the antigen by nirB-driven S. Typhimurium type III secretion system [49].

Schistosoma and Salmonella co-infections
Dual Schistosoma and Salmonella infection is a public health challenge and other schistosomiasis endemics. The interactions of Schistosoma and Salmonella is favorred by the immunosuppression of the host due parasitic infections [50]. As both are water-borne human pathogens common in areas with poor sanitation, the co-existence of Schistosomes and Salmonella infections is a common occurence.
The type of organisms involved, order and time of interval between the infections, the pedigrees of the parasites, infectious agents are all associating factors that appear to determine the synergistic pathogenicity of the co-infection [51]. Another confounding factor in the study of

The effects of antibiotic treatment on co infection Antibiotic Protection
In a bid to treat patients infected with Schistosomiasis, anthelmintic praziquantel (PZQ) is a common therapeutic drug. However, dysbiosis seems an effect associate with this intervention.
A shift in gut microbiota composition pre and post PZQ treatments was seen [60]. Although the gut bacterial population varies between people infected with schistosomiasis and those who do not, the abundance phyla were Bacteroides, then Firmicutes and Proteobacteria between the pre and post-treatment [61]. Furthermore, only limited variations in the relative abundance of taxa among bacterial classes and this variation is not affiliated to age or sex of the participants. Unlike Salmonella spp., Escherichia coli did not benefit from the protective mechanism of attachment to schistosomes [13]. In order to achieve therapeutic levels or treatment efficiacy of the antibiotic used in co-infections study, perturbing the binding mechanism to schistosomes is required to eliminate Salmonella [13].

Antimicrobial treatment failure due to co-infections
It is ascertained that any ineffective not co-administered [63,64].

Salmonella interactions with the microbiome
Salmonella infection in a mouse model has been seen to drastically alter the homeostasis of gut microbiota and thus the intestinal metabolome. The physiological functions and hormone metabolism were significantly altered [65]. S. Typhimuriumis is a prominent competitor with commensal gut microbiota. Once they dominate the gut microbiota population, their invasion signals the onset of infection.
Both intestinal and urinary schistosomiasis will also alters the gut microbiome (Table 2).

Microbiome and co-infection
Commensal microorganisms called gut microbiota are vast number of organism living gastrointestinal (GI) tract of vertebrates. Their functions range from maintenance of energy balance, nutrition and host immunity [69], and the production of antimicrobial products, bacteriophages deployment and enhancing gut barrier integrity [70]. A healthy gut microbiome is a critical defence against colonization of pathogenic or exogenous microorganisms. This effect is referred to as colonization resistance (CR) and helps to minimize exogenous pathogens, which many colonize the gut and ultimately cause infection [65]. An imbalance of these dysbiosis is associated with number of chronic and autoimmune disorders. Besides environmental factors, macrobiota including parasitic helminths with their pathogenic effects including metabolic activity, immune system and lead to infection [65] Of recent, the role of gut microbiome is shedding more lights to health of host and the functions not limited to are the biochemical, immunological and nutritional response of the gut microbiome are more a less biomarkers [68]. To add scholarly evidence to the existing and emerging theories, this review will create literature for a futher study to investigate the role of the gut microbiome in parasitic infection, co-infections, and the antibiotic resistance due to the pathology. The acquired immunity among patients when exposed to helminths, aggravated with bacterial infections and the resulting immune response to the concurrent infections [71]. In a bid to assess the impact of sequential infection of bacteria and helminths on the host, this reviewisvowed to consider the co infection of S. Typhimurium and S. mansoni.

Metabolic response to the co-infection
Metabolomics has been a robust tool in studying metabolic response to series of stimuli and one such is a co-infection [72]. Chromatography coupled to mass spectrometry or 1H nuclear magnetic resonance (NMR) spectroscopy, with the multivariate statistical analysis aid to determine metabolic changes in system response to stress or stimuli [73]. Alternative therapeutic such as personalized medicine based on microbiome might get its roots from the effects of Salmonella in the co-infection provided that, the salmonella serotype is non-invasive and non-pathogenic.
Using the NMR-based Metabolomics and immunological techniques to detect the systemic metabolic and immune responses, respectively, this study concluded Salmonella enterica serovar Typhimurium effects reduction in egg counts and the number of adult worms and relieves symptoms of schistosomiasis [57]. The metabolic disturbance of co-infected mice was compared with S. japonicum,reverted levels of metabolites result from the former infection. Due to inverse immune polarization; the bacteria have been seen to ameliorate S. japonicum induced schistosomiasis in BALB/c mice [57]. In order to explore on this pathogenicity, other forms of Schistosoma should be studied in co-infection with the same serotype of Salmonella.

Immune response to the co-infection
A shift in host immune response from Th1 to Th2 polarization is studied to be an effect of Schistosoma infection of a typical schistosomiasis [57]. The alteration is achieved due to the progress of the disease including cercariae intrusion, migration of larvae, pairing in adult and laying of eggs [74]. Unlike Schistosoma, infection caused by S. Typhimurium only induces Th1 polarization [75].
The clinical significance of the host immune impairment by the combined effects of the S.
Typhimurium and S. mansoni could draw much attention to the interaction between these two species. One instance is the influence of gut microbiota on the generation of Th17 cells. The effector lineage of CD4 T cells with protective abilities against inflammatory and harmful autoimmune conditions are Th17 cells. They mobilize host immunity against microbial pathogens such as Salmonella [76]. Expansion of segmented filamentous bacteria (SFB) is also inhibited with an increase in α-defensin expression of IL-17. Low number of IL-17-producing Th17 cells in the lamina propria signals loss of α-defensin and expansion of SFB [77]. While much attention is paid on bacterial benefits to the host immunity, benign worms and viral species are yet to be explored.

Future Research
Salmonella resistant to multiple antimicrobials worldwide is a threat to global health. The emerging of clones of resistant strains even in the under developed world requires a holistic approach on food chain and distribution system [78]. An improved understanding of the impact of genome variation of bacterial pathogens on pathogen-host and pathogen-environment interactions has the potential to improve quantitative risk assessment and reveal how new pathogens evolve [10]. The physical barrier theory of mammalian cell-docking site for FimH protein [55], begs for a further study despite it is ascertained that the resistance is transient and is observed only during adherence.
The efficacy of antibiotics will be determined by the weekly faecal culture for bacteria responsible for urinary tract infections and stomach disorders. Such study is hoped to ascertain the The study of co-infections involving Schistosoma and Salmonella should be based on model that will explain a wholesome range of parameters. Study of the mucosal cell gene expression, innate and adaptive mucosal immune responses, the virulence expressed by the pathogens involved, microbiota gene expression and the genetic profiling of the host will confer clear explanation to the homeostasis [69].

Conclusion
In a bid to curb with the emerging infectious diseases in Sub-saharan Africa, much paid attention should be equally paid to the treatment inefficacy arising as a result of co-infection. These combined disease mechanism has ways to escaope antimicrobial treatment. We dwelled on coinfections of Salmonella and S. mansoni to ascertain the antibiotic protection phenomenon and functional characteristics of the gut microbiota.