REVIEW PAPER

MECHANISMS FOR SALMONELLA INFECTION AND POTENTIAL MANAGEMENT OPTIONS IN CHICKEN

M. Mkangara1, 2,*, R. Mwakapuja4, J. Chilongola3, P. Ndakidemi1, E. Mbega1 and M. Chacha1

1School of Life Sciences and Bioengineering, Nelson Mandela African Institution of Science and Technology, P. O. Box 447, Arusha, Tanzania.
2Department of Science and Laboratory Technology, Dar es Salaam Institute of Technology, P.O. Box 2958, Dar es Salaam, Tanzania.
3Department of Biochemistry and Molecular Biology, Kilimanjaro Christian Medical University College, P.O Box 2240, Moshi, Kilimanjaro, Tanzania
4Tanzania Veterinary Laboratory Agency, P.O. Box 9254, Dar es Salaam, Tanzania
*Corresponding author’s email: mkangaram@yahoo.com

ABSTRACT

Salmonella enterica is the largest species in genus Salmonella with its serovars responsible for infection in chickens and other warm-blooded hosts. After oral ingestion, Salmonella penetrates the mucosal layer of the gastrointestinal tract (GIT). It then provokes gastroenteritis and systemic infection to chickens of all ages depending on the serovar involved. The paper explains about Salmonella infection via Type Three Secretion System (TTSS) encoded Pathogenicity Islands (PIs) and how the bacterium survives the acidic environment of GIT.  It also explains the roles of TTSS-1 and TTSS-2 in translocation of effectors that interfere with host proteins and later internalisation of Salmonella in Salmonella-containing vacuole (SCV). Other virulence factors such as plasmid, biofilm and lipopolysaccharides are highlighted, and their importance in inducing pathogenicity to host was also included in the paper. Therefore, several factors are geared toward survival, infection, and replication of Salmonella in the host cells. Hence, this article explains the mechanisms of Salmonella infection in chicken, its persistence in different environments and the approaches in controlling chicken salmonellosis.

https://doi.org/10.36899/JAPS.2020.2.0050                                                                   Published online March 02, 2020

INTRODUCTION

                Genus Salmonella is a Gram-negative, rod-shaped; facultative anaerobes bacilli that belongs to family Enterobacteriaceae (García et al., 2011; Popoff and Le Minor, 2015). The genus is divided into two species Salmonella enterica and Salmonella bongori (Ryan et al., 2017). In the classified Salmonella species, there are over 2600 serovars with the majority from S. enterica (Ranieri et al., 2013; Shi et al., 2015). The S. enterica is classified into six different subspecies enterica (I), salamae (II), arizonae (IIIa), diarizonae (IIIb), houtenae (IV) and indica (VI) (Lamas et al., 2018). The subspecies enterica with more than 1500 serovars is of economic importance to chickens and other warm-blooded hosts (Roer et al., 2016). The S. enterica serovar Gallinarum is restricted to all gallinaceous birds and contains two biovars, which are Gallinarum and pullorum (Parvej et al., 2016). The biovars are invasive, highly host adaptive and induce systemic infection to chickens (Xiong et al., 2018). Other serovars in subspecies enterica with broad hosts, invasive but non-adaptive to chickens are S. typhimurium, S. enteritidis, S. heidelberg, S. kentucky, S. montevideo and S. hadar (Andino et al., 2014; Dhanani et al., 2015). They elicit gastroenteritis but rarely induce systemic infection.
                Non-enterica subspecies of S. enterica are related to cold-blooded animals, and their pathogenicity is very limited (Lamas et al., 2018).  The subspecies arizonae, diarizonae and salamae were reported to be found in chickens like resident microbiota with the importance of inhibiting other pathogenic bacteria (Maciel et al., 2017). Similarly, the phages of diarizonae and salamae display activity against pathogenic serovars of subspecies enterica, namely S. typhimurium, S. enteritidis and S. infantis (Lamas et al., 2018). The phages work against pathogenic Salmonella and are essential bactericidal for treatment of salmonellosis in chickens. Other approaches of minimising chicken salmonellosis discussed in this review include probiotics, antibiotics, vaccination, biosecurity measures and natural or purified herbs.
                Colonisation and virulence of S. gallinarum, S. pullorum, S. enteritidis in chickens are mediated by virulence plasmids and the cluster of genes located in chromosomes called Salmonella pathogenicity islands (SPIs) ( IIyas et al., 2017). During the early stage of infection, SPI-1 encoded type three secretion systems (TTSS-1) translocate effectors across the host cell membrane (Hurley et al., 2014). The effectors are essential for bacterial invasion of host intestinal epithelial cell and stimulation of intestinal inflammation (Lorkowiski et al., 2014). Following the introduction of effectors into the epithelial cell of the host, Salmonella alters host cell functions to enable survival, replication and finally, transmission (Fuentes et al., 2008).
                Internalisation of Salmonella occurs in membrane-bound vesicles termed as Salmonella-containing vacuole (SCV). Salmonella expresses the TTSS encoded Salmonella Pathogenicity Island-2 (SPI-2) within the SCV and plays a role of systemic infection (Foley et al., 2013). During systemic infection, the bacteria spread all-over the body fluids and organs of a host including liver, spleen, bone marrow, and other organs rich in phagocytic cells (Barrow et al., 2012). The genetic basis of this ability is not clear. However, breeders and researchers have endeavoured to understand the Salmonella adaptation to its host by studying specific genes with potential roles in disease resistance (Calenge et al., 2010). The functions and contributions of TTSS
and SPIs to infection in the host cells of a chicken are explained in the sections of this article.
Salmonella infection: Salmonella in chickens occurs through horizontal transmission by the faecal-oral route or vertically through the ovarian transmission. In horizontal transmission, the infection arises after the bacterium survives the stomach acidic pH through Peyer's patches and caecal tonsils to invade non-phagocytic cells, the microfold (M) cells colonisation of the GIT (Smith, 2003; Ribet and Cossart, 2015). The M cells are specialised epithelial cells for the identification of the antigenic substance in the GIT (Ohno, 2015). The microfold invasion leads to inflammation, which is followed by phagocytosis of bacteria by heterophils and macrophages on the lumenal surface of the intestine (Jepson and Clark, 2001; Sekelova et al., 2017). The inflammation triggers the drainage of water/fluids into the GIT and causes diarrhoea (Figure 1).

                Salmonella penetrates the lymphatic tissues and blood vessels, targets specific types of cells such as dendritic cells, macrophages, mesenteric lymphatic nodes and later to deeper tissues (Kabir, 2010). Upon penetration to deeper tissues Salmonella spreads and multiplies in several reticuloendothelial organs, bone marrow, gall bladder, and reproductive tract (Stevens et al., 2009). The invasion of Salmonella in the reproductive tract is crucial for transovarian transmission and hatchery contamination (Pande et al., 2016). The transmission is facilitated by the combined activity of effectors, which resulting in Salmonella penetration and internalisation by host tissues (Knodler, 2015). On the other hand, the infected gall bladder continues to secrete bile for digestion (Revolledo and Ferreira, 2012), which makes Salmonella available for reattachment in the gut epithelial cells or released out to contaminate the environment (Lawley et al., 2008). Therefore, persistence and colonisation of Salmonella are also maintained by reattachment in the GIT. Chicken host adaptive serovars, such as S. gallinarum and S. pullorum persist in the liver and spleen and result in a carrier state by shedding live Salmonella for more than a year post-infection (Eng et al., 2015). However, in non-adaptive serovars such as S. typhimurium and S. enteritidis, the bacteriumpersists in faecal material which later enters the food chains (Revolledo and Ferreira, 2012).
                 

Host adaptive strains such as S. gallinarum elicit systemic infection to a broader range of domestic poultry including chickens, turkeys, ducks, and other gallinaceous birds (Clayton et al., 2008). The disease upon Salmonella spp. in chickens is attained when the three phases of invasion, systemic infection and resolution of infection have taken place.
Colonisation and adhesion of Salmonella: Crop is the first chicken’s environment encountered by pathogen after ingestion. The morphology and chemistry of crop are essential in influencing the survival and virulence of Salmonella even in the remainder of the intestinal tract (Crhanova et al., 2011; Durant et al., 1999).  The acidic environment in the crop with less amount of lactic acid is not a threat to Salmonella, unlike other pathogens. However, at higher acidic concentration, the population of Salmonella is highly reduced (Dunkley et al., 2009). Therefore, factors that influence Salmonella colonisation to a particular host species, such as chickens, are complex and occur through many factors involving the host genetic background, the pathogen, and extrinsic pressures (pH and competition of the GIT microflora) (Foleyet al., 2008).
                Generally, adhesins and invasins hold much in the colonisation of Salmonella to host cells (Chousalkar and Gole, 2016; Wagner and Hensel, 2011). Salmonella uses pili or fimbriae to adhere to different body surfaces. The fimbrial adhesion (Fim fimbriae), autotransporter adhesins (e.g. MisL or SadA) and T1SS substrates (e.g. BapA or SiiE) are known adhesins among several large numbers of adhesive proteins in S. enterica (Wagner and Hensel, 2011). Salmonella invades and polarises epithelial cells; thus invasiveness correlates with the concentration of surface-anchored with adhesins (Griessl et al., 2013). The adhesin proteins present at the tip of fimbriae allow Salmonella to colonise the tissues and bind tightly to specific sugars on the target tissue (Pizarro-Cerdá and Cossart, 2006). Furthermore, Salmonella uses fimbriae to bind to M cells of the epithelial lining during infection and stimulate the cell membrane to engulf the bacteria (Jepson and Clark, 2001). After the bacteria is surrounded by the host epithelial cells, trigger a type III secretion device to introduce pore-forming factors and effector molecules into the host cells (Schlumberger and Hardt, 2006; Coburn et al., 2007) (Figure 2).
                Salmonella utilises a device to promote its uptake into the vacuolar environment and live intracellularly within the Salmonella-containing vacuole (SCV) (Steele-Mortimer, 2008). Through the TTSS-2, effector proteins are secreted to SCV and interact with cytoskeletons, which later form the Salmonella-induced filaments (SIF) (Chadfield et al., 2003). The SIFs radiate outward from SCV upon onset of bacterial replication (Knuff and Finlay, 2017). On the other side, the SIFs ease fusion of SCV with endosomes in the host cell and play a role for Salmonella survival and replication (Foley et al., 2013). Thus, the presence of SCV also facilitates Salmonella replication in epithelial cells and macrophages (Figure 3). Furthermore, the SCV in macrophages makes Salmonella uneasy about being cleared by the immune response of the host. Therefore,
inside SCV the Salmonella migrates from intestines to liver, spleen and ovaries and colonise other cells, which later induce them to take up the bacteria (Ricke, 2003) (Figure 3).

Salmonella gallinarum causes systemic disease in chickens after intestinal colonisation in the distal ileum, caecum and bursa of Fabricius (Setta et al., 2012). S. typhimurium and S. enteritidis persist in the digestive tract of a chicken for months without triggering clinical signs. However, these species are severely affecting young chicks, with higher mortality rates (De Buck et al., 2004). The study conducted by Dieye et al. (2009) on S. typhimurium, discovered that the SPI-1 was very useful in colonising both the caecum and spleen in chickens, unlike SPI-2 which was found to colonise the spleen, but not the caecum. Thus, suggesting that S. typhimurium much depends on SPI-1 than on SPI-2 for colonisation of the younger intestinal tract (Rychlik et al., 2009).
                Eswarappa et al. (2010) reported that the Salmonella establishes in the host cell by decreasing the number of acidic lysosomes inside the host cell. This condition is vital for Salmonella survival because the infected cell is left with insufficient acidic lysosomes to target the increasing number of SCVs. Thus, the fold increases of SCVs favour the survival and proliferation of Salmonella inside the host cell. Wiedemann et al. (2015) observed that the majority of Salmonella serotypes are internalised into the host cell through trigger mechanism mediated by TTSS-1 and enclosed in SCV. The Salmonella inside the SCV can quickly multiply and form SIF which delivers nutrients to SCV (Figure 3). However, in some cases Salmonella damage the SCV membrane, triggering vacuole destruction, release Salmonella to the cytosol and enhance Salmonella multiplication in epithelial cells, or allow Salmonella destruction by activated macrophages (Bakowski et al., 2008).
                In line with microbiomes in the intestines, the infection of Salmonella in the GIT is influenced by the potential of its effectors and toxins produced to outcompete other beneficial bacteria in the GIT. Therefore, Salmonella combined effects of effectors are of advantageous during the invasion, penetration to deeper tissues, survival and replication in different host cells.
Salmonella survival in the expense of host cell death: Salmonella induces host cell death using TTSS dependent and independent mechanisms. In the course of the enteric phase of infection, Salmonella adheres to the intestinal epithelial cell, inject effector proteins which interfere with cellular functioning to enhance their replication and survival (Zhang et al., 2018). The apoptosis and pyroptosis are forms of programmed cell death that demonstrate how epithelial cell infected with the pathogen is programmed to die (Behar and Briken, 2019). Both TTSS-1 and TTSS-2 are responsible for triggering apoptosis in epithelial cells infected with Salmonella while caspase-1 is involved in pyroptosis.
                 TTSS independent mechanism of cell death involves intracellular and extracellular signals of caspases. The in vivo and in vitro studies categorise caspases in three subgroups which are initiators, execution/effector and inflammatory (Connolly and Fearnhead, 2017). The initiator caspases (caspases-2, -8,-9 and -10) activate one or more executioner or effector caspases (caspase-3, -6 and -7) by cleavage of their pro-enzymes (McIlwain et al., 2013). Inflammatory caspases (-1,-4 -5, -11, -12, -13, -14) do not function in apoptosis but are instead involved in inflammatory cytokine signalling and other types of cell death such as pyroptosis (Shi et al., 2015). The activation of caspases for eliciting apoptosis employs two pathways. The intracellular pathway (mitochondrial pathway), starts by signal factors from mitochondria and releases cytochrome C in the presence of Apaf-1 activates Apaf-1/ caspase -9 complexes (Shalini et al., 2015). On the other side, the extracellular pathway activates caspase -8 after it has received apoptotic stimuli through death receptors (Tummers and Green, 2017).
                Both caspase -9 and -8 are pro-enzymes which afterwards activate caspase -3 as a final executor of apoptosis (Julien and Wells, 2017). The caspase 3 plays a central role in cleave cellular substrates and express some features associated with apoptosis. The features of apoptosis expressed in the infected epithelial cell include cell shrinkage, chromatin condensation, DNA fragmentation, reduced mitochondrial membrane, cytoskeleton cleavage, cell surface exposure of phosphatidylserine and membrane blebbing (Ramos-Morales, 2012). Upon apoptosis characteristics, the Salmonella are retained within apoptotic bodies and engulfed by phagocytic cells without accompanying inflammatory responses in vivo. (Jorgensen et al., 2017) (Figure 3 green - left). The mechanism assists the survival, dissemination and persistence of Salmonella.
                Small leucine- rich proteoglcan (SlrP) promotes cell death by facilitating the ubiquitylation of thioredoxin under ubiquitin ligase (Narayanan and Edelmann, 2014; Lin and Machner, 2017). This process depletes the thioredoxin level in the host cell and makes a cell vulnerable to oxidative damage and lead to apoptosis. The SlrP also bind to chaperon ERdj3; a protein that binds to unfolded proteins in the endoplasmic reticulum (E.R) for proteasomal degradation (Jeong and Joe, 2016). Cordero-Alba et al. (2016) suggested that by preventing the binding of unfolded proteins, SlrP can lead to the accumulation of unfolded proteins in the E.R which induce apoptosis in vitro. The AvrA (strongly inhibits c-Jun N-terminal kinase (JNK) signal pathway) and SopB are responsible for the delay of apoptosis. To uphold the delay, SopB sustains activation of Akt because failure to activate Akt resulted in increased levels of apoptosis while AvrA via JNK stabilises intestinal tight junctions (Zhang et al., 2015).  The delay is beneficial for the Salmonella to have a stable intracellular niche in order to avoid adaptive immunity (Behnsen et al., 2015). (Figure 3 green - right). The mechanism where Salmonella effectors AvrA and SopB postponed host cell death remains unclear (Zhang et al., 2015).
                Pyroptosis is a type of inflammatory programmed cell death that is coordinated by inflammasome-mediated caspase-1 activation (Walle and Lamkanfi, 2016). Caspase-1 is a central mediator of innate immunity that is not activated in apoptosis. In the course of pyroptosis, there is a competition between the host cell and pathogen control, which struggles to continue to survive and replicate (Jorgensen et al., 2017). The pyroptosis occurs when a pathogen such as Salmonella in the macrophage cell express TTSS-1 effectors (SipB) into the cytoplasm to activate caspase-1. The typical inflammasomes that identify Salmonella in the cytoplasm are NOD-like receptor (NLR) family of proteins, namely NLRP3 and NLRC4 (Xia et al., 2019). This is because all classic inflammasomes contain NLRs (Behnsen et al., 2015). However, NLRC4 inflammasome can sense flagellin and T3SS-1 rod effectors PrgJ and PrgI, and activate caspase‐1 to mediate pyroptosis (Qu et al., 2016). It was revealed that the TTSS-1 translocate SipB which is involved in pyroptosis through direct interaction with caspase-1. The caspase-1 requires inflammasome activated by flagellin and TTSS rod protein PrgJ to produce active interleukin 1β (IL-1β) and interleukin 18 (IL-18), prompt cell lysis and release of proinflammatory intracellular substances (Lamkanfi and Dixit, 2014; Sahoo et al., 2011). The pyroptosis mediated by caspase-1 dependent programmed cell death is unlike apoptosis because of strong inflammatory response. (Figure 3 blue).

Persistence of Salmonella in a host: Host-adapted strains act as a reservoir, and their importance is seen in the persistence of bacteria for microbial survival and transmission of pathogens (Murugadas et al., 2015; Monack, 2013). The persistence of Salmonella inside the chicken epithelial cells is associated with secreted effector proteins that depend on TTSS determined by SPI-1 and SPI-2 (Tierrez and García-del Portillo, 2005). The SPI-1 encoded TTSS is functional in SCV long after bacteria entry and contribute to bacteria growth in epithelial cells (Tierrez and García-del Portillo, 2005).  The SPI-2 also plays the role of distancing the SCV from the producer of reactive oxygen species and reactive nitrogen species (Chakravortty et al., 2002). Several Salmonella strains contain factors that cope with ROS (NADPH oxidase) and RNS (INOS), giving them the influence to persist within the host (Behnsen et al., 2015; Gallois et al., 2001). The SPI-2 contributes to persistent infection in S. pullorum in young chickens; however, the specific association with the long-term persistence of S. pullorum is obscure (Wigley et al., 2001).
                Invasion and translocation of effector protein such as SipB, SipC, and SipD are also required for persistence of Salmonella infections to a host from SPI-1 genes as revealed by Lawley et al. (2008) and Ruby et al. (2012). In order to maintain survival within the SCV, there is translocation of a group of bacterial effectors into the host cell cytosol (Drecktrah et al., 2005). This ability gives rise to chronic infections or persistence within macrophages for the lifetime of the host.
Pathogenicity Islands (PIs) and Salmonella virulence:  Virulence of Salmonella strains is determined by virulence factors which are controlled by virulence genes clustered in regions of the bacteria chromosome known as the pathogenicity islands (Kaur and Jain, 2012). The most studied SPIs include SPI-1, SPI-2, SPI-3, SPI-4, and SPI-5 (McClelland et al., 2001; Foley et al., 2013). Among five pathogenicity islands, the invasive phenotypical genes required for intestinal penetration and invasion of host cells are clustered in a defined region in a chromosome of S. enterica termed as SPI-1 with 40 kb region at centisomes 63 (Winnen et al., 2008). The translocation of virulence proteins into host target cell occurred when SPI-1 and SPI-2 encoded TTSS; however, the roles of SPI-1 and SPI-2 in virulence are entirely different (Schmidt and Hensel, 2004; Que et al., 2013). 
The SPI-1: Function of SPI-1 is identified as 40kb DNA region required for the invasion of host cells and intracellular pathogenesis (Marcus et al., 2000). SPI-1 is an important virulence trait of S. enterica. A recent study by Rosselin et al. (2011) revealed that Salmonella infection might occur independently of the TTSS-1. Generally, TTSS mediate the delivery of proteins by extracellular Salmonella species into the host cells (Kubori et al., 2000). Among a set of effector proteins encoded by SPI-1 and secreted through TTSS are InvJ, SipA/B/C/D, SptP, AvrA, SopA/B/D/E/E2. These proteins interfere with the function of host cell proteins (Lostroh and Lee, 2001). Different scholars have well studied the functions of effector proteins in TTSS-1, and the summary is listed in Table 1.  However, more researches are investigating the genetic aspects of all effectors of TTSS-1 and their association with effectors of TTSS-2 in the process of pathogenesis of Salmonella.

Table 1. Secreted effector proteins of TTSS-1 from Salmonella and their significance in disease.

The SPI-2, SPI-3, SPI-4 and SPI-5: Salmonella pathogenicity islands (SPI) have a significant role in inducing pathogenicity to host cytosol. In addition to that, there are virulence factors that facilitate Salmonella infection to hosts. The virulence factors explained in this article include plasmid, biofilm and lipopolysaccharide layer
                SPI-2 has 39 kb locus, which encodes a second type III secretion referred to as TTSS-2 (Velge et al., 2012). SPI-2 is required for bacteria systemic infection, growth, survival and replication in both epithelial cells and within macrophages of the host (Guiney and Fierer, 2011). Moreover, the SPI-2 components affect the phagosome arrangement and the recruitment of NADPH oxidase to the phagosome membrane (Gallois et al., 2001). Thus, SPI-2 is involved in modifying the intracellular environment encountered by Salmonella (Silva-Herzog and Detweiler, 2010). Among the TTSS-2 effector proteins, SseB/C/D are responsible for promoting pore formation through which proteins reach the host-cell cytoplasm (Jennings et al., 2017). In general, TTSS-1 brings about host cell invasion, inactivation of phagocytic cells, apoptosis and interference with intracellular transport processes (Ohl and Miller, 2001).
                 Virulence phenotype due to SPI-2 is linked to the ability of S. enterica with different serovars to survive in phagocytic cells and replicate within SCV in a variety of membrane-bound cells (Knodler et al., 2010). The SPI-2 encoded TTSS is required for the protection of the pathogen within SCV against effectors of the innate to avoid fusion with the lysosomes (Ruby et al., 2012). The SCVs play critical roles in the survival and proliferation of Salmonella in intestinal cells and macrophages (Vonaesch et al., 2014). The best of the Salmonella within SCV is when more of these bacteria are multiplying and get access to new vesicles using SIFs get in touch with vesicles by projecting out of SCV (Foley et al., 2013). The TTSS encoded SPI-2 enables S. enterica to modify functions of the host cells, and thus, essential for survival and replication of S. enterica inside host macrophages (Monack et al., 2004).
                SPI-3, which is 17 kb large, is accommodated at 10 open reading frames, with the mgtC gene enables Salmonella to grow in a low-magnesium environment (Lee and Lee, 2015). Moreover, it also allows Salmonella to survive in the macrophages (IIyas et al., 2017). The SPI-4 is a 25 kb large island needed for intra-macrophage survival and is likely to carry a type I secretion system involved in toxin secretion and apoptosis (Kiss et al., 2007). It is speculated that SPI-4 is associated with secretion of cytotoxin responsible for infecting macrophages and coding for non-fimbrial adhesins seen in several Salmonella species during intestinal phase of the disease (dos Santos et al., 2019). The sequence analysis of the ±11 kb (25cs) large SPI-5 revealed the presence of six genes, including the SopB, a gene encoding multiple TTSS effector proteins (Rychlik et al., 2009). The role of SPI-5 is mainly associated with enteropathogenesis and in S. typhimurium is vital for systemic infection in chicks (Cao et al., 2014).
Salmonella Plasmid: Salmonella has highly conserved plasmid with 7.8 kb for all serovars with operon of five genes of Salmonella plasmid virulence (spv) locus (Hur et al., 2011). The locus harbours virulent genes in serovars of S. enterica designated as spvRABCD (Osman et al., 2014). The spvR is named first and encodes positive activator for the other four genes, namely spvA, spvB, spvC and spvD (Addwebi et al., 2014). The serovars with spv locus are of veterinary significance, differ from one to another, but all have 7.8kb (Pal et al., 2017). They are involved in intra-macrophage survival of Salmonella serovars (Riychlic et al., 2006). The serovars include S. abortusequi, S. abortusovis, S. choleraesuis, S. dublin and S. gallinarum/pullorum (Barth and Bauerfeind, 2005). However, the broad host serovars such as S. enteritidis and S. typhimurium are also in this group. They have been observed in human and food products from animals including chicken meat and eggs (Barth and Bauerfeind 2005). It has been found that the presence of spv in a chicken leads to the death of the host frequently and rapidly. The signal in spv locus is expressed in term of growth limitation, minimised nutrient supply or lowered pH (Rychlik et al., 2006). The central effector genes of this operon are spvB and spvC, and the existence of spvBC couples a missing virulence plasmid in S. typhimurium. The product of spvR is a proper regulatory protein which is vital for the expression of other spv genes (Wu et al., 2016). They promote survival and rapid growth of Salmonella in the host and affect the interaction of Salmonella with the host immune system (Singh, 2015). 
                Salmonella gallinarum like serovars S. abortusovis, S. heidelberg, S. dublin, S. typhimurium, S. choleraesuis, S. pullorum, S. enteritidis and many more others are reported to contain the Salmonella plasmid virulence (spv) locus. The locus has a vital function of multiplication in the reticuloendothelial tissues in the liver, spleen, reproductive parts (Asten and Dijk, 2005). However, not all serovars may carry virulence gene. This makes virulence plasmid of S. gallinarum/pullorum capable of restoring mouse virulence to S. typhimurium because of horizontal transfer of virulence genes (Marcus et al., 2000).
Biofilm: Biofilm is layers formed by bacteria when sticking to surfaces and start to excrete slimy, a matrix of extracellular polymeric substance (Rossi et al., 2017). The layer anchor and run through different surfaces such as medical implant materials, metals, plastics, soil particles, animal tissue (Lu et al., 2015). The layer contributes to Salmonella resistance to antibiotics and interferences in the host immune response, which with time, causes chronic infection (Parsek and Singh, 2003). The biofilm is difficult to remove even in cleaning procedures and chemical disinfection. Salmonella biofilm was found to increase the ability to resist acidification, desiccation, chlorination, heating, ionisation, radiation and antimicrobial agents (Chylkova et al., 2017). The number of antibiotics that became ineffective to adhesions on exopolysaccharides secreted into host cells like chickens’ intestinal epithelium, or HEp-2 cells was observed during culture conditions (Peng, 2016). It was revealed that S. typhimurium form biofilm on Hep-2 cells in type 1 Fimbria-dependent manner (Ledeboer and Jones, 2005). The extracellular Salmonella biofilms are serovar specific linking with contact surfaces (Koo et al., 2017).
                Biofilm is generally characterized by a mixture of secretions of macromolecules (polysaccharides, glycoproteins, and glycolipids) and extracellular DNA collectively known as extracellular polymeric substances (Koopman et al., 2015). The functions of extracellular polymeric substance are related to concentrating nutrients, inhibiting biocidal agents and increasing hydration to surfaces (Rossi et al., 2017). 
                Descriptions of biofilm macromolecules include 1. Curli (amyloid fimbriae) mediates cell adhesion and invasion with properties of inflammatory responses to a host. 2. Cellulose which is the exopolysaccharide secreted by Salmonella biofilm composed of β (1 → 4)-linked D-glucose units. The two form a hydrophobic network, which is a matrix of the tightly packed cell (Gerstel and Romling, 2003).  3. Biofilm-associated protein (BapA) is a large secreted protein required for biofilm formation (Latasa et al., 2005) 4.  O-antigen capsule is unimportant for multicellular behaviour; however play an important role in attachment and persistence of Salmonella (Barak et al., 2007) and 5. Extracellular DNA inhibits and stabilises biofilm development of Salmonella on abiotic surfaces such as metal, plastic and glass (Cappitelli et al., 2014). All these features are geared with several regulated genes positioned on operons encode adhesins which identify biofilm formation. Biofilm ruins food safety and is the reservoir of Salmonella in the different abiotic and biotic environment and enhancing the likelihood of colonising new host and persistence (Koopman et al., 2015).
Lipopolysaccharides (LPS): Salmonella LPS consists of three components:  an outer O- polysaccharide coat, a middle portion (R core) and inner lipid A coat. (Garmiri et al., 2008). The outer O- polysaccharide coat differentiates strains due to the difference in structure and composition. Salmonella missing the complete sequence of O-sugar repeating units are rough while those with it are called smooth (Murray et al., 2003). Lipopolysaccharide (LPS) in Salmonella is a potent activator of the acute phase and inflammatory reactions which release endotoxin during infection (Liu et al., 2016).
                Lipopolysacharides protect bacteria against host defence mechanisms such as gastric acidity, bile salts and the bactericidal activity of complement and phagocytes (Morgan et al., 2004). Like other bacteria, S. gallinarum, S. pullorum and S. enteritidis have LPS layer which is the complex of lipid and polysaccharide with an influence of attachment to the epithelial cells of the alimentary canal of a chicken (Ramasamy et al., 2014). The study by Guard-Bouldin et al. (2004) on chemotyping of LPS mutant revealed that high molecular mass LPS influence the biology of the avian reproductive tract with loss of production. The LPS in Salmonella is a virulence determinant essential for swarming motility in Salmonella grown in agar to depict behaviour when propagated in solid media (Toguchi et al., 2000). Others are the colonisation of intestinal epithelial cells after penetrating the mucosa layer, serum resistance which is reduced by an increase in chain length in LPS and resistance to killing by macrophages, all of which are vital for successful infection of Salmonella to chicken epithelial cells (Kong et al., 2011).
Acid pH stress and adaptation of Salmonella: Salmonella typhimurium was observed to adapt to different stressed conditions inside gut and host cells due to the presence of a set of genes termed as stimulons (Lianou et al., 2017). The stimulons are expressed under control of positive regulatory elements. A study by Foster and Spector (1995), observed that low pH stress in the gut with S. typhimurium is regulated by RpoS, AtbR, MviA and Fur under the influence of str gene. The regulons OxyR, SoxRS, RpoS and oxidative stress stimulons sodA, katG, katE, and their products prevent S. typhimurium from oxidative damages of DNA, proteins and membranes (Foster and Spector, 1995).  Therefore, adaptation to acid, salt, heat, hydrogen peroxide (H2O2) and oxygen radicals promotes the survival of Salmonella in the adverse environment including acidic stomach, macrophages and phagolysosomes (Álvarez-Ordóñez et al., 2011).
                Phases in acid adaptation occur either by pre-shock or acid shock responses that require protection of Salmonella against severe acid stress (Álvarez-Ordóñezet al., 2010; Baik et al., 1996). Salmonella has been found to respond to the acidic environment through a complex adaptive system called the pre-shock acidification tolerance response proteins (PsATRP). The preshock response is termed when the exponentially growing cells at the pH 7.6 grow to one to two-fold when shifted to up to pH 4.5 and below (Álvarez-Ordóñezet al., 2012). The acid shock response in Salmonella makes cells to cease reproduction and requires alteration of synthesis of over 52 acid shock proteins (Foster, 1991). From the synthesis of over 52 proteins, four are distinctive PsATRP namely, the RpoS ᵟ-factor, Ada, Fur and PhoPQ. The first three RpoS ᵟ-factor, Ada, Fur have enormous tolerance to organic acid stress with lesser effects in inorganic acid stress (Bearson et al., 1998).
                In contrast to the PhoPQ system ( PhoP and PhoQ), the two-component regulatory systems PhoP (identified as Acid Shock Protein-ASP29) and PhoQ proved to be essential for the tolerance to organic acid stress with little effect to it (Foley et al., 2013). Bearson et al. (1998) reported that S. typhimurium RpoS and PhoPQ provided protection against inorganic acids and PhoP- PhoQ represses genes essential for induction of micropinocytosis in macrophages and epithelial cells. Thus, RpoS and FurR offered protection against organic acids induce acid resistance and regulate iron homeostasis (Ramos-Morales, 2012; Foley et al., 2013). Therefore, the ability of Salmonella to tolerate different pH of organic and inorganic acids allows it survives in the crop and the small intestine. These adaptations are essential for colonisation and persistence of Salmonella in the GIT. 
Approaches and challenges for Salmonella control
Probiotics: Roles of probiotics in health and disease of animals are increasingly being recognised. However, they are well implemented in developed countries with facilities and technologies for quality assurance criteria for probiotics compared to developing countries (Park et al., 2016). The essential criteria for probiotics include phenotype and genotype stability, as well as plasmid stability; tolerance to bile and stomach acid and survival and growth in GIT; intestinal epithelial adhesion properties; production of antimicrobial substances; ability to inhibit gut pathogens and immunogenicity (Tuomola et al., 2001).
                Probiotics are non-pathogenic live microorganisms, which in sufficient amount antagonising pathogens by improving host intestinal microbial balance (Servin and Coconnier, 2003; Tellez et al., 2012). Studies have found that probiotics enhance intestinal barrier against deleterious agents and reduce chances of antibiotic use for prevention of infection (Nava et al., 2005; Griggs and Jacob, 2005; Lim et al., 2015). Probiotics have control over the immune response of a host by enhancing innate immunity and regulate intestinal epithelial haemostasis (Vanderpool et al., 2008).
                Mechanisms probiotics use to maintain healthy balances of microorganism within the intestines are competitive exclusion, pathogen antagonism, and stimulation of the immune system (Ritzi et al., 2014). The observation of Kabir (2009) in competitive exclusion reported that the newly hatched chickens were conferred protection against colonisation of S. enteritidis by giving them the suspension of gut content from healthy adult chickens. However, the small amount of acidic pH of probiotics is insignificant to most of Salmonella species which have the mechanism of overcoming acidic pH of the crop, stomach and intestine through acid tolerance response (Álvarez-Ordóñez et al., 2012).
                Generally, the probiotics possess anti-infective properties after adhering to intestinal surfaces and compete for mannose and glycoproteins receptors used by pathogens (McFarland, 2000; Lebeer et al., 2010).
                Pathogens fail to outcompete beneficial bacteria like Lactobacillus and Bifidobacterium strains of intestinal origin (Kailasapathy and Chin, 2000). It has been observed that the use of lactic acid bacteria (LAB) such as Lactobacillus, Streptococcus, Pediococcus, Enterococcus andWeissellain animal feed minimise survival of pathogenic Salmonella spp. in chickens. The LAB inhibit pathogenic bacteria by (i) preventing pathogen adhesion, (ii) producing inhibitory compounds, (iii) competing for nutrients, (iv) modulating the host immune system, (v) improving nutrients digestibility, feeding conversion and (vi) reducing toxins bioavailability (Vieco-Saiz et al., 2019). The bifidobacteria was found to be effective in inhibiting both Gram-positive and Gram-negative bacteria by producing a bacteriocin-like compound, which is toxic to pathogenic bacteria (Vanderpool et al., 2008). A study by Brisbin et al. (2011) reported that lactic acid strains inhibit diarrhoeagenic bacteria by producing metabolites such as acetic and lactic acids which lower the pH and thus useful in inhibiting the growth of pathogenic bacteria in the gastrointestinal tract. Also, Harimurti and Hadisaputro (2015) supported the observations which documented that several probiotics agents through their ability to increase the production of intestinal mucins inhibit adherence of pathogenic bacteria to intestinal epithelial cells.
                Probiotics improve the immune system of chickens (Kechagia et al., 2013). For example, the increased systemic antibody reaction against pathogenic bacterial and viral was observed to chicken received probiotics containing Lactobacillus acidophilus, Bifidobacterium bifidum and Streptococcus faecalis (Otutumi et al., 2012). Additionally, intestinal IgG and serum IgG and IgM were also increased in chicken supplemented with probiotics (Alkhalf et al., 2010). This suggests that the use of probiotics supports the induction of natural antibodies for maintaining chicken health. However, the exact mechanism(s) by which probiotics bacteria bring about the aforementioned immune modulation is not clear and require further research (Choi et al., 2014).
Antibiotics: Since 1960, the chemotherapeutical antibiotics were used to reduce mortality in chickens caused by varieties of pathogens, including Salmonella (Barrow et al., 2012).  However, the extensive use is ill-advised and created concern over the selection pressure for resistant strains of bacteria (De Gelder et al., 2008). Therefore, much use of antimicrobial agents for treatment or promoting growth should be prevented to reduce multidrug resistance strains in different ecosystems (Chattopadhyay, 2014).  For example, the burned of antibiotic use in growth promotion of chickens which started in 1997 and completed in 2006 in Europe and America has significantly reduced antibiotic resistance bacteria in poultry population (Barrow et al., 2012).
                Moreover, resistant bacteria against antibiotics are still dangerous to chicken survival. The evidence is that some newly discovered antibiotics have failed to treat diseases of bacteria, for example, resistance experienced in colistin, which is an antibiotic of last resort (Poirel et al., 2016). Thus, success use of vaccines will be a weapon against antibiotics resistant strains in the chicken industry (Jansen et al., 2018).
Vaccination: Elimination of hosts identified to be at carrier state of Salmonella by test and cull seemed to be of less impact in comparison to vaccination of chickens to prevent infection (Bäumler et al., 2000). However, the use of vaccines is well implemented in developed countries, unlike developing countries where most of the rural farmers live under poor infrastructure and unable to meet the cold chain treatment for vaccines.
                Vaccinations stimulate cell-mediated immune response and reduce clinical signs and shedding of live Salmonella from chickens infected with S. gallinarum, S. pullorum, S. enteritidis and S. typhimurium (Revolledo and Ferreira, 2012). The 9R live vaccine developed in 1956 was used to control Salmonella in poultry and helped to eradicate S. gallinarum and S. pullorum in Europe and America (Smith, 1956; Baumler et al., 2000).  However, there was an outbreak of S. enteritidis in 1960 following the fall of S. gallinarum and S. pullorum (Bäumler et al., 2000).  The observation was that S. enteritidis was found to carry a common antigen O9 which enable it to fill the niche of S. gallinarum/pullorum (Cogan and Humphrey, 2003). The theory suggests that S. gallinarum was able to competitively exclude S. enteritidis from poultry flocks and the elimination of S. gallinarum and S. pullorum in poultry led to an epidemic increase of S. enteritidis infections in chickens in the 1980s (Yang et al., 2018).
                Despite the above challenges, the developed countries have managed to control chicken salmonellosis with huge success (Desin et al., 2013; Andino and Hanning, 2015). Nevertheless, the control of S. gallinarum, S. pullorum, S. typhimurium and S. enteritidis in developing countries has remained a burden in the poultry industry with enormous loss (Rajagopal and Mini, 2013).
Phages therapy: Therapeutical use of bacteriophages was found to be promising in clearing pathogens when introduced to an infected organism (Thiel, 2004). Bacteriophages are defined as viruses that can infect, multiply and kill susceptible bacteria (Connerton et al., 2011). In recent years the use of bacteriophage or their products has been proposed as a possible tool for treatment or prevention of salmonellosis in poultry farms (Sillankorva et al., 2010). However, the obstacles include phage resistant bacteria which emerge rapidly in the course of therapy, narrow host range of many phages and the activeness of phages occur shortly after bacterial infection (Capparelli et al., 2010). Despite these problems, the pros of using phages outweigh cons because phages are bactericidal that can kill and clear pathogens, and their multiplication on the duration of treatment is higher enough to inhibit pathogenic bacteria.
                Phages minimally disrupt normal flora and are equally effective against antibiotic-sensitive and antibiotic-resistant bacteria and can have low inherent toxicities (Loc-Carrillo and Abedon., 2011).  The ΦSH19 and Vi01 are lytic bacteriophages adapted to infect several Salmonella serovars. The ΦSH19 was isolated from pig intestine and revealed a bio-control against strains of S. typhimurium (Hooton et al., 2011). Huang et al. (2018) observed the high capacity of phage LPSE1 in controlling different Salmonella serovars in ready to eat foods after reducing Salmonella count for a range of 0.49 log10 at 4°C to 0.52 log10 at 28∘C.   In connection to these results, Atterbury et al. (2007) also observed the reduction of S. enteritidis by ≥4.2 log10 CFU and S. typhimurium by ≥2.19 log10 CFU in caecal samples of broiler within 24 h after treatment with phages φ151 and φ10, respectively. These phages were isolated from broiler farm, poultry abattoirs and wastewater plant. From the above observations, the bacteriophages are the potential antibacterial agent that can clear pathogens in infected chickens and ready to eat chicken products (Westwater et al., 2003).
Biosecurity measures: Despite vaccines and antibiotics seen efficient in preventing and treating salmonellosis in chicken; still, biosecurity measures are essential in reducing infection between and within chickens and surrounding environments (Agunos et al., 2014). Biosecurity practices are implemented to prevent infection and spread of disease in a farm through isolation, traffic control and sanitation measures (Jeffrey et al., 2001). During isolation, chickens are confined within a controlled environment. The management keeps inside the chickens which have been separated by age group while other animals are kept out. 
                Animals like rodents, reptiles carry vectors such as bugs, ticks and contribute to the spread of salmonellosis in the farm (Jeffrey et al., 2001). Therefore, periodic cleaning of the floor, metal parts inside the farm should be done to break the cycles of diseases (Fasina et al., 2012). Sanitation measures should be taken into account by use of disinfectant to workers getting into a farm, equipment used and vehicles entering the farm. These will minimise infection and reduce antibiotics used for prevention and treatment of salmonellosis.
Natural or purified herbs: Attention of using botanicals as an alternative to antibiotics for the treatment of various diseases in chicken production has increased in the last few decades (Dhama et al., 2015). The herbs, spices and different plant extracts are mostly used in organic chicken production due to growth-promoting effects, antimicrobial properties, and other health-related benefits (Diaz-Sanchez et al., 2015). The positive effects of natural medicines are linked to the activity of bioactive constituents, including alkaloids, terpenoids, phenolics, glycosides, glucosinolate (Wenk, 2006). For this reason, many herbs, spices and plant extracts have activity against pathogens and can be used against diseases and in health promotion of chickens.
                Aloe vera (family Asphodelaceae) comprises of over 75 biologically active compounds with a broad range of pharmacological activities including the anti-inflammatory, antibacterial, antioxidative and antitumor effect (Surjushe et al., 2008). The Aloe species have been observed to be efficacious in preventing bacterial infection in chickens, in different communities around rural settings of Africa (Masimba et al., 2011). A study by Waihenya et al. (2002) observed the antibacterial activity of Aloe secundiflora leaf against S. gallinarum in village chicken after increasing the survival rate of the infected flock with fowl typhoid. In supporting this study, Mlimbe et al. (2016) tested Aloe vera leaf against S. gallinarum and observed no death of infected flock with salmonellosis compared with the control group.  The antibacterial activity of Aloe species is attributed to active phytocompounds flavonoid catechins, anthrones, chromones and anthraquinone (Lopez et al., 2013).
                Bioactive compounds work against pathogens in multiple ways. They can disrupt the cellular membrane of pathogens, stimulate the immune system of a host, protect intestinal mucosa from pathogen colonisation and promote the growth of beneficial bacteria (Windisch and Kroismayr, 2007). The bark of cinnamon (Cinnamomum zeylanicum) significantly reduced S. enteritidis in cecal contents of infected chicken without affecting the total cecal endogenous population (Upadhyaya et al., 2014). These findings are supported by other scholars who revealed the higher antibacterial activity of essential oils of cinnamon (C. zeylanicum) against strains of Salmonella enterica after disrupting bacterial cell membrane (Vazirian et al., 2015; Solarte et al., 2018). Other species with essential oils effective in inhibiting Salmonella spp. in chickens are clove (Eugenia caryophyllata), oregano (Origanum vulgare), common thyme (Thymus vulgaris), and red thyme (Thymus zygis). (Solarte et al., 2018).
                Punica granatum peel, garlic (Allium sativum), pawpaw (Carica papaya), neem (Azadirachta indica)and Citrus species are also among natural antimicrobials reported to be effective in promoting chicken health (Dhama et al., 2015). They stimulate the flow of gastric juices, modify digestive secretion, stabilise microbiome which reduces microbial toxins and improve digestion (Mlimbe et al., 2016; El‐Azzouny et al., 2018). The extracts of P. granatum peel are used as antibacterial, antispasmodic, anti-inflammatory and hemostatic agents in folk medicines (Arun and Singh, 2012). Moreover, the peels are also used as a food supplement to maintain intestinal microbiota and contribute in the modulation of the immune response against pathogenic microbes in chickens. Khan et al. (2018) observed that shiitake mushroom (Lentinula edodes) has higher inhibition against S. enteritidis in broiler chicken because of major active component heteroglycan protein. The heteroglycan proteins are essential in modifying intestinal microbiota and provide them with chances of outcompeting pathogenic bacterial like S. enteritidis.The primary active compounds of Ginkgo biloba, namely Flavonoids (glycosides) and terpenoids (ginkgolide, bilobalide) were reported to prevent biofilm formation in the intestines of chickens (Wu et al., 2016). The biofilms enhance colonisation and persistence of Salmonella spp. in the epithelial layer of intestines (Srivastava et al., 2017)
                Dietary plant-derived phytochemicals are also essential in translational regulation of genes associated with immune regulation (Hoensch and Weigmann, 2018). Many of the genes responsible for metabolism, immunity, antigen presentation and inflammatory response have been reported to be modulated by phytochemicals such as capsaicin from genus Capsicum, oleoresin and cinnamaldehyde (Kim et al., 2010). Du et al. (2016) tested the effects of thymol from  Thymus vulgaris and carvacrol from Origanum vulgare on intestinal integrity and immune response of broiler chickens challenged with Gram-positive bacteria. Results revealed increases of interleukin-1β and TLR-2 mRNA which are critical in inflammatory responses, cell proliferation, differentiation and apoptosis.
                Observed pharmacological activities of natural antimicrobials are attributed to phytocompounds present, thus justify their uses in fighting against infectious diseases. Therefore, the vast of medicinal plants in the globe with several secondary metabolites are the solution towards infectious diseases, including salmonellosis in the chicken industry.
Conclusion: There are more than 2600 Salmonella serovars in the world, and this number keeps on increasing from discoveries. Salmonellosis is a global problem due to the presence of these serovars to a broader population of hosts in different environments from aquatic to terrestrial. The problem is enormous because of the complexity in the mode of infection and the behaviours of Salmonella in escaping the host immune system. Chickens infected with Salmonella may continue to live and shed live Salmonella for an extended period. At this point, a chicken becomes a chronic carrier of Salmonella. The chronic carrier chickens are critical in spreading the disease to the new batches of hatcheries through vertical contamination of the egg yolk. Similar to the vertical transmission of bacteria, the horizontal contamination also magnifies the infection in the cage after chickens eat contaminated feeds. Moreover, the formation of biofilm layers by Salmonella in metal, floor and instrument in abattoirs maintain survival and persistence of Salmonella which in turn contaminate chicken meat along the value chain. The hazards due to Salmonella infection in chickens make human at higher risk of acquiring the diseases than any other organism. Therefore, mode of Salmonella infection to chickens, newly discovered serovars and multidrug-resistant strain of bacteria from different ecosystems necessitate for more scientific information to stakeholders.
                Still little is known about the mechanism of Salmonella infection in chickens. Most of the researches on the mechanism of Salmonella infection were done using mice model and have dominated in developed countries of the world.  Some aspects such as survival of Salmonella in phagocytic cells, functions of some effector proteins of SPI-1, SPI-2 and pathogenicity of Salmonella in the chicken are not clear. The knowledge out of the mice model may be applied to reduce infections in chickens. However, this creates a concern for more investigation on chickens because some serovars which induce systemic infections are highly host adaptive.
                The combined approaches discussed in this review will help reduce Salmonella infection in chickens, and the production of safer products across the world will reduce the zoonosis of the disease and the multidrug-resistant strains of Salmonella spp.

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